@article{curtis_velpen_berends_jennings_haag_minihane_chandra_kay_rimm_cassidy_2024, title={Chronic and postprandial effect of blueberries on cognitive function, alertness, and mood in participants with metabolic syndrome - results from a six-month, double-blind, randomized controlled trial}, volume={119}, ISSN={["1938-3207"]}, DOI={10.1016/j.ajcnut.2023.12.006}, abstractNote={Anthocyanin and blueberry intakes positively associated with cognitive function in population-based studies and cognitive benefits in randomized controlled trials of adults with self-perceived or clinical cognitive dysfunction. To date, adults with metabolic syndrome (MetS) but without cognitive dysfunction are understudied. Cognitive function, mood, alertness, and sleep quality were assessed as secondary end points in MetS participants, postprandially (>24 h) and following 6-mo blueberry intake. A double-blind, randomized controlled trial was conducted, assessing the primary effect of consuming freeze-dried blueberry powder, compared against an isocaloric placebo, on cardiometabolic health >6 mo and a 24 h postprandial period (at baseline). In this secondary analysis of the main study, data from those completing mood, alertness, cognition, and sleep assessments are presented (i.e., n = 115 in the 6 mo study, n = 33 in the postprandial study), using the following: 1) Bond-Lader self-rated scores, 2) electronic cognitive battery (i.e., testing attention, working memory, episodic memory, speed of memory retrieval, executive function, and picture recognition), and 3) the Leeds Sleep Evaluation Questionnaire. Urinary and serum anthocyanin metabolites were quantified, and apolipoprotein E genotype status was determined. Postprandial self-rated calmness significantly improved after 1 cup of blueberries (P = 0.01; q = 0.04; with an 11.6% improvement compared with baseline between 0 and 24 h for the 1 cup group), but all other mood, sleep, and cognitive function parameters were unaffected after postprandial and 6-mo blueberries. Across the ½ and 1 cup groups, microbial metabolites of anthocyanins and chlorogenic acid (i.e., hydroxycinnamic acids, benzoic acids, phenylalanine derivatives, and hippuric acids) and catechin were associated with favorable chronic and postprandial memory, attention, executive function, and calmness. Although self-rated calmness improved postprandially, and significant cognition-metabolite associations were identified, our data did not support strong cognitive, mood, alertness, or sleep quality improvements in MetS participants after blueberry intervention. This trial was registered at clinicaltrials.gov as NCT02035592.}, number={3}, journal={AMERICAN JOURNAL OF CLINICAL NUTRITION}, author={Curtis, Peter J. and Velpen, Vera van der and Berends, Lindsey and Jennings, Amy and Haag, Laura and Minihane, Anne Marie and Chandra, Preeti and Kay, Colin and Rimm, Eric B. and Cassidy, Aedin}, year={2024}, month={Mar}, pages={658–668} }
 @article{munoz_hayes_perkins-veazie_gillitt_munoz_kay_lila_ferruzzi_iorizzo_2024, title={Genotype and ripening method affect carotenoid content and bio-accessibility in banana}, volume={3}, ISSN={["2042-650X"]}, url={https://doi.org/10.1039/D3FO04632J}, DOI={10.1039/D3FO04632J}, abstractNote={This study concludes that the genotype, ripening methods (natural vs. exogenous ethylene application), and carotenoid bioaccessible content should be considered when setting a nutrition goal for vitamin A biofortification in banana-breeding programs.}, journal={FOOD & FUNCTION}, author={Munoz, Bryan and Hayes, Micaela and Perkins-Veazie, Penelope and Gillitt, Nicholas and Munoz, Miguel and Kay, Colin D. and Lila, Mary Ann and Ferruzzi, Mario G. and Iorizzo, Massimo}, year={2024}, month={Mar} }
 @article{vauzour_scholey_white_cohen_cassidy_gillings_irvine_kay_kim_king_et al._2023, title={A combined DHA-rich fish oil and cocoa flavanols intervention does not improve cognition or brain structure in older adults with memory complaints: results from the CANN randomized, controlled parallel-design study}, volume={118}, ISSN={["1938-3207"]}, DOI={10.1016/j.ajcnut.2023.06.008}, abstractNote={There is evidence that both omega-3 long-chain polyunsaturated fatty acids (PUFAs) (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and cocoa flavanols can improve cognitive performance in both healthy individuals and in those with memory complaints. However, their combined effect is unknown.To investigate the combined effect of EPA/DHA and cocoa flavanols (OM3FLAV) on cognitive performance and brain structures in older adults with memory complaints.A randomized placebo-controlled trial of DHA-rich fish oil (providing 1.1 g/d DHA and 0.4 g/d EPA) and a flavanol-rich dark chocolate (providing 500 mg/d flavan-3-ols) was conducted in 259 older adults with either subjective cognitive impairment or mild cognitive impairment. Participants underwent assessment at baseline, 3 mo, and 12 mo. The primary outcome was the number of false-positives on a picture recognition task from the Cognitive Drug Research computerized assessment battery. Secondary outcomes included other cognition and mood outcomes, plasma lipids, brain-derived neurotrophic factor (BDNF), and glucose levels. A subset of 110 participants underwent structural neuroimaging at baseline and at 12 mo.197 participants completed the study. The combined intervention had no significant effect on any cognitive outcomes, with the exception of reaction time variability (P = 0.007), alertness (P < 0.001), and executive function (P < 0.001), with a decline in function observed in the OM3FLAV group (118.6 [SD 25.3] at baseline versus 113.3 [SD 25.4] at 12 mo for executive function) relative to the control, and an associated decrease in cortical volume (P = 0.039). Compared with the control group, OM3FLAV increased plasma HDL, total cholesterol ratio (P < 0.001), and glucose (P = 0.008) and reduced TG concentrations (P < 0.001) by 3 mo, which were sustained to 12 mo, with no effect on BDNF. Changes in plasma EPA and DHA and urinary flavonoid metabolite concentrations confirmed compliance to the intervention.These results suggest that cosupplementation with ω-3 PUFAs and cocoa flavanols for 12 mo does not improve cognitive outcomes in those with cognitive impairment. This trial was registered at clinicaltrials.gov as NCT02525198.}, number={2}, journal={AMERICAN JOURNAL OF CLINICAL NUTRITION}, author={Vauzour, David and Scholey, Andrew and White, David J. and Cohen, Neal J. and Cassidy, Aedin and Gillings, Rachel and Irvine, Michael A. and Kay, Colin D. and Kim, Min and King, Rebecca and et al.}, year={2023}, month={Aug}, pages={369–381} }
 @article{nieman_omar_kay_kasote_sakaguchi_lkhagva_weldemariam_zhang_2023, title={Almond intake alters the acute plasma dihydroxy-octadecenoic acid (DiHOME) response to eccentric exercise}, volume={9}, ISSN={["2296-861X"]}, DOI={10.3389/fnut.2022.1042719}, abstractNote={IntroductionThis investigation determined if 4-weeks ingestion of nutrient-dense almonds mitigated post-exercise inflammation and muscle soreness and damage.}, journal={FRONTIERS IN NUTRITION}, author={Nieman, David C. C. and Omar, Ashraf M. M. and Kay, Colin D. D. and Kasote, Deepak M. M. and Sakaguchi, Camila A. A. and Lkhagva, Ankhbayar and Weldemariam, Mehari Muuz and Zhang, Qibin}, year={2023}, month={Jan} }
 @article{krueger_griffin_beales_lloyd_brown_elison_kay_neilson_tessem_2023, title={Bioavailable Microbial Metabolites of Flavanols Demonstrate Highly Individualized Bioactivity on In Vitro & beta;-Cell Functions Critical for Metabolic Health}, volume={13}, ISSN={["2218-1989"]}, DOI={10.3390/metabo13070801}, abstractNote={Dietary flavanols are known for disease preventative properties but are often poorly absorbed. Gut microbiome flavanol metabolites are more bioavailable and may exert protective activities. Using metabolite mixtures extracted from the urine of rats supplemented with flavanols and treated with or without antibiotics, we investigated their effects on INS-1 832/13 β-cell glucose stimulated insulin secretion (GSIS) capacity. We measured insulin secretion under non-stimulatory (low) and stimulatory (high) glucose levels, insulin secretion fold induction, and total insulin content. We conducted treatment-level comparisons, individual-level dose responses, and a responder vs. non-responder predictive analysis of metabolite composition. While the first two analyses did not elucidate treatment effects, metabolites from 9 of the 28 animals demonstrated significant dose responses, regardless of treatment. Differentiation of responders vs. non-responder revealed that levels of native flavanols and valerolactones approached significance for predicting enhanced GSIS, regardless of treatment. Although treatment-level patterns were not discernable, we conclude that the high inter-individual variability shows that metabolite bioactivity on GSIS capacity is less related to flavanol supplementation or antibiotic treatment and may be more associated with the unique microbiome or metabolome of each animal. These findings suggest flavanol metabolite activities are individualized and point to the need for personalized nutrition practices.}, number={7}, journal={METABOLITES}, author={Krueger, Emily S. S. and Griffin, Laura E. E. and Beales, Joseph L. L. and Lloyd, Trevor S. S. and Brown, Nathan J. J. and Elison, Weston S. S. and Kay, Colin D. D. and Neilson, Andrew P. P. and Tessem, Jeffery S. S.}, year={2023}, month={Jul} }
 @article{parmenter_shinde_croft_murray_bondonno_genoni_christophersen_bindon_kay_mena_et al._2023, title={Performance of Urinary Phenyl-γ-Valerolactones as Biomarkers of Dietary Flavan-3-ol Exposure}, volume={153}, ISSN={["1541-6100"]}, DOI={10.1016/j.tjnut.2023.06.035}, abstractNote={Phenyl-γ-valerolactones (PVLs) have been identified as biomarkers of dietary flavan-3-ol exposure, although their utility requires further characterization. We investigated the performance of a range of PVLs as biomarkers indicative of flavan-3-ol intake. We report the results of 2 companion studies: a 5-way randomized crossover trial (RCT) and an observational cross-sectional study. In the RCT (World Health Organization, Universal Trial Number: U1111-1236-7988), 16 healthy participants consumed flavan-3-ol–rich interventions (of apple, cocoa, black tea, green tea, or water [control]) for 1 d each. First morning void samples and 24-h urine samples were collected with diet standardized throughout. For each participant, 1 intervention period was extended (to 2 d) to monitor PVL kinetics after repeat exposure. In the cross-sectional study, 86 healthy participants collected 24-h urine samples, and concurrent weighed food diaries from which flavan-3-ol consumption was estimated using Phenol-Explorer. A panel of 10 urinary PVLs was quantified using liquid chromatography tandem mass spectrometry. In both studies, 2 urinary PVLs [5-(3ʹ-hydroxyphenyl)-γ-valerolactone-4ʹ-sulfate and putatively identified 5-(4ʹ-hydroxyphenyl)-γ-valerolactone-3ʹ-glucuronide] were the principal compounds excreted (>75%). In the RCT, the sum of these PVLs was significantly higher than the water (control) after each intervention; individually, there was a shift from sulfation toward glucuronidation as the total excretion of PVLs increased across the different interventions. In the extended RCT intervention period, no accumulation of these PVLs was observed after consecutive days of treatment, and after withdrawal of treatment on the third day, there was a return toward negligible PVL excretion. All results were consistent, whether compounds were measured in 24-h urine or first morning void samples. In the observational study, the sum of the principal PVLs correlated dose dependently (Rs = 0.37; P = 0.0004) with dietary flavan-3-ol intake, with similar associations for each individually. Urinary 5-(3ʹ-hydroxyphenyl)-γ-valerolactone-4ʹ-sulfate and putatively identified 5-(4ʹ-hydroxyphenyl)-γ-valerolactone-3ʹ-glucuronide are recommended biomarkers for dietary flavan-3-ol exposure.}, number={8}, journal={JOURNAL OF NUTRITION}, author={Parmenter, Benjamin H. and Shinde, Sujata and Croft, Kevin and Murray, Kevin and Bondonno, Catherine P. and Genoni, Angela and Christophersen, Claus T. and Bindon, Keren and Kay, Colin and Mena, Pedro and et al.}, year={2023}, month={Aug}, pages={2193–2204} }
