W4002: Nutrient Bioavailability--Phytonutrients and Beyond

(Multistate Research Project)

Status: Inactive/Terminating

Project Menu

SAES-422 Reports

Annual/Termination Reports:

[03/24/2019] [07/28/2020] [03/18/2021] [05/26/2022] [07/17/2023]

Date of Annual Report: 03/24/2019

Report Information

Annual Meeting Dates: 02/07/2019 - 02/08/2019
Period the Report Covers: 10/01/2017 - 09/30/2018

Participants

PARTICIPANTS
• Jamie Amengual Terrasa, University of Illinois-Urbana-Campaign (jaume6@illinois.edu)
• Richard Bruno, Ohio State University (bruno.27@osu.edu)
• David Dallas (dave.dallas@oregonstate.edu)
• Frank Duca, University of Arizona (faduca@email.arizona.edu)
• Ingolf Gruen, University of Missouri (gruenI@missouri.edu)
• Kacie Ho, Assistant Professor; University of Hawaii (kacieho@hawaii.edu)
• Emily Ho, Oregon State University (emily.ho@oregonstate.edu)
• Norman Hord, Oregon State University (norman.hord@oregonstate.edu)
• Peng Ji, University of California-Davis (penji@ucdavis.edu)
• Dorothy Klimis, University of Maine (dorothea@maine.edu)
• Ji-Young Lee, University of Connecticut (ji-young.lee@uconn.edu)
• Daniel Lin, Oklahoma State University (dingbo.lin@okstate.edu)
• Yanhong Liu, University of California-Davis (yahliu@ucdavis.edu)
• Brian Lindshield, Kansas State University (blindsh@ksu.edu)
• Brietta Oaks, University of Rhode Island (boaks@uri.edu)
• Lavanya Reddivari, Purdue University (lreddiva@purdue.edu)
• Barry Shane, University of California-Berkeley (bandie@berkeley.edu)
• Milan Shipka, University of Alaska-Fairbanks (mpshipka@alaska.edu)
• Jennifer Teske, University of Arizona (teskeja@email.arizona.edu)
• Connie Weaver, Purdue University (weavercm@purdue.edu)
• Jiujiu Yu, University of Nebraska-Lincoln (jyu18@unl.edu)
• Janos Zempleni, University of Nebraska-Lincoln (jzempleni2@unl.edu)

Brief Summary of Minutes

Meeting Agenda and Minutes

The annual meeting was hosted on the University of California-Davis campus (Walter A Buehler Alumni Center - Founders Room) on Feb 7-8, 2019.

Feb 7, 2019

8 AM - Meeting called to order

Opening remarks were provided by Yanhong Liu (Chair) who welcomed the group and highlighted planned scientific activities. Additional welcoming and administrative-related remarks were provided by Richard Bruno (Secretary) and Milan Shipka (Administrative Advisor). Introductions were then facilitated among meeting participants.

8:30 AM – Scientific Session I

The following investigators provided an annual update on their research progress in relation to W4002 project objectives. Each presentation was approximately 15 minutes in duration followed by 5-10 minutes of questions from participants. Ingolf Gruen presented “Issues of concurrent analysis of methylxanthines and flavan-3-ols”. Jennifer Teske presented “Sleep and obesity: role of stress”. David Sands presented “The search for low glycemic potatoes and nutricrops”. Ji-Young Lee was scheduled to present “Sugar kelp: A new agricultural crop for the prevention of obesity associated disease”, but was unable to attend the meeting due to unforeseen circumstances.

10:00 AM – Executive Session with Deirdra Chester – NIFA National Program Leader

Dr Chester joined the W4002 meeting via Skype for a discussion concerning USDA funding opportunities. It was discussed that the federal shutdown resulted in delays to process awarding of USDA projects, and that priority will be given to process awards prior to issuing a new RFA for the next grant cycle. Dr. Chester offered some non-binding commentary on future RFAs, and indicated that she would inform the group when a new RFA becomes available. Dr. Chester opened up the discussion for questions from W4002 participants.

10:45 AM – Scientific Session II

The following investigators provided an annual update on their research progress in relation to W4002 project objectives: Frank Duca (“Role of the small intestinal microbiota in energy regulation”); Richard Bruno (“Gut-level benefits of phytochemicals for alleviating endotoxemia”); Lavanya Reddivari (“Anthocyanin anti-inflammatory properties – Role of gut bacteria”)

12 PM – Break

1 PM – Administrative Discussion led by Milan Shipka (W4002 Administrative Advisor)

Dr. Shipka presented administrative responsible of the group for annual reporting and directed the group to elect a secretary. The current chair (Yanhong Liu) has completed her elected duties and is outgoing following the meeting. Current secretary (Richard Bruno) will be responsible for preparing and submitting the annual report in coordination with Dr. Shipka, and will host/chair the next annual meeting, likely at Ohio State University (Columbus, Ohio) during spring 2020. Jamie Amengual Terrasa was nominated and unanimously elected to serve as the W4002 secretary to replace the outgoing secretary and to provide assistance with planning of the 2020 meeting.

1:30 PM – Scientific Session III

The following investigators provided an annual update on their research progress in relation to W4002 project objectives, with each 15-minute presentation followed by a Q&A session to stimulate collaborations: Peng Ji (“Risk of iron overload at infancy, a study using neonatal pig model”); Janos Zempleni (“Effects of milk exosomes and their RNA cargos on anti-viral response and postnatal growth”); Yanhong Liu (“Probiotics on intestinal health of weaned pigs”)

2:45 PM - Break

3:00 PM – Scientific Session IV

The following investigators provided an annual update on their research progress in relation to W4002 project objectives, with each 15-minute presentation followed by a Q&A session to stimulate collaborations: Barry Shane (“Genetic modifiers of folate status biomarkers”); Emily Ho (“Dietary bioactive, age-related inflammation and toxicological responses”); Dingbo Lin (“Carotenoid metabolism in mitochondrial biology”); Jaime Amengual (“β-carotene conversion to vitamin A regulates lipid metabolism”); Breitta Oaks (“Fatty acids, cortisol, and lead during pregnancy”)

5:00 PM Day 1 Adjourn

Feb 8, 2019

9 AM - Meeting called to order

9:15 AM – Business Plan Discussion

Richard Bruno (Secretary) discussed annual reporting requirements. Participants were provided information to assemble individual reports for the reporting period, which would be utilized for assembling a composite report for subsequent submission to USDA within 60 days of conclusion of the W4002 meeting. Richard Bruno, in his capacity as incoming chair of W4002, also discussed preparations for the 2020 meeting. The group agreed to hold the meeting in the Ohio State University campus area (Columbus, Ohio) during spring 2020. A survey will be distributed electronically in approximately 6-months to identify preferred meeting dates for W4002 participants.

10:00 AM – Collaborative Activities

W4002 participants assembled in groups to discuss potential collaborative activities in relation to presentations delivered. Participants were provided opportunity to explore and discuss the following federal RFAs as potential collaborative opportunities.

Age-related Microbiota Changes and their Implications in Chronic Disease Prevention, Treatment and Progression (R01 Clinical Trial Optional; https://grants.nih.gov/grants/guide/pa-files/PA-18-738.html; R21 Clinical Trial Optional; https://grants.nih.gov/grants/guide/pa-files/PA-18-739.html)

Advancing Mechanistic Probiotic/Prebiotic and Human Microbiome Research (R01 Clinical Trial Not Allowed; https://grants.nih.gov/grants/guide/pa-files/PA-18-876.html; R01 Clinical Trial Optional; https://grants.nih.gov/grants/guide/pa-files/PA-18-902.html)

Food Specific Molecular Profiles and Biomarkers of Food and Nutrient Intake, and Dietary Exposure (R01 Clinical Trial Optional) (https://grants.nih.gov/grants/guide/pa-files/par-18-727.html)

The Mechanistic Role of the Microbiome in the Pathobiology of Heart, Lung, Blood, and Sleep Diseases (R01 - Clinical Trial Not Allowed) (https://grants.nih.gov/grants/guide/pa-files/PA-18-784.html)

Nutrigenetics and Nutrigenomics Approaches for Nutrition Research (R01 Clinical Trial Optional) (https://grants.nih.gov/grants/guide/pa-files/PA-18-034.html)

Role of Gut Microbiome in Regulating Reproduction and Its Impact on Fertility Status in Women Living with and Without HIV (R01 Clinical Trial Optional) (https://grants.nih.gov/grants/guide/pa-files/PA-18-838.html)

USDA AFRI - Agriculture and Food Research Initiative - Foundational and Applied Science Program (https://nifa.usda.gov/funding-opportunity/agriculture-and-food-research-initiative-foundational-applied-science-program)

12 PM – Meeting adjourned

Accomplishments

Kansas State University (Brian Lindshield). Background: We completed 3 studies focused on micronutrient bioavailability from food aid products. Activities: The first study examined iron outcomes in sorghum-soy versus corn-soy fortified blended foods with whey protein concentrate or more soy to reach equivalent protein levels and different levels of sugar. The second study examined the iron outcomes among rice fortified with different forms of iron. The third study examined iron and zinc outcomes in different Senegalese millet varieties. All 3 studies used rats to assess these outcomes. Outcomes: All fortified blended foods resulted in equal iron outcomes, interestingly in the sorghum-soy fortified blended foods in particular seem to be adequate without the addition of whey protein concentrate. In rice ferric pyrophosphate led to better outcomes that ferric phosphate. However, neither micronizing, nor adding both citric acid and trisodium citrate to, ferric pyrophosphate improved iron outcomes. There were not differences in iron and zinc outcomes found between the different millet varieties.   Ohio State University (Richard Bruno). Background: Green tea extract, which is rich in polyphenolic catechins, alleviates metabolic endotoxemia and NFkB inflammation to protect against obesity and nonalcoholic fatty liver disease. Activities: We conducted studies in obese mice and obese humans to examine the extent to which green tea extract prevents gut-derived endotoxin translocation and systemic TLR4/NFkB inflammatory responses implicated in metabolic disorders. Outcomes: Studies in humans are ongoing.  Studies in mice fed a high-fat diet demonstrate that green tea extract decreased intestinal and adipose TLR4/NFkB inflammation in association with reduced body mass. This was accompanied by decreased circulating endotoxin in association with decreased portal vein endotoxin and greater expression of intestinal tight junction proteins, especially in the distal gut. Functional measures also indicate that green tea extract prevented the absorption of FITC-dextran that was otherwise increased in mice fed a high-fat diet. These data indicate that green tea extract protects against diet-induced obesity consistent with a mechanism involving the gut-adipose axis that limits endotoxin translocation and consequent adipose TLR4/NFκB inflammation by improving gut barrier function. Studies in humans are expected to translate these preclinical findings intro practical dietary recommendations that help to manage the risk of metabolic disorders driven by TLR4/NFkB inflammation.   Oklahoma State University (Dingbo Lin). Background: Carotenoids are a large group of lipophilic pigments. Dietary ingestion is the only source of carotenoids for human nutrition and health. My laboratory focuses on the health benefits of carotenoids and the metabolic enzymes in the prevention of obesity, diabetes, and influenza virus infection. Activities: We used mouse models to determine: 1) astaxanthin alteration of gut microbiome in the wild type and beta-carotene oxygenase 2 (BCO2) knockout mice; 2) BCO2 status in animal energy metabolism and inflammation. Outcomes: We identified the specific profiles of gut microbiome in response to astaxanthin, BCO2 status (with or without BCO2 in mice), and gender. We also characterized that BCO2 expression levels were significantly decreased in the diabetic human liver. Deletion of BCO2 caused low grade inflammation, elevation of blood glucose, and impaired health.     Oregon State University (David Dallas). Background: Human milk evolved to provide nourishment, immunoprotection and support for the development of a commensal-dominant gut microbiome for term infants. Milk proteins are carriers of encrypted bioactive peptides with antimicrobial, immunomodulatory, anti-hypertensive, calcium delivery and gut barrier enhancement functions. These peptides must be released during infant digestion to be biologically relevant. Preterm infants have poor protein digestion and a structurally and functionally immature digestive system. Little evolutionary adaptation to provide optimal nutrition to significantly preterm infants is likely, as these infants rarely survived prior to advances in modern medical care. Therefore, bioactive peptides that evolved to be released within the term infant may be missing in the preterm infant. Differential or sub-optimal release of these bioactive peptides in early premature infants could conceivably alter health outcomes in multiple ways.  Though evidence has shown that the premature infant gut is structurally immature and protease production is decreased, what remains unknown is how these changes impact the overall breakdown of human milk proteins and release of bioactive peptides in the premature infant. There is, therefore, a critical need to determine how prematurity affects protein digestive function, the release of bioactive peptides in the infant gut, and how that ultimately impacts the infant. Our long-term research goal is to identify the optimal protein nourishment for preterm neonates to improve developmental outcomes. Our overall objective of our several funded projects is to examine the release of peptides in the digestive tract of infants, determine their functions and determine which peptides are missing in the preterm infant gut. These projects have potential for significant impact in that the identification of the degree to which digestion and the release of bioactive peptides is impaired for preterm infants will inform ways in which mother's milk and donor milk could be augmented, for example, with enzymatic supplementation or bioactive peptide supplementation to improve infant gut health. Activities: 1) We have determined the peptides released in the stomach of term and preterm infants; 2) We have determined which milk and gastric proteases are responsible for peptide release; 3) We have identified hundreds of released peptides that are homologous with known functional peptides; 4) We have established a database of known bioactive milk peptides from across literature that is open to all. Outcomes: 3 postdoctoral scholars, 2 graduate students and 6 undergraduates were supervised. Fifteen manuscripts were published and 17 research presentation were given. Our research includes collaborations with many other scientists, including neonatologists in Oregon at Oregon Health & Sciences University and Randall Children’s Hospital.   Oregon State University (Emily Ho). Background: Diet plays an important role in mitigating the development and progression of several cancers, including prostate and breast.   This research demonstrates that nutritional strategies that decrease oxidative stress, inflammation, DNA damage and/or target aberrant epigenetic alterations, such as acetylation and methylation, in prostate and breast cancer have the potential to dramatically reduce the incidence of cancer.    Secondly, declining nutritional status may be a critical determinant of healthy aging and susceptibility to environmental insults.  Activities: We have completed two clinical trials investigating the impact of broccoli sprout supplementation in breast and prostate cancer patients.  We have found that supplement are bioavailable and altered expression of AMCR and novel lncRNA.  Unlike breast cancer patients, supplementation did not change proliferations markers in prostate.  We have also employed zebrafish and rodent models to understand the impact of zinc status on exposure to arsenic.  We have discovered that zinc deficiency sensitizes the microbiome to arsenic induced microbiota changes and oxidative stress.  Finally we have utilized aging mouse models to examine the interrelationship between age-related inflammation and microbiome.  We have found that aged mice have higher susceptibility to zinc losses and chronic inflammation that is reversed with zinc supplementation.  Outcomes:  We have identified new risk factors in prostate and breast cancer and offer novel dietary modifications to reduce the incidence of cancer; Gained knowledge of the mechanisms behind the health benefits of micronutrients and phytochemicals such as zinc and compounds derived from cruciferous vegetables; Established low dietary zinc as risk factor for inflammatory processes, DNA damage and cancer risk and identify new biomarkers for human zinc deficiency;  Established function of zinc and changes in zinc metabolism with toxicological stresses, development and aging.   Oregon State University (Norm Hord). Background: Our laboratory studies the effects of nitrate and nitrite because plant foods rich in these ubiquitous anions lower blood pressure, improve athletic performance and alter behavior in animal models and humans. Activities: We used a zebrafish (Danio rerio) to determine the effect of nitrate (606 mg/liter) and nitrite treatment (19.5 mg/ liter) on exercise performance, as measured by oxygen consumption during a strenuous 2 hour swim test, and behavior as indicated by startle response, shuttle box, free swim, and swim zone assays. After three weeks of nitrate and nitrite exposure, fish were euthanized whole body and brains extracted in 4:1 methanol:water and metabolites  analyzed for untargeted metabolomics. Outcomes: Nitrate treatment of zebrafish improved endurance, as indicated by the decreased the oxygen cost of exercise, as observed in humans, while nitrite exposure increased the oxygen cost of exercise. Nitrate treatment was associated with changes in the relative abundance of metabolic fuels for energy production, both at rest and after exercise, and nitrate-induced difference in net utilization of different fuel sources (such as glycolytic and TCA intermediates, fatty acids, lactate and ketone bodies) may contribute to improvements in exercise performance. While nitrite had similar effects as nitrate on the abundance of metabolites at rest, the data suggest that nitrite treatment lead to net depletion of fatty acids for energy production during exercise. Behavioral assays demonstrate that both nitrate and nitrate treatments altered cognitive function in zebrafish. Brain pathway analysis showed significant differences in more than fifty compounds when comparing the metabolites of control fish with the treatments fish. Overall, we found a very significant depletion in many important metabolites involved in the regulation of neuronal membrane potential. Our metabolomics results correlate well with observed behavioral patterns, anxiety and difficulty to learn in fish exposed to nitrite and nitrate.   Purdue University (Lavanya Reddivari). Background: Gut health is integral to overall health. Recent evidence suggests that gut bacteria are implicated in a variety of chronic diseases including colonic inflammation and related disorders such as colitis. Diet is one of the major factors that influence the gut bacterial profiles. Thus, understanding the interaction between dietary bioactive compounds and gut bacteria in the context of colonic inflammation and oxidative stress will aid in developing evidence-based food products to counter chronic diseases in the US and globally. Activities: To determine the effect of potato bioactive polyphenols on gut inflammation, an animal study has been conducted using DSS induced murine colitis model and IL-10 KO mice model. Mice exposed to DSS in drinking water for seven days showed a significant reduction in colon length, increase in spleen weight (splenomegaly) and liver hypertrophy (increase in liver weight) - typical symptoms of colitis. Outcomes: Intestinal permeability, measured by serum levels of FITC-dextran, was significantly elevated in C57BL/6 wild-type mice on control diet after DSS exposure. Mice supplemented with color-fleshed potatoes at 15 and 25% resisted the DSS-induced reduction in colon length. Purple-fleshed potato supplementation reduced splenomegaly and liver hypertrophy. IL-10KO mice on control diet showed splenomegaly, liver hypertrophy, rectal prolapse and fecal occult blood. IL-10KO mice on purple-fleshed potato diet showed a reduction in splenomegaly and liver hypertrophy compared to IL-10KO mice on the control diet and were similar to wild-type mice. We also completed animal experiments using both conventional and microbiota ablated mice to understand the role of microbiota in the anti-inflammatory potential of color-fleshed potatoes.   Purdue University (Connie Weaver). Background: Blueberries and other fruits with high polyphenolic content have been associated with reducing postmenopausal bone loss.  Activities: We determined the effective dose in an OVX animal model and completed a chronic feeding intervention.  Fecal samples were analyzed for gut microbial communities.  Outcomes: We completed the intervention of a clinical trial in postmenopausal women and are completing sample and data analysis. With collaborators, we are exploring antioxidant and anti-inflammatory mechanisms.   University of Arizona (Frank Duca). Background: My lab is focused on determining how different diets and environmental factors contribute to the development of diabetes and obesity. We are interested in how changes in the gut microbiota and metabolites influence gut-brain axis regulation of glucose and energy homeostasis. Activities: Over the past year, the lab has focused on the role of oligofructose, a prebiotic, in increasing intestinal sensing mechanisms during high-fat feeding. We have found that oligofructose improves the ability of the small intestine to sense nutrients, and that this was dependent on the prebiotic altering the gut microbiota. Outcomes: As such, the lab has demonstrated that oligofructose driven improvements in small intestinal microbiota result in improved energy homeostasis, the first study to ever demonstrate a role of prebiotics in altering small intestinal microbiota to improve metabolism.    University of Arizona (Jennifer Teske). Background: The laboratory focuses on the impact of insufficient sleep to chronic disease and health outcomes. We investigate how sleep curtailment due to environmental noise exposure worsens metabolic health and how consumption of Westerns diets exacerbates disease risk during sleep disruption in rodent models. We are also interested in addressing sex differences since women are more sensitive to noise, have worse sleep and a higher prevalence of obesity compared to men. These studies revealed that females are more sensitive to the weight-promoting effects of a palatable western diet and that sleep disruption exacerbates the weight-promoting effects of a palatable western diet in both males and females. Finally, consumption of western diets disrupts calorie intake across the estrous cycle and both sleep disruption and consumption of cafeteria diet reduced estradiol levels. Activities: We performed validation studies to determine effects of sleep disruption and cafeteria diet on sex hormones, tested for an interaction between diet and estrous cycle phase on calorie intake and weight gain, tested for sex differences in sensitivity to cafeteria diet and sleep disruption and characterized combined effect of sleep disruption and cafeteria diet feeding on glucose and liver outcomes in male rats. Outcomes: We provided surgery training and determined proficiency for students at all levels, provided hands training on anthropometrics, energy expenditure, energy intake and estrous cycle determination and scientific writing and presentation skills training for both oral and poster presentations for students at all levels.   University of California-Berkeley (Barry Shane). Background: 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 continue to evaluate genetic risk factors for neural tube defects and to identify putative modifier genes which influence folate and vitamin B12 status, homocysteine levels, and methylation potential using a number of mouse strains and a cohort of students at Trinity College, Dublin. Activities: We carried out candidate gene analyses and genome-wide association scans in 2232 young, healthy Irish subjects to evaluate which common genetic polymorphisms influence red cell folate, serum folate and plasma total homocysteine.  Outcomes: The MTHFR 677C->T (rs1801133) variant was the major genetic modifier of all three folate related biomarkers in this Irish population and reached genome-wide significance for red cell folate (p = 1.37 x 10-17), serum folate (p = 2.82 x 10-11) and plasma total homocysteine (p = 1.26 x 10-19) concentrations. A second polymorphism in the MTHFR gene (rs3753584, p = 1.09 x 10-11) was the only additional MTHFR variant to exhibit any significant independent effect on red cell folate.  Other MTHFR variants, including the 1298A->C variant (rs1801131), appeared to reach genome-wide significance, but these variants shared linkage disequilibrium with MTHFR 677C->T and were not significant when analyzed in MTHFR 677CC homozygotes. Two additional genome-wide significant modifiers of plasma homocysteine were found in the region of the DPEP1 gene on chromosome 16 and the TWISTNB gene on chromosome 7.   University of California-Davis (Peng Ji). Background: Our current research aimed to investigate how early life iron excess affect systemic iron homeostasis and neurodevelopment. Activities: During the reporting period of W4002, we conducted two studies using neonatal piglets as translational model to address research objectives. Outcomes: In study 1, neonatal piglets were randomly assigned to treatments that received different iron supplementation (0, 100 mg i.m. injection, 10 mg/kg·d, or 50 mg/kg·d from birth to postnatal day 21). Our major findings are 1) dietary iron excess in early life cause systemic and brain iron overload in nursing piglets; 2) Piglets received high iron supplement showed behavioral phenotypes of diminished social novelty recognition, however, the sociability were normal among all treatment groups; 3) untargeted metabolomics analysis unveil significant enrichment of purine metabolism in hippocampus of iron overloaded piglets compared to those without iron supplementation; 4) Iron excess increased hippocampal lipid peroxidation and decreased expression myelin basic protein, which may explain altered social novelty preference; 5) mRNA expression of iron regulatory proteins/transporters were altered by iron supplement to the direction that is unfavorable to iron uptake. However, protein expression of ferroportin in gut, the primary iron transporter, was not affected by iron overloading. This may attribute to iron overload during early postnatal period. In study 2, we evaluated the risk and benefits of dietary iron excess on growth and iron homeostasis in newborns with low birth weight using piglet model. Neonatal piglets with either normal birth weight or low birth weight were assigned to either high iron or normal oral iron supplement from birth to postnatal day 21. We are currently working on lab analysis of the samples. Results will be reported in next annual meeting.     University of California-Davis (Yanhong Liu). Background: Recently, a novel concept, non-nutrients, is illuminated to describe a group of dietary compounds which have no nutrients contribution to animal, but have physiological activities beyond provision of bioavailable nutrients. Those dietary compounds include but not limited to phytochemicals, prebiotics, probiotics, etc. Emerging evidence suggested that these non-nutrients provided benefits on animal health and production through different modes of action: regulating nutrient digestibility or absorption, and modulating microbial ecology in the digestive tract and/or immune responses. Activities: We were focusing on several probiotics strains on animal health. We have conducted couple animal trials with pig to evaluate the effects of probiotics (Bacillus subtilis or Bacillus spp.) on disease resistance and immunity of weaned pigs that were experimentally infected with a pathogenic E. coli. Outcomes: We observed very positive benefits of supplementing probiotics in animal feed on weaned pig health and performance. New grant was obtained from National Pork Board to support more research on probiotics in pigs. In one year of W-3002 support, 2 visiting scientists, 4 graduate students, and several undergraduate students were supervised.   University of Connecticut (Ji-young Lee). Project 1 - Treatment of liver fibrosis is very limited as there is currently no effective anti-fibrotic therapy. Spirulina platensis (SP) is a blue-green alga that is widely supplemented in healthy foods. The objective of this study was to determine whether SP supplementation can prevent obesity-induced liver fibrosis in vivo. Male C57BL/6J mice were randomly assigned to a low-fat (LF) or a high-fat/high-sucrose/high-cholesterol (HF) diet, or HF diet supplemented with 2.5% SP (w/w) (HF/SP) for 16 or 20 weeks. There were no significant differences in body weight, activity, energy expenditure, serum lipids, or glucose tolerance between mice on HF and HF/SP diets. However, plasma alanine aminotransferase level was significantly reduced by SP at 16 weeks. Expression of fibrotic markers and trichrome stains showed no differences between HF and HF/SP. Splenocytes isolated from HF/SP-fed mice had lower inflammatory gene expression and cytokine secretion compared to splenocytes from HF-fed mice. SP supplementation did not attenuate HF-induced liver fibrosis. However, the expression and secretion of inflammatory genes in splenocytes were significantly reduced by SP supplementation, demonstrating the anti-inflammatory effects of SP in vivo. Although SP did not show an appreciable effect on the prevention of liver fibrosis in this mouse model, it may be beneficial for other inflammatory conditions. Project 2 - Although the anti-inflammatory effects of astaxanthin (ASTX) have been suggested, the underlying mechanisms have not been fully understood. Particularly, the modulatory action of ASTX in the interplay between nuclear factor E2-related factor 2 (NRF2) and nuclear factor κB (NFκB) to exert its anti-inflammatory effect in macrophages is unknown. The effect of ASTX on mRNA and protein expression of pro-inflammatory and antioxidant genes and/or cellular reactive oxygen species (ROS) accumulation were determined in RAW 264.7 macrophages, bone marrow-derived macrophages (BMDM) from wild-type and Nrf2 deficient mice, and/or splenocytes and peritoneal macrophages of obese mice fed ASTX. The effect of ASTX on M1 and M2 macrophage polarization was evaluated in BMDM. ASTX significantly decreased LPS-induced mRNA expression of interleukin 6 (Il-6) and Il-1β by inhibiting nuclear translocation of NFκB p65; and attenuated LPS-induced ROS with an increase in NRF2 nuclear translocation, concomitantly decreasing NADPH oxidase 2 expression in RAW 264.7 macrophages. In BMDM of WT and Nrf2-deficient mice, ASTX decreased basal and LPS-induced ROS accumulation. The induction of Il-6 mRNA by LPS was repressed by ASTX in both types of BMDM while Il-1β mRNA was decreased only in WT BMDM. Furthermore, ASTX consumption lowered the LPS sensitivity of splenocytes in obese mice. ASTX decreased M1 polarization of BMDM while increasing M2 polarization. ASTX exerts its anti-inflammatory effect by inhibiting the nuclear translocation of NFkB p65 and by preventing ROS accumulation in NRF2-dependent and -independent mechanisms. Thus, ASTX is an agent with anti-inflammatory and antioxidant properties that may be used for the prevention of inflammatory conditions.   University of Hawaii (Kacie Ho). Background: Many agricultural commodities are known to be rich sources of nutrients, vitamins, minerals, and bioactive phytochemicals (e.g., polyphenols, carotenoids), all of which may provide beneficial health effects. However, health impacts and bioactivity of many phytochemicals are limited by their bioaccessibility, i.e., the relative amount of phytochemical that is stable against digestion and available to be absorbed in the small intestines. Our goals are to identify and quantify the major nutrients and phytochemicals (and their potential interactions) in post-harvest commodities across different varieties and to elucidate the effect of food matrix on bioaccessibility. Gaining a better understanding of phytochemical bioaccessibility, namely the effects of plant variety and processing on bioaccessibility, will help to optimally deliver benefits from available crops for the local consumer or to add-value to exported products. Activities:  Bioactive phytochemicals will be extracted from agricultural commodities (e.g. raw fruit vs. processed fruit). Bioaccessibility will be measured by subjecting samples to a simulated digestion to estimate the relative amount that is stable against digestion and available for absorption. Data/results will provide evidence on if certain types of processing or varieties of agricultural products or to provide improved bioaccessibility of bioactive phytochemicals compared to others. This project therefore aims to establish knowledge that can be used to optimize nutrition information/diet so that individuals can more efficiently obtain health-promoting components from their food. This is expected to allow the public to select and process/cook foods in a manner that best optimizes nutrient intakes. This could also help local growers to add-value to special (e.g., nutrient dense or highly bioaccessible) varieties or enable them/industry to make products that can better deliver nutrients. Outcomes: Dr. Kacie Ho is new to the W4002 project (approved Feb. 11, 2019), and outcomes will be reported in future years.   University of Illinois – Urbana-Champaign (Jaume Amengual). Background: Carotenoids are one of the most important bioactive molecules in plants. Among them, β-carotene is particularly important as it is the main precursor of vitamin A in mammals. My laboratory focuses on understanding the role of β-carotene in obesity and atherosclerosis, two diseases deeply related to lipid metabolism. Activities: This past year, my laboratory was focused on elucidating the mechanism(s) by which β-carotene reduces cholesterol and triglyceride plasma levels. Using a mouse model lacking the enzyme involved in conversion of β-carotene to vitamin A, we observed that the bioactive molecule responsible of these effects was retinoic acid, a vitamin A derivative. Mice and hepatic cells exposed to retinoic acid showed a reduced cholesterol and triglyceride secretion rate, which correlated to a reduced apolipoprotein B100 (apoB100) levels, the main component of very-low density lipoproteins (VLDL). The positive effects of β-carotene and retinoic acid on plasma lipid levels were clinically evaluated by using a LDL receptor deficient mice (Ldlr-/- mice). We fed Ldlr-/- mice a diet containing cholesterol and fat for 12 weeks (Control diet) or containing the same components and 50 mg of β-carotene (β-carotene diet) for the same time. We observed that mice fed β-carotene had a lower incidence of atherosclerosis by evaluating the accumulation of macrophages in the aortic root of these mice. Outcomes: This work is currently under preparation, we expect to finish a publication including these data by the end of this year.   University of Maine (Dorothy Klimis-Zacas). Background: Atherosclerosis is a chronic inflammatory, progressive disease of the large arteries that can lead to CVD and stroke. Angiogenesis is the formation of new capillary blood vessels from existing ones and endothelial cell migration and proliferation contribute to the development of angiogenesis; critical in the early stages of atherosclerosis. Wild blueberries (Vaccinium angustifolium) are rich in anthocyanins (ACNs) and phenolic acids (Phen) having an exceptional ranking for antioxidant capacity compared to other berries and fruits. Activities: In one project, we continued to investigate the effect of ACNs and Phen fractions and their combination on endothelial cell migration and angiogenesis and mechanisms thereof, by exploring relevant biomarkers of cell migration and angiogenesis such as RhoA, Rac1 GTPases, AKT, VEGF and eNOS and their gene expression, critical for cell morphology, cytoskeleton integrity, cell permeability, angiogenesis and cell migration. In a second project, targets the role of Red Raspberries (Rubus idaeus) on endothelial function (vasoconstriction and vasodilation) and obesity-induced inflammation by assessing pro-inflammatory markers and their gene expression in hepatic and adipose tissues in an animal model of the Metabolic Syndrome (MetS), the Obese Zucker Rat (OZR). Outputs: For project 1, preliminary results document a differential response of the above bioactive compounds on endothelial cell migration and relevant proteins and their gene expression, based on type of fraction and its concentration. Studies on angiogenesis also document a concentration-depended effect, critical concentrations at which angiogenesis is modulated and differential response based on the different fractions (ACNs or Phen). ACNs seem to inhibit HUVEC migration and angiogenesis while PAs promote this process. In Project 2, preliminary results support the role of Red Raspberries in normalizing the endothelial dysfunction and attenuating inflammation associated with MetS.   University of Missouri (Ingolf Gruen). Background: One of the key elements affecting bioavailability and bioactivity of nutrients is the food matrix that they are in. Thus, the analysis of the concentration of volatile and non-volatile (phyto-) nutrients and the estimation of their release from the food matrix is directly related to their potential bioavailability and bioactivity. Chocolate is made from the fermented, dried, and roasted seeds of the Theobroma cacao tree. It is now understood that cacao, contains a variety of compounds, including well-known flavonoid polyphenols, the consumption of which has positive impacts on human heart health and blood pressure, cancer reduction, LDL cholesterol reduction, and insulin resistance improvements, as numerous in vitro, in vivo, and observational studies have confirmed. A persuasive case has, therefore, been made that cacao is a healthful addition to a balanced diet. However, despite the strong evidence for the healthful qualities of cacao, which has led to an overall increase in consumer purchases of more high-cacao-content chocolate than in previous decades, sales figures still show that there is an unwillingness by many Americans to consume higher-cacao-content chocolate, which tends to be more bitter, a taste modality not readily appreciated by most. Therefore, if the bitterness of cacao could be minimized, higher-cacao-content and lower-sugar chocolate confection sales could capture an even larger segment of the conventional and healthy snack-food market by achieving the elusive combination of being both tasty and healthy. Activities: In the context of this project, we initiated an investigation into the bioactive compounds and the resulting bitterness of cacao and chocolate, specifically our goal is to identify and quantify the complex mixture of important bitter compounds within the three compound classes that are known to be important to cocoa--methylxanthines, flavan-3-ols, and diketopiperazines. After project initiation, cocoa beans were obtained from Ghana, Madagascar, and Peru and have been roasted according to a standard roasting profile by chocolate manufacturer Patric Chocolate, LLC. As an initial preliminary project to show proof-of-concept, we produced three 70% dark chocolates differing only in their roast profile (raw, generic medium roast, generic dark roast), and, in addition to chemical analysis, we had 126 chocolate consumers rate “Overall Liking”, “Perceived Sweetness”, and ”Perceived Bitterness” on 9-point scales. Outcomes: Methods have been developed and validated, and standard curves have been established for the cocoa bitter compounds: Caffeine, Theobromine, Catechin, Epicatechin, and selected Diketopiperazines (DKPs), including cyclo(L-Pro-L-Val), which according to the most recent literature available is considered the most important DKP in regards to cocoa bitterness. Analysis of variance (ANOVA) of our initial cocoa roast showed significant differences (p<0.05) between the chocolates. Significantly lower bitterness and higher liking were seen for both of the roasted chocolates, with the Medium-Roast having the lowest bitterness and highest liking rating. The bitter compounds caffeine, Theobromine, Catechin, and Epicatechin were found in all samples. While we were able to positively identify cyclo(L-Pro-L-Val) in the very dark roasted cocoa using LC-MS-MS, which then allowed us to also detect and quantify this diketopiperazine in other roasts, the concentration of cyclo(L-Pro-L-Val) is apparently considerably lower, i.e. only about 5-10% of that reported in the literature. There are known methods for analysis of bitter flavan-3-ols in plant materials in general, and cacao in particular, but there are also well-defined pitfalls known for such analyses, including the labile and reactive nature of flavan-3-ols, including the monomer of (-)-epicatechin in particular. It is known, for example, that as flavan-3-ols are extracted from the cacao tissue, they begin to oxidize, epimerize, polymerize and otherwise degrade in ways that are quite difficult to characterize. For this reason, we are attempting to circumvent the problem of flavan-3-ol analysis in chocolate by analyzing the compounds directly within the cacao matrix, or by desorbing and analyzing within several brief moments. Our first attempt to use solid-state NMR to analyze the flavan-3-ols in situ did not result in sufficiently intense peaks for the flavan-3-ol compounds within the background of the cacao matrix, even after cocoa butter extraction. We are now pursuing matrix-assisted laser desorption/ionization (MALDI) analysis using solvent-free sample preparation and instrumentation in the Metabolomics center here on the University of Missouri-Columbia campus. Literature suggests that other lipid-rich and waxy samples have lent themselves quite well to analysis using such a technique. We are, therefore, hopeful that this method may also work for analysis of flavan-3-ols in chocolate, though preliminary experiments still must be done.   University of Nebraska – Lincoln (Jiujiu Yu). Background: The NLRP3 inflammasome is a key regulator of innate immune responses, and its aberrant activation is implicated in the pathogenesis of many complex diseases such as gout and atherosclerosis. Targeting NLRP3 inflammasome could hold promise to curb these diseases, but interventions specifically inhibiting NLRP3 inflammasome have not been developed for patient treatment. The current study aimed to identify the food-borne exosome-like nanoparticles (ELNs) that inhibit NLRP3 inflammasome activity. Activities: Nine vegetables or fruits were selected to extract ELNs, which were examined for their inhibitory effects on NLRP3 inflammasome in primary macrophages. Though most of the tested ELNs posed minimal impacts, the ELNs from ginger rhizomes (G-ELNs) strongly inhibited NLRP3 inflammasome activation. The G-ELNs contain lipids, proteins, and RNAs. They were easily taken up by macrophages. G-ELN treatment suppressed the downstream of inflammasome activity including Caspase1 auto-cleavage, IL-1 and IL-18 secretion, and pyroptotic cell death. ASC oligomerization and speck formation assays indicated that G-ELNs blocked assembly of NLRP3 inflammasome. Outcomes: The data suggested that the dietary nanoparticles from ginger represent a new class of NLRP3 inflammasome inhibitor.   University of Nebraska-Lincoln (Janos Zempleni). Background: Virtually every cells produces and secretes exosomes (nanoparticles) loaded with cargos such as various species of RNAs, proteins and lipids. Exosomes play essential roles in cell-to-cell communication. The transfer of exosomes cargos from donor cells to receptor cells alters gene expression and metabolism in receptor cells. We have made the paradigm-shifting discovery that exosomes and their cargos do not exclusively originate from endogenous synthesis but may also be obtained from dietary sources such as bovine milk and chicken eggs. Activities: 1) We have assessed the microRNA cargos in chicken egg yolk, the bioavailability of chicken egg exosomes and their microRNA cargos in humans, and the effects of exosomes and cargos in peripheral blood mononuclear cells. 2) We have conducted a comprehensive analysis of the bioavailability and distribution of fluorophore-labeled milk exosomes and microRNAs in mice. 3) We have developed an exosome and cargo tracking (ECT) mouse. 4) We have assessed storage stability and microRNA cargos in human milk, bovine milk and infant formulas by RNA-sequencing analysis and qRT-PCR. 5) We have assessed the role of glycoproteins on the surface of milk exosomes in absorption and distribution of bovine milk exosomes in mice. 6) We have characterized the composition of exosome-defined, AIN-93G-based diets developed in our laboratory. 7) We demonstrated that depletion of milk exosomes and their RNA cargos elicits phenotypes such as impaired fecundity, aberrant purine metabolism, altered immune function, loss of muscle grip strength, impaired spatial learning and memory, loss of antiviral resistance, and changes in microbial communities and their genomes in the gut. We have phenotypes of depletion also include increased severity of inflammatory bowel disease in Mdr1a-/- mice. 8) We have shown that bovine milk exosomes deliver a large load of microbial RNAs to hosts.   University of Rhode Island (Brietta Oaks). Background: Lead exposure is a major public health concern in Rhode Island. There is evidence that omega-3 fatty acid intake may reduce circulating lead concentrations, but research has been limited and has not been explored in pregnant women, whom are at a higher risk for adverse effects of lead exposure. In addition, omega-3 fatty acid intake may reduce circulating cortisol, a stress hormone which has negative effects during pregnancy if at chronically high concentrations. Activities: We have prepared a proposal to research the association between omega-3 fatty acid intake, lead, and cortisol in pregnant women in Providence, RI. We have established collaborations with outside labs to analyze fatty acid status and blood lead concentrations and have recently set up a lab at University of Rhode Island to conduct the lab analysis for cortisol. Outcomes: We anticipate recruitment will start in May 2019 and we should have preliminary results by February 2020.

Publications

<ol> <li>Abelilla JJ, Liu Y, Stein HH. Digestible indispensable amino acid score (DIAAS) and protein digestibility corrected amino acid score (PDCAAS) in oat protein concentrate measured in 20- to 30-kilogram pigs. J Sci Food Agri. 2018, 98:410-414.</li> </ol>   <ol start="2"> <li>Aguilar-Lozano A, Baier SR, Grove R, Shu J, Giraud D, Mercer KE, Cui J, Badger TM, Adamec J, Andres A, Zempleni J. Concentrations of purine metabolites are elevated in fluids from adults and infants and in livers from mice fed diets depleted of bovine milk exosomes and their RNA cargos. J Nutr 148:1886-1894, 2018</li> </ol>   <ol start="3"> <li>Alvarez B, Gac L, Barrientos T, Teske JA, Perez-Leighton CE. Effects on hedonic feeding and energy expenditure of the non-opioid peptide DYN-A2-17. Neuroscience. 2018, 371(10): 337-345.</li> </ol>   <ol start="4"> <li>Amengual J, García-Carrizo FJ, Arreguín A, Mu&scaron;inović H, Granados N, Palou A, Bonet ML, Ribot J. Retinoic Acid Increases Fatty Acid Oxidation and Irisin Expression in Skeletal Muscle Cells and Impacts Irisin In Vivo. Cell Physiol Biochem. 2018;46(1):187-202</li> </ol>   <ol start="5"> <li>Amengual J, Guo L, Strong A, Madrigal-Matute J, Wang H, Kaushik S, Brodsky JL, Rader DJ, Cuervo AM, Fisher EA. Autophagy Is Required for Sortilin-Mediated Degradation of Apolipoprotein B100. Circ Res. 2018 Feb 16;122(4):568-582.</li> </ol>   <ol start="6"> <li>Ashorn P, Alho L, Allen LH, Ashorn U, Chandrasiri U, Deitchler M, Doyle R, Harjunmaa U,</li> </ol>   <ol start="7"> <li>Bailey RK, Weaver Cm, Daly R, Sahni S, Chocano P, Welch A, Bischoff-Ferrari H. Best Practices for Conducting Observational Research to Assess the Relation between Nutrition and Bone: An International Working Group Summary.  Advances  Accepted </li> <li>Bailey RL, Weaver CM, Murphy S. Using the Dietary Reference Intakes to assess intakes in Research:  Successful Approaches.  Van Horn L, ed.  Academy of Nutrition and Dietetics, Chicago IL, 2019.</li> <li>Bauer, PV, Duca FA, Waise TM, Dranse HJ, Rasmussen BA, Puri A, Rasti M, O’Brien CA, Lam TK. Microbiota in the upper small intestine alters ACSL3-dependent fatty acid sensing pathway to influence whole-body glucose homeostasis. Cell Metab 2018, 27 :573-587</li> </ol>   <ol start="10"> <li>Beaver LM, Lӧhr CV, Clarke JD, Glasser ST, Watson GW, Wong CP, Zhang Z, Williams DE, Dashwood RH, Shannon J, Thuillier P, Ho E (2017) Broccoli Sprouts Delay Prostate Cancer Formation and Decrease Prostate Cancer Severity with a Concurrent Decrease in HDAC3 Protein Expression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) Mice. Curr Dev Nutr. 2017 Dec 26;2(3):nzy002. doi: 10.1093/cdn/nzy002</li> </ol>   <ol start="11"> <li>Bellanger M, Chalmers D, Sabini G, Weaver CM, Lelievre S. The value of global environmental health for primary prevention research of breast cancer.  Cancer Prev Res  In press.</li> <li>Blumberg JB, Frei B, Fulgoni III, VL, Weaver CM, Zeisel SH. Contribution of dietary supplements to nutritional adequacy by socioeconomic subgroups in adults of the United States.  Nutrients  10:  2018  doi:10.3390/nu10010004</li> </ol>   <ol start="13"> <li>Brosnan JT, Mills JL, Ueland PM, Shane B, Fan R, Chiu C-Y, Pangilinan F, Brody LC, Brosnan ME, Pongnopparat T, Molloy AM. Lifestyle, metabolite, and genetic determinants of formate concentrations in a cross-sectional study in young, healthy adults. Am J Clin Nutr. 2018, 107:345-354.</li> </ol>   <ol start="14"> <li>Brown KH, Hess SY, Kortekangas E, Lartey A, Maleta K, Oaks BM, Ocansey E, Okronipa H, Ouédraogo JB, Pulakka A, Somé JW, Stewart CP, Stewart RC, Vosti SA, Jimenez EY, Dewey KG. Predictors and pathways of language and motor development in four large prospective cohorts of young children in Ghana, Malawi, and Burkina Faso. J Child Psychol Psychiatry. 2017 Nov;58(11):1264-1275.</li> </ol>   <ol start="15"> <li>Camara Teixeira D, Cordonier EL, Wijeratne SSK, Huebbe P, Jamin A, Jarecke S, Wiebe M, Zempleni J. A cell death assay for assessing the mitochondrial targeting of proteins. J Nutr Biochem 6:48-54, 2018</li> </ol>   <ol start="16"> <li>Cao S, Wastney ME, Lachcik PJ, Xiao H-H, Weaver CM, Wong M-S. Both Oleanolic acid and a mixture of oleanolic and ursolic acids mimic the effects of fructus ligustri lucidi on bone properties and circulating 1,25-dihydroxycholecalciferol in ovariectomized rat.  J Nutr  148:1-8, 2018</li> <li>Coborn JE, Lessie RE, Rance NE, Sinton CM, Perez-Leighton CE, Teske JA. Noise-induced sleep disruption increases weight gain and decreases energy metabolism is female rats. Int J Obes. 2018. Epub 2018 Dec. 19.</li> </ol>   <ol start="18"> <li>Cristian Del Bo, Valeria Deon, Jonica Campolo, Marisa Porrini, Dorothy Klimis-Zacas and Patrizia Riso. A serving of blueberry (V. corymbosum) reverses endothelial dysfunction in young smokers and non-smokers: a randomized, controlled, crossover study, Food and Function, DOI: 10.1039/c7fo00861a, 2017</li> <li>Cui J. Zempleni J. RNase H2-dependent PCR detects bovine microRNAs in human plasma. [reply: letter to the editor] J Nutr 148:1508, 2018</li> </ol>   <ol start="20"> <li>Curran KM, Bracha S, Wong CP, Beaver LM, Stevens JF, Ho E. (2018) Sulforaphane absorption and histone deacetylase activity following single dosing of broccoli sprout supplement in normal dogs. Vet Med Sci. 2018 4(4):357-363. doi: 10.1002/vms3.118. Epub 2018 Aug 17.</li> </ol>   <ol start="21"> <li>Dashner-Titus EJ, Hoover J, Li L, Lee JH, Du R, Liu KJ, Traber MG, Ho E, Lewis J, Hudson LG. (2018) Metal exposure and oxidative stress markers in pregnant Navajo Birth Cohort Study participants. Free Radic Biol Med. 2018 Apr 30;124:484-492.</li> </ol>   <ol start="22"> <li>Dallas, D. C., Traber, M. (2018) How does breast milk enhance lutein absorption? Journal of Nutrition 148(1): 1-2.</li> </ol>   <ol start="23"> <li>Dallas, D. C., German, J. B. (2017) Enzymes in human milk. In: Isolauri E, Sherman P, Walker W, editors. Intestinal Microbiome: Functional Aspects in Health and Disease. Basel, Switzerland: Karger Publishers; p. 129-36.</li> </ol>   <ol start="24"> <li>Dallas, D. C., Nielsen, S. D. (2018) Milk peptidomics to identify functional peptides and for quality control of dairy products. In Michael Schrader, Lloyd Fricker (Ed.), Peptidomics--Methods and Protocols (1st ed., vol. 1719). P. 223-240. Methods in Molecular Biology, Springer.</li> </ol>   <ol start="25"> <li>Demers-Mathieu, V., Nielsen, S. D., Underwood, M. A., Borghese, R., Dallas, D. C. (2017) Analysis of milk from mothers who delivered prematurely revealed few changes in proteases and protease inhibitors across gestational age at birth and infant postnatal age. Journal of Nutrition 147(6): 1152-1159.</li> </ol>   <ol start="26"> <li>Demers-Mathieu, V., Nielsen, S. D., Underwood, M. A., Borghese, R., Dallas, D. C. (2017) Changes in proteases, antiproteases and bioactive proteins from mother's breast milk to the premature infant stomach. Journal of Pediatric Gastroenterology and Nutrition 66(2): 318-324.</li> </ol>   <ol start="27"> <li>Demers-Mathieu, V., Qu, Y., Underwood, M. A., Borghese, R., Dallas, D. C. (2018) Premature infants have lower gastric digestion capacity for human milk proteins than term infants. Journal of Pediatric Gastroenterology & Nutrition. 66(5): 816-821.</li> </ol>   <ol start="28"> <li>Demers-Mathieu, V., Qu, Y., Underwood, M. A., Dallas, D. C. (2018) The preterm infant stomach actively degrades milk proteins with increasing breakdown across digestion time. Acta Paediatrica. 107(6): 967-974.</li> </ol>   <ol start="29"> <li>Demers-Mathieu, V., Underwood, M. A., Beverly, R. L.*, Dallas, D. C. (2018) Survival of Immunoglobulins from Human Milk to Preterm Infant Gastric Samples at 1, 2, and 3 Hours Postprandial. Neonatology. 114: 242-250.</li> </ol>   <ol start="30"> <li>Demers-Mathieu, V., Underwood, M. A., Beverly, R. L.*, Drud Nielsen, S., Dallas, D. C. (2018) Comparison of human milk immunoglobulin survival during gastric digestion between preterm and term infants. Nutrients, Special Issue on Breastfeeding and Human Lactation. 10(5): 631.</li> </ol>   <ol start="31"> <li>Dewey KG, Oaks BM. U-shaped curve for risk associated with maternal hemoglobin, iron status or iron supplementation. American Journal of Clinical Nutrition. Am J Clin Nutr. 2017 Dec;106(Suppl 6):1694S-1702S.</li> </ol>   <ol start="32"> <li>P Dey, E Mah, J Li, T Jalili, JD Symons, RS Bruno. (2018). Improved hepatic γ-tocopherol status limits oxidative and inflammatory stress-mediated liver injury in db/db mice with nonalcoholic steatohepatitis. J Funct Food, 40, 670-678.</li> </ol>   <ol start="33"> <li>Doepker C, Franke K, Myers E, Goldberger JJ, Lieberman HR, O’Brien C, Peck J, Tenebein M, Weaver C, Wikoff D. Key findings and implications of a recent systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children. Nutrients  10:1536, 2018.</li> </ol>   <ol start="34"> <li>Drewnowski A, Dwyer J, King JC, Weaver CM. Should Nutrient Density Scores Include Food Groups as Well as Nutrients?  Nutr Rev    In press</li> <li>Duca FA, Bauer, PV, Waise TM, Rasmussen BA, Abraham MA, Dranse HJ, Puri A, O’Brien CA, Lam TK. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1 sensing glucoregulatory pathway. Cell Metab 2018, 27 :101-117</li> </ol>   <ol start="36"> <li>Farruggia C, Kim M-.B, Bae M, Lee Y, Pham TX, Yang Y, Han MJ, Park Y-.K, Lee J-.Y. Astaxanthin exerts anti-inflammatory and antioxidant properties in macrophages in NRF2-dependent and independent manners. J Nutr Biochem. 2018, 62:202-209.</li> </ol>   <ol start="37"> <li>Fiorentino NM, Kimmel KA, Suleria HAR, Joseph M, Alavi S, Beyer RS, Lindshield BL. Newly Formulated Fortified Blended Foods Result in Improved Protein Efficiency and Hepatic Iron Levels Compared to CSB+ in Broiler Chickens. Curr Dev Nutr. 2(12): 2018 <a href="https://doi.org/10.1093/cdn/nzy073">https://doi.org/10.1093/cdn/nzy073</a></li> </ol>   <ol start="38"> <li>Gaulke CA, Rolshoven J, Wong CP, Hudson LG, Ho E, Sharpton TJ. Marginal Zinc Deficiency and Environmentally Relevant Concentrations of Arsenic Elicit Combined Effects on the Gut Microbiome (2018). mSphere. 5;3(6). pii: e00521-18. doi: 10.1128/mSphere.00521-18</li> </ol>   <ol start="39"> <li>M Goodus, A Sauerbeck, PG Popovich, RS Bruno, DM McTigue. (2018). Dietary green tea extract prior to spinal cord injury prevents hepatic iron overload but does not improve chronic hepatic and spinal cord pathology in rats. J Neurotrauma, 35(24):2872-2882.</li> </ol>   <ol start="40"> <li>I Hatsu, C Gunther, E Hade, S Vandergriff, N Slesnick, R Williams, R Bruno, J Kennel. (2018). Unaccompanied homeless youth have extremely poor diet quality and nutritional status. Int J Adol Youth, 1-14, doi: <a href="https://doi.org/10.1080/02673843.2018.1538885">https://doi.org/10.1080/02673843.2018.1538885</a></li> </ol>     <ol start="41"> <li>Haufe TC, Ho KKHY, Ferruzzi MG, Neilson AP. Potential Health Effects of Tea. Nutrition Today. 2018, 53(5):213-28.</li> </ol>   <ol start="42"> <li>Ho, KKHY, Schroen K, San Martin-Gonzalez MF, Berton-Carabin CC. Synergistic and antagonistic effects of plant and dairy protein blends on physicochemical stability of lycopene-loaded emulsions. Food Hydrocolloids. 2018, 81:180-190</li> </ol>   <ol start="43"> <li>Hohman EE, Hodges JK, Wastney ME, Lachcik PJ, Han C-Y, Dwyer D, Peacock M, Kosteniuk PJ, Weaver CM. Serum calcium concentration is maintained when bone resorption is suppressed by osteoprotegerin in young growing male rats.  Bone  116:162-170, 2018.</li> </ol>   <ol start="44"> <li>Housley L, Magana AA, Hsu A, Beaver LM, Wong CP, Stevens JF, Choi J, Jiang Y, Bella D, Williams DE, Maier CS, Shannon J, Dashwood RH, and Ho E. (2018) Untargeted Metabolomic Screen Reveals Changes in Human Plasma Metabolite Profiles Following Consumption of Fresh Broccoli Sprouts. Mol Nutr Food Res. 2018 Jan 28. doi: 10.1002/mnfr.201700665.</li> </ol>   <ol start="45"> <li>Jun Huang, Yiwei Zhang, Lin Dong, Qinghan Gao, Lei Yin, Hongfeng Quan, Rong Chen, Xueyan Fu, Dingbo Lin. Ethnopharmacology, phytochemistry, and pharmacology of Cornus officinalis Sieb. Et Zucc. J Ethnopharmacol. 2018, 213:280-301.</li> </ol>   <ol start="46"> <li>Ji P, Lönnerdal B, Kim K, Jinno CN.Iron Oversupplementation Causes Hippocampal Iron Overloading and Impairs Social Novelty Recognition in Nursing Piglets. J Nutr. 2019, doi: 10.1093/jn/nxy227.</li> <li>Jinno C, He Y, Morash D, McNamara E, Zicari S, King A, Stein H, Liu Y. Enzymatic digestion turns food waste into feed for growing pigs. Anim Feed Sci Technol. 2018, 242:48-58.</li> </ol>   <ol start="48"> <li>Jorgensen J, Klein N, Maleta K, Nkhoma M, Oaks BM, Poelman B, Rogerson S, Stewart CP, Zeilani M, Dewey KG. Co-causation of reduced newborn size by maternal undernutrition, infections, and inflammation. Matern Child Nutr. 2018 Jul;14(3):e12585.</li> </ol>   <ol start="49"> <li>Kohrt WM, Wherry SJ, Wolfe P, Sherk VD, Wellington T, Swanson CM, Weaver CM, Boxer RS. Maintenance of serum ionized calcium during exercise attenuates parathyroid hormone and bone resorption responses.  JBMR  33:1326-1334, 2018</li> </ol>   <ol start="50"> <li>Lawlor MR, Weaver CM, Craig BA, Whiting SJ, Baster-Jones ADG, Vatanparast H, McCabe GP. Ch. 4 Peak BMC growth and calcium requirements for Children.  In:  Nutritional Influences of Bone Health.  International Congress Series Proceedings of the 10th International Symposium on Nutritional Aspects of Osteoporosis, Hong Kong. Weaver CM, Bischoff-Ferrari H, Daly, R, Wong M-S, Eds.  Springer   Pg 37-44, 2018.</li> </ol>   <ol start="51"> <li>Lei Wu, Xin Guo, Yi Lyu, Stephen L. Clarke, Edralin A. Lucas, Brenda J. Smith, Deana Hildebrand, Weiqun Wang, Denis M. Medeiros, Xinchun Shen, Dingbo Lin. Targeted metabolomics reveals abnormal hepatic energy metabolism by depletion of β–carotene oxygenase 2 in mice. Scientific Reports 2017 Nov 7;7(1):14624. doi: 10.1038/s41598-017-15222-x.</li> </ol>   <ol start="52"> <li>Leiferman A, Shu J, Grove R, Cui J, Adamec J, Zempleni J. A diet defined by its content of bovine milk exosomes and their RNA cargos has moderate effects on gene expression, amino acid profiles and grip strength in skeletal muscle in C57BL/6 mice. J Nutr Biochem 12:123-128, 2018</li> </ol>   <ol start="53"> <li>Lewis R, Laing E, Weaver CM.   41 Adolescence and acquisition of peak bone mass.  In:  Vitamin D, Fourth Edition. Feldman  Academic Press  London UK. Pg 731-751, 2018.</li> <li>Leyshon BJ, Ji P, Caputo MP, Matt SM, Johnson RW. Dietary Iron Deficiency Impaired Peripheral Immunity but Did Not Alter Brain Microglia in PRRSV-Infected Neonatal Piglets. Front Immunol. 2019, doi: 10.3389/fimmu.2018.03150.</li> </ol>   <ol start="55"> <li>Lillehoj H, Liu Y, Calsamiglia S, Fernandez-Miyakawa ME, Chi F, Cravens RL, Oh S, Gay CG. Phytochemicals as potential antibiotic alternatives to promote growth and enhance host health: a Report from the Second International Symposium on Alternatives to Antibiotics. Vet Res. 2018, 46:76-93.</li> </ol>   <ol start="56"> <li>Liu Y, Oliveira MSF, Stein H. Canola meal produced from high-protein or conventional varieties of canola seeds may substitute soybean meal in diets for gestating and lactating sows without compromising sow or litter productivity. J Anim Sci. 2018, 96:5179-5187.</li> </ol>   <ol start="57"> <li>Liu Y, Jha R, Stein HH. Nutritional composition, gross energy concentration, and in vitro digestibility of dry matter in 46 sources of bakery meals. J Anim Sci. 2018, 96:4685-4692.</li> <li>Liu Y, Choe J, Lee JJ, Kim J, Campbell JM, Polo J, Crenshaw JD, Pettigrew JE, Song M. Spray-dried plasma attenuates inflammation and lethargic behaviors of pregnant mice caused by lipopolysaccharide. PLoS ONE. 2018, 13(9):e0203427.</li> </ol>   <ol start="59"> <li>Liu Y, Espinosa CD, Abelilla JJ, Casas GA, Lagos LV, Lee SA, Kwon WB, Mathai JK, Navarro DMDL, Jaworski NW, Stein HH. Non-antibiotic feed additives in diets for pigs. Anim Nutr. 2018, 4:113-125.</li> </ol>   <ol start="60"> <li>Liu Y, Kil DY, Perez-Mendoza VG, Song M, Pettigrew JE. Supplementation of different fat sources affects growth performance and carcass composition of finishing pigs. J Anim Sci Biotech. 2018, 9:56-63</li> </ol>   <ol start="61"> <li>Liu Y, Choe J, Kim S, Kim B, Campbell JM, Polo J, Crenshaw JD, Pettigrew JE, Song M. Dietary spray-dried plasma improves intestinal morphology of mated female mice under stress condition. J Anim Sci Technol. 2018, 60:10-15.</li> </ol>   <ol start="62"> <li>Lobene AJ, McCabe LD, Stone MS, Kindler JM, Bailey RL, Mosfegh AJ, Rhodes DG, Goldman JD, McCabe GP, Weaver CM. Ch. 6 Dietary minerals, mineral ratios, and bone. In:  Nutritional Influences of Bone Health.  International Congress Series Proceedings of the 10th International Symposium on Nutritional Aspects of Osteoporosis, Hong Kong. Weaver CM, Bischoff-Ferrari H, Daly, R, Wong M-S, Eds.  Springer   Pg 53-67, 2018.</li> </ol>   <ol start="63"> <li>Yi Lyu, Lei Wu, Fan Wang, Xinchun Shen, Dingbo Lin. Carotenoid supplementation and retinoic acid in regulation of immunoglobulin A production and gut microbiome dysbiosis. Exp Biol Med (Maywood). 2018, 243(7):613-620.</li> </ol>   <ol start="64"> <li>Maiz Rodriguez M. A blueberry-enriched diet may aid in the amelioration of bone loss in ovariectomized rat model.  PhD Thesis  Purdue University, 2019.</li> </ol>   <ol start="65"> <li>Manca S, Upadhyaya B, Mutai E, Desaulniers AT, Cederberg RA, White BR, Zempleni J. Milk exosomes are bioavailable and distinct microRNA cargos have unique distribution patterns. Sci Rep 8:11321, 2018</li> </ol>   <ol start="66"> <li>JD McDonald, E Mah, C Chitchumroonchokchai, EJ Reverri, J Li, JS Volek, FA Villamena, RS Bruno. (2018). Co-ingestion of whole eggs or egg whites with glucose protects against postprandial hyperglycemia-induced oxidative stress and dysregulated arginine metabolism in association with improved vascular endothelial function in prediabetic men. Br J Nutr, 120(8):901-913.</li> </ol>   <ol start="67"> <li>JD McDonald, E Mah, C Chitchumroonchokchai, P Dey, AN Labyk, FA Villamena, JS Volek, RS Bruno (2018). Dairy milk proteins attenuate hyperglycemia-induced impairments in vascular endothelial function in adults with prediabetes by limiting increases in glycemia and oxidative stress that reduce nitric oxide bioavailability. J Nutr Biochem, 63:165-176.</li> </ol>   <ol start="68"> <li>JD McDonald, E Mah, P Dey, BD Olmstead, GY Sasaki, FA Villamena, RS Bruno. (2018). Dairy milk, regardless of fat content, protects against postprandial hyperglycemia-mediated impairments in vascular endothelial function in adults with prediabetes by limiting oxidative stress responses that reduce nitric oxide bioavailability. J Nutr Biochem, 63:129-139.</li> </ol>   <ol start="69"> <li>JD McDonald, C Chitchumroonchokchai, J Li, E Mah, AN Labyk, EJ Reverri, KD Ballard, JS Volek, RS Bruno. (2018). Replacing carbohydrate during a glucose challenge with the egg white portion or whole eggs protects against postprandial impairments in vascular endothelial function in prediabetic men by limiting increases in glycemia and lipid peroxidation. Br J Nutr, 119(3):259-270.</li> </ol>   <ol start="70"> <li>McKenney-Drake M, Moghbel MC, Paydary K, Alloosh M, Houshmand S, Moe S, Salaati A, Sturek JM, Territo PR, Weaver C, Werner TJ, Flemming Hoilund-Carlsen P, Sturek M, Alai A. 18F-NaF and 18F-FDG as molecular probes in the evaluation of atherosclerosis.  Europ J Nucl Med Mol Imaging  45:2190-2200, 2018.</li> </ol>   <ol start="71"> <li>Mithen R, Ho, E (2018)  Isothiocyanates for Human Health.  Mol Nutr Food Res. 2018 Sep;62(18):e1870079. doi: 10.1002/mnfr.201870079. PMID:30246304 (Note: Mithen and Ho, Guest Editors for Sept Special Issue “Isothiocyanates” for Mol Nutr Food Res.)</li> </ol>   <ol start="72"> <li>Murray, N. M., O'Riordan, D., Jacquier, J.-C., O'Sullivan, M., Holton, T. A., Wynne, K., Robinson, R. C., Barile, D., Nielsen, S. D., Dallas, D. C. (2018) Peptidomic screening of bitter and non-bitter sodium caseinate hydrolysate fractions for bioactive peptides. Journal of Dairy Science. 101(4): 2826-2837.</li> </ol>   <ol start="73"> <li>Murray, N. M., O'Riordan, D., Jacquier, J.-C., O'Sullivan, M., Cohen, J., Heymann, H., Barile, D., Dallas, D. C. (2017) Validation of a paper-disk approach to facilitate the sensory evaluation of bitterness in dairy protein hydrolysates from a newly developed food-grade fractionation system. Journal of Sensory Studies 32(3): e12266.</li> </ol>   <ol start="74"> <li>Nielsen, S. D., Beverly, R. L.*, Underwood, M. A., Dallas, D. C. (2018) Release of functional peptides from mother’s milk and fortifier proteins in the premature infant stomach. PLOS One. 13(11):e0208204. doi.org/10.1371/journal.pone.0208204</li> </ol>   <ol start="75"> <li>Nielsen, S. D., Beverly, R. L.*, Dallas, D. C. (2018) Milk proteins are predigested within the mammary gland. Journal of Mammary Gland Biology and Neoplasia. 22(4): 251-261.</li> </ol>   <ol start="76"> <li>Nielsen, S. D., Beverly, R. L., Dallas, D. C. (2017) Peptides released from foremilk and hindmilk proteins by breast milk proteases are highly similar. Frontiers in Nutrition, Nutrition Methodology 4(54).</li> </ol>   <ol start="77"> <li>Nielsen, S. D., Beverly, R. L., Qu, Y., Dallas, D. C. (2017) Milk bioactive peptide database: A comprehensive database of milk protein-derived bioactive peptides and novel visualization. Food Chemistry 232: 673-682.</li> </ol>   <ol start="78"> <li>Nutritional Influences of Bone Health. International Congress Series Proceedings of the 10th International Symposium on Nutritional Aspects of Osteoporosis, Hong Kong.   Weaver CM, Bischoff-Ferrari H, Daly, R, Wong M-S, Eds.  Springer </li> </ol>   <ol start="79"> <li>Panagiotis Tsakiroglou, Sharon Ashworth, James Webber, Cristian DelBo and Dorothy Klimis-Zacas, Anthocyanins and Phenolic acids extracted from wild blueberries (V. angustifolium) differentially modulate endothelial cell migration through RhoA and RAC1, J. Cell. Biochem., 2018, DOI:10.1002/jcb.28383</li> </ol>   <ol start="80"> <li>Penugonda K, Fiorentino N, Alavi S, Lindshield BL. Bioavailable Iron and Vitamin A in Newly Formulated, Extruded Corn, Soybean, Sorghum and Cowpea Fortified-Blended Foods in the In-vitro Digestion/Caco-2 Cell Model. Curr Dev Nutr. 2(7): 2018 <a href="https://doi.org/10.1093/cdn/nzy021">https://doi.org/10.1093/cdn/nzy021</a></li> </ol>   <ol start="81"> <li>Picariello, G., Addeo, F., Ferranti, P., Nocerino, R., Paparo, L., Passariello, A., Robinson, R. C., Barile, D., Dallas, D. C., Berni Canani, R. (2016) Antibody-independent identification of bovine milk-derived peptides in breast-milk. Food & Function 7(8): 3402-3409.</li> </ol>   <ol start="82"> <li>Rizzoli R, et al. Benefits and safety of dietary protein for bone health.  An experts consensus paper endorse by the European Society for Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and by the International Osteoporosis Foundation.  Osteoporos Intl. </li> </ol>   <ol start="83"> <li>R Pei, DM DiMarco, KK Putt, DA Martin, C Chitchumroonchokchai, RS Bruno, BW Bolling (2018). Pre-meal low-fat yogurt consumption reduces postprandial inflammation and markers of endotoxin exposure in healthy premenopausal women in a randomized controlled trial. J Nutr, 148:1-7.</li> </ol>   <ol start="84"> <li>Pham T X, Lee Y, Bae M, Hu S, Kang H, Kim M-.B, Park Y-.K, Lee J-.Y. Spirulina supplementation in a mouse model of liver fibrosis reduced the pro-inflammatory response of splenocytes. Br J Nutr. 2019 (In press).</li> </ol>   <ol start="85"> <li>Prado EL, Phuka J, Ocansey E, Maleta K, Ashorn P, Ashorn U, Adu-Afarwuah S, Oaks BM, Lartey A, Dewey KG. A method to develop vocabulary checklists in new languages and their validity to assess early language development. J Health Popul Nutr. 2018 May 11;37(1):13.</li> </ol>   <ol start="86"> <li>Prado EL, Ashorn U, Phuka J, Maleta K, Sadalaki J, Oaks BM, Haskell M, Allen LH, Vosti SA, Ashorn P, Dewey KG. Associations of maternal nutrition during pregnancy and post-partum with maternal cognition and caregiving. Matern Child Nutr. 2018 Apr;14(2):e12546.</li> </ol>   <ol start="87"> <li>Prado EL, Abbeddou S, Adu-Afarwuah S, Arimond M, Ashorn P, Ashorn U, Bendabenda J, Oaks BM, Stewart CP, Laugero KD, Adu-Afarwuah S, Lartey A, Vosti SA, Ashorn P, Dewey KG. Maternal plasma cholesterol and duration of pregnancy: a prospective cohort study in Ghana. Matern Child Nutr. 2017 Oct;13(4):e12418.</li> </ol>   <ol start="88"> <li>Reddivari L, Wang T, Wu B, Li S. Potato: An Anti-inflammatory Food?. Am J Potato Res. Invited Review. 2018. https://doi.org/10.1007/s12230-018-09699-z</li> </ol>   <ol start="89"> <li>Reddivari L, Veeramachaneni DNR, Walters WA, Lozupone C, Palmer J, Hewage MKK, Bhatnagar R, Amir A, Kennett MJ, Knight R, Vanamala JKP. Perinatal Bisphenol A Exposure Induces Chronic Inflammation in Rabbit Offspring via Modulation of Gut Bacteria and Their Metabolites. mSystems. 2017 2(5).</li> </ol>   <ol start="90"> <li>Schröder A, Corstens MN, Ho KKHY, Schroën K, Berton‐Carabin CC. Pickering Emulsions. Emulsion‐based Systems for Delivery of Food Active Compounds: Formation, Application, Health and Safety. 2018, 3:29-67. (Book chapter)</li> </ol>   <ol start="91"> <li>Shams-White MM, Chung M, Fu Z, Insogna KL, Karlsen MC, LeBoff MS, Shapses SA, Sackey J, Shi J, Wallace TC, Weaver CM. Animal versus plant protein and adult bone health: a systematic review and meta-analysis from the National Osteoporosis Foundation.  PLOS One  13:e0192459.</li> </ol>   <ol start="92"> <li>Shane B, Pangilinan F, Mills JL, Fan R, Gong T, Cropp CD, Kim Y, Ueland PM, Bailey-Wilson JE, Wilson AF, Brody LC, Molloy AM. The 677C->T variant of MTHFR is the major genetic modifier of biomarkers of folate status in a young healthy Irish population. Am J Clin Nutr. 2018, 108:1334-1341.</li> </ol>   <ol start="93"> <li>Stremke E, McCabe L, McCabe G, Martin B, Moe S, Roudebush Veterans Administration Medical Center, Weaver C, Peacock M, Hill Gallant K. Twenty-four-hour urine phosphorus as a biomarker of dietary phosphorus intake and absorption in CKD.  Clin J Am Soc Nephrol.  13:1002-1012, 2018.</li> <li>Swanson B, Zempleni J, Nordgren T, Romberger D, Heires A. Bovine milk-derived exosomes enhance inflammation and promote M1 polarization following agricultural dust exposure in mice. J Nutr Biochem 3:110-120, 2018</li> </ol>   <ol start="95"> <li>Taylor K. Bloedon, Rock E. Braithwaite, Imogene A. Carson, Dorothy J. Klimis-Zacas, Impact of whole berry fruit consumption on exercise-induced oxidative stress and inflammation: a systematic review and meta-analysis, Nutrition Reviews, 2019 (accepted)</li> </ol>   <ol start="96"> <li>MG Traber, GR Buettner, RS Bruno. (2018). The relationship between vitamin C status, the gut-liver axis, and metabolic syndrome. Redox Biology, 21:101091. <a href="https://doi.org/10.1016/j.redox.2018.101091">https://doi.org/10.1016/j.redox.2018.101091</a></li> </ol>   <ol start="97"> <li>Vanamala JKP, Massey AR, Pinnamaneni SR, Reddivari L, Reardon KF. Grain and sweet sorghum (Sorghum bicolor L. Moench) serves as a novel source of bioactive compounds for human health. Crit Rev Food Sci Nutr. 2017, 1-15.</li> </ol>   <ol start="98"> <li>Vorland CJ, Martin BR, Weaver CM, Peacock M, Hill Gallant KM. Phosphorus balance in adolescent girls and the effect of supplemental dietary calcium.  JBRM Plus 2:103-108, 2018.</li> </ol>   <ol start="99"> <li>Wallace TC, Bultman S, D'Adamo C, Daniel CR, Debelius J, Ho E, Eliassen H, Lemanne D, Mukherjee P, Seyfried TN, Tian Q, Vahdat LT. (2018) Personalized Nutrition in Disrupting Cancer - Proceedings From the 2017 American College of Nutrition Annual Meeting. J Am Coll Nutr. 4:1-14. doi: 10.1080/07315724.2018.1500499. [Epub ahead of print]</li> </ol>   <ol start="100"> <li>Wang L, Sadri M, Giraud D, Zempleni J. RNase H2-dependent PCR and elimination of confounders in sample collection, storage and analysis strengthen evidence that microRNAs in bovine milk are bioavailable in humans. J Nutr 148:153-159, 2018</li> </ol>   <ol start="101"> <li>Wang Q, Yu J, Kadungure T, Beyene J, Zhang H, Lu Q. ARMMs as a versatile platform for intracellular delivery of macromolecules. Nat. Commun., 9: 960 (2018).</li> </ol>   <ol start="102"> <li>Weaver CM, Bailey R, McCabe L, Moshfegh A, Rhodes D, Goldman J, Lobene A, McCabe G. Mineral Intake Ratios are a Weak but Significant, Factor in Blood Pressure Variability in U.S. Adults.  J Nutr   148:1845-1851, 2018.</li> </ol>   <ol start="103"> <li>Weaver CM, Peacock M. Calcium  Adv Nutr:  Int Rev J  In press.</li> </ol>   <ol start="104"> <li>Weaver CM. Ensuring adequate calcium with concern for safety.  Nutr Today.  52:90-92, 2017.</li> </ol>   <ol start="105"> <li>Weaver CM, Stone M, Lobene AJ, Cladis DP, Hodges JK. What is the evidence base for a potassium requirement? Nutr Today  53:184-195, 2018.</li> </ol>   <ol start="106"> <li>Weaver CM. The quest for evidence for calcium requirements for bone during pregnancy and lactation.  Am J Clin Nutr  109:3-4, 2019.</li> </ol>   <ol start="107"> <li>Weaver CM, Bischoff-Ferrari H, Daly, R, Wong M-S, Eds. Springer  In Press.  Lewis R, Laing E, Weaver CM.    41 Adolescence and acquisition of peak bone mass.  In:  Vitamin D, Fourth Edition. Feldman  Academic Press  London UK. Pg 731-751, 2018.</li> </ol>   <ol start="108"> <li>Wright CS, Laing EM, Pollock NK, Hausman DB, Weaver CM, Martin BR, McCabe GP, Peacock M, Warden SJ, Gallant HK, Lewis RD. Serum 25-hydroxyvitamin D and intact parathyroid hormone influences muscle outcomes in children and adolescents.  J Bone Miner Res  33:1940-1947, 2018.</li> </ol>   <ol start="109"> <li>Xia Xiong, Bie Tan, Minho Song, Peng Ji, Kwangwook Kim, Yulong Yin and Yanhong Liu. Nutritional Intervention for the Intestinal Development and Health of Weaned Pigs. Front Vet Sci. 2019, doi: 10.3389/fvets.2019.00046</li> </ol>   <ol start="110"> <li>Yali Yu, Lijun Wang, Ying Wang, Dingbo Lin, Jingbo Liu. Hepatoprotective effect of albumin peptides from corn germ meal on chronic alcohol-induced liver injury in mice. J Food Sci. 2017 Dec; 82(12): 2997-3004.</li> </ol>   <ol start="111"> <li>F Zhong, M Xu, RS Bruno, KD Ballard, J Zhang, J Zhu. (2018). Comparative metabolomics elucidates postprandial metabolic modifications in plasma of obese individuals with metabolic syndrome. J Proteome Res, 17(8):2850-2860.</li> </ol>