 @article{cremonini_daveri_iglesias_kang_wang_gray_mastaloudis_kay_hester_wood_et al._2022, title={A randomized placebo-controlled cross-over study on the effects of anthocyanins on inflammatory and metabolic responses to a high-fat meal in healthy subjects}, volume={51}, ISSN={["2213-2317"]}, DOI={10.1016/j.redox.2022.102273}, abstractNote={This study investigated the effects of supplementation with a cyanidin- and delphinidin-rich extract (CDRE) on the postprandial dysmetabolism, inflammation, and redox and insulin signaling, triggered by the consumption of a high fat meal (HFM) in healthy individuals. Participants (n = 25) consumed a 1026-kcal HFM simultaneously with either the CDRE providing 320.4 mg of anthocyanins (90% cyanidin and delphinidin) or placebo. Diets were randomly assigned in a double blind, placebo-controlled crossover design. Blood was collected prior to (fasted, time 0), and for 5 h after meal consumption; plasma, serum, and peripheral blood mononuclear cells (PBMC) were isolated. AC metabolites were detected in serum as early as 30 min after CDRE consumption. The CDRE mitigated HFM-induced endotoxemia, reducing increases in plasma LPS and LPS-binding protein. The CDRE also reduced other events associated with HFM-triggered postprandial dysmetabolism including: i) plasma glucose and triglyceride increases; ii) TNFα and NOX4 upregulation in PBMC; and iii) JNK1/2 activation in PBMC. The CDRE did not significantly affect HFM-mediated increases in plasma insulin, GLP-1, GLP-2, GIP, and LDL- and HDL-cholesterol, and IKK phosphorylation in PBMC. In summary, dietary AC, i.e. cyanidin and delphinidin, exerted beneficial actions against unhealthy diets by modulating the associated postprandial dysmetabolism, endotoxemia, alterations of glycemia and lipidemia, and redox and insulin signaling.}, journal={REDOX BIOLOGY}, author={Cremonini, Eleonora and Daveri, Elena and Iglesias, Dario E. and Kang, Jiye and Wang, Ziwei and Gray, Russell and Mastaloudis, Angela and Kay, Colin D. and Hester, Shelly N. and Wood, Steven M. and et al.}, year={2022}, month={May} }
 @article{curtis_berends_velpen_jennings_haag_chandra_kay_rimm_cassidy_2022, title={Blueberry anthocyanin intake attenuates the postprandial cardiometabolic effect of an energy-dense food challenge: Results from a double blind, randomized controlled trial in metabolic syndrome participants}, volume={41}, ISSN={["1532-1983"]}, url={https://doi.org/10.1016/j.clnu.2021.11.030}, DOI={10.1016/j.clnu.2021.11.030}, abstractNote={Whilst the cardioprotective effects of blueberry intake have been shown in prospective studies and short-term randomized controlled trials (RCTs), it is unknown whether anthocyanin-rich blueberries can attenuate the postprandial, cardiometabolic dysfunction which follows energy-dense food intakes; especially in at-risk populations. We therefore examined whether adding blueberries to a high-fat/high-sugar meal affected the postprandial cardiometabolic response over 24 h.A parallel, double-blind RCT (n = 45; age 63.4 ± 7.4 years; 64% male; BMI 31.4 ± 3.1 kg/m2) was conducted in participants with metabolic syndrome. After baseline assessments, an energy-dense drink (969 Kcals, 64.5 g fat, 84.5 g carbohydrate, 17.9 g protein) was consumed with either 26 g (freeze-dried) blueberries (equivalent to 1 cup/150 g fresh blueberries) or 26 g isocaloric matched placebo. Repeat blood samples (30, 60, 90, 120, 180, 360 min and 24 h), a 24 h urine collection and vascular measures (at 3, 6, and 24 h) were performed. Insulin and glucose, lipoprotein levels, endothelial function (flow mediated dilatation (FMD)), aortic and systemic arterial stiffness (pulse wave velocity (PWV), Augmentation Index (AIx) respectively), blood pressure (BP), and anthocyanin metabolism (serum and 24 h urine) were assessed.Blueberries favorably affected postprandial (0-24 h) concentrations of glucose (p < 0.001), insulin (p < 0.01), total cholesterol (p = 0.04), HDL-C, large HDL particles (L-HDL-P) (both p < 0.01), extra-large HDL particles (XL-HDL-P; p = 0.04) and Apo-A1 (p = 0.01), but not LDL-C, TG, or Apo-B. After a transient higher peak glucose concentration at 1 h after blueberry intake ([8.2 mmol/L, 95%CI: 7.7, 8.8] vs placebo [6.9 mmol/L, 95%CI: 6.4, 7.4]; p = 0.001), blueberries significantly attenuated 3 h glucose ([4.3 mmol/L, 95%CI: 3.8, 4.8] vs placebo [5.1 mmol/L, 95%CI: 4.6, 5.6]; p = 0.03) and insulin concentrations (blueberry: [23.4 pmol/L, 95%CI: 15.4, 31.3] vs placebo [52.9 pmol/L, 95%CI: 41.0, 64.8]; p = 0.0001). Blueberries also improved HDL-C ([1.12 mmol/L, 95%CI: 1.06, 1.19] vs placebo [1.08 mmol/L, 95%CI: 1.02, 1.14]; p = 0.04) at 90 min and XL-HDLP levels ([0.38 × 10-6, 95%CI: 0.35, 0.42] vs placebo [0.35 × 10-6, 95%CI: 0.32, 0.39]; p = 0.02) at 3 h. Likewise, significant improvements were observed 6 h after blueberries for HDL-C ([1.17 mmol/L, 95%CI: 1.11, 1.24] vs placebo [1.10 mmol/L, 95%CI: 1.03, 1.16]; p < 0.001), Apo-A1 ([1.37 mmol/L, 95%CI: 1.32, 1.41] vs placebo [1.31 mmol/L, 95%CI: 1.27, 1.35]; p = 0.003), L-HDLP ([0.70 × 10-6, 95%CI: 0.60, 0.81] vs placebo [0.59 × 10-6, 95%CI: 0.50, 0.68]; p = 0.003) and XL-HDLP ([0.44 × 10-6, 95%CI: 0.40, 0.48] vs placebo [0.40 × 10-6, 95%CI: 0.36, 0.44]; p < 0.001). Similarly, total cholesterol levels were significantly lower 24 h after blueberries ([4.9 mmol/L, 95%CI: 4.6, 5.1] vs placebo [5.0 mmol/L, 95%CI: 4.8, 5.3]; p = 0.04). Conversely, no effects were observed for FMD, PWV, AIx and BP. As anticipated, total anthocyanin-derived phenolic acid metabolite concentrations significantly increased in the 24 h after blueberry intake; especially hippuric acid (6-7-fold serum increase, 10-fold urinary increase). In exploratory analysis, a range of serum/urine metabolites were associated with favorable changes in total cholesterol, HDL-C, XL-HDLP and Apo-A1 (R = 0.43 to 0.50).For the first time, in an at-risk population, we show that single-exposure to the equivalent of 1 cup blueberries (provided as freeze-dried powder) attenuates the deleterious postprandial effects of consuming an energy-dense high-fat/high-sugar meal over 24 h; reducing insulinaemia and glucose levels, lowering cholesterol, and improving HDL-C, fractions of HDL-P and Apo-A1. Consequently, intake of anthocyanin-rich blueberries may reduce the acute cardiometabolic burden of energy-dense meals.NCT02035592 at www.clinicaltrials.gov.}, number={1}, journal={CLINICAL NUTRITION}, author={Curtis, Peter J. and Berends, Lindsey and Velpen, Vera and Jennings, Amy and Haag, Laura and Chandra, Preeti and Kay, Colin D. and Rimm, Eric B. and Cassidy, Aedin}, year={2022}, month={Jan}, pages={165–176} }
 @article{lila_hoskin_grace_xiong_strauch_ferruzzi_iorizzo_kay_2022, title={Boosting the Bioaccessibility of Dietary Bioactives by Delivery as Protein-Polyphenol Aggregate Particles}, volume={4}, ISSN={["1520-5118"]}, url={https://doi.org/10.1021/acs.jafc.2c00398}, DOI={10.1021/acs.jafc.2c00398}, abstractNote={Protein-polyphenol aggregate particles concurrently fortify a functional food product with healthy dietary proteins and concentrated polyphenols. However, what impact does ingestion of aggregate particles have on ultimate health relevance of either the polyphenolic molecules in the matrix or the protein molecules? Because human health benefits are contingent on bioavailability after ingestion, the fate of these molecules during transit in the gastrointestinal tract (GIT) will dictate their utility as functional food ingredients. This brief review explores diverse applications of protein-polyphenol particles in the food industry and the bioaccessibility of both bioactive polyphenolic compounds and edible proteins. Evidence to date suggests that complexation of phytoactive polyphenolics effectively enhances their health-relevant impacts, specifically because the phytoactives are protected in the protein matrix during transit in the GIT, allowing intact, non-degraded molecules to reach the colon for catabolism at the gut microbiome level, a prerequisite to realize the health benefits of these active compounds.}, journal={JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY}, publisher={American Chemical Society (ACS)}, author={Lila, Mary Ann and Hoskin, Roberta Targino and Grace, Mary H. and Xiong, Jia and Strauch, Renee and Ferruzzi, Mario and Iorizzo, Massimo and Kay, Colin}, year={2022}, month={Apr} }
 @article{racine_iglesias-carres_herring_ferruzzi_kay_tessem_neilson_2022, title={Cocoa Extract Exerts Sex-Specific Effects in an Aggressive Hyper-Glycemia Model: A Pilot Study}, volume={1}, url={https://doi.org/10.20944/preprints202112.0110.v2}, DOI={10.20944/preprints202112.0110.v2}, abstractNote={Type 2 diabetes (T2D) is characterized by hyperglycemia and insulin resistance. Cocoa may slow T2D development and progression. This study employed male and female BTBR.Cg-Lepob/ob/WiscJ and wild type (WT) controls to assess the potential for cocoa to ameliorate progressive T2D and compare responses between sexes. Mice received diet without (WT, ob/ob) or with cocoa extract (ob/ob + c) for 10 weeks. Glucose and insulin tolerance tests (GTT/ITT) were conducted at weeks 1, 5 and 2, 6, respectively. Cocoa provided mild non-significant protection against weight gain vs. ob/ob control in males but not females. Male ob/ob + c had increasing fasting glucose at weeks 1 and 5 GTTs, with significantly higher levels of fasting glucose than ob/ob control at week 5. This was not seen in females. Cocoa protected against elevated 4-hour fasting glucose in week 2, but not week 6, ITTs. Cocoa partly suppressed hyperinsulinemia in males but significantly amplified it in females and protected against loss of beta cell area in females only. The mechanisms of these sex-specific effects remain to be elucidated. This study informs additional experiments with larger sample sizes and demonstrates that sex differences must be considered when designing dietary interventions for T2D.}, publisher={MDPI AG}, author={Racine, Kathryn C. and Iglesias-Carres, Lisard and Herring, Jacob A. and Ferruzzi, Mario G. and Kay, Colin D. and Tessem, Jeffery S. and Neilson, Andrew P.}, year={2022}, month={Jan} }
 @article{racine_iglesias-carres_herring_ferruzzi_kay_tessem_neilson_2022, title={Cocoa extract exerts sex-specific anti-diabetic effects in an aggressive type-2 diabetes model: A pilot study}, volume={626}, ISSN={["1090-2104"]}, DOI={10.1016/j.bbrc.2022.08.018}, abstractNote={Type 2 diabetes (T2D) is characterized by hyperglycemia and insulin resistance. Cocoa may slow T2D development and progression. This study employed male and female BTBR.Cg-Lepob/ob/WiscJ (ob/ob) and wild type (WT) controls to assess the potential for cocoa to ameliorate progressive T2D and compare responses between sexes. Mice received diet without (WT, ob/ob) or with cocoa extract (ob/ob + c) for 10 weeks. Acute cocoa reduced fasting hyperglycemia in females, but not males, after 2 weeks. Chronic cocoa supplementation (6-10 weeks) ameliorated hyperinsulinemia in males and worsened hyperlipidemia and hyperinsulinemia in females, yet also preserved and enhanced beta cell survival in females. The underlying mechanisms of these differences warrant further study. If sex differences are apparent in subsequent preclinical studies, clinical studies will be warranted to establish whether these differences are relevant in humans. Sex differences may need to be considered when designing human dietary interventions for T2D.}, journal={BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS}, author={Racine, Kathryn C. and Iglesias-Carres, Lisard and Herring, Jacob A. and Ferruzzi, Mario G. and Kay, Colin D. and Tessem, Jeffery S. and Neilson, Andrew P.}, year={2022}, month={Oct}, pages={205–210} }
 @article{rathinasabapathy_lomax_srikanth_esposito_kay_komarnytsky_2022, title={Effect of Wild Blueberry Metabolites on Biomarkers of Gastrointestinal and Immune Health In Vitro}, volume={2}, url={https://doi.org/10.3390/immuno2020019}, DOI={10.3390/immuno2020019}, abstractNote={Wild blueberries (Vaccinium angustifolium Aiton.) are a rich source of dietary fiber and (poly)phenols with gastrointestinal and immune health-promoting properties, however, their mechanisms of action on the intestinal epithelial cells and transient tissue macrophages remain to be elucidated. In this study, we evaluated the individual effects of anthocyanins, short-chain fatty acids (metabolites derived from fiber), and a series of hydroxycinnamic and hydroxybenzoic acid metabolites common to anthocyanins and other polyphenols on epithelial gut homeostasis in human colon epithelial CCD-18 cells and murine RAW 264.7 macrophages. Gastrointestinal cell migration was enhanced in response to anthocyanin glucosides with the maximum effect observed for malvidin-3-glucoside, and a structural subset of hydroxybenzoic acids, especially 2-hydroxybenzoic acid. Enhanced staining for ZO-1 protein in the junctional complexes was observed in CCD-18 cells treated with malvidin and butyrate, as well as several phenolic metabolites, including hydroxybenzoic and hydroxycinnamic acids. Nitric oxide production and pro-inflammatory gene expression profiles in the LPS-stimulated macrophages were mostly affected by treatments with 3-caffeoylquinic (chlorogenic) and 3,4-dihydroxycinnamic (caffeic) acids, as well as 2-hydroxybenzoic acid. This study lays the foundation for future investigations evaluating the effects of dietary interventions on managing gastrointestinal and inflammatory pathophysiological outcomes.}, number={2}, journal={Immuno}, publisher={MDPI AG}, author={Rathinasabapathy, Thirumurugan and Lomax, Jade and Srikanth, Kavin and Esposito, Debora and Kay, Colin D. and Komarnytsky, Slavko}, year={2022}, month={Mar}, pages={293–306} }