Impact Statements

University of Rhode Island (Brietta Oaks). This research aims to help inform nutritional programs and practice for pregnant women at risk of lead exposure. Our aim is to determine micronutrients that pregnant women can use to reduce circulating lead concentrations.

Date of Annual Report: 07/28/2020

Report Information

Annual Meeting Dates: 06/12/2020 - 06/12/2020
Period the Report Covers: 10/01/2018 - 09/30/2019

Participants

Richard Bruno (Chair), Ohio State University
Jaume Amengual (Secretary), University of Illinois

Brief Summary of Minutes

Annual Meeting Dates: The annual meeting was cancelled due to the COVID-19 pandemic. A tentative meeting will take place in early 2021.

Meeting agenda and minutes

Virtual business meeting to establish the action plan and next year’s agenda. The participants agreed to hold their officer position until next year’s in person meeting.

Accomplishments

Ohio State University (Richard Bruno). Background: Green tea extract (GTE), which is rich in polyphenolic catechins, alleviates metabolic endotoxemia and NFkB inflammation to protect against obesity and nonalcoholic fatty liver disease. Activities: Based on established evidence in rodent models, we are actively conducted a randomized placebo-controlled trial to examine GTE to alleviate metabolic endotoxemia by improving gut barrier function in persons with metabolic syndrome. A separate study in rodents is examining dietary supplementation of epigallocatechin (EGCG) vs (+)-catechin (CAT) relative to GTE to ameliorate endotoxemia and nonalcoholic steatohepatitis in mice. Outcomes: Studies in humans are ongoing.  Studies in mice fed a high-fat diet demonstrate that EGCG and CAT similarly protect against endotoxin-TLR4-NFκB inflammation in NASH, but that these catechins exert differential prebiotic and antimicrobial activities. Thus, the catechin-mediated shifts in microbiota composition are unlikely to be entirely responsible for their benefits along the gut-liver axis. In addition, a lack of additive benefit of intact GTE on NASH-associated pathology suggests that catechins are fully responsible for its hepatoprotective activities. Studies in humans are expected to translate these preclinical findings into practical dietary recommendations that help to manage the risk of metabolic disorders driven by TLR4/NFkB inflammation.   University of Arizona (Jennifer Teske). Background: The laboratory focuses on the impact of insufficient sleep on chronic disease and health outcomes. We investigate how sleep curtailment due to environmental noise exposure worsens metabolic health and how the consumption of Western diets exacerbates disease risk during sleep disruption in rodent models. We are also interested in addressing sex differences since women are more sensitive to noise, have a worse sleep and a higher prevalence of obesity compared to men. These studies revealed that females are more vulnerable to the weight-promoting effects of a palatable Western diet and that sleep disruption exacerbates the weight-promoting effects of a palatable Western diet in both males and females. Finally, consumption of Western diets disrupts calorie intake across the estrous cycle, and both sleep disruption and consumption of cafeteria diet reduced estradiol levels. Activities: Conducted analyses to determine the influence of sleep, diet, and sex on micronutrient intake and the role of sex hormones on weight gain in male and females rats. Outcomes: We provided hands-on training and determined proficiency for students at all levels, provided training on anthropometrics, energy expenditure, energy intake, and estrous cycle determination and scientific writing and presentation skills training for both oral and poster presentations for students at all levels.   University of Arizona (Frank Duca). Background: The gut microbiota is a salient contributor to metabolic homeostasis. Obesity is associated with increased consumption of a Western diet, high in fat and sugar, and low in dietary fiber. Increased fiber consumption leads to weight loss, possibly via increased production of short-chain fatty acids (SCFAs), metabolic byproducts of bacterial fermentation of non-digestible carbohydrates. As such, our lab is interested in how SCFAs can improve metabolic homeostasis. Activities: First, we aimed to determine how different diets lead to increased SCFA levels in the intestine and circulation. We performed a fasting-refeeding study in chow, high-fat diet (HFD), and HFD supplemented with 10% prebiotic in rats and collected luminal gut contents and plasma at 0,2,4,6,8 hours post refeeding of an isocaloric meal. Outcomes: We found that chow-fed, but not HFD fed, rats exhibit postprandial rises in SCFA levels in the cecum, which were significantly increased compared to HFD. Supplementation of prebiotics to the HFD partially restored the rise in SCFAs after a meal. However, we found no differences among dietary treatments in the circulation for any of the SCFAs. University of California Davis (Peng Ji). Background: Our researches use young pigs as a preclinical model and investigate the health benefits and risks of dietary supplements (e.g., micronutrients, plant extracts, and essential oils). One of the research themes aims to determine the metabolic response to and neurological effect of iron deficiency and overload in early development. The prevalence of iron deficiency anemia (IDA) in young children under age 5 is above 40% in many resource-constrained settings but drops below 10% in many developed countries. In contrast to the urgent need of iron treatment, prophylactic iron was commonly given to infants and young children, even those without iron deficiency, through supplements or fortified infant formula and food. Despite extensive research on the consequence of early-life IDA, limited research has evaluated the risk of iron overload in early childhood. Activity: Two studies were completed during this review period. In study 1, suckling piglets were orally administered different doses of iron supplements to induce IDA, iron repletion (I.R.), and iron overload (I.O.). To assess iron absorption and metabolism, we determined iron content in different tissues/organ where iron is absorbed, stored, utilized, and recycled. Moreover, gene and protein expression of iron regulatory proteins were analyzed in the tissue/organ mentioned above. To assess metabolic response to different iron status, we employed an untargeted metabolomics approach to determine >140 metabolites in plasma and cerebrospinal fluid samples. To evaluate the neurological consequence of early-life IDA and I.O., we performed a behavioral test for sociability and hippocampal-dependent cognition and analyzed the dendritic complexity of hippocampal neurons. In study 2, postweaning piglets were fed diets containing different concentrations of iron to induce IDA, I.R. and I.O., and challenged with enterotoxigenic E. coli that is known to specifically infection pigs. To assess the effects of iron status on resilience to enteric infection and gut microbiota, we determined the severity and duration of diarrhea post-pathogen challenge and performed 16s rRNA sequencing on colon contents and fecal materials.Outcome: The first study led to two papers published in the Journal of Nutrition and several presentations in the American Society of Nutrition Conference and Animal Science conferences. We have been writing manuscripts for the results of study 2. Our other research and collaborative activity also contribute to 3 publications during this review period. University of California Davis (Yanhong Liu). Background: Recently, a novel concept, non-nutrients, is illuminated to describe a group of dietary compounds that have no nutritional contribution to the animal, but have physiological activities beyond provision of bioavailable nutrients. Those dietary compounds include phytochemicals, prebiotics, probiotics, etc. Emerging evidence suggested that these non-nutrients provided benefits on animal health and production through different modes of action: regulating nutrient digestibility or absorption, and modulating microbial ecology in the digestive tract and/or immune responses. Activities: We were focusing on several probiotics strains on animal health. We have conducted couple of animal trials with pigs to evaluate the effects of probiotics (Bacillus subtilis or Bacillus pumilus) on disease resistance and immunity of weaned pigs that were experimentally infected with a pathogenic E. coli. Outcomes: We observed very positive benefits of supplementing probiotics in animal feed on weaned pig health and performance. In one year of W-4002 support, 1 visiting scientist, 5 graduate students, and several undergraduate students were supervised. Oregon State University (Emily Ho). Background: Diet plays an essential role in mitigating the development and progression of several cancers, including prostate and breast. This research demonstrates that nutritional strategies that decrease oxidative stress, inflammation, DNA damage and/or target aberrant epigenetic alterations, such as acetylation and methylation, have the potential to dramatically reduce the incidence of cancer. Secondly, declining nutritional status may be a critical determinant of healthy aging and susceptibility to environmental insults.  The research program has focused on bioactive compounds derived from cruciferous vegetables and zinc nutrition. Activities: We have completed a clinical trial investigating the impact of broccoli sprout supplementation in prostate cancer patients.  We have found that supplements are bioavailable and altered expression of AMCR and novel lncRNA. Unlike breast cancer patients, supplementation did not change proliferation markers in prostate. We have also identified additional epigenetic mechanisms involving the acetylation of CCAR2 in chemoprevention of sulforaphane.  We have also employed cell culture models and rodent models to understand the impact of zinc status on exposure to arsenic. We have discovered that zinc deficiency sensitizes the pancreatic islet cells to oxidative stress and altered function.  Outcomes: We have identified new risk factors in prostate and breast cancer and offer novel dietary modifications to reduce the incidence of cancer; Gained knowledge of the mechanisms behind the health benefits of micronutrients and phytochemicals such as zinc and compounds derived from cruciferous vegetables; Established low dietary zinc as a risk factor for inflammatory processes, DNA damage and cancer risk and identify new biomarkers for human zinc deficiency;  Established function of zinc and changes in zinc metabolism with toxicological stresses, development, and aging. Oregon State University (Norman Hord). Background: Dietary nitrate supplementation improves exercise performance by reducing the oxygen cost of exercise, increasing exercise tolerance, and metabolic efficiency. However, the mechanisms for these performance effects in skeletal muscle is not well understood. Dietary exposure to nitrates and nitrites occurs mainly from vegetable sources. This exposure is associated with cardiovascular health benefits and improved athletic performance while, in the context of processed meats consumption, is associated with increased gastrointestinal cancer risk. Dietary nitrite and nitrate can act as reservoirs for nitric oxide (NO) production with its reduction to NO potentiated in acidic or hypoxic areas, such as contracting skeletal muscle. We used dietary nitrate and nitrite in a zebrafish model to show that dietary nitrate improves exercise performance by lowering the oxygen cost of physical activity. Activities: This project addresses two W4002 project objectives related to the metabolism and efficacy of dietary nitrate to improve the performance of zebrafish during endurance exercise. We utilize untargeted (LC/MS-MS) metabolomics and targeted (1H-NMR) spectroscopic methods to interrogate nitrate-dependent changes in metabolic fuels in the whole zebrafish and zebrafish muscle, brain, and liver at rest and during endurance exercise. Outcomes: Building on performance improvement data in whole zebrafish due to nitrate treatment, we now show that nitrate treatment significantly increased skeletal muscle nitrate concentrations 2.5-fold at baseline and exercise significantly decreased muscle concentrations in nitrate-treated to levels found in control, untreated skeletal muscle. As expected, nitrate exposure decreased the oxygen cost of exercise during an endurance protocol. Metabolomics data revealed an increase in phosphocreatine (PCr), creatine (Cr), adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD), glycolytic, fatty acid and tricarboxylic acid cycle (TCA) intermediates in nitrate-treated skeletal muscle at rest and a concomitant decrease after peak exercise. Notably, exercise did not change or increased; these metabolites in control skeletal muscle. We conclude that nitrate may improve performance by increasing the availability of metabolic fuels (ATP, NAD, glycolytic and TCA intermediates, PCr, lactate, pyruvate, acyl carnitines and phospholipids) in rested zebrafish skeletal muscle. Oregon State University (David Dallas). Background: Our lab examines the digestion of milk protein and the release of bioactive peptides in infants and adults. Activities: This year, we have examined the survival of bioactive peptides across the mammary gland to the infant's stomach, intestine, and stool and published on most of these. We have demonstrated that these peptides have antimicrobial and immunomodulatory actions. We have also conducted human trials where bioactive proteins, casein glycomacropeptide, was fed to adult subjects, and intestinal samples were collected. Using mass spectrometry-based glycopeptidomics, we demonstrated that some glycomacropeptide survives intact to the intestine, but most are in the form of glycopeptide fragments of the original. We have demonstrated that glycomacropeptide has immunomodulatory actions in vitro. We are designing a clinical trial to test the effect of GMP on the adult gut microbiota and the immune system. We also examined the digestion of human milk and recombinant antibodies in preterm infants and determined the extent to which they survive. This project was performed to inform the design of future antibody-based therapies in infants. Outcomes: We identified thousands of milk peptides in the infant's stomach, intestine, and stool, many of which are bioactive. We identified bioactive fractions of these. We demonstrated the extent to which antibodies survive in infants and bioactive peptides survive in the adult digestive tract. University of Illinois – Urbana-Champaign (Jaume Amengual). Background: β-carotene is the primary precursor of vitamin A in mammals, and a potent antioxidant in lipid-rich environments. My laboratory focuses on understanding the role of β-carotene in obesity and atherosclerosis, two diseases deeply related to lipid metabolism. Activities: This past year, my laboratory was focused on elucidating the mechanism(s) by which β-carotene reduces cholesterol and triglyceride plasma concentrations. Using a mouse model lacking the enzyme involved in the conversion of β-carotene to vitamin A (β-carotene oxygenase 1, BCO1), we study the bioactive properties of intact β-carotene and its derivatives (vitamin A and retinoic acid). The positive effects of β-carotene and retinoic acid on plasma lipid concentrations were clinically evaluated by using a low-density lipoprotein receptor (LDLR) deficient mice (Ldlr-/- mice). By combining Ldlr-/- mice and Bco1-/- mice, we have successfully generated a humanized mouse model in which β-carotene accumulates in tissues, plasma, and atherosclerotic lesions. Outcomes: The characterization of this mouse model is currently under preparation. University of Illinois – Urbana-Champaign (Juan Andrade). Background: Our laboratory is focused on the design and optimization of novel delivery routes of micronutrients, and the development of cutting-edge tools to detect micronutrients in foods. Activities: Project 1: Characterization of legume-based protein nanoparticles. Nanoaggregates based on pea protein isolate containing vitamin D were characterized in terms of stability and bioavailability in an animal model of vitamin D deficiency. We found that the dispersion of vitamin D in nanoaggregates enhances its oral bioavailability and bioefficacy. Project 2: Low-cost micronutrient sensors. We have created a paper-based, smartphone-assisted assay for the inexpensive determination of iron in fortified flours. Outcomes: This technology can be used to assert the quality of fortified flours by companies as well as monitoring their compliance by government inspectors in low-income settings. Kansas State University (Brian Lindshield). Background: Our laboratory designs and experiment on fortified food products to analyze their potential in the promotion of health and prevention of disease. Activities and Outcomes: We completed the analysis and write up of results from rat fortified blended foods and fortified rice studies. We plan to submit our results for publication in the near future. We plan to do a follow-up study with the rice before submitting a combined manuscript for both for publication. We have plans in place for a study to determine whether saliva can be used to assess iron bioavailability and status as a less invasive measure than blood. Montana State University (David Sands). Background: Crop plants are generally selected by plant breeders for the yield-limiting traits, including disease and insect resistance. Nutritional traits are seldom considered. Activities and Outcomes: In the past decade we have succeeded in developing high lysine spring wheat (3 cultivars), high lysine tomatoes (3 cultivars), high protein/low glycemic oats (Proatina-commercialized), low glycemic peas (commercialized), low glycemic potatoes 6 cultivars) and Camelina sativa microgreens (high omega-3 line currently on a space flight. Development of nutritious lines of crops is easily done if plant breeders are aware of the breeder’s dilemma (yield versus nutrition) and if they are given selection tools that are easily adapted to high throughput screening. The traits that we targeted included high lysine that can be assayed by lysine knockout mutants of E. coli. Low glycemic traits can be assayed by observation of starch granule structure revealing high amylose: low amylopectin ratios. High protein oats were assayed using NIR spectroscopy. These oats are one source of plant sourced protein in high demand. Three manuscripts and several patents are in preparation. Oklahoma State University (Dingbo Lin). Background: Carotenoids are a large group of lipophilic pigments. Dietary ingestion is the only source of carotenoids for human nutrition and health. My laboratory focuses on the health benefits of carotenoids and the metabolic enzymes in the prevention of obesity, diabetes, and influenza virus infection. Activities: We used mouse models to determine: 1) astaxanthin alteration of gut microbiome in the wild type and beta-carotene oxygenase 2 (BCO2) knockout mice; 2) BCO2 as a protein in mitochondrial function; and 3) wheat germs in improving gut microbiome homeostasis in mice. Outcomes: We identified the specific profiles of gut microbiome in response to astaxanthin and wheat germs. We also characterized that BCO2 expression levels significantly impacted retinal mitochondrial morphology and function. The Deletion of BCO2 caused low-grade inflammation and elevation of blood glucose. University of Rhode Island (Brietta Oaks). Background: Lead exposure is a major public health concern in Rhode Island. There is evidence that omega-3 fatty acid intake may reduce circulating lead concentrations, but research has been limited and has not been explored in pregnant women, whom are at a higher risk for adverse effects of lead exposure. In addition, omega-3 fatty acid intake may reduce circulating cortisol, a stress hormone, which has negative effects during pregnancy if at chronically high concentrations. Activities: This research project did not get funded during this timeframe, so time was spent conducting literature reviews and writing a new grant to the Rhode Island Foundation. Outcomes: We received the grant from the Rhode Island foundation and will begin data collection as soon as regulations around research during COVID-19 allow research activity. Purdue University (Lavanya Reddivari). Background: Determine the efficacy and mechanisms of action of nutrients and dietary bioactive compounds towards improved health. Inflammatory bowel disease (IBD) diminishes the quality of life as well as promotes risk for colon cancer. There is a growing interest in safe and effective preventive strategies against IBD. Naturally occurring flavonoid compounds are promising preventive and therapeutic candidates against IBD due to their poor bioavailability leading to greater levels in the intestine and their ability to modulate immune signaling mediators in the gut. Activities: We used different genotypes of maize and potato to investigate the anti-inflammatory properties of flavan-4-ols and anthocyanins (two types of flavonoids) in mice models of colonic inflammation. Supplementation with maize kernels containing flavan-4-ols (red kernels) and potatoes containing anthocyanins (red and purple tubers) suppressed the relative expression of several chronic inflammatory markers. Gut permeability, an important marker of colitis, was also suppressed in animals consuming flavonoid-containing diets. Outcomes: These results suggest the protective effect of flavan-4-ols and anthocyanins and provide a rationale to optimize genotypes and processing conditions to improve phytonutrient content for better dietary benefits. University of Maine (Dorothy Klimis-Zacas). Background: With the aging population and the increase in obesity and diabetes worldwide, health care professionals predict an increase in ulcers and chronic wounds.  Additionally, pressure ulcers present in many patients with chronic diseases, as well as conditions associated with burns and the need for tissue regeneration and repair, involve balanced wound healing. Unbalanced wound healing and tissue repair can lead to severe outcomes such as septicemia, which comes with high mortality rates. At the present time, there are no effective treatments to speed up wound healing and improve tissue remodeling. Thus, there is a need to develop effective, new cost-effective therapies that have no deleterious side effects and enable patients to recover faster and improve the quality of their lives.  Our results from previous years documented a differential response of wild blueberry extracts on endothelial cell migration and relevant proteins and their gene expression, based on type of fraction and its concentration. Studies on angiogenesis also documented a concentration-depended effect, critical concentrations at which angiogenesis is modulated and differential response based on the different fractions (ACNs, anthocyanins or Phen, phenolic acids). ACNs seem to inhibit HUVEC migration and angiogenesis while P.A.s promote this process.  Thus, the goal of the present project is to investigate anthocyanin (ACNs) and phenolic acid (Phen) fractions and their combination extracted from wild blueberry powder on wound healing and angiogenesis in an animal model. The objectives of this project are to 1) validate our in vitro results with an in vivo model and 2) design a prototype (patch or spray) embedded with phenolic acids of a specific concentration. This patch or spray will be designed to be applied quickly and easily in any type of wound injury, providing anti-inflammatory and antimicrobial protection, as well as faster tissue repair and prevention of tissue fibrosis. Activities: During the first year of this project, I formed a team to aid in the development of a biomedical prototype for wound healing and conduct customer discovery and market analysis. From the above experience, we have been able to shape our approach for our in vivo, a preclinical research study that began September 2019, and the development and commercialization of our product to meet the specific needs of stakeholders. The preclinical study was completed, and data are presently analyzed.  Endpoints under study are speed of wound healing, protein activity and gene expression of several proteins responsible for inflammation, angiogenesis and tissue regeneration.  Another project initiated in 2017 and was completed in 2019, targeted the role of Red Raspberries (Rubus idaeus) on endothelial function (vasoconstriction and vasodilation) and obesity-induced inflammation by assessing pro-inflammatory markers and their gene expression in hepatic and adipose tissues in an animal model of the Metabolic Syndrome (MetS), the Obese Zucker Rat (OZR). Preliminary results support the role of Red Raspberries in normalizing the endothelial dysfunction and attenuating inflammation associated with MetS. Manuscripts are under review. Outcomes: Results from the period covered were disseminated in the form of posters and oral presentations at the biannual Health Benefits Symposium in Portland, and as oral presentations at the American Society for Nutrition, Baltimore. Additionally, T.V. interviews were given, and newspaper articles were published on the projects described above. University of Missouri (Ingolf Gruen). Background: One of the key elements affecting bioavailability and bioactivity of nutrients is the food matrix that they are in. Thus, the analysis of the concentration of volatile and non-volatile (phyto-) nutrients, and the estimation of their release from the food matrix is directly related to their potential bioavailability and bioactivity. Chocolate is made from the fermented, dried, and roasted seeds of the Theobroma cacao tree. It is now understood that cacao, contains a variety of compounds, including well-known flavonoid polyphenols, the consumption of which has positive impacts on human heart health and blood pressure, cancer reduction, LDL cholesterol reduction, and insulin resistance improvements, as numerous in vitro, in vivo, and observational studies have confirmed. However, there is an unwillingness by many Americans to consume higher-cacao-content chocolate, which is more bitter. Therefore, if the bitterness of cacao could be minimized, higher-cacao-content and lower-sugar chocolate confection sales could capture an even larger segment of the conventional and healthy snack-food market by achieving the elusive combination of being both tasty and healthy. Activities:  We produced three 70% dark chocolates differing only in their roast profile (raw, generic medium roast, generic dark roast), and had 126 chocolate consumers rate Overall Liking, perceived sweetness, and perceived bitterness on 9-point scales. Outcomes: Analysis of variance (ANOVA) showed significant differences (p<0.05) in the chocolates for all three characteristics. Significantly lower bitterness and higher liking were seen for both of the roasted chocolates, with the Medium-Roast having the lowest bitterness and highest liking rating (p<0.05). Roasting also significantly increased the sweetness of the chocolates (p<0.05). Differences in bitterness and liking ratings between 70% dark chocolate made from raw and roasted cacao were quite striking. Specifically, we found a 21% reduction in bitterness between the Raw and the Medium-Roast chocolate, which is also correlated with a 27% increase in liking for the Medium-Roast chocolate. Furthermore, bitterness was 8% lower, and liking was 10% higher for the Medium-Roast chocolate compared to the Dark-Roast chocolate. University of Nebraska-Lincoln (Janos Zempleni). Background: Virtually every cell produces and secretes exosomes (nanoparticles) loaded with cargos such as various species of RNAs, proteins, and lipids. Exosomes play essential roles in cell-to-cell communication. The transfer of exosomes cargos from donor cells to receptor cells alters gene expression and metabolism in receptor cells. Activities: We have made the paradigm-shifting discovery that exosomes and their cargos do not exclusively originate from endogenous synthesis but may also be obtained from dietary sources such as bovine milk and chicken eggs. Outcomes: 1) We have show that milk exosomes alter the gut microbiome. 2) We have shown that milk exosomes do not elicit an immune response if administered orally to mice or added to cultures of human peripheral blood mononuclear cells ex vivo. This is an important observation, because milk exosomes are candidates for delivering chemotherapeutics to brain cancer patients. 3) We have identified glycans on the surface of milk exosomes essential for exosome absorption by mucosal cells in the G.I. tract. 4) We have shown that milk exosomes carry microbial mRNAs, and that the mRNAs are bioavailable in humans and increase the survival of an influenza A. challenge in mice. 5) We have shown that dietary depletion of milk exosomes causes a loss of fecundity due to loss of oocyte implantation and embryo adhesion. 6) We have shown that maternal knockout of exosome and microRNA biogenesis impairs growth and G.I. health in wild-type pups fostered to the dams. 7) We have shown that milk exosomes select for polymorphisms and mutations in gut microbiome cultures, and exosome-free media selects for mutations in gut pathogens that increases virulence 8) We have shown that milk exosomes and their microRNA cargos are bioavailable and accumulate primarily in the G.I. mucosa, liver and brain. University of Connecticut (Ji-Young Lee). Background: Liver fibrosis, characterized by excessive accumulation of extracellular matrix, results from the dysregulated wound-healing response in the liver caused by alcohol, chronic hepatitis, viral infection, immune system imbalance, and obesity-related disorders. The activation of hepatic stellate cells (HSCs) is an essential event in the development of liver fibrosis. Quiescent HSCs (qHSCs) are transdifferentiated into myofibroblast-like cells (i.e., activated HSCs (aHSCs) in the injured liver, which have high expression of α smooth muscle actin (αSMA), a myofibroblast marker, and produce ECM proteins such as procollagen type I α1 (COL1A1). Fucoxanthin (FCX), a xanthophyll carotenoid, is abundant in edible brown seaweeds. Studies have demonstrated that FCX exerts antioxidant, anti-inflammatory, neuroprotective, and anti-proliferative effects. However, whether FCX has anti-fibrogenic properties in HSCs has never been determined. Activities: We evaluated the effect of FCX on fibrogenesis in LX-2 cells, a human HSC cell line, as well as primary human and mouse HSCs to gain insight into its potential role in the development of liver fibrosis. Outcomes: FCX significantly decreased basal and transforming growth factor β1 (TGFβ1)-induced mRNA levels of fibrogenic genes with concomitant decreases in their protein levels in LX-2 cells. The phosphorylation of SMA- and MAD-related protein (SMAD3) was increased by TGFβ1, which was attenuated by FCX. Importantly, when LX-2 cells were treated with FCX and SIS3, a SMAD3 inhibitor, there was synergistic repression of fibrogenic gene expression. The anti-fibrogenic effect of FCX was also confirmed in primary human HSCs. FCX prevented TGFβ1-induced accumulation of reactive oxygen species by diminishing mRNA level of NADPH oxidase 4 (NOX4) in LX-2 cells. When FCX was present during the activation of quiescent mouse primary HSCs, it decreased the expression of fibrogenic genes while diminishing intracellular lipid droplets. The results suggest that FCX exerts an anti-fibrogenic effect in HSCs primarily by preventing TGFβ1-induced pro-fibrogenic genes expression via inhibition of SMAD3 activation and by inhibiting the activation of quiescent HSCs. The University of Hawaii at Manoa (Kacie KHY Ho). Background: Many agricultural commodities are known to be rich sources of nutrients, vitamins, minerals, and bioactive phytochemicals (e.g., polyphenols, carotenoids), all of which may provide beneficial health effects. However, health impacts and bioactivity of many phytochemicals are limited by bioaccessibility, i.e., the relative amount of phytochemical that is stable against digestion and available to be absorbed in the small intestines. The technical goals of this research proposal are to identify and quantify the major nutrients and phytochemicals (and their potential interactions) in post-harvest commodities across different varieties and to elucidate the effect of the food matrix on bioaccessibility. Gaining a better understanding of phytochemical bioaccessibility, namely the effects of plant variety and processing on bioaccessibility, will help to optimally deliver benefits from available crops for the local consumer or to add-value to exported products. Activities: Bioactive phytochemicals will be extracted from agricultural commodities (e.g., raw fruit vs. processed fruit). Bioaccessibility will be measured by subjecting samples to simulated digestion to estimate the relative amount that is stable against digestion and available for absorption. Data/results will provide information on if certain types of processing or varieties of agricultural products or to provide improved bioaccessibility of bioactive phytochemicals compared to others. So far, work has been completed for papaya (Carica papaya) to compare carotenoid content and bioaccessibility across cultivars. Work on Hawaiian taro (Colocasia esculenta) has been initiated to determine the effect of thermal processing on carotenoid and polyphenol bioaccessibility across 4 different cultivars (results still pending). Outcomes: Research was completed to compare carotenoid content and bioaccessibility from different papaya (Carica papaya) cultivars (Laie gold, Rainbow, Kapoho Solo, Sunrise, and Sunset). Similar to previous research, our findings indicated that differences in carotenoid content existed across different cultivars, with all tested cultivars containing significant amounts of beta-carotene and beta-cryptoxanthin. Two cultivars were red-fleshed and contained lycopene (~1089-1570 μg/100g). Beta-carotene and beta-cryptoxanthin bioaccessibility were significantly greater in Rainbow cultivars compared to others. Lycopene bioaccessibility was significantly higher for Sunrise, a GMO red-fleshed cultivar, compared to Sunset, a non-GMO red-fleshed cultivar. Overall, the findings suggest that significant differences in both carotenoid content and bioaccessibility can exist depending on the cultivar. This work was accepted for presentation at the 2020 American Oil Chemists’ Society Meeting

Publications

<ol> <li>MG Traber, GR Buettner, RS Bruno. (2019). The relationship between vitamin C status, the gut-liver axis, and metabolic syndrome. Redox Biology (Invited Review), 21:101091. doi: 10.1016/j.redox.2018.101091</li> <li>I Hatsu, C Gunther, E Hade, S Vandergriff, N Slesnick, R Williams, R Bruno, J Kennel. (2019). Unaccompanied homeless youth have extremely poor diet quality and nutritional status. Int J Adol Youth, 24:3, 319-332. doi: 10.1080/02673843.2018.1538885</li> <li>P Dey, GY Sasaki, P Wei, L Wang, J Li, C Chitchumroonchokchai, J Zhu, D McTigue, Z Yu, RS Bruno. (2019). Green tea extract prevents obesity in male mice by alleviating gut dysbiosis in association with improved intestinal barrier function that limits endotoxin translocation and adipose inflammation. J Nutr Biochem, 67:78-89.</li> <li>LE Griffin, DW Fausnacht, JL Tuzo, AK Addington, KC Racine, H Zhang, MD Hughes, KM England, RS Bruno, SF O’Keefe, AP Neilson, AC Stewart. (2019). Flavanol supplementation protects against obesity-associated increases in systemic IL-6 levels without inhibiting body mass gain in mice fed a high-fat diet. Nutr Res, 66:32-47.</li> <li>R Williams, A Rose, RS Bruno, A Hanks, J Kennel, J McDonald, C Gunther. (2019). Examination of the relationship of diet quality with cardiometabolic risk factors in apparently healthy college students. J Am Coll Health, 8:148. doi: 10.4103/jehp.jehp_12_19.</li> <li>P Dey, JB Kim, C Chitchumroonchokchai, J Li, GY Sasaki, BD Olmstead, KL Stock, JM Thomas-Ahner, SK Clinton, RS Bruno. (2019). Green tea extract inhibits early oncogenic responses in mice with nonalcoholic steatohepatitis. Food Funct, 10, 6351-6361.</li> <li>GY Sasaki, J Li, MJ Cichon, KM Riedl, RE Kopec, RS Bruno. (2019). Green tea extract treatment in obese mice with nonalcoholic steatohepatitis restores the hepatic metabolome in association with limiting endotoxemia-TLR4-NFkB-mediated inflammation. Mol Nutr Food Res, 63(24):e1900811. doi: 10.1002/mnfr.201900811.</li> <li>BK Alba, AE Stanhewicz, P Dey, RS Bruno, WL Kenney, LM Alexander. (2020). Controlled feeding of an 8-day high dairy cheese diet prevents sodium-induced endothelial dysfunction in the cutaneous microcirculation through reductions in superoxide. J Nutr, 150(1):55-63; doi: 10.1093/jn/nxz205.</li> <li>KM Hirahatake, RS Bruno, BW Bolling, C Blesso, LM Alexander, SH Adams. (2019). Dairy foods and dairy fats: new perspectives on pathways implicated in cardiometabolic health. Adv Nutr, 11(2):266-279. doi: 10.1093/advances/nmz105.</li> <li>KM Ranard, MJ Kuchan, RS Bruno, JM Juraska, JW Erdman. (2020). Synthetic α-tocopherol, compared with natural α-tocopherol, downregulates myelin genes in cerebella of adolescent Ttpa-null mice. J Nutr, 150(5):1031-1040. doi: 10.1093/jn/nxz330.</li> <li>JK Hodges, J Zhu, Z Yu, Y Vodovotz, G Brock, GY Sasaki, P Dey, RS Bruno. (2020) Intestinal-level anti-inflammatory bioactivities of catechin-rich green tea: Rationale, design, and methods of a double-blind, randomized, placebo-controlled crossover trial in metabolic syndrome and healthy adults. Contemp Clin Trials Commun. 17:100495. doi: 10.1016/j.conctc.2019.100495</li> <li>MM Kemski, CA Rappleye, K Dabrowski, RS Bruno, M Wick. (2020). Transcriptomic response to soybean meal-based diets as the first formulated feed in juvenile yellow perch (Perca flavescens). Sci Rep, 10(1):3998. doi: 10.1038/s41598-020-59691-z.</li> <li>Coborn JE, Lessie RE, Rance NE, Sinton CM, Perez-Leighton CE, Teske JA. Noise-induced sleep disruption increases weight gain and decreases energy metabolism is female rats. 2019. Int J Obes (Lond). 43(9):1759-1768.</li> <li>Waise TM, Rasti M, Duca FA, Zhang SY, Bauer PV, Rhodes CJ, Lam TK. Inhibition of Upper Small Intestinal mTOR Lowers Plasma Glucose Levels by Inhibiting Glucose Production. Nat Commun 2019, 10(1):704.</li> <li>Ji P, Lönnerdal B, Kim K, Jinno CN. Iron Oversupplementation Causes Hippocampal Iron Overloading and Impairs Social Novelty Recognition in Nursing Piglets. J Nutr. 2019, 149(3):398-405.</li> <li>Ji P, Nonnecke EB, Doan N, Lönnerdal B, Tan B. Excess Iron Enhances Purine Catabolism Through Activation of Xanthine Oxidase and Impairs Myelination in the Hippocampus of Nursing Piglets. J Nutr. 2019, 149(11):1911-1919.</li> <li>Wu Z, Tan B, Liu Y, Dunn J, Guerola PM, Tortajada M, Cao Z, Ji P. Chemical Composition and Antioxidant Properties of Essential Oils from Peppermint, Native Spearmint and Scotch Molecules. 2019, 24(15): 2825</li> <li>Xiong X, Tan B, Song M, Ji P, Kim K, Yin Y, Liu Y. Nutritional Intervention for the Intestinal Development and Health of Weaned Pigs. Front Vet Sci. 2019, 6:46</li> <li>Leyshon BJ, Ji P, Caputo MP, Matt SM, Johnson RW. Dietary Iron Deficiency Impaired Peripheral Immunity but Did Not Alter Brain Microglia in PRRSV-Infected Neonatal Piglets. Front Immunol. 2019, 9:3150</li> <li>Kovanda L, Zhang W, Wei X, Luo J, Wu X, Atwill ER, Vaessen S, Li X, Liu Y. 2019. In vitro antimicrobial activities of organic acids and their derivatives on several species of Gram-negative and Gram-positive bacteria. Molecules. 24:E3770.</li> <li>Xiong X, Lv D, Liu Y, Song M, Zou L, Xiao D, Yin Y. 2019. Effect of glucose, soya oil and glutamine on protein expression and mammalian target of rapamycin complex 1 pathway of jejunal crypt enterocytes in weaned piglets. Br J Nutr. 18:1-8. </li> <li>Kim K, He Y, Xiong X, Ehrlich A, Li X, Raybould H, Atwill ER, Maga EA, Jørgensen J, Liu Y. 2019. Dietary supplementation of Bacillus subtilisinfluenced intestinal health of weaned pigs experimentally infected a pathogenic  coli. J Anim Sci Biotechnol. 10:52-63. </li> <li>Liu Y, Ji P. 2019. Dietary factors in prevention of pediatric Escherichia coli infection: a model using domestic piglets. ILAR J. 1:1-19. </li> <li>Xiong X., Tan B, Song M, Ji P, Kim K, Liu Y. 2019. Nutritional intervention for the intestinal development and health of weaned pigs. Frontiers Vet Sci. 6:46-59. </li> <li>Kim K, Ehrlich A, Perng A, Chase JA, Raybould H, Li X, Atwill ER, Whelan R, Sokale A, Liu Y. 2019. Algae-derived β-glucan enhanced gut health and immune responses of weaned pigs experimentally infected with a pathogenic  coli. Anim Feed Sci Technol. 248:114-125.</li> <li>Wong CP, Dashner-Titus EJ, Alvarez SC, Chase TT, Hudson LG, Ho E. (2019) Zinc Deficiency and Arsenic Exposure Can Act Both Independently or Cooperatively to Affect Zinc Status, Oxidative Stress, and Inflammatory Response. Biol Trace Elem Res.. doi: 1007/s12011-019- 1631-z</li> <li>Rajendran P, Johnson G, Li L, Chen YS, Dashwood M, Nguyen N, Ulusan A, Ertem F, Zhang M, Li J, Sun D, Huang Y, Wang S, Leung HC, Lieberman D, Beaver L, Ho E, Bedford M, Chang K, Vilar E, Dashwood R. (2019) Acetylation of CCAR2 Establishes a BET/BRD9 Acetyl Switch in Response to Combined Deacetylase and Bromodomain Inhibition. Cancer Res. 2019 Mar 1;79(5):918-927. doi: 10.1158/0008-5472.CAN-18-2003. Epub 2019 Jan 14. PMID: 30643017</li> <li>Cao AL, Beaver LM, Wong CP, Hudson LG, Ho E. (2019) Zinc deficiency alters the susceptibility of pancreatic beta cells (INS-1) to arsenic exposure. Biometals. 2019 Dec;32(6):845-859. doi: 10.1007/s10534-019-00217-0. Epub 2019 Sep 21</li> <li>Wallace TC, Bultman S, D'Adamo C, Daniel CR, Debelius J, Ho E, Eliassen H, Lemanne D, Mukherjee P, Seyfried TN, Tian Q, Vahdat LT (2019). Personalized Nutrition in Disrupting Cancer - Proceedings From the 2017 American College of Nutrition Annual Meeting. J Am Coll Nutr. 2019 Jan;38(1):1-14. doi: 10.1080/07315724.2018.1500499.</li> <li>Zhang Z, Garzotto M, Davis EW 2nd, Mori M, Stoller WA, Farris PE, Wong CP, Beaver LM, Thomas GV, Williams DE, Dashwood RH, Hendrix DA, Ho E, Shannon J. Sulforaphane Bioavailability and Chemopreventive Activity in Men Presenting for Biopsy of the Prostate Gland: A Randomized Controlled Trial. Nutr Cancer. 2020;72(1):74-87. doi: 10.1080/01635581.2019.1619783.</li> </ol> <ol> <li>Moua, ED, Hu, C, Day, N, Hord, NG and Takata, Y. (2020) Coffee consumption and C-Reactive protein levels: a systematic review and meta-analysis. Nutrients, 12(5), 1349; <a href="https://doi.org/10.3390/nu12051349">https://doi.org/10.3390/nu12051349</a></li> <li>Axton, ER, Beaver, LM, Lindsey St. Mary, L, Truong, L, Logan, CR, Spagnoli, S, Mary C. Prater, MC, Keller, RM, Garcia-Jaramillo, M, Ehrlicher, SE, Stierwalt, HD, Newsom, SA, Robinson, MM, Tanguay, RL, Stevens, JF and Hord, NG  (2019) Treatment with nitrate but not nitrite lowers the oxygen cost of exercise and decreases glycolytic intermediates while increasing fatty acid metabolites in exercised zebrafish, J Nutr, 149 (12): 2120–2132.</li> <li>Beverly, R. L., Huston, R. K., Markell, A. M., McCulley, E. A., Martin, R. L., Dallas, D. C (2019). Milk peptides survive in vivo gastrointestinal digestion and are excreted in the stool of infants. Journal of Nutrition. doi: 10.1093/jn/nxz326</li> <li>Demers-Mathieu, V., Huston, R. K., Markell, A. M., McCulley, E. A., Martin, R., Dallas, D. C. (2019) Antenatal influenza A-specific IgA, IgM and IgG antibodies in mother’s own breast milk and donor breast milk, gastric contents and stools from preterm infants. Nutrients. 11(7), 1585; https://doi.org/10.3390/nu11071585</li> <li>Casavale, K.O., Ahuja, J., Wu, X., Li, Y., Quam, J., Olson, R., Pehrsson, P., Allen, L., Balentine, D., Hanspal, M., Hayward, D., Hines, E. P., McClung, J. P., Perrine, C. G., Belfort, M. B., Dallas, D. C., German, J. B., Kim J., McGuire, M., McGuire, M., Morrow, A. L., Neville, M. Nommsen-Rivers, L., Rasmussen, K. M., Zemplini, J., Lynch, C. (2019) NIH workshop on human milk composition: summary and visions for a research program. American Journal of Clinical Nutrition. https://doi.org/10.1093/ajcn/nqz123</li> <li>Demers-Mathieu, V., Huston, R. K., Markell, A. M., McCulley, E. A., Martin, R. L., Spooner, M., Dallas, D. C. (2019) Differences in maternal immunoglobulins within mother’s own breast milk and donor breast milk and across digestion in preterm infants. Nutrients. 11 (4): 920. doi: 10.3390/nu11040920</li> <li>Beverly, R. L., Underwood, M. A., Dallas, D. C. (2019) Peptidomics analysis of milk protein-derived peptides released over time in the preterm infant stomach. Journal of Proteome Research. 18 (3): 912-922. DOI: 10.1021/acs.jproteome.8b00604</li> </ol> <ol start="38"> <li>Coronel J, Pinos I, Amengual J. β-carotene in Obesity Research: Technical Considerations and Current Status of the Field. Nutrients. 2019 April 13;11(4)</li> <li>Amengual J, Barrett TJ. Monocytes and macrophages in atherogenesis. Curr Opin Lipidol. 2019 Oct; 30(5):401-408.</li> <li>Amengual J. Bioactive properties of Carotenoids in Human Health. Nutrients. 2019. Oct 6;11(10).</li> <li>Almajwal, AM, Abulmeaty, MMA, Feng, H, Alruwaili, NW, Dominguez-Uscanga, A, Razak, S, ElSadek, MF, Andrade, JE. Stabilization of Vitamin D in Pea Protein Isolate Nanoemulsions Increases its bioefficacy in Rats. Nutrients. 11(1): 75 (2019)</li> <li>Waller, AW, Toc, M, Rigsby, DJ, Gaytan-Martinez, M, Andrade, JE. Development of a Paper-Based Sensor Compatible with a Mobile Phone for the Detection of Common Iron Formulas Used in Fortified Foods within Resource-Limited Settings. Nutrients. 11(7) (2019)</li> <li>Miller M, Middendorf G, Wood S, Lutter S, Jones S, Lindshield B. Food Insecurity and Assistance on Campus: A Survey of the Student Body. Online Journal of Rural Research and Policy 2019,14(2). </li> <li>Regier GK, Lilja N, Lindshield BL. Nutrient Cost Effectiveness of Fortified Blended Food Aid Products. Food Nutr Bull. 2019, 40(3): 326-339.</li> <li>Delimont NM, Katz, BB, Fiorentino NM, Kimmel KA, Haub MD, Rosenkranz SK, Tomich JM, Lindshield BL. Salivary cystatin S.N. binds to phytic acid and is a predictor of non-heme iron bioavailability with phytic acid supplementation. Curr Dev Nutr. 2019, 3(7).</li> <li>Delimont NM, Vahl CI, Kayanda R, Msuya W, Mulford M, Alberghine P, Praygo G, Mngara J, Alavi S, Lindshield BL. Complementary Feeding of Sorghum-Based and Corn-Based Fortified Blended Foods Results in Similar Iron, Vitamin A and Anthropometric Outcomes in the MFFAPP Tanzania Efficacy Study. Curr Dev Nutr. 2019, 3(6).</li> <li>Fiorentino NM, Kimmel KA, Suleria HAR, Joseph M, Alavi S, Beyer RS, Lindshield BL. Novel Formulated Fortified Blended Foods Result in Improved Protein Efficiency and Hepatic Iron Levels Compared to CSB+ in Broiler Chickens. Curr Dev Nutr. 2018, 2(12).</li> <li>Penugonda K, Fiorentino N, Alavi S, Lindshield BL. Bioavailable Iron and Vitamin A in Newly Formulated, Extruded Corn, Soybean, Sorghum and Cowpea Fortified-Blended Foods in the In-vitro Digestion/Caco-2 Cell Model. Curr Dev Nutr. 2018, 2(7).</li> <li>Alavi S, Ruan S, Adapa SS, Joseph M, Lindshield B, and Chilukuri S. Use of grain sorghum in extruded products developed for gluten-free and food aid applications. In Sorghum: State of the Art and Future Perspectives. Eds. Ciampitti, I., and Prasad, V. 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Impact Statements

The University of Hawaii at Manoa (Kacie KHY Ho). This work will aim to impact the general public by providing knowledge that can be used to optimize nutrition and diet. Generated knowledge will not only provide information that can be disseminated to the general public, but also to local growers (who could choose to grow varieties that are higher in target nutrients) and the food industry (who could use the knowledge to develop more bioavailable food products).

Date of Annual Report: 03/18/2021

Report Information

Annual Meeting Dates: 01/27/2021 - 01/27/2021
Period the Report Covers: 10/01/2019 - 09/30/2020

Participants

Richard Bruno
Jaume Amengual
Kacie Ho
Jinzeng Yang
Dorothy Klimis-Zacas
Lavanya Reddivari
Frank Duca
Janos Zempleni
David Dallas
Peng Ji
Juan E Andrade
John Paul SanGiovanni
Brian Lindshield
Emily Ho
Brietta Oaks
Lisa Hans
Mallory Koenings
David Gang

Brief Summary of Minutes

Virtual Zoom Meeting (4:00 – 8:00 PM, EST)

4:00 Introductions

4:20 Lisa Hans and Mallory Koenings - USDA Updates

5:00 Business Meeting

Richard Bruno - Meeting Format Overview

Current Secretary Jaume Amengual was promoted to Chair

Kacie Ho was elected as new Secretary.

5:45 Station Reports Session I

Ohio State University, Richard Bruno: Advances in bioactive food component research

University of Illinois Urbana Champaign, Jaume Amengual: Effects of beta-carotene on vitamin A production in atherosclerosis and obesity

University of Hawaii at Manoa, Kacie Ho: Phytochemical composition and bioaccessibility of Hawaii Commodities

University of Hawaii at Manoa, Jinzeng Yang: Effects of Bioactive Compounds on skeletal muscle growth and diabetes prevention

University of Maine, Dorothy Klimis‐Zacas: A novel role of wild blueberry bioactives on cell migration and angiogenesis related to wound healing and tissue regeneration

Purdue University, Lavanya Reddivari: Anti-colitic effects of Flavonoids: Role of gut bacteria

6:30 Open Q&A Panel Discussion

6:45 Station Reports Session II

University of Arizona, Frank Duca: Role of gut-brain axis in regulating food intake and glucose production

University of Nebraska-Lincoln, Janos Zempleni: Milk exosomes

Oregon State University, David Dallas: milk protein and peptide digestion and bioactivity

University of California-Davis, Peng Ji: Early-life iron nutrition and development

University of Florida, Juan E Andrade: Sensors for detection and proteins for delivery of micronutrients in foods for low-income settings