 @article{li_rushing_schroder_sumner_kay_2022, title={Exploring the Contribution of (Poly)phenols to the Dietary Exposome Using High Resolution Mass Spectrometry Untargeted Metabolomics}, volume={2}, ISSN={["1613-4133"]}, url={https://doi.org/10.1002/mnfr.202100922}, DOI={10.1002/mnfr.202100922}, abstractNote={ScopeThis study presents a workflow to construct a Dietary Exposome Library (DEL) comprised of phytochemicals and their metabolites derived from host and gut microbiome metabolism for use in peak identification/annotation of untargeted metabolomics datasets.}, journal={MOLECULAR NUTRITION & FOOD RESEARCH}, publisher={Wiley}, author={Li, Yuan-Yuan and Rushing, Blake and Schroder, Madison and Sumner, Susan and Kay, Colin D.}, year={2022}, month={Feb} }
 @article{diaz_foegeding_stapleton_kay_iorizzo_ferruzzi_lila_2022, title={Foaming and sensory characteristics of protein-polyphenol particles in a food matrix}, url={https://doi.org/10.1016/j.foodhyd.2021.107148}, DOI={10.1016/j.foodhyd.2021.107148}, abstractNote={As food ingredients, protein-polyphenol aggregate particles provide a combination of structural and health-relevant functional benefits. Particles made by complexing whey (WPI) or rice (RPI) protein isolates and blueberry (BB) extracts were evaluated for foaming properties (foam volume, stability, and yield stress) using a high energy-input foaming operation (with an Ultra Power Mixer), and then also compared at low energy-input (foamed using a hand-held mixer). In the high energy-input foaming operation, whey protein rapidly formed foams (within 2 min). Whey protein-blueberry (WPI-BB) particles significantly improved yield stress and foam stability (2-fold) as compared to foams made with unmodified WPI. Rice protein required longer (>8 min) to produce foams, but foams were significantly more stable (longer drainage half-life) both when the protein was unmodified (RPI) or formulated as particles (RPI-BB). Protein-polyphenol particle foams (WPI-BB or RPI-BB) had a much greater proportion of smaller sized bubbles than polyphenol-free foams. WPI foams formed for descriptive analysis using the low energy-input method rapidly produced structures with fine, stable bubbles resistant to breakdown in the mouth, while those made with RPI had fewer, larger and looser bubbles which broke more easily after mixing and in the mouth. Inclusion of WPI-BB or RPI-BB particles enhanced palatability of protein isolates in a model (protein bars) food system as compared to non-complexed proteins. The complexed aggregate particles also provided sweetness, dark berry and dried fruit flavors and minimized bitterness and astringency. This work provides a context for understanding the utilization of protein-polyphenol particles as multifunctional ingredients that simultaneously deliver concentrated polyphenols associated with health benefits.}, journal={Food Hydrocolloids}, author={Diaz, Joscelin T. and Foegeding, E. Allen and Stapleton, Lee and Kay, Colin and Iorizzo, Massimo and Ferruzzi, Mario G. and Lila, Mary Ann}, year={2022}, month={Feb} }
 @article{griffin_kohrt_rathore_kay_grabowska_neilson_2022, title={Microbial Metabolites of Flavanols in Urine are Associated with Enhanced Anti-Proliferative Activity in Bladder Cancer Cells In Vitro}, volume={74}, ISSN={["1532-7914"]}, url={https://doi.org/10.1080/01635581.2020.1869277}, DOI={10.1080/01635581.2020.1869277}, abstractNote={Dietary flavanols and their metabolites are excreted primarily via the urine, suggesting uroepithelial cells as a site of activity due to lengthy exposure to high concentrations of these compounds. Flavanols are metabolized by the gut microbiota to numerous bioavailable metabolites. The observed effects of flavanols, including cancer chemoprevention, may be due in part to the activities of microbial metabolites. Most in vitro mechanistic work in this area relies on a limited pool of commercially available or synthesized flavanol microbial metabolites, and little work has been done in the area of bladder cancer. The impact of physiologically relevant mixtures of native flavanols and their metabolites generated in vivo remains unknown. Rats were fed various flavanols after which 48 h urine samples, approximating the total bioavailable metabolome, were collected. Urine samples were profiled by UPLC-MS/MS, and their anti-proliferative activities were assayed in vitro in four bladder cancer cell models. Significant interindividual variability was observed for chemical profiles and anti-proliferative activities. Concentrations of microbial metabolites (valerolactones, phenylalkyl acids and hippuric acids) were positively associated with reduced bladder cancer cell proliferation in vitro, while native flavanols were poorly correlated with activity. These results suggest that microbial metabolites may be the primary compounds responsible for chemoprevention in uroepithelial cell following flavanol consumption. Furthermore, this highlights the potential for exploiting knowledge about individual genetics, microbiome profiles, flavonoid metabolism profiles, tumor characteristics, etc. to design personalized dietary interventions for cancer prevention and/or adjuvant therapy to reduce bladder cancer incidence and improve outcomes.}, number={1}, journal={NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL}, author={Griffin, Laura E. and Kohrt, Sarah E. and Rathore, Atul and Kay, Colin D. and Grabowska, Magdalena M. and Neilson, Andrew P.}, year={2022}, month={Jan}, pages={194–210} }
 @article{grace_hoskin_hayes_iorizzo_kay_ferruzzi_lila_2022, title={Spray-dried and freeze-dried protein-spinach particles; effect of drying technique and protein type on the bioaccessibility of carotenoids, chlorophylls, and phenolics}, volume={388}, ISSN={["1873-7072"]}, DOI={10.1016/j.foodchem.2022.133017}, abstractNote={The effects of protein carrier and drying technique on the concentration and bioaccessibility of lipophilic compounds (lutein, β-carotene, chlorophylls a and b) and hydrophilic flavonoids in freeze-dried (FD) or spray-dried (SD) spinach juice and protein-spinach particles were investigated. Carotenoid and chlorophyll contents were highest in FD spinach juice without protein (147 and 1355 mg/100 g, respectively). For both SD and FD protein-spinach particles, SPI best protected carotenoids and chlorophylls (123 and 1160 mg/g, respectively), although the bioaccessibility of lipophilic compounds in WPI particles was higher than SPI particles (p < 0.05). For flavonoids, the drying technique was more important than the type of carrier, since FD particles had higher total flavonoids than SD. However, SD particles had higher bioaccessibility for most flavonoids (40-90 %) compared to FD (<20 %). The drying method and protein carrier can be designed to produce protein-spinach ingredients with desired concentration of compounds and bioaccessibility.}, journal={FOOD CHEMISTRY}, author={Grace, Mary H. and Hoskin, Roberta T. and Hayes, Micaela and Iorizzo, Massimo and Kay, Colin and Ferruzzi, Mario G. and Lila, Mary Ann}, year={2022}, month={Sep} }
 @misc{kay_strauch_granillo_bame_xiong_mast_burton-freeman_kay_lila_2022, title={The berry health tool chest - an evidence map and interactive resource}, volume={80}, ISSN={["1753-4887"]}, DOI={10.1093/nutrit/nuab011}, abstractNote={Abstract}, number={1}, journal={NUTRITION REVIEWS}, author={Kay, Kristine L. and Strauch, Renee C. and Granillo, Cheryl D. and Bame, Megan W. and Xiong, Jia and Mast, Aubrey C. and Burton-Freeman, Britt and Kay, Colin D. and Lila, Mary Ann}, year={2022}, month={Jan}, pages={68–77} }
 @article{virdee_saini_kay_neilson_kwan_helfrich_mooney_smith_2021, title={An enriched biosignature of gut microbiota-dependent metabolites characterizes maternal plasma in a mouse model of fetal alcohol spectrum disorder}, volume={11}, ISSN={["2045-2322"]}, url={https://europepmc.org/articles/PMC7794323}, DOI={10.1038/s41598-020-80093-8}, abstractNote={Abstract}, number={1}, journal={SCIENTIFIC REPORTS}, author={Virdee, Manjot S. and Saini, Nipun and Kay, Colin D. and Neilson, Andrew P. and Kwan, Sze Ting Cecilia and Helfrich, Kaylee K. and Mooney, Sandra M. and Smith, Susan M.}, year={2021}, month={Jan} }
 @article{racine_iglesias-carres_herring_ferruzzi_kay_tessem_neilson_2021, title={Cocoa Extract Exerts Sex-Specific Effects in an Aggressive Hyper-Glycemia Model: A Pilot Study}, volume={12}, url={https://doi.org/10.20944/preprints202112.0110.v1}, DOI={10.20944/preprints202112.0110.v1}, abstractNote={Type 2 diabetes (T2D) is characterized by hyperglycemia and insulin resistance. Cocoa may slow T2D development and progression. This study employed male and female BTBR.Cg-Lepob/ob/WiscJ and wild type (WT) controls to assess the potential for cocoa to ameliorate progressive T2D and compare responses between sexes. Mice received diet without (WT, ob/ob) or with cocoa extract (ob/ob + c) for 10 weeks. Glucose and insulin tolerance tests (GTT/ITT) were conducted at weeks 1, 5 and 2, 6, respectively. Cocoa provided mild non-significant protection against weight gain vs. ob/ob control in males but not females. Male ob/ob + c had increasing fasting glucose at weeks 1 and 5 GTTs, with significantly higher levels of fasting glucose than ob/ob control at week 5. This was not seen in females. Cocoa protected against elevated 4-hour fasting glucose in week 2, but not week 6, ITTs. Cocoa partly suppressed hyperinsulinemia in males but significantly amplified it in females and protected against loss of beta cell area in females only. The mechanisms of these sex-specific effects remain to be elucidated. This study informs additional experiments with larger sample sizes and demonstrates that sex differences must be considered when designing dietary interventions for T2D.}, publisher={MDPI AG}, author={Racine, Kathryn C. and Iglesias-Carres, Lisard and Herring, Jacob A. and Ferruzzi, Mario G. and Kay, Colin D. and Tessem, Jeffery S. and Neilson, Andrew P.}, year={2021}, month={Dec} }
 @article{mengist_bostan_young_kay_gillitt_ballington_kay_ferruzzi_ashrafi_lila_et al._2021, title={High-density linkage map construction and identification of loci regulating fruit quality traits in blueberry}, volume={8}, ISSN={["2052-7276"]}, url={https://doi.org/10.1038/s41438-021-00605-z}, DOI={10.1038/s41438-021-00605-z}, abstractNote={Abstract}, number={1}, journal={HORTICULTURE RESEARCH}, author={Mengist, Molla F. and Bostan, Hamed and Young, Elisheba and Kay, Kristine L. and Gillitt, Nicholas and Ballington, James and Kay, Colin D. and Ferruzzi, Mario G. and Ashrafi, Hamid and Lila, Mary Ann and et al.}, year={2021}, month={Dec} }
 @article{hayes_corbin_nunn_pottorff_kay_lila_iorrizo_ferruzzi_2021, title={Influence of simulated food and oral processing on carotenoid and chlorophyll in vitro bioaccessibility among six spinach genotypes}, volume={5}, ISSN={["2042-650X"]}, url={https://doi.org/10.1039/D1FO00600B}, DOI={10.1039/D1FO00600B}, abstractNote={Spinach processing and simulated mastication impact the bioaccessibility of carotenoids and chlorophylls with a spinach matrix.}, journal={FOOD & FUNCTION}, publisher={Royal Society of Chemistry (RSC)}, author={Hayes, Micaela and Corbin, Sydney and Nunn, Candace and Pottorff, Marti and Kay, Colin D. and Lila, Mary Ann and Iorrizo, Massimo and Ferruzzi, Mario G.}, year={2021}, month={May} }
 @article{huang_xiao_zhang_sandhu_chandra_kay_edirisinghe_burton-freeman_2021, title={Strawberry Consumption, Cardiometabolic Risk Factors, and Vascular Function: A Randomized Controlled Trial in Adults with Moderate Hypercholesterolemia}, volume={151}, ISSN={["1541-6100"]}, DOI={10.1093/jn/nxab034}, abstractNote={BACKGROUND
Certain fruits, such as strawberries, may impart cardiometabolic benefits due to their phytochemical content.