7:30 Open Q&A Panel Discussion

7:45 Meeting Summary & Adjournment

Accomplishments

University of Florida, Gainesville (Juan Andrade). Background: Project 1. Characterization of sensors for iron determination to support food fortification programs in low-income countries. In low-income countries, tools to monitor fortification processes are lacking, which represent a significant hurdle to improve nutrient delivery to populations. Project 2. Evaluation of efficacy of bioactives against parasites. Diarrhea worldwide affects the growth and health of children under five. The zoonotic protozoan Cryptosporidium parvum is one of the top three leading causes of diarrhea worldwide. Activities: Project 1. We have characterized and validated a low-cost, smartphone assisted paper-based sensor for determination of iron in fortified flours. Project 2. We have shown that essential oils from hops byproducts and from aromatic plants such as thyme and oregano. Outcomes: Project 1. The paper-based sensor is capable of measuring different types of added iron into flours such a maize and wheat. We are continuing the validation of the sensor using maize samples from different countries and fortified with different iron types, including NaFeEDTA. Project 2. We are currently evaluating the role of these plant extracts on the inhibition of bacterial growth in vitro. Montana State University, Bozeman (David Sands). Background: Crop plants are generally selected by plant breeders for the yield limiting traits including disease and insect resistance. The bioavailability of nutritional components of food crops are seldom considered. Activities: In the past year we have scaled up winter field production of our EM-1 line of high lysine spring wheat. We have distributed a “high amylose” cultivar of potatoes to 5 Tribal Reservations in two states. Selections with traits associated with high amylose can be assayed by observation of starch granule structure revealing high amylose: low amylopectin ratios. High protein oat selections were assayed using NIR spectroscopy, now in high demand as plant sourced proteins. Outcomes: Three manuscripts (Microgreens, The Preliminary Screen for Low Glycemic Potatoes, and Plasmid Curing in a Food Crop) are in preparation. Several commercial and non-profit interests have been established to scale up production of the high lysine wheats, the low glycemic field peas, and the high amylose potatoes, all selected for their dietary components associated with improved health. University of Hawaii at Manoa (Kacie KHY Ho). Background: Many agricultural commodities are known to be rich sources of nutrients, vitamins, minerals, and bioactive phytochemicals, all of which may provide beneficial health effects. The technical goals of this research are to identify and quantify the major nutrients and phytochemicals (and their potential interactions) in post-harvest commodities across different varieties and to elucidate the effect of food matrix on bioaccessibility. Activities: Papayas of different cultivars were collected from different locations to observe the effect of papaya type and growing conditions on phytochemical profile. Aside from identifying and quantifying the major carotenoid compounds, in-vitro bioaccessibility tests were conducted to observe differences in bioaccessibility. Outcomes: Our findings indicated that differences in carotenoid content existed across different cultivars, with all tested cultivars containing significant amounts of beta-carotene and beta-cryptoxanthin. Two cultivars were red-fleshed and contained lycopene (~1089-1570 μg/100g). Overall, the findings suggest that significant differences in both carotenoid content and bioaccessibility can exist depending on the cultivar. University of Hawaii at Manoa (Jinzeng Yang). Background: Diet, including specific nutrients and bioactive food components, play a vital role in improving health and reducing the risk for chronic diseases. Papaya fruit has high amounts of vitamin C, vitamin A, vitamin E, and carotenes, and is very popular in Hawaii. Besides fruits, papaya leaves have been used as therapeutic remedies to treat asthma, worming, dysentery, cancer, and infectious diseases. The leaf aqueous extract accelerates wound healing, whereas the leaf methanol extract has exhibited vasodilating and antioxidant effects. Recent reports demonstrated that papaya leave extract can significantly reduce blood glucose level in STZ-induced diabetic rats. Activities: My laboratory's previous research expertise in animal models and molecular biology were crucial. My laboratory maintains two colonies of myosatin prodomain transgenic mice, which have enhanced muscle growth due to functional depression of myostatin gene. A project is planned to use these mice and their wild-type control littermates to study the effects of papaya leaf and other tropical specialty crops on diabetes prevention. Outcomes: (1) Determine the bioavailability of nutrients and bioactive food components. (2) Determine the efficacy and mechanisms of action of nutrients to improve health. University of Rhode Island, Kingston (Brietta Oaks). Background: Lead exposure is a major public health concern in Rhode Island. There is evidence that omega-3 fatty acid intake may reduce circulating lead concentrations, but research has been limited and has not been explored in pregnant women, whom are at a higher risk for adverse effects of lead exposure. In addition, omega-3 fatty acid intake may reduce circulating cortisol, a stress hormone which has negative effects during pregnancy if at chronically high concentrations. Activities: We updated our IRB approval to be in line with policies for research during COVID-19. We have also updated our data collection instruments so we are ready to begin data collection once COVID-19 restrictions on data collection allow us to conduct our research. In addition, we conducted a survey of prenatal vitamin use among pregnant women in Rhode Island to determine the impact of WIC (Women, Infants, and Children) enrollment on prenatal supplement use. Outcomes: We determined that women enrolled in WIC are equally using prenatal supplements as women not enrolled in WIC with more than 90% using prenatal supplements during pregnancy, although women enrolled in WIC are more likely to use prescription prenatal supplements. University of Arizona, Tucson (Jennifer Teske). Background: The laboratory focuses on the impact of insufficient sleep on chronic disease and health outcomes, which includes the metabolism of nutrients. We investigate how sleep curtailment due to environmental noise exposure worsens metabolic health and how consumption of Westerns diets exacerbates disease risk during sleep disruption in rodent models. We are also interested in addressing sex differences since women are more sensitive to noise, have worse sleep and a higher prevalence of obesity compared to men. Activities: Conducted analyzes to determine the influence of sleep, diet and sex on micronutrient intake and the role of sex hormones on weight gain in male and females rats. Outcomes: We provided hands-on training and determined proficiency for students at all levels, provided training on anthropometrics, energy expenditure, energy intake and estrous cycle determination and scientific writing and presentation skills training for both oral and poster presentations for students at all levels. University of California, Berkeley (Barry Shane). Background: Our laboratory is interested in biochemical nutrition, in particular, one carbon metabolism. We study how genetic variations influence the risk and susceptibility to birth defects. Activities: 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 continue to evaluate genetic risk factors for neural tube defects and to identify putative modifier genes which influence folate and vitamin B12 status, homocysteine levels, and methylation potential using a number of mouse strains and a cohort of students at Trinity College, Dublin. We screened the human genome for common genetic polymorphisms that influence folate-status biomarkers in healthy individuals. Candidate gene analyses and genome-wide association scans were conducted in 2232 young, healthy Irish subjects to evaluate which common genetic polymorphisms influence red cell folate, serum folate and plasma total homocysteine. Outcomes: The methylenetetrahydrofolate reductase (MTHFR) 677C->T (rs1801133) variant was the major genetic modifier of all three folate related biomarkers in this Irish population and reached genome-wide significance for red cell folate, serum folate, and plasma total homocysteine levels. A second polymorphism in the MTHFR gene (rs3753584) was the only additional variant to exhibit any significant independent effect on red cell folate levels. University of Maine, Orono (Dorothy Klimis-Zacas). Background: With the aging population and the increase in obesity and diabetes world-wide, health care professionals predict an increase in ulcers and chronic wounds. Unbalanced wound healing and tissue repair can lead to severe outcomes such as septicemia. Our results documented a differential response of wild blueberry extracts on endothelial cell migration and relevant proteins and their gene expression. Studies on angiogenesis also documented a concentration-depended effect, critical concentrations at which angiogenesis is modulated and differential response based on the different fractions (ACNs, anthocyanins or Phen, phenolic acids). ACNs seem to inhibit HUVEC migration and angiogenesis while PAs promote this process. Thus, the goal of the present project is to investigate ACNs and Phen fractions and their combination extracted from wild blueberry powder on wound healing and angiogenesis in an animal model. Activities: 1) validate our in vitro results with an in vivo model and 2) design a prototype (patch or spray) embedded with Phen of a specific concentration. Outcomes: During the first year of this project I formed a team to aid in the development of a biomedical prototype for wound healing and conduct customer discovery and market analysis. The pre-clinical study was completed and data showed that the phenolic acid extract at a specific concentration promoted wound closure by 20% over the control. We tested these prototypes in pre-clinical studies during September and October 2020 and we are presently analyzing the tissues for the above parameters. University of California, Davis (Peng Ji). Background: Our research uses young pigs as a preclinical model to investigate health benefits and risks of dietary supplements. One of research themes aims to determine the metabolic response to and neurological effect of iron deficiency and overload in early life. Prevalence of iron deficiency anemia (IDA) in young children under age 5 is above 40% in many resource-constrained settings, but drops below 10% in many developed countries. However, prophylactic iron in forms of oral supplements or fortified food (e.g. infant formula) was commonly given to infants in many developed countries without screening of iron status. In contrast to the urgent need of iron treatment, there is a rising concern over the risk of dietary iron overexposure in high-income countries. We hypothesize dietary iron overexposure in early life lead to tissue iron overload and deficiency which may adversely affect neuronal development and alter metabolic functions. Activities: We performed animal trial to assess the neurological and metabolic consequences of iron excess and deficiency. Iron status were determined through analysis of plasma iron, transferrin saturation and iron concentration in various tissues/organs. In order to evaluate neuronal development, we analyzed dendritic complexity of hippocampal neurons. Outcomes: Results from the study suggested that developing hippocampal iron status is susceptible to the changes of dietary iron in early life. Iron excess and deficiency altered the dendritic complexity differently in young pigs. Plasma metabolites was not affected at PD21, whereas 24 metabolites in plasma and Cerebrospinal fluid were altered by dietary iron.     University of Arizona, Tucson (Frank Duca). Background: Project 1. Determine the bioavailability (absorption, distribution, metabolism, elimination) of nutrients and bioactive food components. Short-chain fatty acids (SCFAs) are produced by bacterial fermentation in the GI tract. However, whether SCFAs are produced acutely in a postprandial manner is completely unknown. Along these same lines, it is unknown how different diets affect acute SCFA production. Project 2. Determine the efficacy and mechanisms of action of nutrients and dietary bioactive compounds towards improved health. Exogenous SCFA supplementation and increased endogenous SCFA production have been shown to improve glucose homeostasis, however the mechanisms remain unknown. Activities: Project 1. We performed an extensive time course study to determine levels of SCFAs in the small intestine, large intestine, colon, portal vein, and vena cava at 0,2,4,6,8hr following an iso-caloric meal in chow-fed, high-fat diet-fed, and high-fat diet supplemented with 10% oligofructose, a prebiotic, rats. Project 2. We performed in-vivo basal insulin glucose clamps during SCFA colonic infusion coupled with various vagotomies and co-administration of GLP-1 receptor antagonist to determine if SCFAs activate a gut-brain-liver axis to lower hepatic glucose production.  Outcomes: Project 1. We found that while SCFA levels were comparable between chow, HFD, and HFD+OFS for all sites after fasting, re-feeding resulted in a substantial increase in postprandial SCFAs in the cecum and circulation in chow and HFD+OFS rats, but not in HFD rats. Interestingly, this data demonstrates that previous studies measuring fasting levels of SCFAs are not representative of actual SCFA production, and that obesity from HFD-feeding in rats is associated with a blunted postprandial SCFA postprandial response. Project 2. We found that SCFAs lower hepatic glucose production that is dependent upon GLP-1 receptor signaling and celiac branch vagal afferents and hepatic vagal efferents. Kansas State University, Manhattan (Brian Lindshield). Background: Our laboratory designs and experiment on fortified food products to analyze their potential in the promotion of health and prevention of disease. Activities and Outcomes: We completed the analysis and write up of results from rat fortified blended foods and fortified rice studies. We have plans in place for a study to determine whether saliva can be used to assess iron bioavailability and status as a less invasive measure than blood. Oregon State University, Corvallis (David Dallas). Background: Our lab examines the digestion of milk protein and release of bioactive peptides in infants and adults. Activities: This year, we examined the survival of milk and recombinant antibodies across the digestive tract of infants. We also assessed differences in survival of peptides in the stomach of preterm and term infants. We also examined the peptides released in various cheeses. We also examined the effects of various donor milk microbial reduction techniques on the survival of a key breast milk lipase that helps infants digest breast milk fat. We also worked to develop a novel technique to identify glycoproteins and glycopeptides in milk via mass spectrometry. Outcomes: We demonstrated that recombinant antibodies do not survive intact within the term and preterm infant digestive tract, but that to some extent, milk antibodies do. This demonstrates that the structure of milk antibodies makes them uniquely resistant to digestion, which allows them to exert their protective functions within the gut. We found that the peptide profile in the preterm infant gut differs from that of that term infant gut and that many of these differences are key bioactive peptides. We also demonstrated that thousands of different peptides are present in cheeses, that this varies by cheese variety and rind vs. interior, and that many of these peptides are bioactive, with antimicrobial, ACE-inhibitory and immunomodulatory actions. We demonstrated that high-pressure processing and UV-C processing better preserved breast milk lipase compared with holder pasteurization. We developed a high-throughput method for identification of hundreds of unique glycopeptides in human milk. University of Connecticut, Storrs (Ji-Young Lee). Background: Alcoholic hepatitis (AH) is the progressive form of alcoholic liver disease. Activities: As macrophages play a crucial role in the development of AH, we determine the effect of astaxanthin, a xanthophyll carotenoid, on alcohol-induced inflammation and oxidative stress in macrophages. Outcomes: We found that astaxanthin exerts anti-inflammatory and antioxidant properties in macrophages exposed to alcohol via the modulation of sirtuin 1.  Oregon State University, Corvallis (Emily Ho). Background: Diet plays an important role in mitigating the development and progression of several cancers, including prostate and breast. This research demonstrates that nutritional strategies that decrease oxidative stress, inflammation, DNA damage and/or target aberrant epigenetic alterations, such as acetylation and methylation, have the potential to dramatically reduce the incidence of cancer. Secondly, declining nutritional status may be a critical determinant of healthy aging and susceptibility to environmental insults. The research program has focused on bioactives derived from cruciferous vegetables and zinc nutrition. Activities: We have complete clinical trials investigating the impact of broccoli sprout supplementation in prostate cancer. We have found that supplement are bioavailable and altered expression of AMCR and novel lncRNA. Unlike breast cancer patients, supplementation did not change proliferations markers in prostate. We have also identified additional epigenetic mechanisms involving the acetylation of CCAR2 in chemoprevention of sulforaphane. We have also employed cell culture models and rodent models to understand the impact of zinc status on exposure to arsenic. We have discovered that zinc deficiency sensitizes the pancreatic islet cells to oxidative stress and altered function. Outcomes: We have identified new risk factors in prostate and breast cancer and offer novel dietary modifications to reduce the incidence of cancer. We gained knowledge of the mechanisms behind the health benefits of zinc and compounds derived from vegetables. We established low dietary zinc as risk factor for inflammatory processes, DNA damage and cancer risk and identify new biomarkers for human zinc deficiency. University of Connecticut, Storrs (Christopher N Blesso). Background: Diets rich in saturated fat contribute to elevations in blood cholesterol and a detrimental shifting of gut bacterial populations, both of which are implicated in the development of chronic diseases. Milk fat is relatively enriched in saturated fat compared with other dietary fats, however, it is naturally encased in a polar lipid-containing milk fat globule membrane. My research laboratory has shown in animal studies that cow's milk polar lipids (MPLs) may impart health benefits through lowering blood cholesterol and altering gut bacteria. However, very little research has been conducted to investigate how dietary MPLs impact serum cholesterol and gut bacteria in humans. The major objective of this project is to examine whether the daily consumption of milk fat with and without additional MPLs influences blood cholesterol and gut microbiota in humans. The major objective of this project aligns with one of the primary objectives of the W4002 Multi-State project, that is to “Determine the efficacy and mechanisms of action of nutrients and dietary bioactive compounds towards improved health.” Activities: We have initiated a human nutrition intervention study. Healthy adults will be recruited to participate in a randomized single-blind, controlled, crossover study. Participants will consume 20 g of milk fat daily in the form of either a reconstituted MPL-rich dairy beverage  or a control dairy beverage. Outcomes: So far, 12 participants have completed our intervention study. One graduate student (Master's degree-level) was trained in the agricultural sciences (specifically, Nutritional Sciences) on techniques related to measuring lipoprotein metabolism and human gut microbiota composition. University of Nebraska, Lincoln (Jiujiu Yu). Background: Dietary exosome-like nanoparticles (ELNs) have recently been identified in many vegetables and fruits. Emerging evidence indicates that these dietary ELNs are bioavailable and regulate gene expression in the consumers. Activities: Our group tried to extract ELNs from edible mushrooms and assess their anti-inflammatory functions. We found that ELNs are present in seven commonly consumed mushrooms we tested. These ELNs are membrane-bound nanoparticles composed of lipids, proteins, and RNAs. Outcomes: Remarkably, shiitake mushroom-derived ELNs (S-ELNs) demonstrate potent anti-inflammatory function in cell culture and chemical-induced acute liver injury. University of Nebraska, Lincoln (Janos Zempleni). Background: Almost every cell produces and secretes exosomes (nanoparticles) loaded with cargos such as various species of RNAs, proteins and lipids. Exosomes play essential roles in cell-to-cell communication. Activities: We have made the paradigm-shifting discovery that exosomes and their cargos do not exclusively originate in endogenous synthesis but may also be obtained from dietary sources such as human and bovine milk. Outcomes: 1) We demonstrated that milk exosomes alter the gut microbiome. 2) We demonstrated that milk exosomes do not elicit an immune response if administered orally to mice or added to cultures of human peripheral blood mononuclear cells. 3) We identified modifications in the milk exosome proteome that increase the delivery of RNA therapeutics to brain tumors. 4) We identified glycans on the surface of milk exosomes essential for exosome absorption by mucosal cells in the GI tract. 5) We demonstrated that milk exosomes carry microbial mRNAs, and that the mRNAs are bioavailable in humans and increase the survival of an influenza A. challenge in mice. 6) We discovered that dietary exosome depletion decreases litter size and postnatal growth and survival in mice. 7) We demonstrated that maternal knockout of exosome and microRNA biogenesis impairs growth and GI health in wild-type pups fostered to the dams. 8) We demonstrated that milk exosomes select genetic variations in bacteria from the murine gut. 9)  Depletion of milk exosomes in cultures of a gut pathogen, C. difficile, increases both proliferation rates and toxin production, leading to an increase in weight loss in mice challenged with the bacteria. 10) We demonstrated that milk exosomes and their microRNA cargos are bioavailable and accumulate primarily in the GI mucosa, liver and brain. Oklahoma State University, Stillwater (Dingbo Lin). Background: Our laboratory in interested in the interplay between microbiome and carotenoids. Activities: We analyzed the absorption and accumulation of astaxanthin and zeaxanthin as bioactive carotenoids in a mouse feeding study and the beneficial effects in fecal metabolome. Outcomes: We observed a shift in gut microbiome homeostasis, tight junction, and hepatic oxidative stress parameters that align with the protective role of these carotenoids in health and inflammation. University of Missouri, Columbia (Ingolf Gruen). Background: Chocolate is made from the fermented, dried, and roasted seeds of the Theobroma cacao tree, an important agricultural food crop which contains bioactive flavonoid polyphenols with beneficial health effects such as antioxidant status, cardiovascular and endocrine system functions, and cancer prevention. However, products which have the highest levels of cacao flavonoids such as high-cacao-percentage dark chocolate are known to be quite bitter, a taste modality that is not readily appreciated. Activities: We aim to modify cacao roasting on consumer perceptions of bitterness. Chemical and sensory analysis of the roasted chocolate treatments were carried out. Cacao was fermented and dried at origin before being roasted at different temperatures and times. Bitter compounds were analyzed by HPLC and sensory evaluation. Outcomes: We observed significant decreases for certain bitter compounds as roasting progressed, whereas othes increased. Some of these effects could be attributed to moisture loss. Sensory evaluations findings showed that reduction of bitterness, sourness, and astringency are correlated with increased liking of our chocolates. We also noted that consumers appear to have a preference for increased cocoa intensity and roast times. University of Arizona, Tucson (John Paul SanGiovanni). Background: Exosomes are extracellular vesicles whose contents mediate cellular communication programs involved in processes of extracellular matrix remodeling, innate immunomodulation, lipid transport and cell survival (apoptosis and stress response). All of these processes are implicated in the pathophysiology of age-related macular degeneration (AMD). Activities: Our long-term goal is to develop prognostically and therapeutically valuable exosome-based interventions for AMD. Outcomes: Over the past year, we are coordinating and setting up the research team to carry out these experiments. Purdue University, West Lafayette (Lavanya Reddivari). Background: Plant-based diets are associated with reduced incidence of many chronic diseases. Given the vast array of flavonoids and the complexity of plant food metabolome interactions, it is difficult to identify with certainty the specific class(es) of flavonoids in the food matrix that are anti-inflammatory. Activities: To address this, we have developed four maize near-isogenic lines (NILs); a line that lacked both anthocyanins and phlobaphenes, a second NIL containing phlobaphenes, a third line had anthocyanins, and a fourth line that contained both anthocyanins and phlobaphenes. We used preclinical models to understand the mechanisms of action of these bioactive compounds in reducing colitis. Outcomes: Our results suggest that phlobaphenes in the food matrix are effective in improving mucus thickness and barrier integrity and function. Anthocyanins and phlobaphenes both reduced inflammation and improved gut bacterial diversity and ameliorated DSS-induced colitis. This project provided a platform to exchange ideas and share research data with collaborating researchers. University of Illinois, Urbana Champaign (Jaume Amengual). Background: β-carotene is the primary precursor of vitamin A in mammals, which is crucial for life. My laboratory focuses on understanding the role of β-carotene and vitamin A in lipid metabolism. More specifically, we are interested in the role of these nutrients in obesity, atherosclerosis, and non-alcoholic fatty liver disease. Activities:  Using clinical and preclinical models, we observed that the conversion of β-carotene to vitamin A favors the reduction of “bad” cholesterol. We developed a specific mouse model that mimics the accumulation of β-carotene in atherosclerotic lesions. Outcomes: Over the past year, we unveiled the role of β-carotene and vitamin A on plasma cholesterol levels and its relationship to atherosclerosis development. Ohio State University, Columbus (Richard Bruno). Background. Green tea is rich in catechins, which have anti-inflammatory benefits along the gut-liver axis that thwart obesity-associated nonalcoholic fatty liver disease. While the Ohio station has well-documented these effects in rodents, translational interventions are needed. Activities. We conducted a placebo-controlled, double-blind randomized controlled trial in obese persons to test the hypothesis that a green tea catechin-rich confection would attenuate metabolic endotoxemia in association with decreasing gastrointestinal permeability. This intervention remains underway, but two separate LC-MS techniques have been validated to assess the benefits of green tea to restore gut barrier functions. The first approach is a multi-sugar probe test to assess changes in gut permeability. The second approach consists of assessing a panel of 10 straight chain and branched chain SCFA. Outcomes. LC-MS studies were conducted to establish ionization conditions of the sugar probes, evaluate appropriate stable isotope internal standards to quantify these sugar probes, and to perform a pilot study in humans. Rigorous analytical procedures have been validated. In a pilot study, healthy persons followed a low-polyphenol diet with or without the daily consumption of green tea catechins. Findings indicated no changes in gastric permeability based on urinary sucrose elimination, a tendency for small intestinal permeability to decrease based on reduced urinary lactulose/mannitol, and a significant decrease in large intestinal permeability based on reduced urinary sucralose/erythritol. Separate LC-MS studies also validated the simultaneous assessment of fecal metabolites. These SCFA signatures are expected to correlate with specific populations of commensal and pathogenic gut bacteria to inform the efficacy of green tea catechins to improve gut barrier function.