OBJECTIVES
Study aims were to assess the effects of strawberry intake on cardiometabolic risk factors and vascular endothelial function in adults with moderate hypercholesterolemia.


METHODS
This study was a randomized, controlled, double-blinded, 2-arm, 2-period (4-wk/period) crossover trial. Adults (n = 34; male/female 1:1; mean ± SEM age, 53 ± 1 y; BMI, 31 ± 1 kg/m2;  LDL cholesterol, 133 ± 3 mg/dL) were randomly allocated to 1 of 2 study sequences in a 1:1 ratio. Participants drank study beverages twice daily containing freeze-dried strawberry powder (2 × 25 g) or energy-, volume-matched control powder for 4 wk separated by a 4-wk washout. The primary outcome variable was the difference in fasting LDL cholesterol after 4-wk interventions. Secondary outcomes were metabolic markers, inflammation, quantitative (poly)phenolic metabolomics, flow-mediated dilation (FMD), and blood pressure (BP), with the latter (FMD, BP) also assessed acutely at 1 h and 2 h after a 50-g bolus strawberry or control beverage. Mixed-model analysis of repeated measures via PROC MIXED, PC-SAS was performed on primary and secondary outcome variables.


RESULTS
LDL cholesterol did not differ after the 4-wk interventions (P > 0.05), nor did fasting total cholesterol, triglycerides, glucose, insulin, high-sensitivity C-reactive protein, FMD, or BP (all P > 0.05). Significant intervention-by-hour interaction for FMD (P = 0.03) and BP (P = 0.05) revealed increased FMD at 1 h after strawberry compared with control by 1.5 ± 0.38% (P = 0.0008) and attenuated systolic BP at 2 h by 3.1 ± 0.99 mmHg (P = 0.02). Select phenolic metabolites increased significantly (P < 0.05) in blood following strawberry consumption while others decreased, including 3-(4-methoxyphenyl)propanoic acid-3-O-glucuronide, which was significantly correlated with increased FMD (P < 0.05).


CONCLUSION
Strawberries may improve vascular health, independent of other metabolic changes. The effect may be related to changes in microbial-derived phenolic metabolites after strawberry consumption influencing endothelial function. Data support inclusion of strawberries in a heart-healthy diet in adults with moderate hypercholesterolemia.This trial was registered at clinicaltrials.gov as NCT02612090.}, number={6}, journal={JOURNAL OF NUTRITION}, author={Huang, Leailin and Xiao, Di and Zhang, Xuhuiqun and Sandhu, Amandeep K. and Chandra, Preeti and Kay, Colin and Edirisinghe, Indika and Burton-Freeman, Britt}, year={2021}, month={Jun}, pages={1517–1526} }
 @article{nieman_gillitt_chen_zhang_sha_kay_chandra_kay_lila_2020, title={Blueberry and/or Banana Consumption Mitigate Arachidonic, Cytochrome P450 Oxylipin Generation During Recovery From 75-Km Cycling: A Randomized Trial}, volume={7}, ISSN={["2296-861X"]}, DOI={10.3389/fnut.2020.00121}, abstractNote={Oxylipins are bioactive lipid oxidation products, have vital regulatory roles in numerous physiological processes including inflammation, and can be impacted by diet. This study determined if 2-weeks of blueberry and/or acute banana ingestion influenced generation of n-6 and n-3 PUFA-derived oxylipins during recovery from exercise-induced physiological stress. Cyclists (n = 59, 39 ± 2 years of age) were randomized to freeze-dried blueberry or placebo groups, and ingested 26 grams/d (1 cup/d blueberries equivalent) for 2 weeks. Cyclists reported to the lab in an overnight fasted state and engaged in a 75-km cycling time trial (185.5 ± 5.2 min). Cyclists from each group (blueberry, placebo) were further randomized to ingestion of a water-only control or water with a carbohydrate source (Cavendish bananas, 0.2 g/kg carbohydrate every 15 min) during exercise. Blood samples were collected pre- and post-2-weeks blueberry supplementation, and 0, 1.5, 3, 5, 24, and 48 h-post-exercise. Plasma oxylipins and blueberry and banana metabolites were measured with UPLC–tandem MS/MS. Significant time by treatment effects (eight time points, four groups) were found for 24 blueberry- and seven banana-derived phenolic metabolites in plasma (FDR adjusted p < 0.05). Significant post-exercise increases were observed for 64 of 67 identified plasma oxylipins. When oxylipins were grouped relative to fatty acid substrate [arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), α-linolenic acid (ALA), linoleic acid (LA)], and enzyme systems [cytochrome P450 (CYP), lipoxygenase (LOX)], banana and blueberry ingestion were independently associated with significant post-exercise reductions in pro-inflammatory ARA-CYP hydroxy- and dihydroxy-eicosatetraenoic acids (HETEs, DiHETrEs) (treatment effects, FDR adjusted p < 0.05). These trial differences were especially apparent within the first 3 h of recovery. In summary, heavy exertion evoked a transient but robust increase in plasma levels of oxylipins in cyclists, with a strong attenuation effect linked to both chronic blueberry and acute banana intake on pro-inflammatory ARA-CYP oxylipins.}, journal={FRONTIERS IN NUTRITION}, author={Nieman, David C. and Gillitt, Nicholas D. and Chen, Guan-Yuan and Zhang, Qibin and Sha, Wei and Kay, Colin D. and Chandra, Preeti and Kay, Kristine L. and Lila, Mary Ann}, year={2020}, month={Aug} }
 @article{mengist_burtch_debelo_pottorff_bostan_nunn_corbin_kay_bassil_hummer_et al._2020, title={Development of a genetic framework to improve the efficiency of bioactive delivery from blueberry}, volume={10}, ISSN={["2045-2322"]}, url={https://europepmc.org/articles/PMC7560831}, DOI={10.1038/s41598-020-74280-w}, abstractNote={Abstract}, number={1}, journal={SCIENTIFIC REPORTS}, author={Mengist, Molla F. and Burtch, Haley and Debelo, Hawi and Pottorff, Marti and Bostan, Hamed and Nunn, Candace and Corbin, Sydney and Kay, Colin D. and Bassil, Nahla and Hummer, Kim and et al.}, year={2020}, month={Oct} }
 @article{hayes_pottorff_kay_van deynze_osorio-marin_lila_iorrizo_ferruzzi_2020, title={In Vitro Bioaccessibility of Carotenoids and Chlorophylls in a Diverse Collection of Spinach Accessions and Commercial Cultivars}, volume={68}, ISSN={["1520-5118"]}, DOI={10.1021/acs.jafc.0c00158}, abstractNote={Spinach, a nutrient-dense, green-leafy vegetable, is a rich source of carotenoid and chlorophyll bioactives. While the content of bioactives is known to vary with the genotype, variation in bioaccessibility is unknown. Bioaccessibility was explored in 71 greenhouse-grown spinach genotypes in fall and spring 2018/2019. Spinach was phenotyped for its greenness, leaf texture, leaf shape, and SPAD chlorophyll content. Postharvest, spinach was washed, blanched, and homogenized prior to assessment of bioactive bioaccessibility using a novel high-throughput in vitro digestion model followed by high-performance liquid chromatography with a photodiode array detector analysis. There was a significant variation in the bioaccessible content for all bioactives (p < 0.05), except for chlorophyll b (p = 0.063) in spring-grown spinach. The correlation coefficients of bioaccessible contents between seasons reveal that lutein (r = 0.52) and β-carotene (r = 0.55) were correlated to a greater extent than chlorophyll a (r = 0.38) and chlorophyll b (r = 0.19). The results suggest that carotenoid and chlorophyll bioaccessible contents may vary based on spinach genotypes and may be stable across seasons.}, number={11}, journal={JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY}, author={Hayes, Micaela and Pottorff, Marti and Kay, Colin and Van Deynze, Allen and Osorio-Marin, Juliana and Lila, Mary Ann and Iorrizo, Massimo and Ferruzzi, Mario G.}, year={2020}, month={Mar}, pages={3495–3505} }
 @article{kay_clifford_mena_mcdougall_andres-lacueva_cassidy_del rio_kuhnert_manach_pereira-caro_et al._2020, title={Recommendations for standardizing nomenclature for dietary (poly)phenol catabolites}, volume={112}, ISSN={["1938-3207"]}, url={https://europepmc.org/articles/PMC7528558}, DOI={10.1093/ajcn/nqaa204}, abstractNote={ABSTRACT There is a lack of focus on the protective health effects of phytochemicals in dietary guidelines. Although a number of chemical libraries and databases contain dietary phytochemicals belonging to the plant metabolome, they are not entirely relevant to human health because many constituents are extensively metabolized within the body following ingestion. This is especially apparent for the highly abundant dietary (poly)phenols, for which the situation is compounded by confusion regarding their bioavailability and metabolism, partially because of the variety of nomenclatures and trivial names used to describe compounds arising from microbial catabolism in the gastrointestinal tract. This confusion, which is perpetuated in online chemical/metabolite databases, will hinder future discovery of bioactivities and affect the establishment of future dietary guidelines if steps are not taken to overcome these issues. In order to resolve this situation, a nomenclature system for phenolic catabolites and their human phase II metabolites is proposed in this article and the basis of its format outlined. Previous names used in the literature are cited along with the recommended nomenclature, International Union of Pure and Applied Chemistry terminology, and, where appropriate, Chemical Abstracts Service numbers, InChIKey, and accurate mass.}, number={4}, journal={AMERICAN JOURNAL OF CLINICAL NUTRITION}, author={Kay, Colin D. and Clifford, Michael N. and Mena, Pedro and McDougall, Gordon J. and Andres-Lacueva, Cristina and Cassidy, Aedin and Del Rio, Daniele and Kuhnert, Nikolai and Manach, Claudine and Pereira-Caro, Gema and et al.}, year={2020}, month={Oct}, pages={1051–1068} }
 @article{lloyd_griffin_krueger_beales_barlow_sheets_ekpo_ross_chandra_rathore_et al._2020, title={Supplemental treatment options for diabetes: how flavanol metabolites improve beta-cell function}, volume={34}, ISSN={["1530-6860"]}, DOI={10.1096/fasebj.2020.34.s1.05762}, abstractNote={Diabetes is one of the fastest growing non‐infectious diseases in the world. Current treatments are composed of pharmaceutical agents that enhance insulin sensitivity and eventual insulin monotherapy. Type 2 diabetes is characterized by insulin insensitivity of peripheral tissue, glucose intolerance, and β‐cell dysfunction. Dietary interventions may benefit patients with diabetes, and various plant derived flavonoids have been shown to exert anti‐diabetic effects. While these flavonoids are large, difficult to absorb, and rarely found in circulation, gut bacteria metabolize these into smaller metabolites which can be observed in circulation. We hypothesize that these gut bacteria derived flavanoid metabolites are absorbed and have direct effects on β‐cell function. Male outbred wistar rats were fed one of three diets in the presence or absence of antibiotic treatment: standard diet, standard diet supplemented with catechin hydrate and epicatechin, or standard diet supplemented with grape seed extract. Total urine was collected from the animals (representing the total amount of absorbed metabolites), then metabolites were extracted and reconstituted in water. Here we present data regarding the in vitro effects of these absorbed gut bacteria derived flavanoids on INS‐1 832/13 β‐cell insulin secretion and proliferation. This study sheds further light on the potential ability of flavanoids and their gut bacteria derived metabolites to enhance functional β‐cell mass.}, journal={FASEB JOURNAL}, author={Lloyd, Trevor and Griffin, Laura and Krueger, Emily and Beales, Joseph and Barlow, Andrew and Sheets, Jared and Ekpo, Idongesit and Ross, Mimi and Chandra, Preeti and Rathore, Atul and et al.}, year={2020}, month={Apr} }
 @misc{frank_fukagawa_bilia_johnson_kwon_prakash_miyazawa_clifford_kay_crozier_et al._2020, title={Terms and nomenclature used for plant-derived components in nutrition and related research: efforts toward harmonization}, volume={78}, ISSN={["1753-4887"]}, DOI={10.1093/nutrit/nuz081}, abstractNote={Abstract}, number={6}, journal={NUTRITION REVIEWS}, author={Frank, Jan and Fukagawa, Naomi K. and Bilia, Anna R. and Johnson, Elizabeth J. and Kwon, Oran and Prakash, Vish and Miyazawa, Teruo and Clifford, Michael N. and Kay, Colin D. and Crozier, Alan and et al.}, year={2020}, month={Jun}, pages={451–458} }
 @article{burtch_ferruzzi_kay_lila_iorrizo_mengist_2019, title={Adaptation of an in Vitro Digestion Model for High Throughput Phenolic Bioaccessibility Phenotyping Within Cultivated (highbush) Blueberry Varieties (P06-004-19)}, volume={3}, DOI={10.1093/cdn/nzz031.P06-004-19}, abstractNote={Objectives
Modern breeding strategies have advanced our knowledge of factors influencing phenolic content in plant foods such as highbush (HB) blueberries. However, potential traits related to phenolic bioavailability remain unknown due to limitations in phenotyping methods. In vitro digestion models have proven useful for estimation of phytochemical bioavailability, however, these models remain inefficient for screening large germplasm collections. High throughput (HT) models suitable for screening of larger HB blueberry populations are needed to advance our knowledge of genotypes and genetic factors influencing phenolic density and bioavailability.