Publications

<ol> <li>Waller, AW, Andrade, JE, Mejia, LA. Performance factors influencing efficacy and effectiveness of iron fortification programs of condiments for improving anemia prevalence and iron status in populations: A systematic review. Nutrients. 12(2), 275 (2020)</li> <li>Waller, AW, Dominguez-Uscanga, A, Lopez Barrera, E, Andrade, JE, Andrade, JM. Stakeholder’s Perceptions of Mexico’s Federal Corn Flour Fortification Program: A Qualitative Study. Nutrients. 12(2), 433; (2020)</li> <li>Sands, D.C., and Baker C.S. (2020). Parasites of parasites- The toothpick project. 78:5-6.</li> <li>Ho KKHY, Redan BW. Impact of thermal processing on the nutrients, phytochemicals, and metal contaminants in edible algae. Crit Rev Food Sci Nutr. 2020, 1-19.</li> <li>Ho KKHY, Ferruzzi MG, Wightman JD. Potential health benefits of (poly) phenols derived from fruit and 100% fruit juice. Nutr rev. 2020, 78(2), 145-174.</li> <li>Li B, Cui W, Yang J. 2020. Enhanced skeletal muscle growth in myostatin-deficient transgenic pigs had improved glucose uptake in stretozotocin -induced diabetes. Transgenic Research.</li> <li>Zeng F, Zhao C, Wu X, Dong R, Li G, Zhu Q, Zheng E, Liu D, Yang J, Moisyadi S, Urschitz J, Li Z, Wu Z. 2020. Bacteria-induced expression of the pig-derived protegrin-1 transgene specifically in the respiratory tract of mice enhances resistance to airway bacterial infection. Scientific Reports. 2020 Sep 29;10(1):16020. doi: 10.1038/s41598-020-73084-2.</li> <li>Oaks BM, Adu-Afarwuah, Kumordzie S, Laudenslager ML, Smith DL, Lin J, Young RR, Arnold CD, Bentil H, Okronipa H, Ocansey M, Dewey KG. Impact of a nutritional supplement during gestation and early childhood on child salivary cortisol, hair cortisol, and telomere length at 4-6 years of age: a follow-up of a randomized controlled trial. Stress. 2020 Sep;23(5):597-606.</li> <li>Davis JN, Oaks BM, Engle-Stone R. The double burden of malnutrition: a systematic review of operational definitions. Current Developments in Nutrition. 2020 Sep;4(9):nzaa127.</li> <li>Williams A, Addo Y; Guo J; Ismaily S; Namaste S; Oaks BM; Rohner F; Suchdev P; Young M; Peerson J; Flores-Ayala R; Engle-Stone R. Intra-individual double burden of overweight or obesity and micronutrient deficiencies or anemia among women of reproductive age in 17 population-based surveys. American Journal of Clinical Nutrition. 2020 Aug 1;112(Supplement_1):478S-487S.</li> <li>Engle-Stone R; Guo J; Ismaily S; Addo Y; Ahmed T; Oaks BM; Suchdev P; Flores-Ayala R; Williams A. Intra-individual double burden of overweight and micronutrient deficiencies or anemia among preschool children in 24 population-based surveys. American Journal of Clinical Nutrition. 2020 Aug 1;112(Supplement_1):468S-477S.</li> <li>Adams KP, Adu-Afarwuah S, Mridha MK, Oaks BM, Matias SL, Arnold CD, Kumordzie SM, Okronipa H, Ocansey ME, Dewey KG. The impact of maternal supplementation during pregnancy and the first 6 months postpartum on the growth status of the next child born after the intervention period: Follow-up results from Bangladesh and Ghana. Maternal and Child Nutrition. 2020 Apr;16(2):e12927.</li> <li>Kumordzie SM, Okronipa H, Arimond M, Adu-Afarwuah S, Ocansey ME, Young RR, Bentil HJ, Tamakloe SM, Oaks BM, Dewey Maternal and child factors associated with child body fatness in a Ghanaian cohort. Public Health Nutrition. 2020 Feb;23(2):309-318.</li> <li>Adu-Afarwuah, Young RR, Lartey A, Okronipa H, Ashorn P, Ashorn U, Oaks BM, Dewey KG. Supplementation with small-quantity lipid-based nutrient supplements does not increase child morbidity in a semi-urban setting in Ghana: a secondary outcome non-inferiority analysis of the iLiNS-DYAD randomized controlled trial. Journal of Nutrition. 2020 Feb;150(2)382-393.</li> <li>Ocansey ME, Adu-Afarwuah S, Kumordzie SM, Okronipa H, Young RR, Tamakloe SM, Oaks BM, Dewey KG, Prado EL. The association of early linear growth and haemoglobin concentration with later cognitive, motor and social-emotional development at preschool age in Ghana. Maternal and Child Nutrition. 2019 Oct;15(4):e12834.</li> <li>Wang, Y-C., Wu, M-T., Tang, F-Y., Chen, D-Y., Ko, H-A., Shane, B., Huang, W-N. and Chieng, E-P. (2019). MTHFR C677T Polymorphism Increases Methotrexate Sensitivity via the inhibition of S-adenosylmethionine and De Novo Purine Synthesis. Clin. Sci. 133: 253-267.</li> <li>Maruvada , Patrick J Stover, P. J., Mason, J. B., Bailey, R. L., Davis, C. D., Field, M., Finnell, R. H., Garza, C., Green, R., Gueant, J.-L., Jacques, P. F., Johnston, B., Klurfeld, D. M., Lamers, Y., MacFarlane, A., Miller, J. W., Molloy, A. M., O’Connor, D. L., Pfeiffer, C. M., Potischman, N. A., Rodricks, J. V., Rosenberg, I. H., Shane, B., Selhub, J., Ross, S. A., Stabler, S. P., Trasler, J., Yamini, S. and Zappala, G. (2020). Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop. Am. J. Clin. Nutr. 112: 1390-1403.</li> <li>Tsakiroglou P, Weber J, Ashworth S, Del Bo’ C, Klimis-Zacas D. Angiogenesis is differentially modulated by anthocyanin and phenolic acid extracts from wild blueberry (V. angustifolium) through PI3K pathway. J. Med Food, 2020, 1-10, DOI: 10.1089/jmf.2020.0066</li> <li>VandenAkker, N., Vendrame, S., Tsakiroglou, P, McGilvey M, Klimis-Zacas, D. Whole red raspberry (Rubus idaeus) enriched-diet is hepatoprotective in the OZR, a model of the Metabolic Syndrome. J. Med Food, 2020, 1–8, DOI: 10.1089/jmf.2020.0130</li> <li>VandenAkker, N., Vendrame, S., Tsakiroglou, P., Klimis-Zacas, D. Red raspberry (Rubus idaeus) consumption restores the impaired vasoconstriction and vasorelaxation in the aorta of the obese Zucker rat, a model of the Metabolic Syndrome. J. Berry Research, 2021, In print</li> <li>Kalea, AZ, Klimis-Zacas D. Challenges and Insights amidst the Covid-19 pandemic: Nutrition, the immune system and disease risk, Curr Opin Clin Nutr Metab Care, 2020, 23:233-235.</li> <li>Kristo, A., & Klimis-Zacas, D. Gut microbiota and polyphenols. In: “The Gut Microbiome: Bench to Bedside”. DES Tech Publications, 2021, Accepted</li> <li>Doan N, Liu Y, Xiong X, Kim K, Wu Z, Bravo DM, Blanchard A, Ji P. Organic selenium supplement partially alleviated diquat- induced oxidative insults and hepatic metabolic stress in nursery pigs. British Journal of Nutrition, 2020, 124(1): 23-33.</li> <li>Qi M, Tan B, Wang J, Liao S, Li J, Cui Z, Shao Y, Ji P, Yin Y. Postnatal growth retardation is associated with deteriorated intestinal mucosal barrier function using a porcine model. Journal of Cellular Physiology. 2020, DOI: 10.1002/jcp.30028</li> <li>Kim K, Ji P, Song M, Che TM, Bravo D, Pettigrew JE, Liu Y. Dietary plant extracts modulate gene expression profiles in alveolar macrophages of pigs experimentally infected with porcine reproductive and respiratory syndrome virus. Journal of Animal Science and Biotechnology, 2020, 11: 74-87.</li> <li>Perng V, Li C, Navazesh SE, Klocke CR, Pinneles DK, Lein PJ, Ji P. Iron deficiency and iron excess differently affect dendritic architecture of pyramidal neurons in the hippocampus. Journal of Nutrition. 2020, DOI: 10.1093/jn/nxaa326</li> <li>Duca FA, Lam TKT. Bye, bye, bile: how altered bile acid composition changes small intestinal lipid sensing. Gut. 2020, 69(9):1549-1550.</li> <li>Ward EJ, Lindshield BL. Performance, behavior, and perceptions of an open educational resource derived interactive educational resource by online and campus university students. Res Learn Technol. 2020, 28:2386.</li> <li>Ward EJ, Suleria HAR, Joseph M, Chambers IV E, Alavi S, Lindshield BL. Soy Protein is and Efficacious Alternative to Whey Protein in Sorghum-Soy Fortified Blended Food in Rats. Curr Dev Nutr. 2020, 4(8).</li> <li>Robinson, R. C., Nielsen, S. D., Dallas, D. C., Barile, D. B. (2020) Can cheese mites, maggots and molds enhance bioactivity? Peptidomic investigation of functional peptides in four traditional cheeses. Food & Function.</li> <li>Lueangsakulthai, J., Kim, B. J., Demers-Mathieu, V., Sah, B. N. P., Woo, Y., Olyaei, A., O’Connor, A. Scottoline, B. P., Dallas, D. C. (2020) Effect of digestion on stability of palivizumab IgG1 in the infant gastrointestinal tract. Accepted at Pediatric Research.</li> <li>Koh, J., Victor, A., Yeo, G., Qu, Y., Dallas, D. C. (2020) Effect of alternative processing techniques for donor breast milk on bile salt-stimulated lipase. Frontiers in Nutrition.</li> <li>Kim, B. J., Dallas, D. C. (2020) Systematic examination of protein extraction, proteolytic glycopeptide enrichment and MS/MS fragmentation techniques for site-specific profiling of human milk N-glycoproteins. Talanta: 121811.</li> <li>Nielsen, S. D., Beverly, R. L., Underwood, M. A., Dallas, D. C. (2020). Differences and similarities in the peptide profile of preterm and term mother’s milk and preterm and term infant gastric samples. Nutrients. 12(9), 2825;</li> <li>Rackerby, B., Kim, H. J., Dallas, D. C., Park, S. H. (2020). Understanding the Effects of Dietary Components on the Gut Microbiome and Human Health. Food Science and Biotechnology. Food Science and Biotechnology, 29(11), 1463-1474; DOI: 10.1007/s10068-020-00811-w</li> <li>Beverly, R. L., Huston, R. K., Markell, A. M., McCulley, E. A., Martin, R. L., Dallas, D. C. (2020). Differences in human milk peptide release along the gastrointestinal tract between preterm and term infants. Clinical Nutrition.</li> <li>Sah, B. N. P., Lueangsakulthai, J., Hauser, B. R., Demers-Mathieu, V., Scottoline, B. P., Pastey, M. K., Dallas, D. C. (2020). Purification of Antibodies from Human Milk and Infant Digestates for Viral Inhibition Assays. Frontiers in Nutrition, section Nutritional Immunology.</li> <li>Lueangsakulthai, J., Sah, B. N. P., Scottoline, B. P., Dallas, D. C. (2020). Survival of recombinant monoclonal and naturally-occurring human milk immunoglobulins A and G specific to respiratory syncytial virus F protein across simulated human infant gastrointestinal digestion. Journal of Functional Foods. 73(104115);</li> <li>Sah, B. N. P., Hauser, B. R., Lueangsakulthai, J., Kim, B. J., Scottoline, B. P., Pastey, M. K., Dallas, D. C. (2020). Partial Degradation of Recombinant Antibody Functional Activity During Infant Gastrointestinal Digestion: Implications For Oral Antibody Supplementation. Frontiers in Nutrition, Nutritional Immunology. 7(130); 10.3389/fnut.2020.00130</li> <li>Demers-Mathieu, V. Qu, Y., Sah, B. N. P., Lueangsakulthai, J., Underwood, M. A., Scottoline, B., Dallas, D. C. (2020). Binding and neutralizing capacity of respiratory syncytial virus (RSV)-specific recombinant IgG against RSV in human milk, gastric and intestinal fluids from infants. Nutrients. Nutritional Immunology. 12(7), 1904;</li> <li>Demers-Mathieu, V., Huston, R. K., Markell, A. M., McCulley, E. A., Martin, R. L., Dallas, D. C. (2020). Impact of pertussis-specific IgA, IgM, and IgG antibodies in mother’s own breast milk and donor breast milk during preterm infant digestion. Pediatric Research.</li> <li>Kim, B. J., Lueangsakulthai, J., Sah, B. N. P., Scottoline, B., P., Dallas D. C. (2020). Quantitative Analysis of Antibody Digestion Across the Infant Digestive Tract Using Mass Spectrometry with Parallel Reaction Monitoring. Foods. 9(6), 759;</li> <li>Demers-Mathieu, V. Huston, R. K., Dallas, D. C. (2020) Cytokine expression by human macrophage-like cells derived from the monocytic cell line THP-1 differs between treatment with milk from preterm- and term-delivering mothers and pasteurized donor milk. Molecules. 25(10), 2376.</li> <li>Lueangsakulthai, J., Sah, B. N. P. , Scottoline, B. P., Dallas, D. C. (2020) Survival of Respiratory Syncytial Virus F Protein-Specific Recombinant Monoclonal Antibodies (IgG, IgA and sIgA) and Naturally-Occurring Antibodies (IgG and sIgA/IgA) in an Ex Vivo Infant Digestion Model. Nutrients. Nutritional Immunology. 12(3), 621;</li> <li>Weinborn, V., Li, Y., Shah, I. M., Yu, H., Dallas, D. C., German, J. B., Mills, D. A., Chen, X., Barile, D. (2020) Production of functional mimics of human milk oligosaccharides by enzymatic glycosylation of bovine milk oligosaccharides. International Dairy Journal. 102. doi: 10.1016/j.idairyj.2019.104583.</li> <li>Kang, Y. Lee, M. Bae, Y-.K. Park, J-.Y. Lee. Astaxanthin inhibits alcohol-induced inflammation and oxidative stress in macrophages in a sirtuin 1-dependent manner. J Nutr Biochem 2020; 85:108477. epub ahead of print on August 12, 2020.</li> <li>M-.B. Kim, Y. Lee, M. Bae, H. Kang, T.X. Pham, S. Hu, J-.Y. Lee, Y-.K Park. Comprehensive characterization of metabolic, inflammatory and fibrotic changes in a mouse model of non-alcoholic steatohepatitis. J Nutr Biochem 2020; 85:108463. epub ahead of print on July 10, 2020.</li> <li>Hu, M. Bae, Y-.K. Park, J-.Y. Lee. n-3 PUFA inhibit TGFb1-induced pro-fibrogenic gene expression by ameliorating the repression of PPARg in hepatic stellate cells. J Nutr Biochem 2020; 85;108478. epub ahead of print on June 15, 2020.</li> <li>Bae, Y. Lee, T. X. Pham, Y-.K. Park, S. Hu, J-.Y. Lee. Astaxanthin inhibits the reduction of glycolysis during the activation of hepatic stellate cells. Life Sci 2020; 256: 117926. epub ahead of print on June 12, 2020.</li> <li>C. Donepudi, G. J. Smith, O. Aladeloku, Y. Lee, S. J. Toro, M. Phof, A. L. Slitt, J-.Y. Lee, J. D. Schuetz, L. Wang, J. E. Manautou. Lack of multidrug-resistance associated protein 4 worsens partial hepatectomy-induced hepatic steatosis. Toxicol Sci 2020; 175:301-311. epub ahead of print on March 6, 2020.</li> <li>L. Miller, C. Jiang, G. H. Norris, C. Carcia, S. Seibel, L. Anto, J-.Y. Lee, C. N. Blesso. Cow’s milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota, and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet. J Nutr Biochem 2020; 79: 108351. epub ahead of print on Jan 23, 2020.</li> <li>Bae, M-.B. Kim, Y-.K. Park, J-.Y. Lee. Health benefits of fucoxanthin in the prevention of chronic disease. BBA Mol Cell Biol of Lipids 2020; 1865:158618. epub ahead of print on January 10, 2020.</li> <li>Hu, E-.H. Cho, J-.Y. Lee. Histone deacetylase 9: Its role in the pathogenesis of diabetes and other chronic diseases. Diabetes Metab J 2020; 44: 234-244. epub ahead of print on March 24, 2020</li> <li>Hu, S. Hu, E. Fleming, J-.Y. Lee, Y. Luo. Chitosan-Caseinate-Dextran Ternary Complex Nanoparticles for Potential Oral Delivery of Astaxanthin with Significantly Improved Bioactivity. Int J. Biol Macromole 2020; 151: 747-756.</li> <li>Hu, J-.Y. Lee, Y. Luo. Nanoparticles targeting hepatic stellate cells for the treatment of liver fibrosis. Engeneered Sci 2019; 6:12-21.</li> <li>Wong CP, Dashner-Titus EJ, Alvarez SC, Chase TT, Hudson LG, Ho E. (2019) Zinc Deficiency and Arsenic Exposure Can Act Both Independently or Cooperatively to Affect Zinc Status, Oxidative Stress, and Inflammatory Response. Biol Trace Elem Res.. doi: 1007/s12011-019- 1631-z</li> <li>Rajendran P, Johnson G, Li L, Chen YS, Dashwood M, Nguyen N, Ulusan A, Ertem F, Zhang M, Li J, Sun D, Huang Y, Wang S, Leung HC, Lieberman D, Beaver L, Ho E, Bedford M, Chang K, Vilar E, Dashwood R. (2019) Acetylation of CCAR2 Establishes a BET/BRD9 Acetyl Switch in Response to Combined Deacetylase and Bromodomain Inhibition. Cancer Res. 2019 Mar 1;79(5):918-927. doi: 10.1158/0008-5472.CAN-18-2003. Epub 2019 Jan 14. PMID: 3064301</li> <li>Cao AL, Beaver LM, Wong CP, Hudson LG, Ho E. (2019) Zinc deficiency alters the susceptibility of pancreatic beta cells (INS-1) to arsenic exposure. 2019 Dec;32(6):845-859. doi: 10.1007/s10534-019-00217-0. Epub 2019 Sep 21</li> <li>Wallace TC, Bultman S, D'Adamo C, Daniel CR, Debelius J, Ho E, Eliassen H, Lemanne D, Mukherjee P, Seyfried TN, Tian Q, Vahdat LT (2019). Personalized Nutrition in Disrupting Cancer - Proceedings From the 2017 American College of Nutrition Annual Meeting. J Am Coll Nutr. 2019 Jan;38(1):1-14. doi: 10.1080/07315724.2018.1500499.</li> <li>Zhang Z, Garzotto M, Davis EW 2nd, Mori M, Stoller WA, Farris PE, Wong CP, Beaver LM, Thomas GV, Williams DE, Dashwood RH, Hendrix DA, Ho E, Shannon J. Sulforaphane Bioavailability and Chemopreventive Activity in Men Presenting for Biopsy of the Prostate Gland: A Randomized Controlled Trial. Nutr Cancer. 2020;72(1):74-87. doi: 10.1080/01635581.2019.1619783.</li> <li>Norris GH, Milard M, Michalski MC, Blesso CN. Protective properties of milk sphingomyelin against dysfunctional lipid metabolism, gut dysbiosis, and inflammation. J Nutr Biochem. 2019 Nov;73:108224. doi: 10.1016/j.jnutbio.2019.108224. Epub 2019 Aug 15.</li> <li>Millar CL, Jiang C, Norris GH, Garcia C, Seibel S, Anto L, Lee JY, Blesso CN. Cow's milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet. J Nutr Biochem. 2020 Jan 23;79:108351. doi: 10.1016/j.jnutbio.2020.108351.</li> <li>Hirahatake KM, Bruno RS, Bolling BW, Blesso C, Alexander LM, Adams SH. Dairy Foods and Dairy Fats: New Perspectives on Pathways Implicated in Cardiometabolic Health. Adv Nutr. 2020 Mar 1;11(2):266-279. doi: 10.1093/advances/nmz105.</li> <li>Anto L, Warykas SW, Torres-Gonzalez M, Blesso CN. Milk Polar Lipids: Underappreciated Lipids with Emerging Health Benefits. Nutrients. 2020 Apr 4;12(4). pii: E1001. doi: 10.3390/nu12041001.</li> <li>Liu B, Lu Y, Chen X, Muthuraj PG, Li X, Pattabiraman M, Zempleni J, Kachman SD, Natarajan SK, Yu J*. <a href="https://www.ncbi.nlm.nih.gov/pubmed/32069862/">Protective Role of Shiitake Mushroom-Derived Exosome-Like Nanoparticles in D-Galactosamine and Lipopolysaccharide-Induced Acute Liver Injury in Mice. </a>Nutrients. 2020 Feb 13;12(2). doi: 10.3390/nu12020477.</li> <li>Mutai E, Ramer-Tait AE, Zempleni J. MicroRNAs in bovine milk exosomes are bioavailable in humans but do not elicit a robust pro-inflammatory cytokine response. BMC exRNA 2:2, 2020</li> <li>Liu, B, Lu Y, Chen X, Muthuraj, PG, L X, Pattabiraman M, Zempleni J, Kachman SD, Natarajan SK, Yu J. Protective role of shiitake mushroom-derived exosome-like nanoparticles in D-galactosamine and lipopolysaccharide-induced liver injury in mice. Nutrients 12:477, 2020</li> <li>Sadri M, Shu J, Kachman SD, Cui J, Zempleni J. Milk exosomes and microRNAs cross the placenta and promote embryo survival in mice. Reproduction 160:501-509, 2020</li> <li>Zempleni J. Letter to the editor (regarding Perspective: The Role of Human Breast-Milk Extracellular Vesicles in Child Health and Disease by D. O’Reilly et al., published in AN on 24 August 2020). Adv Nutr (in press)</li> <li>Lei Wu, Peiran Lu, Xin Guo, Kun Song, Yi Lyu, James Bothwell,Jinglong Wu, Olivia Hawkins, Stephen L. Clarke, Edralin A. Lucas, Brenda J. Smith, Winyoo CHowanadisai, Steve Hartson, Jerry Ritchey, Weiqun Wang, Denis Medeiros, Shitao Li, Dingbo Lin. 2021. β-carotene oxygenase 2 deficiency-triggered mitochondrial oxidative stress promotes inflammation and metabolic disorders. Free Radical Biology Medicine.</li> <li>Lei Wu, Yi Lyu, Ramkumar Srinivasagan, Jinlong Wu, Babajide Ojo, Minghua Tang, Guadalupe Davilla El-Rassi, Katherine Metzinger, Brenda J Smith, Edralin A Lucas, Stephen L Clarke, Winyoo Chowanadisai, Xinchun Shen, Hui He, Tyrrell Conway, Johannes von Lintig, Dingbo Lin. 2020. Astaxanthin-shifted gut microbiota is associated with inflammation and metabolic homeostasis in mice. J Nutr. 2020 Oct 12;150(10):2687-2698. doi: 10.1093/jn/nxaa222.</li> <li>Hall F, Reddivari L, Liceaga AM. Identification and characterization of edible cricket peptides on hypertensive and glycemic in vitro inhibition and their anti-Inflammatory activity on RAW 264.7 macrophage cells. Nutrients. 2020, 12 (11):3588</li> <li>Bao Y, Reddivari L, Huang JY. Novel cold plasma-assisted extraction for phenolic compounds from tomato pomace. Innov Food Sci Emerg Technol. 2020, 65:102445</li> <li>Bao Y, Reddivari L, Huang JY. Enhancement of phenolic compounds extraction from grape pomace by high voltage atmospheric cold plasma. LWT. 2020, 133:109970</li> <li>Wu B, Bhatnagar RS, Indukuri V, Chopra S, March K, Cordero N, Chopra S, Reddivari L. Intestinal mucosal barrier function restoration in mice by maize diet containing enriched flavan-4-ols. Nutrients. 2020, 12(4):896</li> <li>Cladis DP, Li S, Reddivari L, Cox A, Ferruzzi MG, Weaver CM*. A 90-day oral toxicity study of blueberry polyphenols in ovariectomized Sprague-Dawley rats. Food Chem Toxicol. 2020, 139:111254</li> <li>Sidorov E, Bejar C, Xu C, Ray B, Reddivari L, Chainakul J, Vanamala JKP, Sanghera DK. Potential metabolite biomarkers for acute versus chronic stage of ischemic stroke: A pilot study. J Stroke Cerebrovascular Dis. 2020, 29(4):104618</li> <li>Zhou F, Wu X, Pinos I, Abraham BM, Barrett TJ, von Lintig J, Fisher EA, Amengual J. β-Carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice. J Lipid Res. 2020 Nov;61(11):1491-1503.</li> <li>Amengual J, Coronel J, Marques C, Aradillas-García C, Morales JMV, Andrade FCD, Erdman JW, Teran-Garcia M. β-Carotene Oxygenase 1 Activity Modulates Circulating Cholesterol Concentrations in Mice and Humans. J Nutr. 2020 Aug 1;150(8):2023-2030.</li> <li>Josefs T, Barrett TJ, Brown EJ, Quezada A, Wu X, Voisin M, Amengual J, Fisher EA. Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice. JCI Insight. 2020 Apr 9;5(7):e134796.</li> <li>Miller AP, Coronel J, Amengual J. The role of β-carotene and vitamin A in atherogenesis: Evidences from preclinical and clinical studies. Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Nov;1865(11):158635.</li> <li>LE Griffin, DW Fausnacht, JL Tuzo, AK Addington, KC Racine, H Zhang, MD Hughes, KM England, RS Bruno, SF O’Keefe, AP Neilson, AC Stewart. (2019). Flavanol supplementation protects against obesity-associated increases in systemic IL-6 levels without inhibiting body mass gain in mice fed a high-fat diet. Nutr Res, 66:32-47.</li> <li>R Williams, A Rose, RS Bruno, A Hanks, J Kennel, J McDonald, C Gunther. (2019). Examination of the relationship of diet quality with cardiometabolic risk factors in apparently healthy college students. J Am Coll Health, 8:148. doi: 10.4103/jehp.jehp_12_19.</li> <li>P Dey, JB Kim, C Chitchumroonchokchai, J Li, GY Sasaki, BD Olmstead, KL Stock, JM Thomas-Ahner, SK Clinton, RS Bruno. (2019). Green tea extract inhibits early oncogenic responses in mice with nonalcoholic steatohepatitis. Food Funct, 10, 6351-6361.</li> <li>GY Sasaki, J Li, MJ Cichon, KM Riedl, RE Kopec, RS Bruno. (2019). Green tea extract treatment in obese mice with nonalcoholic steatohepatitis restores the hepatic metabolome in association with limiting endotoxemia-TLR4-NFkB-mediated inflammation. Mol Nutr Food Res, 63(24):e1900811. doi: 10.1002/mnfr.201900811.</li> <li>BK Alba, AE Stanhewicz, P Dey, RS Bruno, WL Kenney, LM Alexander. (2020). Controlled feeding of an 8-day high dairy cheese diet prevents sodium-induced endothelial dysfunction in the cutaneous microcirculation through reductions in superoxide. J Nutr, 150(1):55-63; doi: 10.1093/jn/nxz205.</li> <li>KM Hirahatake, RS Bruno, BW Bolling, C Blesso, LM Alexander, SH Adams. (2019). Dairy foods and dairy fats: new perspectives on pathways implicated in cardiometabolic health. Adv Nutr, 11(2):266-279. doi: 10.1093/advances/nmz105.</li> <li>KM Ranard, MJ Kuchan, RS Bruno, JM Juraska, JW Erdman. (2020). Synthetic α-tocopherol, compared with natural α-tocopherol, downregulates myelin genes in cerebella of adolescent Ttpa-null mice. J Nutr, 150(5):1031-1040. doi: 10.1093/jn/nxz330.</li> <li>JK Hodges, J Zhu, Z Yu, Y Vodovotz, G Brock, GY Sasaki, P Dey, RS Bruno. (2020) Intestinal-level anti-inflammatory bioactivities of catechin-rich green tea: Rationale, design, and methods of a double-blind, randomized, placebo-controlled crossover trial in metabolic syndrome and healthy adults. Contemp Clin Trials Commun. 17:100495. doi: 10.1016/j.conctc.2019.100495</li> <li>MM Kemski, CA Rappleye, K Dabrowski, RS Bruno, M Wick. (2020). Transcriptomic response to soybean meal-based diets as the first formulated feed in juvenile yellow perch (Perca flavescens). Sci Rep, 10(1):3998. doi: 10.1038/s41598-020-59691-z.</li> <li>MJ Kuchan, KM Ranard, P Dey, S Jeon, GY Sasaki, KJ Schimpf, RS Bruno, M Neuringer, JW Erdman Jr. (2020). Infant rhesus macaque brain α-tocopherol stereoisomer profile is differentially impacted by source of α-tocopherol in infant formula. J Nutr, doi: 10.1093/jn/nxaa174.</li> <li>P Dey, BD Olmstead, GY Sasaki, Y Vodovotz, Z Yu, RS Bruno (2020). Epigallocatechin gallate but not catechin prevents nonalcoholic steatohepatitis in mice similar to green tea extract while differentially affecting the gut microbiota. J Nutr Biochem, doi: 10.1016/j.jnutbio.2020.108455.</li> <li>WR Quarles, A Pokala, E Shaw, J Ortega, L Hillman, R Jimenez-Flores, RS Bruno. (202x). Alleviation of metabolic endotoxemia by milk fat globule membrane: Rationale, design, and methods of a double-blind, randomized controlled, crossover dietary intervention trial in adults with metabolic syndrome. Curr Dev Nutr, 4(9):nzaa130. doi: 10.1093/cdn/nzaa130.</li> <li>JK Hodges, GY Sasaki, RS Bruno. (2020). Anti-inflammatory activities of green tea catechins along the gut-liver axis in nonalcoholic fatty liver disease: lessons learned from preclinical and human studies. J Nutr Biochem, 2020;85:108478. doi: 10.1016/j.jnutbio.2020.108478.</li> </ol>   Abstracts, Presentations, and Other Publications <ol> <li>Andrade, JE, Waller AW, Gaytán Martínez M. In-Country Method Validation of a Paper-based, Smartphone-assisted Iron Sensor for the Food Fortification Programs. ASN Annual Conference (virtual). June 2020</li> <li>Dominguez-Uscanga A, Aycart DF, Witola WH, Andrade JE. In vitro efficacy of Thymol and a Thymol ester against Cryptosporidium parvum. IFT Annual Conference (virtual). June 2020</li> <li>Office of the Vice President for Research, University of Maine, Klimis-Zacas, D. Wild Blueberries aid in wound healing, in 2019 Research report: Global Impact, Local Relevance, 2020</li> <li>Sands, D.C. The toothpick method: a novel and better way to kill weeds with biocontrol fungi. Keynote and webinar co-host. December 16, 2020. WASCAL: Biocontrol of Weeds for Food Security in West Africa: The Case of Striga.</li> <li>Sands, D.C. Bioherbicide Development for C. thistle and field bindweed. December 3, 2020. Montana Organic Association Annual Conference: MSU Research Updates with the Organic Advisory and Education Council.</li> <li>Sands, D. C. The latest scientific developments linked to fusarium oxysporum bioherbicide. September 30, 2020. Biocontrol Africa/New Ag International Conference. <a href="https://informaconnect.com/new-ag-international-and-biocontrol-africa-virtual/">https://informaconnect.com/new-ag-international-and-biocontrol-africa-virtual/</a></li> <li>Sands, David and Claire Baker. 2020. Parasites of parasites: The toothpick project. Haustorium; 78:5.Youtube video: McArthur  100 and Change     <a href="https://www.youtube.com/watch?v=YD38kjJqyiE&feature=emb_logo">https://www.youtube.com/watch?v=YD38kjJqyiE&feature=emb_logo</a> </li> <li>Zempleni J, Sadri M, Zhou F. Exosomes and microRNAs in maternal milk are important for growth and gut health during lactation in murine pups. American Society for Exosomes and Microvesicles, November 17, 2020 (virtual meeting) [short talk, delivered by using Zoom]. Extracellular Vesicle and Circulating Nucleic Acid (EVCNA) Journal. 2020 (in press)</li> <li>NIFA blog regarding research sponsored by NIFA/USDA (2020-67017-30834) “Milk exosome-driven evolution of antibiotic-resistant gut pathogens”:</li> <li>National Institute of Food and Agriculture website: <a href="https://urldefense.proofpoint.com/v2/url?u=https-3A__nifa.usda.gov_blog_milk-2Dfindings-2Dmay-2Dhelp-2Dinfants&d=DwMGaQ&c=Cu5g146wZdoqVuKpTNsYHeFX_rg6kWhlkLF8Eft-wwo&r=ytvP_VccoDC5CA7IW8JCkoVSmtrHVpGjxHDTAl93H5A&m=znGH7xduA3ckwRjx2RTm0y3uh3YHmOt0IiWnSwNTO_8&s=IXuj2fqjx6VSd6fPbap78igimpEooFQD4XKKRzvGaS4&e=">https://nifa.usda.gov/blog/milk-findings-may-help-infants</a></li> <li>NIFA twitter regarding research sponsored by NIFA/USDA (2020-67017-30834) “Milk exosome-driven evolution of antibiotic-resistant gut pathogens”: National Institute of Food and Agriculture Twitter: <a href="https://urldefense.proofpoint.com/v2/url?u=https-3A__twitter.com_usda-5Fnifa&d=DwMGaQ&c=Cu5g146wZdoqVuKpTNsYHeFX_rg6kWhlkLF8Eft-wwo&r=ytvP_VccoDC5CA7IW8JCkoVSmtrHVpGjxHDTAl93H5A&m=znGH7xduA3ckwRjx2RTm0y3uh3YHmOt0IiWnSwNTO_8&s=4ZFBkBNDikRpOZf6VSAEzhaqCMwVt8wWfYPKvu2PNx4&e=">https://twitter.com/usda_nifa</a></li> <li>USDA blog regarding research sponsored by NIFA/USDA (2020-67017-30834) “Milk exosome-driven evolution of antibiotic-resistant gut pathogens”: USDA website: <a href="https://urldefense.proofpoint.com/v2/url?u=https-3A__www.usda.gov_media_blog_2020_06_01_milk-2Dfindings-2Dmay-2Dhelp-2Dinfants-2Dworldwide&d=DwMGaQ&c=Cu5g146wZdoqVuKpTNsYHeFX_rg6kWhlkLF8Eft-wwo&r=ytvP_VccoDC5CA7IW8JCkoVSmtrHVpGjxHDTAl93H5A&m=znGH7xduA3ckwRjx2RTm0y3uh3YHmOt0IiWnSwNTO_8&s=A7pVbcj3qD4SqieaNEi9EMQxsTPphaDHJRNelSM5Faw&e=">https://www.usda.gov/media/blog/2020/06/01/milk-findings-may-help-infants-worldwide</a></li> <li>Nature Outlook “Do the microRNAs we eat affect gene expression?:</li> </ol> <a href="https://www.nature.com/articles/d41586-020-01767-x">https://www.nature.com/articles/d41586-020-01767-x</a> and <a href="https://urldefense.proofpoint.com/v2/url?u=https-3A__www.nature.com_collections_hibdgeeijf&d=DwMFaQ&c=Cu5g146wZdoqVuKpTNsYHeFX_rg6kWhlkLF8Eft-wwo&r=ytvP_VccoDC5CA7IW8JCkoVSmtrHVpGjxHDTAl93H5A&m=SMDepXnr63krAUvLQXslApjXxUoU68MDbulCdLJGl7o&s=l0G9easDItupWaoKGMASk1E6kbiOQGTL1zqwYCVS3UE&e=">https://www.nature.com/collections/hibdgeeijf</a>. Nature. June 17, 2020. Nature 582, S10-S11 (2020), doi: 10.1038/d41586-020-01767-x

Impact Statements

Ohio State University, Columbus (Richard Bruno). Obesity closely aligns with a number of cardiometabolic disorders, including nonalcoholic fatty liver disease, that are provoke by gut barrier dysfunction. Our newly established LC-MS procedures will advance an understanding of the health-promoting bioactivities of green tea polyphenols, and can be immediately transferrable to assess the efficacy of other bioactive food components to improve gut barrier functions that limit systemic inflammatory responses.

Date of Annual Report: 05/26/2022

Report Information

Annual Meeting Dates: 03/07/2022 - 03/07/2022
Period the Report Covers: 10/01/2020 - 09/30/2021

Participants

Richard Bruno;
Jaume Amengual;
Kacie Ho;
Allison Ehrlich;
Janos Zempleni;
Emily Ho;
Ji-Young Lee;
Lisa Jahns,;
Urszula Iwaniec;
Lavanya Reddivari;
Elad Tako;
David Dallas;
Peng Ji;
Yanghong Liu;
Frank Duca,;
David Gang;
Jinzeng Yang;
Urszula Iwaniec;
Dingbo (Daniel) Lin;

Brief Summary of Minutes

Virtual Zoom Meeting (4:00-8:00 PM EST)

4:00 Introductions

4:20 Business Meeting

Meeting Format Overview

Current Chair: Jaume Amengual

Current Secretary: Kacie Ho (to be promoted to chair)

Election: Incoming Secretary –Peng Ji elected

Discussion of next meeting (in-person vs virtual)

In-person preferred if COVID-19 conditions continue to improve University of Hawaii at Manoa to host in Honolulu, HI. Tentative dates for May are preferred.

Upcoming project renewal

To work on after the submission of the Final Report for 2020-2021

Required Structure of Annual Report (due date April 25^th)

4:40 Station Reports Session I – 5-6 Members (5 min + 2 min for questions)

- Kacie Ho – Nutrients and phytochemicals from Hawaii commodities

- Richard Bruno – Bioavailability and anti-inflammatory bioactivity of green tea catechins

- Allison Ehrlich – Modulation of gut immune function by dietary AhR ligands

- Janos Zempleni – Milk Exosomes in nutrition and drug delivery

- Emily Ho - TBD

- Ji-Young Lee – Research on alcohol-induced diseases

5:30 Open Q&A Panel Discussion (Break-out Rooms)

5:45 Lisa Jahns, our NIFA representative, will cover important topics such funding opportunities for faculty, trainees, and institutions.

6:15 Station Reports Session II – 5-6 Members (5 min + 2 min for questions)

- Urszula Iwaniec – Isoliquiritigenin and bone

- Lavanya Reddivari – Bioactive compound and gut bacteria interaction in gut health

- Elad Tako – TBD

- David Dallas - Milk protein and peptide digestion and bioactivity

- Peng Ji - Use of Symbiotics to Mitigate Adverse Effect of Iron Excess in Formula-Fed Piglets

- Yanghong Liu – Cellular iron status modulates immunometabolism in macrophage cells

- Frank Duca - Plant-based flour and fibers impact metabolic homeostasis

7:15 Open Q&A Panel Discussion (Break-out Rooms)

7:30 Meeting Summary & Adjournment

Accomplishments

University of Illinois at Urbana-Champaign (Jaume Amengual). Background: β-carotene is the primary precursor of vitamin A in mammals, which is crucial for life. My laboratory focuses on understanding the dietary and pharmacological factors controlling carotenoid uptake. Activities:  We developed a specific mouse model that mimics the accumulation of β-carotene to study the role of bioactive compounds implicated in carotenoid uptake. Outcomes: Over the past year, we unveiled the role of fenretinide on carotenoid and vitamin E uptake in mammals. University of Florida, Gainesville  (Juan Andrade). Background: In low-middle income countries, tools to monitor fortification processes are lacking and represent a hurdle to improve food and nutrition security of vulnerable populations. Activities: We validated a low-cost, smartphone-assisted, paper-based sensor to measure iron in fortified foods. The paper-based sensor measures different types of added iron into flours. We are continuing the validation of the sensor using maize samples from different countries and fortified with different iron types. Outcomes: Our work supports current rice and maize fortification programs in Bangladesh and Mexico, respectively, and provides tools to improve food and nutrition security. Background: Diarrhea worldwide affects the growth and health of children under five. Cryptosporidium parvum, a zoonotic protozoan, is one of the top three leading causes of diarrhea worldwide. Activities: We have shown that volatile terpenes (thymol) and their modifications (thymol-octanoate) can inhibit the growth and infectivity of Cryptosporidium in vitro. Outcomes: The esterification of octanoic acid on thymol can improve the safety margins of addition to mammalian cells and offer enhanced physicochemical properties that could make it more suitable for diverse applications as an antiparasitic agent. University of Nebraska-Lincoln (Janos Zempleni). Background: Exosomes are nanoparticles (~100 nm) that play crucial roles in cell-to-cell communication. We have discovered that exosomes and their cargos do not originate exclusively in endogenous synthesis but may also be absorbed from dietary sources such as milk. Activities: We demonstrated that milk exosomes play an important role in cognitive function and brain health in neonate and juvenile mice and probably human infants. In the drug delivery realm, we developed a novel bovine cell line that secretes milk exosomes. Cells were amenable to genetic engineering, thereby enabling the development of milk exosomes with properties conducive to optimal drug delivery. Outcomes: Since our research showed that exosomes play a key role in cognitive function, this work has broader impacts for improving infant formula for optimal brain health. The generated bovine cell line can greatly improve future pharmaceuticals, such as drugs for brain tumors.   University of Nebraska-Lincoln (Jiujiu Yu). Background: Dietary exosome-like nanoparticles (ELNs) have recently been identified in many vegetables and fruits. Emerging evidence indicates that these dietary ELNs have beneficial functions in the consumers. Honey has been used as a medicinal food worldwide for many centuries. However, it remains unknown if honey contains such ELNs. Activities: We have investigated if honey contain such ELNs. After identification of ELNs in honey, we further explored the functions of honey ELNs in cell culture and animal disease model. Outcomes: We found ELNs as a new component in honey. These honey ELNs demonstrated potent anti-inflammatory functions in cell culture, as well as in a chemical-induced acute liver injury mouse model. A microRNA miR4057 in these honey ELNs was identified in inhibiting inflammation. Our studies change how people think of bioactive components in honey and also contribute to scientific understanding of medicinal functions of honey. University of Nebraska-Lincoln (Satish Kumar Natarajan).  Background: Our goals are to determine the bioavailability of nutrients and bioactive components and to determine the efficacy and mechanisms of action of these compounds towards improved health. Activities: In macadamia nuts, we identified high levels of palmitoleate and oleate and observed a protective ability against saturated free fatty acid-induced placental trophoblast lipoapoptosis. Outcomes: We are working on elucidating the protective role of macadamia nut supplementation against maternal obesity-induced placental trophoblast lipoapoptosis. The Ohio State University, Columbus (Richard Bruno). Background: Our team aims to define the extent to which the physiological stress of obesity alters absorption and pharmacokinetics of green tea catechins. We are also defining anti-inflammatory activities of green tea polyphenols at the intestinal level in populations at heightened cardiometabolic risk. Activities: We conducted two human clinical trials to define the pharmacokinetics and gut-level anti-inflammatory activities of green tea polyphenols in persons with obesity and metabolic syndrome. Healthy persons and obese persons were provided a fecal sample for gut microbiome assessments prior to ingesting green tea polyphenols (a mixture of epigallocatechin gallate, epigallocatechin, epicatechin, and epicatechin gallate). We established that the oral bioavailability of green tea polyphenols was reduced among obese persons compared with healthy persons. In a separate randomized controlled trial, persons with metabolic syndrome and healthy persons were provided placebo or green tea extract-enriched confections (equivalent to 5 cups of tea per day) for 1-month. Fecal calprotectin, a biomarker of intestinal inflammation, was lowered in response to the green tea confection. Measures of gut permeability indicated that green tea reduced small intestinal but not colonic permeability. Outcomes: These findings support the conclusion that green tea polyphenols provide anti-inflammatory function at the gut to protect against gut barrier dysfunction. Continued study is underway to link improved gut health to potential improvements in systemic inflammation. University of Maine, Orono (Dorothy Klimis-Zacas). Background: Wounds occur in over 15 million people with approximately $60 billion spent annually on wound care. At the present time, there are no effective treatments to speed up wound healing and improve tissue remodeling. Thus, there is need to develop effective, new cost-effective therapies that enable patients to recover faster and improve their quality of life. Activities: Pre-clinical studies demonstrated the efficacy of non-fidelity biomedical prototypes composed of wild blueberry extract(s) to promote angiogenesis, re-epithelialization, vascularization, collagen formation and attenuate inflammation related to wound healing. We developed two biomedical prototype products from wild blueberry extracts for trans dermal application to release the wild blueberry bioactives and promote wound healing. We also completed pre-clinical studies with animal models, to determine the role of non-fidelity biomedical prototypes on the speed of wound closure, angiogenesis, re-epithelialization, collagen formation and inflammation related to wound healing as well as gene expression of several proteins responsible for inflammation, angiogenesis and tissue regeneration. Outcomes: Phenolic acid extracts at specific concentrations significantly induced faster wound closure by 15% over the control and significantly increased re-epithelialization and vascularization compared to control. Additionally, upregulation of genes associated with vascularization was observed with the wild blueberry extract. Cornell University, Ithaca (Elad Tako). Background: Resveratrol and pterostilbene, polyphenolic compounds found in grapes, are associated with health benefits and are known to chelate iron (Fe) and zinc (Zn), however studies using in vitro and in vivo models are not elucidated. Activities: An in vivo study was conducted, beneficial morphological and microbial changes with concomitant increases in the serum Fe and Zn were detected. Outcomes: In vivo exposure to stilbenes demonstrated a significant bacterial-host interaction that contributed to enhancements in human health (intestinal functionality, morphology and physiological status).  Background: Zinc (Zn) deficiency affects 17% of the world's population. Accurate assessment of Zn status is difficult, hence, sensitive and specific biological markers of Zn physiological status are needed. Activities: Development of the Zn status index (ZSI) concept, which consists of a three-pillar formula: (1) a zinc biomarker (LA:DGLA ratio), (2) mRNA gene expression of Zn-related proteins, and (3) gut microbiome profiling to provide a clear assessment of Zn physiological status and degree of Zn deficiency with respect to assessing dietary Zn manipulation. Outcomes: Development of the ZSI, a statistical model trained on data from these studies, was built to give an accurate estimation of Zn physiological status. Background: The consumption of teff (Eragrostis tef), a gluten-free cereal grain, has increased due to its dense nutrient composition including complex carbohydrates, unsaturated fatty acids, trace minerals (especially Fe), and phytochemicals. Activities: In vivo study was conducted and data demonstrated a significant improvement in intestinal functionality, morphology and microbiome. Outcomes: Teff appeared to represent a promising staple food crop and should be further evaluated. Oklahoma State University, Stillwater (Dingbo Lin). Background: Oxygenized carotenoids, such as zeaxanthin and astaxanthin are fat-soluble pigments rich in colorful diets. The goals of my research is focused on further understanding their metabolism and function in human health and diseases. Activities: We analyzed the absorption and accumulation of astaxanthin and zeaxanthin as bioactive carotenoids in mouse feeding studies and human participants using whole salmon filets. We also tested the health beneficial effect of these carotenoids in fecal metabolome, gut microbiome homeostasis shift, tight junction, and hepatic oxidative stress to elucidate the protective role of these carotenoids in chronic inflammation. Outcome: The results suggested that those xanthophylls are health beneficials in humans through the regulation of the host and gut microbiome interaction.   University of Missouri, Columbia (Ingolf Gruen). Background: 1. How cacao is processed and its origin have a large impact on the flavor of chocolate. 2. Using Greek yogurt in the production of frozen yogurt may impact consumer liking of frozen yogurt. Activities: 1. Roasting conditions for cocoa leading to the lowest concentration of bitter compounds and the degree of liking were determined for cocoa beans sourced from three different locations. 2. Frozen yogurt made with varying amounts of Greek yogurt was compared to that made with regular yogurt. Outcomes: 1. Higher roasting temperatures decreased cocoa bitterness due to the decrease of some bitter chemicals (epicatechin, procyanidin B2), whereas for catechin and cyclo(Proline-Valine), significant increases were observed. Reduction of bitterness, sourness, and astringency were all correlated with increased liking of the chocolates. The chocolate industry can use this information to optimize roasting condition to minimize bitterness and maximize liking of high cocoa containing chocolate. 2. Using Greek instead of regular yogurt in frozen yogurt increases bitterness, alkaline, and iciness, which were negative drivers of liking, but if the amount of Greek yogurt is limited to 10%, then the product is acceptable to consumers. University of Arizona, Tucson (Frank Duca).  Background: Dietary fiber is known to improve metabolic health, however it is unknown whether certain plant-based fibers are more effective than others. Activities: We performed extensive long-term dietary studies, with mice maintained on a high-fat diet that was supplemented with different plant-based dietary fibers: beta-glucan, oligofructose, pectin, wheat dextrin, cellulose, and resistant starch. Outcomes: We found that wheat dextrin and oligofructose supplementation resulted in reduced body weight gain and adiposity, and improved glucose tolerance and insulin sensitivity. University of Arizona, Tucson (Jennifer Teske). Background: We focus on the impact of insufficient sleep on chronic disease and health outcomes including how sleep affects bioavailability. We investigate how sleep curtailment due to environmental noise exposure worsens metabolic health and how consumption of Western diets exacerbates disease risk during sleep disruption in rodent models. We are also interested in addressing sex differences since women are more sensitive to noise, have worse sleep and a higher prevalence of obesity compared to men. Activities: Analyses were conducted to determine the influence of sleep, diet and sex on micronutrient intake and the role of sex hormones on weight gain in male and females rats. Outcomes: We provided virtual and hands-on training and determined proficiency for students at all levels (high school, undergraduate and graduate), provided training on anthropometrics, energy expenditure, energy intake and estrous cycle determination and scientific writing and presentation skills training for both oral and poster presentations for students. University of Connecticut, Storrs (Christopher Blesso). Background: Diets rich in saturated fat contribute to elevated blood cholesterol and a detrimental shifting of gut bacterial populations, both of which are implicated in the development of chronic diseases. Milk fat is relatively enriched in saturated fat compared with other fats, however, it is naturally encased in a polar lipid membrane. My team has shown in animal studies that cow's milk polar lipids (MPLs) may impart health benefits by lowering blood cholesterol and altering gut bacteria. However, little research has been conducted in humans to show these effects. The major objective of this project is to examine whether the daily consumption of milk fat with and without additional MPLs influences blood cholesterol and gut microbiota in humans. Activities: We completed a human nutrition intervention pilot study that compared MPLs-rich powder to a nutritionally matched milk fat-containing control powder in a randomized, single-blinded crossover study. Outcomes: We learned that the addition of MPLs in the diet can increase the levels of lipid metabolites with potentially bioactive properties in the stool and blood circulation of healthy adults. Furthermore, consuming additional milk polar lipids on top of milk fat can alleviate potential effects on obesity, particularly abdominal obesity. This may lead to value-added usage of inexpensive dairy co-products rich in milk polar lipids, which would normally be discarded and underutilized. Knowledge gained from this study will also be important moving forward to study the health effects of milk lipids in human populations at greater risk for heart disease, such as those with central/abdominal obesity and high blood lipids levels. This may lead to recommendations to choose dairy products with higher content of milk polar lipids to obtain health benefits we observed. University of Connecticut, Storrs (Ji-Young Lee). Background: Alcoholic hepatitis (AH) is the progressive form of alcoholic liver disease. Activities: As macrophages play a crucial role in the development of AH, we determined the effect of astaxanthin, an oxygenated carotenoid, and nicotinamide riboside (NR), a NAD+ precursor, on alcohol-induced inflammation and oxidative stress in macrophages. Outcomes: We found that astaxanthin and NR inhibit inflammation and oxidative stress in macrophages exposed to alcohol via the modulation of sirtruin 1 and histone deacetylase 4.  Kansas State University, Manhattan (Brian Lindshield). I successfully recruited and onboarded a new graduate research assistant, to conduct research toward the project goals. We have made progress on systematic literature review and on the preliminary steps towards an animal study we plan to conduct, likely in the summer of 2022. Oregon State University, Corvallis (Emily Ho). Background: Diet plays an important role in mitigating the development and progression of several cancers, as well as immune dysfunction. This research demonstrates that nutritional strategies that decrease inflammation and/or target aberrant epigenetic alterations have the potential to dramatically reduce the incidence of cancer. Secondly, age-related decline in nutritional status may be a critical determinant of healthy aging and susceptibility to infection or other environmental insults.  Activities: We investigated the impact of broccoli sprout supplementation on the microbiome and metabolome in healthy human subjects.  We also employed cell culture models and rodent models to understand the impact of zinc status on age related inflammation and the gut microbiome. Outcomes:  We identified new risk factors in cancer and offer novel dietary modifications to reduce the incidence of cancer; Gained knowledge of the mechanisms behind the health benefits of micronutrients and phytochemicals such as zinc and compounds derived from cruciferous vegetables; Identified that gut bacteria could be a critical driving factor in differential responses to cruciferous vegetables, Established low dietary zinc as risk factor for inflammatory processes, DNA damage and cancer risk and helped identify new biomarkers for human zinc deficiency and cruciferous vegetable intake;  Established function of zinc and changes in zinc metabolism with immune function and aging. Oregon State University, Corvallis (David Dallas). Background: Our lab examines the digestion of milk protein and release of bioactive peptides in infants and adults. Activities: We examined the survival of milk and recombinant antibodies across the digestive tract of infants. We also assessed differences in survival of peptides in the stomach of preterm and term infants and examined the peptides released in various cheeses. We also examined the effects of various donor milk microbial reduction techniques on the survival of a key breast milk lipase that helps infants digest breast milk fat. We also developed a novel technique to identify glycoproteins and glycopeptides in milk via mass spectrometry. We also developed a mass spectrometry technique to measure glycomacropeptides from bovine milk kappa-casein and their survival across digestion. Outcomes: We demonstrated that recombinant antibodies do not survive intact within the term and preterm infant digestive tract, but that to some extent, milk antibodies do. This demonstrates that the structure of milk antibodies makes them uniquely resistant to digestion, which allows them to exert their protective functions within the gut. We found that the peptide profile in the preterm infant gut differs from that of that term infant gut and that many of these differences are key bioactive peptides. We also demonstrated that thousands of different peptides are present in cheeses, that this varies by cheese variety and rind vs. interior, and that many of these peptides are bioactive, with antimicrobial, ACE-inhibitory and immunomodulatory actions. We demonstrated that high pressure processing and UV-C processing better preserved breast milk lipase compared with holder pasteurization. We developed a high-throughput method for identification of hundreds of unique glycopeptides in human milk. We demonstrated that glycomacropeptide does not survive digestion in the adult jejunum, but a large number of fragment forms are created, many of which have potential bioactivity in the gut. Oregon State University, Corvallis (Urszula Iwaniec). Background: Advanced age is the strongest risk factor for osteoporosis. The immunomodulator rapamycin (Sirolimus), a macrolide compound, extends lifespan in numerous experimental model organisms and is being investigated as a potential therapeutic to slow human aging. However, little is known about the effects of rapamycin on bone. Activities: We evaluated the impact of rapamycin treatment on bone mass, architecture, and indices of bone turnover in healthy adult (16-20 weeks old at treatment initiation) female wild-type (ICR) and Nrf2-/- mice, a mouse model for oxidative damage and aging-related disease vulnerability. Rapamycin (4 mg/kg body weight) was administered by intraperitoneal injection every other day for 12 weeks. Outcomes: Mice treated with rapamycin exhibited lower femur bone mineral content, bone mineral density, and bone volume compared to vehicle-treated mice. Rapamycin also had negative effects on cortical and cancellous bone microarchitecture. Mechanistically, rapamycin-treated mice had lower levels of bone formation in the distal femur metaphysis compared to vehicle-treated mice which occurred co-incidentally with increased serum CTX-1, a marker of global bone resorption. University of California, Davis (Peng Ji). Background: Early-life nutrition is crucial for growth, development, and host resilience to infectious diseases. My current research is focusing on understanding health benefits and risks of micronutrient deficiency and excess and dietary bioactives. Activities: In the current review period, my lab customized 24 sets of individual housing and automatic milk feeding systems for caring neonatal piglets which can simulate formula-fed human infants. We used systems biology approach to evaluate the role of dietary prebiotics and synbiotics in iron absorption and utilization, systemic metabolism (e.g. untargeted metabolomics) and in modulation of gut microbiome in the milk-fed neonatal piglet model. This translational research aimed to explore the dietary supplements that could mitigate potential adverse effects of iron excess in non-anemic infants fed an iron-fortified formula. In addition, our research on iron has expanded to cell biology by investigating how iron status affects immunometabolism in macrophage cells in vitro. Outcomes: Iron supplementation and fortification is commonly practiced in most developed countries. The general public are increasingly concerned over the risk of dietary iron overexposure in iron-replete infants. Results from the current work could improve our understanding about developmental consequence of dietary iron excess and the effectiveness of dietary interventions.        University of California, Davis (Yanhong Liu). Background: Emerging evidence suggests that non-nutrients provide benefits on animal health and production through different modes of action: regulating nutrient digestibility or absorption, and modulating microbial ecology in the digestive tract and/or immune responses. Activities: We have conducted several pig trials to evaluate the effects of probiotics (Bacillus subtilis or Bacillus spp.) or combination of phytochemicals on disease resistance and immunity of weaned pigs that were experimentally infected with a pathogenic E. coli. Outcomes: We observed benefits of supplementing several specific probiotics or a mixture of phytochemicals in animal feed on weaned pig health and performance. We completed a grant that was obtained from National Pork Board to support more research on probiotics in pigs. In one year of W4002 support, 6 graduate students and several undergraduate students were mentored and supervised. The use of antibiotics in livestock animals and poultry is extremely important to control and treat infectious diseases, but also increase the public's concerns in the spread of antimicrobial resistance and antibiotic residue. Our findings in nutrition interventions on promoting animal health and performance are important to reduce the use of antibiotics in livestock animals and mitigate antimicrobial resistance.   University of California, Davis (Allison Ehrlich). Background: Understanding the mechanism of how specific nutritional components promote or disrupt intestinal health can impact dietary recommendations towards improving health. We hypothesized that the immunoregulatory phytochemical, indole-3-carbinol (I3C), which is found in cruciferous vegetables, will act similarly to non-dietary, high affinity, aryl hydrocarbon receptor (AhR) ligands and promote immune regulation. Activities: In non-obese diabetic (NOD) genetic strain of mice, we found that an I3C-supplemented diet led to strong AhR activation in the small intestine but minimal systemic AhR activity. Dietary I3C increased a type of proinflammatory cell called Th17 cells in the small intestine. Additionally, changes in gut microbiome was observed within one week of I3C supplementation. Outcomes: Unlike other mice, NOD mice express the lower affinity AhRd allele. This genetic difference may represent an additional factor controlling AhR-mediated immune modulation. Humans express AhR with similar ligand sensitivity to the mouse AhRd allele, thus the NOD model may be more appropriate for predicting immune modulation in humans. Collectively, these data provide insight for how AhR activation from dietary components can improve human gut health. University of Hawaii at Manoa (Jinzeng Yang). Background: Peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor, serves as a crucial regulator of fat formation and storage (adipogenesis, lipogenesis, lipid storage) and whole-body insulin sensitivity. These are mechanisms that can affect the quality of animal meat and can provide insight into human health. Activities: We generated skeletal muscle-specific PPARγ over-expression transgenic pigs. In this pig model, we studied the effects of PPARγ on muscle fiber type switching and fat deposition in skeletal muscle. Outcomes: Intramuscular fat (a quality parameter of pork) was significantly increased in PPARγ pigs with no changes in lean meat ratio. Proteomics analyses demonstrated that oxidative metabolism of fatty acids and respiratory chain were activated in PPARγ pigs, thus, gathering more Ca2+ in PPARγ pigs. These results support that skeletal muscle-specific over-expression of PPARγ can promote oxidative fiber formation and intramuscular fat deposition. Overall, this knowledge can be used to improve meat quality without increasing fat content. This generated knowledge regarding fat and muscle metabolism also provides insight into human health related to obesity and metabolic diseases such as diabetes.                                                                                                   We also tested a new type of papaya, with seeds that were frozen for a long period of time and treated with “bioactive” chemicals. Based on the supplier of the seeds (confidential), the (non-GMO) papaya seeds can be only used for one generation. We planted the seeds in March 2020 and collected papaya yield and quality data. The size of papaya and yield per plant were impressive. (3-8 pounds per papaya, with about 14 papaya per plant). Further data collection and nutrition analysis will be conducted on the papaya fruits. University of Hawaii at Manoa (Kacie Ho). Background: Tropical commodities are rich in bioactive compounds, however content and bioaccessibility (how available a component is for absorption after digestion) are limited by factors such as growing conditions, varietal differences, and processing. Activities: Nutrients and phytochemicals (carotenoids and polyphenols) were identified in unique taro varieties. Bioaccessibility of carotenoids was also assessed. Additionally, mineral content was measured from edible seaweeds (cultivated and wild collected). Outcomes: Carotenoid content varied across taro variety. One taro variety exhibited high beta-carotene content and was a bioaccessible source of carotenoids. Seaweed samples were rich in essential minerals, but some were high in inorganic arsenic. Purdue University, West-Lafayette (Lavanya Reddivari). Background: Research suggests that whole food containing anthocyanins is effective against colitis compared to isolated anthocyanins because of low stability and colonic bioavailability. In whole foods, anthocyanins exist in complexation with cell wall materials such as pectin and cellulose. Moreover, dietary fibers can modulate gut microbiota composition, metabolism, inflammation and barrier function to reduce colitis. Activities: We optimized the complexation protocols for anthocyanins and dietary fibers and showed that the complexation improves the stability of anthocyanins against high pH and temperature and thereby increases the colonic availability of anthocyanins. Outcomes: The complexes were stable against in vitro gastrointestinal digestion compared to isolated anthocyanins. University of Rhode Island, Kingston (Brietta Oaks). Background: Lead exposure is a major public health concern in Rhode Island. There is evidence that omega-3 fatty acid intake may reduce circulating lead concentrations, but research has been limited and has not been explored in pregnant women, whom are at a higher risk for adverse effects of lead exposure. In addition, omega-3 fatty acid intake may reduce circulating cortisol, a stress hormone which has negative effects during pregnancy if at chronically high concentrations. Activities: A new PhD student joined the project this year and is leading recruitment, data collection, and analysis. The PhD student is interested in vitamin D and has added a vitamin D component to the project. He drafted the new study protocol to add this additional blood tube collection and received IRB approval. We are now in the stage of identifying clinics that will allow us to recruit women for the study. Outcomes: A literature review was completed which supported the addition of vitamin D to this project.

Publications

<ol> <li>Arballo J, Amengual J, Erdman JW. Lycopene: A Critical Review of Digestion, Absorption, Metabolism, and Excretion. Antioxidants (Basel). 2021 Feb;10(3):342. </li> </ol> <ol start="2"> <li>Amengual J, Ogando Y, Nikain C, Quezada A, Qian, Vaisar T, Fisher EA. Short Term Acyl-CoA:Cholesterol Acyltransferase Inhibition, Combined with Apoprotein A1 Over-expression, Promotes Atherosclerosis Inflammation Resolution Mice. Mol Pharmacol. 2021 Mar;99(3):175-183. </li> </ol> <ol start="3"> <li>Miller AP, Black M, Amengual J. Fenretinide inhibits vitamin A formation from β-carotene and regulates carotenoid levels in mice. Biochim Biophys Acta Mol Cell Biol Lipids. 2021. Nov 4;1867(2):159070 </li> </ol> <ol start="4"> <li>Akkam Y, Rababah T, Costa R, Almajwal A, Feng H, Andrade Laborde JE, Abulmeaty MM, Razak S. Pea Protein Nanoemulsion Effectively Stabilizes Vitamin D in Food Products: A Potential Supplementation during the COVID-19 Pandemic. Nanomaterials. 11(4):887. (2021) </li> </ol> <ol start="5"> <li>Andrade JE, Atahar Ali ANM, Chowdhury R, Crost B, Hoffmann V, Mustafa S, Shaima NF. Rice fortification in Bangladesh: Technical feasibility and regulatory requirement for introducing rice fortification in public modern storage/distribution of fortified rice through PFDS channels. IFPRI Working Paper. (2021) <a href="https://doi.org/10.2499/p15738coll2.134540%0b">https://doi.org/10.2499/p15738coll2.134540 </a></li> <li>Dominguez-Uzcanga, A, Aycart, DF, Li, K, Witola, WH, Andrade Laborde, JE.  Anti-protozoal activity of Thymol and a Thymol ester against Cryptosporidium parvum in cell culture International Journal for Parasitology: Drugs and Drug Resistance. 15:126-133. (2021)</li> <li>Mutai E, Ramer-Tait AE, Zempleni J. MicroRNAs in bovine milk exosomes are bioavailable in humans but do not elicit a robust pro-inflammatory cytokine response. BMC exRNA 2:2, 2020 </li> <li>Liu, B, Lu Y, Chen X, Muthuraj, PG, Li X, Pattabiraman M, Zempleni J, Kachman SD, Natarajan SK, Yu J. Protective role of shiitake mushroom-derived exosome-like nanoparticles in D-galactosamine and lipopolysaccharide-induced liver injury in mice. Nutrients 12:477, 2020 </li> <li>Sadri M, Shu J, Kachman SD, Cui J, Zempleni J. Milk exosomes and microRNAs cross the placenta and promote embryo survival in mice. Reproduction 160:501-509, 2020 </li> <li>Zempleni J. Letter to the editor (regarding Perspective: The role of human breast-milk extracellular vesicles in child health and disease by D. O’Reilly et al., published in AN on 24 August 2020). Adv Nutr 12:280, 2021 </li> </ol> <ol start="11"> <li>Sukreet S, Pereira Braga C, An TT, Adamec J, Cui J, Trible B, Zempleni J. Isolation of extracellular vesicles from byproducts of cheese making by tangential flow filtration yields heterogeneous fractions of nanoparticles. J Dairy Sci 104:9478-9493, 2021 </li> <li>Khanam A. Yu J, Zempleni J. Class A scavenger receptor-1/2 facilitates the uptake of bovine milk exosomes in murine bone marrow-derived macrophages and C57BL/6J mice. Am J Physiol Cell Physiol 321:C606-C614, 2021 </li> <li>Ogunnaike M, Wang, H, Zempleni J. Bovine mammary alveolar MAC-T cells afford a tool for studies of bovine milk exosomes in drug delivery. Int J Pharm 610:121263, 2021</li> <li>Ong SL, Blenkiron C, Haines S, Acevedo-Fani A, Leite JAS, Zempleni J, Anderson RA, McCann MJ. Ruminant milk-derived extracellular vesicles: a nutritional and therapeutic opportunity? Nutrients 13:2505, 2021 </li> <li>Goodus MT, Carson KE, Sauerbeck AD, Dey P, Alfredo AN, Popovich PG, Bruno RS, McTigue DM. Liver inflammation at the time of spinal cord injury enhances intraspinal pathology, liver injury, metabolic syndrome and locomotor deficits. Exp Neurol. 2021;342:113725. </li> <li>Chen L, Zhang S, Sun X, McDonald JD, Bruno RS, Zhu J. Application of comparative lipidomics to elucidate postprandial metabolic excursions following dairy milk ingestion in individuals with prediabetes. J Proteome Res. 2021;20:2583-95. </li> <li>Bruno RS, Pokala A, Torres-Gonzalez M, Blesso CN. Cardiometabolic Health Benefits of Dairy-Milk Polar Lipids. Nutrition Reviews. 2021 Dec 8;79(Suppl 2):16-35. doi: 10.1093/nutrit/nuab085. Review. PubMed PMID: 34879146; PubMed Central PMCID: PMC8653938. </li> <li>Bruno RS, Neilson AP, Lambert JD, Moustaid-Moussa N. Journal of nutritional biochemistry special issue: Polyphenols, obesity, and cardiometabolic health. J Nutr Biochem. 2021;89:108565. </li> <li>Traber MG, Bruno RS. Chapter 7 - vitamin e. In: Present knowledge in nutrition, 11th edition (Marriott BP, Birt DF, Stallings VA, Yates AA, editor). Academic Press; 2020. </li> <li>Quarles WR, Pokala A, Shaw EL, et al. Alleviation of metabolic endotoxemia by milk fat globule membrane: Rationale, design, and methods of a double-blind, randomized, controlled, crossover dietary intervention in adults with metabolic syndrome. Curr Dev Nutr. 2020;4:nzaa130. </li> <li>Kuchan MJ, Ranard KM, Dey P, et al. Infant rhesus macaque brain α-tocopherol stereoisomer profile is differentially impacted by the source of α-tocopherol in infant formula. J Nutr. 2020;150:2305-13. </li> </ol> <ol start="22"> <li>Kemski MM, Rappleye CA, Dabrowski K, Bruno RS, Wick M. Transcriptomic response to soybean meal-based diets as the first formulated feed in juvenile yellow perch (perca flavescens). Sci Rep. 2020;10:3998. </li> <li>Hodges JK, Zhu J, Yu Z, et al. Intestinal-level anti-inflammatory bioactivities of catechin-rich green tea: Rationale, design, and methods of a double-blind, randomized, placebo-controlled crossover trial in metabolic syndrome and healthy adults. Contemp Clin Trials Commun. 2020;17:100495. </li> <li>Hodges JK, Sasaki GY, Bruno RS. Anti-inflammatory activities of green tea catechins along the gut–liver axis in nonalcoholic fatty liver disease: Lessons learned from preclinical and human studies. J Nutr Biochem. 2020;85:108478. </li> <li>Dey P, Olmstead BD, Sasaki GY, Vodovotz Y, Yu Z, Bruno RS. Epigallocatechin gallate but not catechin prevents nonalcoholic steatohepatitis in mice similar to green tea extract while differentially affecting the gut microbiota. J Nutr Biochem. 2020;84:108455. </li> <li>Chatelaine H, Dey P, Mo X, Mah E, Bruno RS, Kopec RE. Vitamin a and d absorption in adults with metabolic syndrome versus healthy controls - a pilot study utilizing targeted and untargeted lc-ms lipidomics. Mol Nutr Food Res. 2020:e2000413. </li> <li>Alba BK, Stanhewicz AE, Dey P, Bruno RS, Kenney WL, Alexander LM. Controlled feeding of an 8-d, high-dairy cheese diet prevents sodium-induced endothelial dysfunction in the cutaneous microcirculation of healthy, older adults through reductions in superoxide. J Nutr. 2020;150:55-63. </li> <li>Kalea A, Klimis-Zacas D. Nutrition precision and nature: the focus on the individual, not the average individual. Curr Opin in Clin Nutri and Metabol Care, 2021; 24(4), 1363-1950 </li> <li>VandenAkker, N, Tsakiroglou, P, Vendrame S, Klimis-Zacas D. Red raspberry (Rubus idaeus) consumption restores the impaired Phenylephrine-induced vasoconstriction and Acetylcholine-induced vasorelaxation in the aorta of the obese Zucker rat, a model of the Metabolic Syndrome. J. Berry Res. 2021; 11 89–101 <a href="https://doi.org/10.3233/JBR-200567">https://doi.org/10.3233/JBR-200567</a> </li> <li>Martino H, Kolba N, and Tako E. Yacon (Smallanthus sonchifolius) flour soluble extract</li> <li>improve intestinal bacterial populations, membrane functionality and morphology in Vivo (Gallus gallus). Food Research International. Volume 137, November 2020, 109705. </li> <li>Carboni J, Reed S, Kolba N, Eshel A, Koren O, and Tako E. Alterations in the Intestinal Morphology, Gut Microbiota, and Trace Mineral Status Following Intra-Amniotic Administration (Gallus gallus) of Teff (Eragrostis tef) Seed Extracts. Nutrients. 2020 Oct 2;12(10):3020. doi: 10.3390/nu12103020. </li> </ol> <ol start="33"> <li>Tako E. Dietary Plant-Origin Bio-Active Compounds, Intestinal Functionality, and Microbiome.Nutrients. 2020 Oct 22;12(11):E3223. <a href="https://doi.org/10.3390/nu12113223">https://doi.org/10.3390/nu12113223</a>. </li> </ol> <ol start="34"> <li>Garcia-Rodriguez A, Moreno-Olivas F, Marcos R, Tako E, Marques CNH, Mahler GJ. The Role of Metal Oxide Nanoparticles, Escherichia coli, and Lactobacillus rhamnosus on Small Intestinal Enzyme Activity. Environmental Science: Nano, 2020, 7, 3940-3964. <a href="https://doi.org/10.1039/D0EN01001D">https://doi.org/10.1039/D0EN01001D</a>.  </li> <li>Broad RC, Bonneau JP, Beasley JT, Roden S, Sadowski P, Berger B, Tako E, Hellens RP, Johnson AAT. Effect of OsGGP Constitutive Overexpression in Rice on Ascorbate Biosynthesis, Stress Tolerance, and Iron Bioavailability. Front Plant Sci. 2020 Dec 3;11:595439. <a href="https://doi.or/10.3389/fpls.2020.595439">https://doi.or/10.3389/fpls.2020.595439</a>. eCollection 2020 </li> <li>Juste Contin Gomes M, Stampini Duarte Martino H, Tako E. Effects of Iron and Zinc </li> <li>Biofortified Foods on Gut Microbiota In Vivo (Gallus gallus): A Systematic Review. Nutrients. 2021 Jan 9;13(1):189. <a href="https://doi.org/10.3390/nu13010189">https://doi.org/10.3390/nu13010189</a>. </li> <li>Pereira da Silva B, Stampini Duarte Martino H, Tako E. Plant origin prebiotics affect duodenal brush border membrane functionality and morphology, in vivo (Gallus gallus). Food and Function. 2021.<a href="https://doi.org/10.1039/D1FO01159F"> https://doi.org/10.1039/D1FO01159F</a> </li> </ol> <ol start="39"> <li>Agrizzi Verediano T, Stampini Duarte Martino H, Cristina Dias Paes M, Tako E. Effects of Anthocyanin on Intestinal Health: A Systematic Review. Nutrients. 2021 Apr 17;13(4):1331. <a href="http://doi.org/10.3390/nu13041331">https://doi.org/10.3390/nu13041331</a>. </li> <li>Martinez O, Jaqueline T, Mariana G, Celi R, Frederico B, Tako E, Queiroz V, Martino H. Dry heated sorghum BRS 305 hybrid flour as a source of resistant starch and tannins improves inflammation and oxidative stress in Wistar rats fed with a high-fat high-fructose diet. Food and Function, 2021, <a href="https://doi.org/10.1039/D1FO00802A">https://doi.org/10.1039/D1FO00802A</a>. </li> </ol> <ol start="41"> <li>Juste Contin Gomes M, Kolba N, Kim D, Eshel A, Koren O, Tako E. Modifications in the Intestinal Functionality, Morphology and Microbiome Following Intra-Amniotic Administration (Gallus gallus) of Grape (Vitis vinifera) Stilbenes (Resveratrol and Pterostilbene). Nutrients. Nutrients 2021, 13(9), 3247; <a href="https://doi.org/10.3390/nu13093247">https://doi.org/10.3390/nu13093247</a>. </li> </ol> <ol start="42"> <li>Cheng J, Bar H, Tako E. Zinc Status Index (ZSI) for Quantification of Zinc Physiological Status. 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Impact Statements

University of Rhode Island, Kingston (Brietta Oaks). This data will be used as preliminary data on the current nutritional status of pregnant women in Rhode Island as we prepare for data collection of our main study, which aims to help inform nutritional programs and practice for pregnant women at risk of lead exposure. Our objective is to determine micronutrients that pregnant women can use to reduce circulating lead concentrations.

Date of Annual Report: 07/17/2023

Report Information

Annual Meeting Dates: 05/25/2023 - 05/26/2023
Period the Report Covers: 10/01/2021 - 09/30/2022

Participants

Jaume Amengual;
Richard Bruno;
Frank Duca;
Allison Ehrlich;
David Gang (Advisor);
Michael Giroux;
Emily Ho; Kacie Ho (Chair);
Urszula Iwaniec;
Peng Ji;
Lydia Kaume (NIFA National Program Leader);
Qing Li (invited guest);
Dingbo Lin;
Brian Lindshield;
Yanghong Liu;
Sathish Natarajan;
Lavanya Reddivari;
Pavel Somavat;
Jennifer Teske;
Jinzeng Yang;
Janos Zempleni;

Brief Summary of Minutes

Annual Meeting was held in person at University of Hawaiʻi at Mānoa (Honolulu, HI) and offered online participation via zoom.

0900 – 0915 (day 1): Welcomes and Introduction (Kacie Ho and Walter Bowen)

0915 – 0945: David Gang (administrative advisor) briefly talked about the history of multistate program and the importance of interstate collaboration. He updated the project renewal regarding reviewers’ comments and addressed the new report template that should highlight the impacts of research.

0945 – 1015: Station report session 1 (research highlights presented by investigator, 10 min talk + 5 min discussion)

Mike Giroux, Montana State University - Engineering Crops for Increased Nutrition and Quality

Janos Zempleni, University of Nebraska-Lincoln - Milk Exosomes in Nutrition and Drug Delivery

1030 – 1200: Station report session 2

Kacie Ho, University of Hawaiʻi at Mānoa - Leveraging Nutrients and Phytochemicals from Hawaii Commodities and Food Matrices

Jinzeng Yang, University of Hawaiʻi at Mānoa - Nutrition Studies for Hawaii Specialty Crops and Foods

Qing Li, University of Hawaiʻi at Mānoa - Medicine and Food Homology: Action Targets of Phytonutrients against Alzheimer’s and Obesity

Sathish Kumar Natarajan, University of Nebraska-Lincoln - Bioactive Nutrient Interventions to Mitigate Placental Damage During Maternal Obesity

Jennifer Teske, University of Arizona - Sleep and Obesity: Sex Differences

Frank Duca, University of Arizona - Role of Prebiotics in Metabolic Homeostasis

1330 – 1500: Field trip to Lyon Arboretum

1530 – 1630: Station report session 3

Peng Ji, University of California Davis - Role of Iron in Modulating Gut Microbiota and Immunometabolism”

Yanhong Liu, University of California Davis - Organic Acid Derivatives on Gut Health of Young Pigs

Urszula Iwaniec, Oregon State University - Diet Composition Influences the Effect of High Fat Diets on one in Growing Male Mice

Daniel (Dingbo) Lin, Oklahoma State University - Carotenoid Metabolism and Gut Microbiome in Health and Diseases

1645 – 1730: Station report session 4

Brian Lindshield, Kansas State University - Iron

Lavanya Reddivari, Purdue University - Physicochemical Properties of Dietary Fibers in Fiber Intolerance

0900 – 0930 (day 2): Lydia Kaume joined meeting online and gave an update on NIFA National Programs and leaders.

0930 – 1015: Station report session 5

Jaume Amengual Terrasa, University of Illinois at Urbana – role of dietary β-carotene in cardiovascular health

Pavel Somavat, University of Missouri - Colored Corn Phytochemicals for Novel Applications

Rich Bruno, The Ohio State University - Gut-level cardiometabolic benefits of green tea polyphenols in metabolic syndrome

1030 – 1430: Business meeting session

Administrative and executive: David Gang (Advisor), Kacie Ho (Chair), Peng Ji (Secretary)

Election: Peng Ji was elected as incoming chair and Lavanya Reddivari was elected as incoming secretary.

Project renew: David and Kacie shared details of reviewers’ comments and the group discussed and revised accordingly during business meeting. The proposal had been submitted after the annual meeting.

Collaboration: The group also discussed mechanisms to enhance interstate collaborations.

Future annual meeting: next annual meeting will be hosted at University of California Davis (CA) with a tentative date in May 2024.