Methods
An established low throughput (LT) three stage in vitro digestion model previously used for fruit phenolics was adapted to reduce tissue amounts, digestion volume and modified enzyme concentrations allowing for compatibility with a robotic fluid handling system (TECAN EVO) for HT. Bioaccessibility of phenolics from commercial HB blueberries was optimized for HT and validated against the LT method. The HT model was then used to screen phenolic bioaccessibility in a subset of 33 individual blueberry genotypes derived from a mapping population of Draper x Jewel (DxJ) genotypes.


Results
Bioaccessibility of anthocyanins (ANC), flavonols (FLAV), flavan-3-ols (F3L) and phenolic acids (PA) were well correlated (R = 0.92) between HT and LT methods. Calculated CV ranged from 2-14% for HT and for LT 2-20% respectively suggesting good reproducibility. Phenolic content within the DxJ subset ranged from 31.7-81.1 mg/100 g fw. Approximately, 60% of the phenolics were ANC with chlorogenic acid (28%), FLAV (< 1%) and F3L (12%) accounting for the rest. Variation in bioaccessibility was observed within all phenolic classes with ANC (0.3-11.7; P < 0.001), Acylated ANC (7.9-31.8; P < 0.001), FLAV (14.4-52.7; P = 0.001), FL3(1.5-72.9; P = 0.002) and PA (0.2-7.9; P = < 0.001).


Conclusions
A HT in vitro digestion model provides a novel tool for phenotyping phenolic bioaccessibility in blueberry fruit. Application to a subset of DxJ genotypes further suggest that variation in phenolic bioaccessibility exist and highlights the need for investigation of diversity panels and mapping populations.


Funding Sources
Foundation for Food and Agriculture Research.}, number={Supplement 1}, journal={Current Developments in Nutrition}, publisher={Oxford University Press}, author={Burtch, Haley and Ferruzzi, Mario and Kay, Colin and Lila, Mary and Iorrizo, Massimo and Mengist, Molla}, year={2019}, month={Jun} }
 @article{curtis_van der velpen_berends_jennings_feelisch_umpleby_evans_fernandez_meiss_minnion_et al._2019, title={Blueberries improve biomarkers of cardiometabolic function in participants with metabolic syndrome—results from a 6-month, double-blind, randomized controlled trial}, volume={109}, ISSN={0002-9165 1938-3207}, url={http://dx.doi.org/10.1093/ajcn/nqy380}, DOI={10.1093/ajcn/nqy380}, abstractNote={ABSTRACT Background Anthocyanin-rich blueberry intake is associated with reduced type 2 diabetes and cardiovascular disease (CVD) risk in prospective studies, although long-term randomized controlled trials (RCTs) have not been conducted in at-risk populations. Objective In the longest-duration RCT to date, we examined the effect of 6-mo blueberry intake on insulin resistance and cardiometabolic function in metabolic syndrome. Methods A double-blind, parallel RCT (n = 115; age 63 ± 7 y; 68% male; body mass index 31.2 ± 3.0 kg/m2) was conducted, which fed 2 dietarily achievable blueberry intakes [equivalent to 1/2 and 1 cup/d (75/150 g)] compared with matched placebo. Insulin resistance was assessed via the homeostasis model assessment of insulin resistance (primary endpoint) and confirmed by [6-6-2H2]-glucose-labeled, 2-step hyperinsulinemic clamp (n = 20). Clinically relevant cardiometabolic endpoints [including flow-mediated dilatation, augmentation index, lipoprotein status (by nuclear magnetic resonance spectroscopy), and nitric oxide (NO)-related metabolite assay] and anthocyanin metabolism were assessed. Results A daily intake of 1 cup of blueberries improved endothelial function (flow-mediated dilatation: +1.45%; 95% CI: 0.83%, 2.1%; P = 0.003), systemic arterial stiffness (augmentation index: –2.24%; 95% CI: –3.97%, –0.61%; P = 0.04) and attenuated cyclic guanosine monophosphate concentrations. In statin nonusers (n = 71), elevated high-density lipoprotein cholesterol (+0.08 mmol/L; P = 0.03), high-density lipoprotein particle density (+0.48n, ×10–6; P = 0.002) and apolipoprotein A-I (+0.05 g/L; P = 0.01) concentrations were observed following the 1-cup/d intervention. Treatment compliance was 94.1% (wrapper returns) and total concentrations of anthocyanin-derived phenolic acid metabolites significantly increased, dose-dependently, in serum and 24-h urine (P < 0.01 and P < 0.001, respectively). Insulin resistance, pulse wave velocity, blood pressure, NO, and overall plasma thiol status were unaffected. Likewise, a half cup per day had no effect on any biomarkers. Conclusions Despite insulin resistance remaining unchanged we show, to our knowledge, the first sustained improvements in vascular function, lipid status, and underlying NO bioactivity following 1 cup blueberries/d. With effect sizes predictive of 12–15% reductions in CVD risk, blueberries should be included in dietary strategies to reduce individual and population CVD risk. This study was registered at clinicaltrials.gov as NCT02035592.}, number={6}, journal={The American Journal of Clinical Nutrition}, publisher={Oxford University Press (OUP)}, author={Curtis, Peter J and van der Velpen, Vera and Berends, Lindsey and Jennings, Amy and Feelisch, Martin and Umpleby, A Margot and Evans, Mark and Fernandez, Bernadette O and Meiss, Mia S and Minnion, Magdalena and et al.}, year={2019}, month={May}, pages={1535–1545} }
 @article{chandra_rathore_kay_everhart_curtis_burton-freeman_cassidy_kay_2019, title={Contribution of Berry Polyphenols to the Human Metabolome}, url={https://www.mdpi.com/1420-3049/24/23/4220}, DOI={10.3390/molecules24234220}, abstractNote={Diets rich in berries provide health benefits, however, the contribution of berry phytochemicals to the human metabolome is largely unknown. The present study aimed to establish the impact of berry phytochemicals on the human metabolome. A “systematic review strategy” was utilized to characterize the phytochemical composition of the berries most commonly consumed in the USA; (poly)phenols, primarily anthocyanins, comprised the majority of reported plant secondary metabolites. A reference standard library and tandem mass spectrometry (MS/MS) quantitative metabolomics methodology were developed and applied to serum/plasma samples from a blueberry and a strawberry intervention, revealing a diversity of benzoic, cinnamic, phenylacetic, 3-(phenyl)propanoic and hippuric acids, and benzyldehydes. 3-Phenylpropanoic, 2-hydroxybenzoic, and hippuric acid were highly abundant (mean > 1 µM). Few metabolites at concentrations above 100 nM changed significantly in either intervention. Significant intervention effects (P < 0.05) were observed for plasma/serum 2-hydroxybenzoic acid and hippuric acid in the blueberry intervention, and for 3-methoxyphenylacetic acid and 4-hydroxyphenylacetic acid in the strawberry intervention. However, significant within-group effects for change from baseline were prevalent, suggesting that high inter-individual variability precluded significant treatment effects. Berry consumption in general appears to cause a fluctuation in the pools of small molecule metabolites already present at baseline, rather than the appearance of unique berry-derived metabolites, which likely reflects the ubiquitous nature of (poly)phenols in the background diet.}, journal={Molecules}, author={Chandra, Preeti and Rathore, Atul S and Kay, Kristine and Everhart, Jessica L. and Curtis, Peter and Burton-Freeman, Britt and Cassidy, Aedin and Kay, Colin}, year={2019}, month={Nov} }
 @article{hayes_pottorff_kay_van deynze_osorio-marin_lila_iorrizo_ferruzzi_2019, title={Diversity in the Bioaccessibility of Carotenoid and Chlorophyll Compounds in 69 Spinach Genotypes (P06-007-19)}, volume={3}, DOI={10.1093/cdn/nzz031.P06-007-19}, abstractNote={Objectives
Spinach is one of the most nutrient dense and popular green leafy vegetables. Known as a rich source of pro-vitamin A carotenoids and chlorophylls, the variation in content of these bioactives has been associated with differences in genetics, environment and processing. However, beyond processing, factors affecting their bioavailability remain relatively unknown. Establishing the presence of diversity in bioaccessibility, a phenotypical surrogate for bioavailability, of phytochemicals from public germplasm collections and commercial cultivars would provide critical information to breeders seeking to improve the nutritional value of the material used in their programs.


Methods
69 spinach accessions from both the USDA Germplasm Resource Information Network (GRIN) and the Center for Genetic Resources (CGN), the Netherlands, and selected commercial varieties were greenhouse-grown during the Fall 2018 season at Piedmont Research Station, NC, harvested, washed, blanched (100°C, 2 min) and homogenized (30 sec). Carotenoid and chlorophyll bioaccessibility were determined from spinach homogenates formulated with 5% canola oil using a high-throughput, three-phase in vitro digestion followed by centrifugation and filtration to isolate the micellar fraction. Transfer of lutein (LUT), β-carotene (BC) and pheophytin A (Phe A) and B (Phe B) from spinach to micellar fractions was quantified by LC to determine bioaccessibility.


Results
LUT and BC were well recovered through in vitro digestion while chlorophylls were quantitatively converted to corresponding pheophytins. Relative bioaccessibility for all phytochemicals was found to be significantly different across genotypes, as determined by ANOVA analysis. LUT bioaccessibiltiy ranged from 9.4-30.6% (P = 0.01), BC (12.9-42.5%; P < 0.001), PheA (24.5-51%; P = < 0.001), and PheB (19.8-46.9% P = < 0.001). Absolute bioaccessible content ranged from 0.6-8.2 and 0.9-3.7 mg/100 g fw spinach for LUT and BC, respectively.