1430: Adjourn

Accomplishments

Montana State University (Mike Giroux). (Background) Our goal is to create and test increased amylose pasta, prepared from high and normal amylose durum wheat and/or chickpea flour. We have created increased amylose durum by selecting for mutations in individual seed starch synthesis genes.  We will be preparing pasta made from chickpeas blended with normal and high amylose durum semolina.  The pastas nutritional content will be measured and we will then measure the degree to which the increased nutrition pastas can improve human health. (Activities) Creation of high and intermediate amylose durum by identifying unique starch synthase alleles. Field testing of durum isolines varying in amylose content.  Milling and pasta preparation from durum varying in amylose content.  Begin screening chickpea varieties for amylose content and plan experimental approach. (Outcomes) Developed low and high amylose durum that can be used as a breeding parent to select for increased amylose in durum.  University of Nebraska-Lincoln (Janos Zempleni). (Background) Most cells produce and secrete exosomes (nanoparticles) loaded with cargo such as various species of RNAs, proteins and lipids. Exosomes play essential roles in cell-to-cell communication through regulating gene expression and metabolism of receptor cells. We have made the paradigm-shifting discovery that exosomes do not exclusively originate in endogenous synthesis but may also be obtained from dietary sources such as human and bovine milk. (Activities and outcomes) 1) We demonstrated that milk exosomes select genomic variants in bacteria including pathogens and alter bacterial purine metabolism and the pathogenicity in the murine gut. 2) We demonstrated that the oral bioavailability of cow’s milk exosomes is 50% in mice. 3) We genetically engineered milk exosomes for optimal delivery of therapeutics to diseased tissues. Our protocol used milk exosomes as a vehicle and successfully delivered protein-coding plasmids to the brain when exosomes are administered through nasal spray. 4) We have developed a proprietary technology to make “universal” milk exosomes, which deliver therapeutics to any tissue of choice. University of Nebraska-Lincoln (Sathish Kumar Natarajan). (Background) Omega-3 and Omega-6 fatty acids are important for neonatal development and health. Dietary derived Omega-3 and Omega-6 fatty acids exert their effects through their metabolites including oxylipins and specialized pro-resolving mediators. (Activities and outcomes) We have demonstrated that diverse panel of oxylipins from the lipoxygenase pathway in the human placenta present at the time of delivery. Omega-3 and omega-6 derived oxylipins levels influenced fetal birth length and weight percentiles. We have also showed Shilajit supplementation (natural tar-like substance found in the mountains ranges of Himalaya) increased gene expression of collagen synthesis in recreationally trained men in our study. University of Hawaii (Kacie Ho). (Background) Various foods contain both beneficial nutrients and bioactive compounds but may also contain potentially toxic contaminants as well. Our lab investigates both the beneficial and potentially hazardous compounds in food. Additionally, we study encapsulation techniques (e.g. nanoparticles and emulsions) and how these food structures can help to improve nutrient retention, stability, and bioavailability. (Activities) Over the past year, we measured beneficial mineral nutrients and heavy metal toxicants in various edible seaweeds. Additionally, we characterized different nanoparticle/emulsion structures to determine physical and chemical stability. (Outcomes) We found that many seaweeds in Hawaii contain beneficial nutrients, such as Zinc and Magnesium in high quantities. However, we observed that some species were also very high in heavy metals, including Arsenic. These findings indicate the need for heavy metal monitoring for edible seaweeds. Additionally, the question of bioaccessibility and bioavailability from these non-terrestrial edible plants will be addressed in future research. University of Hawaii (Jinzeng Yang). (Background) Obesity and diabetes are becoming a national health problem worldwide. Skeletal muscles provide the physiological foundation of physical activity and fitness. Active skeletal muscle effectively regulates metabolic activities and energy balance. Preservation of muscle mass in obesity, insulin resistance/type II diabetes is important for effective treatment and prevention of these diseases. Studies from laboratory animal models and complementary medical practices have implied that nutrients from special plants or herbs contain antidiabetic, antioxidant, anti-obese, anti-hypertensive, and anti-inflammatory properties. Seaweed and tropical papaya, which are widely available in Asian and Pacific countries, have been used as home remedies for centuries. There is evidence that C. papaya leaves reduce symptoms of asthma, worming and dysentery.  (Activities) Myostatin propeptide-transgenic mice (MLC-pro) have been maintained by Dr. Yang’s laboratory and used for studying effects of enhanced muscle on diabetes prevention and blood glucose control in prediabetic mice. 40 Animals of both wild-type control and transgenic mice at about 4 months of age were used for high-fat feeding for inducing prediabetic condition, then used for studying the effects of papaya leaf extract on blood glucose control and lipid profiles. (Outcomes) Our study in transgenic mice indicates that depression of myostatin function by its propeptide produces dramatic muscle mass at the growth stage and less fat at older ages. There are effects of the restricted diet alone on weight loss and blood glucose level in diet-induced prediabetic mice. Papaya leaf juice and restricted diet-treated group showed significant improvements in blood glucose level, total cholesterol, LDL-c, and triglyceride levels. University of Arizona (Frank Duca). (Background) The impact of the diet and intestinal microbiome is vastly understudied in regard to bacterially-derived metabolites that can impact host health. We aim to study the role of both the small and distal intestine microbiota on generating metabolites that can impact energy and glucose homeostasis. (Activities) In healthy chow-fed-, high-fat diet-induced obese-, and high-fat supplemented with oligofructose- rats, we examined the production of short-chain fatty acids (SCFAs) as well as small intestinal metabolites, like bile acids. (Outcomes) We discovered that obesity is associated with decreased postprandial production of SCFAs that is partially rescued with oligofructose treatment. Furthermore, postprandially, obese rats exhibit reduced portal vein levels of butyrate, implicating a potential role of hepatic butyrate signaling in metabolic homeostasis. Additionally, we found that high-fat feeding results in a drastic change in the small intestinal metabolome, especially in bile acids. Supplementation with oligofructose shifts the bile acid profile back towards healthy chow-fed rats. University of Arizona (Jennifer Teske). (Background) The laboratory focuses on the impact of insufficient sleep on chronic disease and health outcomes, which includes the metabolism of nutrients. We investigate how sleep curtailment due to environmental noise exposure worsens metabolic health and how consumption of Western diets exacerbates disease risk during sleep disruption in rodent models as well as addressing sex differences since women are more sensitive to noise, have worse sleep and a higher prevalence of obesity compared to men. (Activities) Collaborative research grants were submitted that included Dr. Sands from Montana State University. Analysis was conducted to determine the influence of sleep, diet and sex on micronutrient intake and the role of sex hormones on weight gain in male and females rats. (Outcomes) Awarded grants from the National Science Foundation to fund undergraduate research. We provided virtual and hands-on training and determined proficiency for students at all levels (high school, undergraduate and graduate), provided training on anthropometrics, energy expenditure, energy intake and estrous cycle determination and scientific writing and presentation skills training for both oral and poster presentations for students. University of California Davis (Yanhong Liu). (Background) Emerging evidence suggested that functional amino acids, organic acid derivatives, and a group of non-nutrient bioactives, such as phytochemicals, and pre-and pro-biotics, may provide benefits to animal health and production through different modes of action: regulating nutrient digestibility and absorption, or modulating microbial ecology in the digestive tract and/or immune responses. (Activities) We conducted pig trials to evaluate the effects of probiotics (Bacillus subtilis or Bacillus spp.), a combination of phytochemicals, or glycerides of organic acids on disease resistance and immunity of weaned pigs that were experimentally infected with a pathogenic E. coli. (Outcomes) We observed the beneficial effects of dietary supplementing probiotics and a mixture of phytochemicals on postweaning growth and gut health and resilience to enteric pathogens in weaned pigs. We received a grant from the Novo Nordisk Foundation to explore dietary strategies that could reduce post-weaning diarrhea and the use of antibiotics. University of California Davis (Peng Ji). (Background) Iron supplementation in the forms of oral drops and fortified formula and complementary food is universally given in infancy without a careful screening of iron status. Previous studies from our lab showed excess iron intake through oral drops increased enteric iron flow and fecal iron concentration. Iron is an essential nutrient for most microorganisms, but few research has evaluated the impact of iron overflow on gut microbiome. (Activities) We use milk replacer-fed piglets to simulate human infants and evaluated the effects of iron-fortified milk replacer on trace mineral homeostasis, growth performance, gut development and microbiome. (Outcomes) The study showed that iron-fortified milk replacer reduced liver zinc concentration, increase iron concentration in colon digesta and feces, increased beta-diversity and relative abundance of potential pathogens (Escherichia-Shigella and Clostridium sensu stricto 1) compared to the low iron milk which significantly increased the abundance of lactobacillus. University of California Davis (Allison Ehrlich). (Background) Understanding the mechanism of action of how specific nutritional components promote or disrupt intestinal homeostasis can impact dietary recommendations towards improving health. We hypothesized that the immunoregulatory phytochemcial, indole-3-carbinol (I3C) which is found in cruciferous vegetables, will act similarly to non-dietary, high affinity, aryl hydrocarbon receptor ligands AhR ligands and promote immune regulation. During digestion, I3C is metabolized into ligands for the aryl hydrocarbon receptor (AhR), a transcription factor that when systemically activated prevents T1D. (Activities) In NOD mice, we found that an I3C-supplemented diet led to strong AhR activation in the small intestine but minimal systemic AhR activity. Consistent with the compartmentalization of AhR activation, dietary I3C increased a type of proinflammatory cell called Th17 cells, and decreased immunoregulatory CX3CR1+ macrophages in the small intestine. The immune modulation in the gut was accompanied by alterations to the intestinal microbiome. We identified several gut microbes that were correlated with an increase in Th17 cells and a decrease in immunoregulatory macrophages that were influenced by dietary I3C. Using AhR knockout mice both as specific pathogen-free and newly derived as germ free, we found that Th17 cells and CX3CR1+ macrophages are regulated by both dietary ligands and the microbiome via AhR.  (Outcomes) Humans express an AhR with similar ligand sensitivity to the murine AhRd allele, thus the NOD model may be more appropriate for predicting immune modulation in humans in response to dietary AhR ligands. Two manuscripts are currently in preparation on these data demonstrating that genetics, diet, and the host microbiome are important considerations in the outcome of dietary AhR ligands on the gut immune system.     Oregon State University (Urszula Iwaniec). (Background) Licorice root, either in whole root powder or more concentrated extract form, is often used as an ingredient in dietary supplements, homeopathic remedies, and candies. Licorice root is consumed by older women based, in part, on the belief that, as a natural botanical estrogen, it attenuates common menopausal symptoms, including weight gain and bone loss. Isoliquiritigenin (ILQ) is a phenolic compound found in licorice root that contributes to its activity. (Activities) We performed a dose-ranging study using young estrogen-depleted rats to determine whether dietary ILQ alters bone metabolism and if the effects are associated with estrogen receptor signaling.  Six-week-old ovariectomized rats were fed diets containing 0, 100, 250 or 750 ppm ILQ for 7 days. Gene expression in femur and uterus, biomarkers of bone turnover, body composition, and uterine weight and epithelial morphology were determined. (Outcomes) We observed a dose-dependent increase in serum ILQ but no change in the serum marker of global bone formation. Contrastingly, ILQ administration reduced the serum marker of global bone resorption and tartrate-resistant acid phosphatase expression in osteoclast culture. ILQ treatment and endogenous estrogen production had limited overlap in gene expression in femur and uterus. However, the highest dose of ILQ resulted in uterine epithelial cell hyperplasia in 2 of 5 animals. Oregon State University (David Dallas). (Background) Our lab examines the digestion of milk protein and the release of bioactive peptides in infants and adults. (Activities) We examined the effect of heat treatments on retention of bioactive proteins in common donor human milk and the survival of bovine milk kappa-casein glycomacropeptide within the gastrointestinal tract of adults. We also assessed whether peptides present in intestinal digests from preterm infant could cross the intestinal epithelium in vivo and in vitro (a Caco-2 cell model) and modulate the immune response of macrophage cells (THP1 cells). (Outcomes) We found that vat pasteurization or Holder pasteurization preserved the bioactive proteins in human milk to a much greater extent than ultra-high temperature processing and retort processing. We observed that about 10% of in vivo and in vitro preterm infant human milk intestinal digest-derived peptides could cross the epithelial cell monolayer and modulate the cytokine production of macrophage cells, while digested human milk varied in capacity to regulate intestinal cell immune response and correlated this with specific sets of proteins. We demonstrated that glycomacropeptide does not survive digestion in the adult jejunum, but many fragment forms are created, many of which have potential bioactivity in the gut. Oregon State University (Emily Ho). (Background) Diet plays an important role in mitigating the development and progression of several cancers, as well as immune dysfunction. This research demonstrates that the microbiome may be a key factor in individual differences in the metabolism and bioactivity of phytochemicals derived from cruciferous vegetables. Secondly, age-related decline in nutritional status may be a critical determinant of healthy aging and susceptibility to infection or other environmental insults. The research program has focused on bioactives derived from cruciferous vegetables and zinc nutrition. (Activities) We have completed investigating the impact of broccoli sprout supplementation on the microbiome and metabolome in healthy human subjects. We have also employed cell culture models and rodent models to understand the impact of zinc status on age-related inflammation and the gut microbiome. (Outcomes) We identified that the gut microbiota could be a critical driving factor in differential responses to cruciferous vegetables, established low dietary zinc as a risk factor for inflammatory processes, DNA damage, and cancer risk, and helped identify new biomarkers for human zinc deficiency and cruciferous vegetable intake. We also established the biological function of zinc and changes in zinc metabolism with immune activation and aging. Oklahoma State University (Dingbo Lin). (Background) Oxygenized carotenoids, such as zeaxanthin and astaxanthin are fat-soluble pigments rich in colorful diets. The goals of my research focus on further understanding their metabolism and function in human health and diseases. (Activities) In this funding period, we further explored the problems of the absorption efficacy and metabolism of dietary carotenoids in human subjects and mouse models. (Outcomes) The results showed consumption of salmon significantly increased plasma astaxanthin contents. There were three isomers of astaxanthins identified in the human plasma samples. Dietary zeaxanthin enhanced the richness of microbiota populations in tryptophan metabolism. Kansas State University (Brian Lindshield). (Background) Previously we investigated the rice diets with soy protein isolate and soybean oil was supplemented with a USDA MR24 vitamin/mineral blend and one of four iron fortificants: Ferric phosphate, Ferric pyrophosphate, micronized ferric pyrophosphate, or ferric pyrophosphate with trisodium citrate (TSC) and citric acid (CA) in rats. Unfortunately, the study had to be stopped early because of poor growth with these diets, although hemoglobin concentrations in the ferric pyrophosphate, micronized ferric pyrophosphate, or ferric pyrophosphate were significantly higher than ferric phosphate and AIN93-G Group. We wanted to repeat this study with AIN93-G diets with extruded rice flour to replace the carbohydrates given the limitations of our previous study. (Activities) The only difference in the study was that we chose to add TSC+CA to the ferric phosphate to see if it would improve its bioavailability since hemoglobin concentrations were lower in our previous study. (Outcomes) We just completed the study before the end of this reporting period. The diets were well consumed and there were no significant differences in body weight between groups. Purdue University (Lavanya Reddivari). (Background) Fiber solubility, fermentation rate and structural complexity affect fiber tolerance, gut barrier function, and gut microbiota. (Activities) We evaluated resistant maltodextrins (RMD), high methoxyl pectin (HMP), inulin (ChIn), and wheat bran (WB) for their impacts on gut fermentation, microbiome and enteric immunity in gnotobiotic IL-10 KO mouse model. (Outcomes) Fecal SCFAs were higher in mice consuming fiber-supplemented diets compared to a control diet. Mice on ChIn and RMD showed intolerance-associated symptoms such as diarrhea and weight loss. ChIn reduced the expression of mucin and tight junction genes, and reduced mucus thickness indicating barrier dysfunction. RMD increased colon, cecum, and spleen weights along with an increase in IL-6 gene expression indicating inflammation. WB did not show any intolerance-associated symptoms or inflammation. HMP supplementation increased SCFAs without any intolerance symptoms, except for increased gut permeability. Overall, structural complexity appears to be the most influential property in fiber tolerance. University of Illinois Urbana-Champaign (Jaume Amengual). (Background) Carotenoids are rich in fruits and vegetables, and therefore, are major components of healthy diets. Carotenoids can be found in large amounts in humans, and are precursors of vitamin A. (Activities) Over the past year, we utilized preclinical approaches such as cell culture and mouse models to study the metabolism of carotenoids and vitamin A. (Outcomes) We were able to target vitamin A production from carotenoids accumulated in the adipose tissue. As a result, we observed a reduction in adipose tissue size, suggesting that carotenoids accumulated in the adipose tissue could be utilized to reduce obesity. University of Missouri Columbia (Pavel Somavat). (Background) Colored corn varieties contain disproportionately higher anthocyanin and polyphenolic contents and these varieties, adapted to the midwestern climatic conditions can be utilized for economically extracting value-added phytochemicals, benefitting different agro-industrial sectors supplementing the lower economic value of conventional yellow dent corn. (Activities) Our research aims to evaluate the conventionally bred and colored corn varieties developed by the USDA-ARS colored corn breeding program at the University of Missouri for their milling characteristics and polyphenolic contents with the objective of identifying the most promising varieties for further breeding efforts. We also utilize colored corn varieties for the preparation of shelf-stable natural red colorants using spray and freeze-drying methods and evaluate physiochemical properties of the prepared color extracts. (Outcomes) Although, the commercial maize morado variety contained the highest anthocyanins, total phenols, and condensed tannins, four of the fourteen Missouri grown experimental varieties, namely, HM20, HM21, PBP, and AP were identified to be rich sources of polyphenolic compounds and antioxidant activities. These varieties were identified for subsequent breeding cycles. The Ohio State University (Richard Bruno). (Background) Obesity-related cardiometabolic disorders are driven by inflammation, oxidative stress, and gut dysbiosis. Green tea catechins protect against cardiometabolic disorders by anti-inflammatory, antioxidant, and prebiotic activities but whether obesity alters catechin bioavailability was unknown. (Activities) To address this knowledge gap, the Ohio Station completed a clinical study examining catechin bioavailability in obese and healthy persons following consumption of a novel catechin-rich green tea extract (GTE) confection. Biospecimens collected from participants up to 24 hours after the consumption of GTE confection were analyzed catechin compounds using LCMS and metagenomics. (Outcomes) Obesity reduced bioavailability of all GTE catechins by 24–27% and their maximum plasma concentrations by 18–36%. Metabolites of GTE catechins, specifically two γ-valerolactones, were unaffected by obesity, and total urinary elimination of these metabolites was approximately doubled that of total catechins regardless of health status. Although α-diversity of gut microbiota was lower in obese persons, Slackia was the only catechin-metabolizing bacteria altered by obesity. These findings indicate that obesity reduces catechin bioavailability without affecting valerolactone generation, urinary catechin elimination, or substantially altered gut microbiota populations, suggesting a gut-level mechanism that limits catechin absorption in obese persons. University of Rhode Island (Brietta Oaks). (Background) Lead exposure is a major public health concern in Rhode Island. There is evidence that omega-3 fatty acid intake may reduce circulating lead concentrations, but research has been limited and has not been explored in pregnant women, who are at a higher risk for adverse effects of lead exposure. In addition, omega-3 fatty acid intake may reduce circulating cortisol, a stress hormone that has negative effects during pregnancy if at chronically high concentrations. (Activities) The study is currently in progress. Pregnant women are actively being recruited from The Women, Infants & Children Program (WIC) offices several times a week. (Outcomes) We have enrolled 11 women and 10 have completed all data and sample collection, including surveys, saliva collection, and blood draw. In our preliminary data, women so far have blood lead concentrations that are within normal limits however fall into the category of vitamin D deficiency or insufficiency. Cornell University (Elad Tako). (Background) Bioactives from natural food items (e.g. phytochemicals and bioactive peptides) play an important role in modulating gut microbiota, enteric immunity, and gut barrier functions. Our research involves evaluating gut health-promoting effects of chia-derived bioactive peptides, probiotics, black corn extracts (BCE), fractions of Concord grapes (Vitis labrusca L.) and catechin derivatives. (Activities) We conducted separate studies using animal models to evaluate intestinal microbiota, enteric immunity and gut barrier functions in response to dietary supplementation of 1) the effects of the intra-amniotic administration of the hydrolyzed chia protein and the probiotic Lacticaseibacillus paracasei, BCE, grape puree included the grape skin, endocarp, mesocarp, and juice but not the seeds on gut health, and the synthetic catechin pentaacetate and catechin pentabutanoate (two new ester derivatives of catechin). (Outcomes) Results suggest that hydrolyzed chia protein or a probiotic promoted positive changes in terms of intestinal inflammation, barrier, and morphology, improving intestinal health. The BCE promoted positive changes in the cecum microbiome and maintained intestinal morphology and functionality. The grape puree treatment resulted in higher Clostridium numbers and lower Bifidobacterium numbers when compared to all other groups. In contrast, catechin and its synthetic derivatives significantly decreased Clostridium genera and E. coli species density and decreased expression of genes encoding iron and zinc transporter in the duodenum. University of Connecticut (Ji-Young Lee). (Background) Alcoholic hepatitis (AH) is a progressive form of alcoholic liver disease. Hepatocytes and macrophages play a crucial role in the development of AH. (Activities) We determine the effect of astaxanthin, a xanthophyll carotenoid, and nicotinamide riboside, a NAD+ precursor, on alcohol-induced inflammation and oxidative stress in hepatocytes and macrophages with an elucidation of mechanisms of action. (Outcomes) We found that astaxanthin and NR inhibited inflammation and oxidative stress in hepatocytes and macrophages exposed to alcohol by preventing mitochondrial dysfunctions. University of Maine (Dorothy Klimis-Zacas). (Background) Wounds occur in over 15 million people with approximately $60 billion spent annually on wound care. Deficient vascularization is a significant factor that promotes chronic and non-healing wounds, ultimately resulting in amputation. Currently, most clinical wound treatments are antibiotics for infection control. Chronic wounds such as diabetic foot ulcers, ischemic limbs, and pressure ulcers lack treatments that promote wound healing and improve tissue remodeling. Thus, there is an urgent need to develop effective, cost-efficient, natural sources-derived therapies that have no deleterious side effects. (Activities) We have completed the preclinical study that aims to determine the efficacy of non-fidelity biomedical prototype(s) composed of wild blueberry extract(s) to promote angiogenesis, re-epithelialization, vascularization, collagen formation, and anti-inflammation related to wound healing. Meanwhile, we developed a second prototype based on nanocarrier technology for effective transdermal delivery of the wild blueberry extract. The product was tested with an animal model. Analyses are taking place in 2023. (Outcomes) Results from animal studies showed that the serum/gel prototype at specific concentrations significantly promoted wound closure by 12% over the control and increased re-epithelialization, vascularization, collagen formation and decreased the inflammatory response compared to the control. The effects are mediated, in part, through regulating gene expression.

Publications

<ul> <li>Hogg, A., P. Carr, J. Eberly, C. Chen, C. Kowatch-Carlson, F. Crutcher, P. Lamb, K. McNamara, E. Haney, K. Kephart, V. Smith, L. Dykes, X. Chen, L. Huang, and M.J. Giroux. (2022) Registration of ‘Lustre’ Durum Wheat.   Journal of Plant Registrations 16:576-584. https://doi.org/10.1002/plr2.20214</li> <li>Zempleni J. Letter to the editor (regarding Perspective: The role of human breast-milk extracellular vesicles in child health and disease by D. O’Reilly et al., published in Advances in Nutrition on 24 August 2020). Adv Nutr 12:280, 2021.</li> <li>Sukreet S, Pereira Braga C, An TT, Adamec J, Cui J, Trible B, Zempleni J. Isolation of extracellular vesicles from byproducts of cheese making by tangential flow filtration yields heterogeneous fractions of nanoparticles. J Dairy Sci 104:9478-9493, 2021.</li> <li>Khanam A. Yu J, Zempleni J. Class A scavenger receptor-1/2 facilitates the uptake of bovine milk exosomes in murine bone marrow-derived macrophages and C57BL/6J mice. Am J Physiol Cell Physiol 321:C606-C614, 2021.</li> <li>Ogunnaike M, Wang, H, Zempleni J. Bovine mammary alveolar MAC-T cells afford a tool for studies of bovine milk exosomes in drug delivery. Int J Pharm 610:121263, 2021.</li> <li>Wang H, Wu D, Sukreet S, Delaney A, Belfort MB, Zempleni J. Quantitation of exosomes and their microRNA cargos in frozen human milk. JPGN Reports 3:e172, 2022.</li> <li>Mutai E, Ngu AKH, Zempleni J. Preliminary evidence that lectins in infant soy formula apparently bind bovine milk exosomes and prevent their absorption in healthy adults. BMC Nutr 8:7, 2022.</li> <li>Sukreet S, Pereira Braga C, An, TT, Adamec J, Cui J, Zempleni J. Ultrasonication of milk decreases the content of exosomes and microRNAs in an exosome-defined rodent diet. J Nutr 152:961-970, 2022.</li> <li>Sadri M,* Wang H,* Kuroishi T,* Li Y, Zempleni J. Holocarboxylase synthetase knockout is embryonic lethal in mice. PLoS One 17:e0265539, 2022.</li> <li>Zhou F, Ebea P, Mutai E, Wang H, Sukreet S, Navazesh S, Dogan H, Li W, Cui J, Ji P, Ramirez DMO,* Zempleni J.* Small extracellular vesicles in milk cross the blood-brain barrier in murine cerebral cortex endothelial cells and promote dendritic complexity in the hippocampus and brain function in C57BL/6J mice. Front Nutr 9:838543, 2022.</li> <li>Ngu A, Wang S, Wang H, Khanam A, Zempleni J. Milk exosomes in nutrition and drug delivery. Am J Physiol Cell Physiol 322:C865-C874, 2022.</li> <li>Munir J, Ngu A, Wang H, Ramirez DMO, Zempleni J. Review: Milk small extracellular vesicles for use in the delivery of therapeutics. Pharm Res (online ahead of print), 2022.</li> <li>Li G, Ho KKHY, Zuo YY. Relative dye adsorption method for determining the hydrophobicity of nanoparticles. The Journal of Physical Chemistry C. 2021;126(1):832-7.</li> <li>Ho KKHY, Redan BW. Impact of thermal processing on the nutrients, phytochemicals, and metal contaminants in edible algae. Critical reviews in food science and nutrition. 2021;62(2):508-26</li> <li>Li G, Cao Z, Ho KKHY, Zuo YY. Quantitative determination of the hydrophobicity of nanoparticles. Analytical Chemistry. 2022;94(4):2078-86.</li> <li>Thompson M, Ulu A, Mukherjee M, Yuil-Valdes AG, Thoene M, Van Ormer M, Slotkowski R, Mauch T, Anderson-Berry A, Hanson CK, Nordgren TM, Natarajan SK. Something Smells Fishy: How Lipid Mediators Impact the Maternal-Fetal Interface and Neonatal Development. Biomedicines. 2023 Jan 10;11(1):171. doi: 10.3390/biomedicines11010171. PMID: 36672679. Review.</li> <li>Muthuraj PG, Krishnamoorthy C, Anderson-Berry A, Hanson C, Natarajan SK. Novel Therapeutic Nutrients Molecules That Protect against Zika Virus Infection with a Special Note on Palmitoleate. Nutrients. 2022 Dec 27;15(1):124. doi: 10.3390/nu15010124. PMID: 36615782. Review.</li> <li>Neltner TJ, Sahoo PK, Smith RW, Anders JPV, Arnett JE, Schmidt RJ, Johnson GO, Natarajan SK, Housh TJ. Effects of 8 Weeks of Shilajit Supplementation on Serum Pro-c1α1, a Biomarker of Type 1 Collagen Synthesis: A Randomized Control Trial. J Diet Suppl. 2022 Dec 22:1-12. doi: 10.1080/19390211.2022.2157522. Online ahead of print. PMID: 36546868</li> <li>Ro SH, Bae J, Jang Y, Myers JF, Chung S, Yu J, Natarajan SK, Franco R, Song HS. Arsenic Toxicity on Metabolism and Autophagy in Adipose and Muscle Tissues. Antioxidants (Basel). 2022 Mar 31;11(4):689. doi: 10.3390/antiox11040689. PMID: 35453374. Review.</li> <li>Thompson M, Ulu A, Yuil-Valdes AG, Mukherjee M, Thoene M, Van Ormer M, Slotkowski R, Lyden E, Anderson Berry A, Hanson CK, Nordgren TM, Natarajan SK. Omega-6 and Omega-3 Fatty Acid-Derived Oxylipins from the Lipoxygenase Pathway in Maternal and Umbilical Cord Plasma at Delivery and Their Relationship with Infant Growth. Int J Mol Sci. 2022 Jan 9;23(2):708. doi: 10.3390/ijms23020708. PMID: 35054892.</li> <li>Meyer RK, Bime MA, Duca FA. Small intestinal metabolomics analysis reveals differentially regulated metabolite profiles in obese rats and with prebiotic supplementation. Metabolomics. 2022, 18(8):60.</li> <li>Meyer RK, Lane AI, Weninger SN, Martinez TM, Kangath A, Laubitz D, Duca FA. Oligofructose restores postprandial short-chain fatty acid levels during high-fat feeding. Obesity (Silver Spring). 2022, 30(7):1442-1452.</li> <li>Wachsmuth HR, Weninger SN, Duca FA. Role of the gut-brain axis in energy and glucose metabolism. Exp Mol Med. 2022, 54(4):377-392.</li> <li>Yue JTY, Duca FA, Lam TKT. Silencing gut CCK cells alters gut reaction to sugar. Nat Neurosci. 2022, 25(2):136-138.</li> <li>Howard EJ, Lam TKT, Duca FA. The Gut Microbiome: Connecting Diet, Glucose Homeostasis, and Disease. Annu Rev Med. 2022, 73:469-481.</li> <li>Smith KA, Pugh JN, Duca FA, Close GL, Ormsbee MJ. Gastrointestinal pathophysiology during endurance exercise: endocrine, microbiome, and nutritional influences. Eur J Appl Physiol. 2021, 121(10):2657-2674.</li> <li>Mattar P, Uribe-Cerda S, Pezoa C, Guarnieri T, Kotz CM, Teske JA, Morselli E, Perez-Leighton C. Brain site specific regulation of hedonic intake by orexin and DYN peptides: Role of the PVN and obesity. Nutr Neurosci, 2022, 25(5)5:1105-1114.</li> <li>Jinno, C., X. Li, and Y. Liu. 2022. Dietary supplementation of Bacillus subtilis or antibiotics modified intestinal microbiome of weaned pigs under enterotoxigenic Escherichia coli infection. Frontiers Microbiol. 2022. 1064328.</li> <li>Wong, B. T., S. Park, L. Kovanda, Y. He, K. Kim, S. Xu, C. Lingga, M. Hejna, E. Wall, R. Sripathy, X. Li, and Y. Liu. 2022. Dietary supplementation of botanical blends enhanced performance and disease resistance of weaned pigs experimentally infected with enterotoxigenic Escherichia coli F18. J. Anim. Sci. skac353.</li> <li>Kim, K., M. Song, Y. Liu, and P. Ji. 2022. Enterotoxigenic Escherichia coli infection of weaned pigs: Intestinal challenges and nutritional intervention to enhance disease resistance. Front. Immunol. doi: 10.3389/fimmu.2022.885253.</li> <li>Kim, K., C. Jinno, P. Ji, Y. Liu. 2022. Trace amounts of antibiotic altered metabolomic and microbial profiles of weaned pigs infected with a pathogenic E. coli. J. Anim. Sci. Biotechnol. 13:59-73.</li> <li>Kim K, He Y, Jinno C, Kovanda L, Li X, Bravo D, Cox E, Liu Y. 2022. Supplementation of oligosaccharide-based polymer enhanced growth and disease resistance of weaned pigs by modulating intestinal integrity and systemic immunity. J Anim Sci Biotechnol. 13:10-23.</li> <li>He Y, Jinno J, Li C, Johnson SL, Xue H, Liu Y, Ji P. 2022. Effects of a blend of essential oils, medium-chain fatty acids and a toxin-adsorbing mineral on diarrhea and gut microbiome of weanling pigs experimentally infected with a pathogenic E. coli. J Anim Sci. 100:skab365.</li> <li>Qi M, Tan B, Wang J, Liao S, Deng Y, Ji P, Song T, Zha A, Yin Y. The microbiota-gut-brain axis: A novel nutritional therapeutic target for growth retardation. Crit Rev Food Sci Nutr. 2022;62(18):4867-4892. doi: 10.1080/10408398.2021.1879004. Epub 2021 Feb 1. Review. PubMed PMID: 33523720.</li> <li>Qi M, Tan B, Wang J, Liao S, Li J, Cui Z, Shao Y, Ji P, Yin Y. Postnatal growth retardation is associated with deteriorated intestinal mucosal barrier function using a porcine model. J Cell Physiol. 2021 Apr;236(4):2631-2648. doi: 10.1002/jcp.30028. Epub 2020 Aug 27. PubMed PMID: 32853405.</li> <li>Perng V, Navazesh SE, Park J, Arballo JR, Ji P. Iron deficiency and overload modulate the inflammatory responses and metabolism of alveolar macrophages. Nutrients. 2022 Jul 28;14(15):3100.</li> <li>Perng V, Li C, Klocke CR, Navazesh SE, Pinneles DK, Lein PJ, Ji P. Iron deficiency and iron excess differently affect dendritic architecture of pyramidal neurons in the hippocampus of piglets. The Journal of nutrition. 2021 Jan;151(1):235-44.</li> <li>Kebreab E, Mendez J, Ji P, Lee JJ, Seo S. Supplementation of exogenous β-mannanase to low-protein diets improves feed conversion efficiency in lactating dairy cows. Animal Production Science. 2022 Sep 16;63(1):70-7.</li> <li>McMillen SA, Dean R, Dihardja E, Ji P, Lönnerdal B. Benefits and Risks of Early Life Iron Supplementation. Nutrients. 2022 Oct 19;14(20):4380.</li> <li>Martin SA, Riordan RT, Wang R, Yu Z, Aguirre-Burk AM, Wong CP, Olson DA, Branscum AJ, Turner RT, Iwaniec UT, Perez VI. Rapamycin impairs bone accrual in young adult mice independent of Nrf2. Exp Gerontol. 2021, 154:111516. doi: 10.1016/j.exger.2021.111516. PMID: 34389472. Reported and described in last year’s report (manuscript was in press).</li> <li>Joyce KM, Wong CP, Scriven IA, Olson DA, Doerge DR, Branscum AJ, Sattgast LH, Helferich WG, Turner RT, Iwaniec UT. Isoliquiritigenin decreases bone resorption and osteoclast differentiation. Mol Nutr Food Res. 2022, 66(11):e2100974. doi: 10.1002/mnfr.202100974. PMID: 35319818</li> <li>Liang, N., Koh, J., Kim, B. J., Ozturk, G., Barile, D., Dallas, D. C. (Accepted August 22, 2022). Structural and functional changes of bioactive proteins in human milk treated by vat-pasteurization, retort sterilization, ultra-high temperature pasteurization, freeze-thawing and homogenization. Front Nutr. https://doi.org/10.3389/fnut.2022.926814</li> <li>Koh, J., Kim, B. J., Qu, Y., Dallas, D. C. (2022) Mass spectral profiling of caseinomacropeptide extracted from feeding material and jejunal fluid using three methods–ethanol precipitation, perchloric acid precipitation, and ultrafiltration. Food Chemistry. https://doi.org/10.1016/j.foodchem.2022.133864</li> <li>Demers-Mathieu, V., Underwood, M. A., Dallas, D. C. (Accepted July 20, 2022). Premature delivery impacts the concentration of plasminogen activators and a plasminogen activator inhibitor in human milk. Frontiers in Pediatrics. Neonatology. DOI: 10.3389/fped.2022.917179</li> <li>Liang, N., Kim, B. J., Dallas, D. C. (Accepted May, 2022). Bioavailability of peptides derived from the in vitro digestion of human milk assessed by Caco-2 cell monolayers. Journal of Agricultural and Food Chemistry. https://doi.org/10.1021/acs.jafc.2c01246</li> <li>Koh, J., Kim, B. J., Qu, Y., Dallas, D. C. (Nov 2021). Top-down glycopeptidomics reveal intact glycomacropeptide is digested to a wide array of peptides in the human jejunum. Journal of Nutrition. DOI: 10.1093/jn/nxab400</li> <li>Liang, N., Beverly, R., Gorton, M., Scottoline, B. P., Dallas, D. C. (Nov 2021). 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Impact Statements

University of Hawaii (Jinzeng Yang). We continuously support public education on consumption of tropical fruits and promotion of local production through website and public events in cooperation with CTAHR extension agents and fruit grower association. Also, educational materials about restricted diet with supplementations from tropical plants such as papaya leaf and seaweeds for diabetes management are very useful information for better diet and health living.