Conclusions
Results suggest that carotenoid and chlorophyll bioaccessibility may vary based on spinach genotype. The relationship of bioaccessibility to quality traits and potential interactions with agronomic (GxE) and processing (GxP) conditions remain to be explored.


Funding Sources
Foundation for Food and Agriculture Research.}, number={Supplement 1}, journal={Current Developments in Nutrition}, publisher={Oxford University Press}, author={Hayes, Micaela and Pottorff, Marti and Kay, Colin and Van Deynze, Allen and Osorio-Marin, Jualiana and Lila, Mary and Iorrizo, Massimo and Ferruzzi, Mario}, year={2019}, month={Jun} }
 @article{kay_everhart_rathore_2019, title={Managing Risks Associated with Establishing the Metabolome of Dietary Phytochemicals (P06-010-19)}, volume={3}, DOI={10.1093/cdn/nzz031.P06-010-19}, abstractNote={Objectives
Establishing the metabolome of dietary phytochemicals is complicated by the influence of the microbiome. Due to large numbers of human, microbial and hybrid human-microbial metabolites, false-positive identification via mass spectrometry (MS) is probable. Users must be aware of the influence of matrix and instrumental background environment upon the mass spectrum, which produce spectral features arising from fragmentation, gas-phase artifacts, molecular rearrangement, quasi-molecular ion or radical formation. Hydroxylated cyclic and polycyclic structures such as polyphenols are prone to multiple gas-phase artifacts, including water elimination (loss -17), hydrogen elimination (-1), radical fragmentation (loss -15, -14), Retro-Diels-Alder reactions (C-ring electron rearrangement; + or -2), or combinations thereof. In-source fragmentation is often observed for phase II conjugates, such as sulfate, glucuronide and glycine. Finally, polyphenol metabolites such as valerolactones, benzoic, phenylpropanoic and phenylacetic acids, are also products of MS fragmentation. As there are few reference standards available for confirmation or optimization, false-positive identification is likely. The objective of the present study was to highlight limitations with MS to ensure researchers make appropriate assumptions from their spectral data.


Methods
A quantitative metabolomics database comprising optimized spectral signals for fragmentation profiling of over 400 poly/phenols and metabolites was established using a UHPLC-coupled electrospray triple quadrupole-linear ion trap mass spectrometer (SCIEX QTRAP 6500+). Methods were established and utilized to interrogate over 3000 biospecimens derived from studies feeding various polyphenol-rich diets.


Results
Scanning for numerous metabolites reported in the literature using single transition monitoring, in both neat and extracted human and animal tissue matrices consistently identify peaks which were either artifacts, isomers, fragments or background noise, as confirmed relative to authentic reference standards.


Conclusions
Without ample MS experience, method development, validation and data interrogation, falsely identified metabolites will continue to occur and undoubtedly hinder future discovery.


Funding Sources
NIFA-USDA Hatch 1011757.}, number={Supplement 1}, journal={Current Developments in Nutrition}, publisher={Oxford University Press}, author={Kay, Colin and Everhart, Jessica and Rathore, Atul}, year={2019}, month={Jun} }
 @article{warner_rodriguez-ramiro_o’connell_kay_2018, title={Cardiovascular Mechanisms of Action of Anthocyanins May Be Associated with the Impact of Microbial Metabolites on Heme Oxygenase-1 in Vascular Smooth Muscle Cells}, volume={23}, ISSN={1420-3049}, url={http://dx.doi.org/10.3390/molecules23040898}, DOI={10.3390/molecules23040898}, abstractNote={Anthocyanins are reported to have cardio-protective effects, although their mechanisms of action remain elusive. We aimed to explore the effects of microbial metabolites common to anthocyanins and other flavonoids on vascular smooth muscle heme oxygenase-1 (HO-1) expression. Thirteen phenolic metabolites identified by previous anthocyanin human feeding studies, as well as 28 unique mixtures of metabolites and their known precursor structures were explored for their activity on HO-1 protein expression in rat aortic smooth muscle cells (RASMCs). No phenolic metabolites were active when treated in isolation; however, five mixtures of phenolic metabolites significantly increased HO-1 protein expression (127.4–116.6%, p ≤ 0.03). The present study demonstrates that phenolic metabolites of anthocyanins differentially affect HO-1 activity, often having additive, synergistic or nullifying effects.}, number={4}, journal={Molecules}, publisher={MDPI AG}, author={Warner, Emily and Rodriguez-Ramiro, Ildefonso and O’Connell, Maria and Kay, Colin}, year={2018}, month={Apr}, pages={898} }
 @article{ahmad_rich_koch_croft_ferruzzi_kay_hodgson_ward_2018, title={Effect of adding milk to black tea on vascular function in healthy men and women: a randomised controlled crossover trial}, volume={9}, ISSN={2042-6496 2042-650X}, url={http://dx.doi.org/10.1039/c8fo01019f}, DOI={10.1039/c8fo01019f}, abstractNote={Addition of milk to black tea alters the acute/short-term benefical effect of regular black tea consumption on vascular function and blood pressure.}, number={12}, journal={Food & Function}, publisher={Royal Society of Chemistry (RSC)}, author={Ahmad, Adilah F. and Rich, Lisa and Koch, Henrietta and Croft, Kevin D. and Ferruzzi, Mario G. and Kay, Colin D. and Hodgson, Jonathan M. and Ward, Natalie C.}, year={2018}, pages={6307–6314} }
 @article{nieman_kay_rathore_grace_strauch_stephan_sakaguchi_lila_2018, title={Increased Plasma Levels of Gut-Derived Phenolics Linked to Walking and Running Following 2-Weeks Flavonoid Supplementation}, volume={10}, url={https://doi.org/10.20944/preprints201810.0287.v1}, DOI={10.20944/preprints201810.0287.v1}, abstractNote={Using a randomized, double-blinded, placebo-controlled, parallel group design, this investigation determined if the combination of 2-weeks flavonoid supplementation (329 mg/day, quercetin, anthocyanins, flavan-3-ols mixture) and a 45-minute walking bout (62.2&plusmn;0.9% VO2max) enhanced the translocation of gut-derived phenolics into circulation in a group of walkers (N = 77). The walkers (flavonoid, placebo groups) were randomized to either sit or walk briskly on treadmills for 45 minutes (thus four groups: placebo-sit, placebo-walk, flavonoid-sit, flavonoid-walk). A comparator group of runners (N = 19) ingested a double flavonoid dose for 2 weeks (658 mg/day) and ran for 2.5 h (69.2&plusmn;1.2% VO2max). Four blood samples were collected (pre- and post-supplementation, immediately-post- and 24-h post-exercise/rest). Of the 76 metabolites detected in this targeted analysis, 15 increased after the 2.5-h run, and when grouped were also elevated post-exercise (versus placebo-sit) for the placebo- and flavonoid-walking groups (P < 0.05). A secondary analysis showed that pre-study plasma concentrations of gut-derived phenolics in the runners were 40% higher compared to walkers (P = 0.031). These data indicate that acute exercise bouts (brisk walking, intensive running) are linked to an increased translocation of gut-derived phenolics into circulation, an effect that is amplified when combined with a 2-week period of increased flavonoid intake or chronic training as a runner.}, publisher={MDPI AG}, author={Nieman, David C. and Kay, Colin D. and Rathore, Artul S. and Grace, Mary H. and Strauch, Renee C. and Stephan, Ella H. and Sakaguchi, Camila A. and Lila, Mary Ann}, year={2018}, month={Oct} }
 @article{nieman_kay_rathore_grace_strauch_stephan_sakaguchi_lila_2018, title={Increased Plasma Levels of Gut-Derived Phenolics Linked to Walking and Running Following Two Weeks of Flavonoid Supplementation}, volume={10}, url={http://www.mdpi.com/2072-6643/10/11/1718}, DOI={10.3390/nu10111718}, abstractNote={Using a randomized, double-blinded, placebo-controlled, parallel group design, this investigation determined if the combination of two weeks of flavonoid supplementation (329 mg/day, quercetin, anthocyanins, flavan-3-ols mixture) and a 45-minute walking bout (62.2 ± 0.9% VO2max (maximal oxygen consumption rate)) enhanced the translocation of gut-derived phenolics into circulation in a group of walkers (n = 77). The walkers (flavonoid, placebo groups) were randomized to either sit or walk briskly on treadmills for 45 min (thus, four groups: placebo–sit, placebo–walk, flavonoid–sit, flavonoid–walk). A comparator group of runners (n = 19) ingested a double flavonoid dose for two weeks (658 mg/day) and ran for 2.5 h (69.2 ± 1.2% VO2max). Four blood samples were collected (pre- and post-supplementation, immediately post- and 24 h post-exercise/rest). Of the 76 metabolites detected in this targeted analysis, 15 increased after the 2.5 h run, and when grouped were also elevated post-exercise (versus placebo–sit) for the placebo– and flavonoid–walking groups (p < 0.05). A secondary analysis showed that pre-study plasma concentrations of gut-derived phenolics in the runners were 40% higher compared to walkers (p = 0.031). These data indicate that acute exercise bouts (brisk walking, intensive running) are linked to an increased translocation of gut-derived phenolics into circulation, an effect that is amplified when combined with a two-week period of increased flavonoid intake or chronic training as a runner.}, number={11}, journal={Nutrients}, author={Nieman, David C. and Kay, Colin and Rathore, Atul S and Grace, Mary H. and Strauch, Renee C. and Stephan, Ella H. and Sakaguchi, Camila A. and Lila, Mary Ann}, year={2018}, month={Nov} }
 @article{williamson_kay_crozier_2018, title={The Bioavailability, Transport, and Bioactivity of Dietary Flavonoids: A Review from a Historical Perspective}, volume={17}, ISSN={1541-4337}, url={http://dx.doi.org/10.1111/1541-4337.12351}, DOI={10.1111/1541-4337.12351}, abstractNote={Abstract}, number={5}, journal={Comprehensive Reviews in Food Science and Food Safety}, publisher={Wiley}, author={Williamson, Gary and Kay, Colin D. and Crozier, Alan}, year={2018}, month={Jul}, pages={1054–1112} }
 @article{kay_pereira-caro_ludwig_clifford_crozier_2017, title={Anthocyanins and Flavanones Are More Bioavailable than Previously Perceived: A Review of Recent Evidence}, volume={8}, ISSN={["1941-1421"]}, DOI={10.1146/annurev-food-030216-025636}, abstractNote={ This review considers recent investigations on the bioavailability of anthocyanins and flavanones. Both flavonoids are significant dietary components and are considered to be poorly bioavailable, as only low levels of phase II metabolites appear in the circulatory system and are excreted in urine. However, when lower molecular weight phenolic and aromatic ring-fission catabolites, produced primarily by the action of the colonic microbiota, are taken into account, it is evident that anthocyanins and flavanones are much more bioavailable than previously envisaged. The metabolic events to which these flavonoids are subjected as they pass along the gastrointestinal tract and are absorbed into the circulatory system prior to their rapid elimination by renal excretion are highlighted. Studies on the impact of other food components and the probiotic intake on flavonoid bioavailability are summarized, as is the bioactivity of metabolites and catabolites assayed using a variety of in vitro model systems. }, journal={ANNUAL REVIEW OF FOOD SCIENCE AND TECHNOLOGY, VOL 8}, author={Kay, Colin D. and Pereira-Caro, Gema and Ludwig, Iziar A. and Clifford, Michael N. and Crozier, Alan}, year={2017}, pages={155–180} }
 @article{nieman_ramamoorthy_kay_goodman_capps_shue_heyl_grace_lila_2017, title={Influence of Ingesting a Flavonoid-Rich Supplement On the Human Metabolome and Concentration of Urine Phenolics}, volume={31}, DOI={10.1096/fasebj.31.1_supplement.972.26}, abstractNote={A variety of polyphenol‐rich supplements (juices, extracts, purified flavonoids) have been tested at low to high doses for varying lengths of time, typically with study participants at high disease risk. Results have been mixed, perhaps because of short dosing periods, low subject numbers, and the lack of focus on whole body metabolic responses. This study evaluated the effect of ingesting a flavonoid‐rich supplement (329 mg/d) on total urine phenolics and shifts in plasma metabolites in overweight/obese female adults using untargeted, global metabolomics procedures. Participants (N=103, 18–65 y, BMI ≥ 25 kg/m2) were randomized to flavonoid or placebo groups for 12 weeks, with blood and 24‐h urine samples collected pre‐study, 4‐ and 12‐weeks in a parallel design. Supplements were prepared as chewable tablets, and included vitamin C, wild bilberry fruit extract, green tea leaf extract, quercetin, caffeine, and omega 3 fatty acids. One serving (4 chewable tablets) contained 50 kilocalories, 100 mg vitamin C, 60 mg n3‐PUFA (24 mg docosahexaenoic acid, 36 mg eicosapentaenoic acid), 107 mg caffeine, and 329 mg total flavonoids. Analysis of pre‐ and post‐study 3‐day food records revealed the flavonoid supplement increased dietary intake by 217% (138±23.0 to 437±20.1 mg/day) compared to placebo (interaction effect, p<0.001). At 4‐weeks, urine total phenolics increased 24% in the flavonoid group above placebo, with similar changes at 12‐weeks (interaction effect, P=0.041). Groups did not differ in traditional markers of inflammation (IL‐6, MCP‐1, CRP) or oxidative stress (oxLDL, FRAP). Metabolomics data indicated shifts in 63 plasma metabolites in the flavonoid versus placebo group, with 70% of these from the lipid and xenobiotics super pathways. The largest fold changes were measured for three gut‐derived phenolics including 3‐methoxycatechol sulfate, 3‐(3‐hydroxyphenyl)propanoic acid sulfate, and 1,2,3‐benzenetriol sulfate (interaction effects, p≤0.050). Small group differences in 29 metabolites from the lipid super pathway were more than likely related to the combined influence of green tea extract and caffeine. This randomized clinical trial of overweight/obese women showed that 12‐weeks ingestion of a mixed flavonoid‐nutrient supplement was associated with a corresponding increase in urine total phenolics and gut‐derived phenolic metabolites. The lack of change in traditional measures of inflammation and oxidative stress in this study is consistent with other 10‐ to 12‐week polyphenol supplementation investigations, and supports the strategy of using metabolomics procedures to better define physiological responses in humans.}, number={Supplement 1}, journal={The FASEB Journal}, author={Nieman, David C. and Ramamoorthy, Sivapriya and Kay, Colin D. and Goodman, Courtney L. and Capps, Christopher R. and Shue, Zachary L. and Heyl, Nicole and Grace, Mary H. and Lila, Mary Ann}, year={2017}, pages={972.26} }
 @article{nieman_ramamoorthy_kay_goodman_capps_shue_heyl_grace_lila_2017, title={Influence of Ingesting a Flavonoid-Rich Supplement on the Metabolome and Concentration of Urine Phenolics in Overweight/Obese Women}, volume={16}, ISSN={["1535-3907"]}, url={http://dx.doi.org/10.1021/acs.jproteome.7b00196}, DOI={10.1021/acs.jproteome.7b00196}, abstractNote={This study evaluated the effect of ingesting a flavonoid-rich supplement (329 mg/d) on total urine phenolics and shifts in plasma metabolites in overweight/obese female adults using untargeted metabolomics procedures. Participants (N = 103, 18-65 y, BMI ≥ 25 kg/m2) were randomized to flavonoid (F) or placebo (P) groups for 12 weeks with blood and 24 h urine samples collected prestudy and after 4 and 12 weeks in a parallel design. Supplements were prepared as chewable tablets and included vitamin C, wild bilberry fruit extract, green tea leaf extract, quercetin, caffeine, and omega 3 fatty acids. At 4 weeks, urine total phenolics increased 24% in F versus P with similar changes at 12 weeks (interaction effect, P = 0.041). Groups did not differ in markers of inflammation (IL-6, MCP-1, CRP) or oxidative stress (oxLDL, FRAP). Metabolomics data indicated shifts in 63 biochemicals in F versus P with 70% from the lipid and xenobiotics superpathways. The largest fold changes in F were measured for three gut-derived phenolics including 3-methoxycatechol sulfate, 3-(3-hydroxyphenyl)propanoic acid sulfate, and 1,2,3-benzenetriol sulfate (interaction effects, p ≤ 0.050). This randomized clinical trial of overweight/obese women showed that 12 weeks ingestion of a mixed flavonoid nutrient supplement was associated with a corresponding increase in urine total phenolics and gut-derived phenolic metabolites.}, number={8}, journal={JOURNAL OF PROTEOME RESEARCH}, author={Nieman, David C. and Ramamoorthy, Sivapriya and Kay, Colin D. and Goodman, Courtney L. and Capps, Christopher R. and Shue, Zack L. and Heyl, Nicole and Grace, Mary H. and Lila, Mary A.}, year={2017}, month={Aug}, pages={2924–2935} }
 @article{warner_smith_zhang_raheem_o'hagan_o'connell_kay_2017, title={Signatures of anthocyanin metabolites identified in humans inhibit biomarkers of vascular inflammation in human endothelial cells}, volume={61}, DOI={10.1002/mnfr.201700053}, abstractNote={Scope The physiological relevance of contemporary cell culture studies is often perplexing, given the use of unmetabolized phytochemicals at supraphysiological concentrations. We investigated the activity of physiologically relevant anthocyanin metabolite signatures, derived from a previous pharmacokinetics study of 500 mg 13C5‐cyanidin‐3‐glucoside in eight healthy participants, on soluble vascular adhesion molecule‐1 (VCAM‐1) and interleukin‐6 (IL‐6) in human endothelial cells. Methods and results Signatures of peak metabolites (previously identified at 1, 6, and 24 h post‐bolus) were reproduced using pure standards and effects were investigated across concentrations ten‐fold lower and higher than observed mean (<5 μM) serum levels. Tumor necrosis factor‐α (TNF‐α)‐stimulated VCAM‐1 was reduced in response to all treatments, with maximal effects observed for the 6 and 24 h profiles. Profiles tested at ten‐fold below mean serum concentrations (0.19–0.44 μM) remained active. IL‐6 was reduced in response to 1, 6, and 24 h profiles, with maximal effects observed for 6 h and 24 h profiles at concentrations above 2 μM. Protein responses were reflected by reductions in VCAM‐1 and IL‐6 mRNA, however there was no effect on phosphorylated NFκB‐p65 expression. Conclusion Signatures of anthocyanin metabolites following dietary consumption reduce VCAM‐1 and IL‐6 production, providing evidence of physiologically relevant biological activity.}, number={9}, journal={Molecular Nutrition & Food Research}, author={Warner, E. F. and Smith, M. J. and Zhang, Q. Z. and Raheem, K. S. and O'Hagan, D. and O'Connell, M. A. and Kay, Colin}, year={2017} }
 @article{acute benefits of the microbial-derived isoflavone metabolite equol on arterial stiffness in men prospectively recruited according to equol producer phenotype: a double-blind randomized controlled trial, 2_2016, volume={103}, number={3}, journal={The American journal of clinical nutrition}, publisher={Oxford University Press}, year={2016}, pages={694–702} }
 @article{common phenolic metabolites of flavonoids, but not their unmetabolized precursors, reduce the secretion of vascular cellular adhesion molecules by human endothelial cells--3_2016, volume={146}, number={3}, journal={The Journal of nutrition}, publisher={Oxford University Press}, year={2016}, pages={465–473} }
 @inproceedings{kay_2016, title={Elucidating metabolic signatures of phytochemical consumption}, volume={252}, booktitle={ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY}, author={Kay, Colin}, year={2016} }
 @article{amin_czank_raheem_zhang_botting_cassidy_kay_2015, title={Anthocyanins and their physiologically relevant metabolites alter the expression of IL-6 and VCAM-1 in CD40L and oxidized LDL challenged vascular endothelial cells}, volume={59}, ISSN={1613-4125}, url={http://dx.doi.org/10.1002/MNFR.201400803}, DOI={10.1002/MNFR.201400803}, abstractNote={ScopeIn vitro and in vivo studies suggest that dietary anthocyanins modulate cardiovascular disease risk; however, given anthocyanins extensive metabolism, it is likely that their degradation products and conjugated metabolites are responsible for this reported bioactivity.}, number={6}, journal={Molecular Nutrition & Food Research}, publisher={Wiley}, author={Amin, Hiren P. and Czank, Charles and Raheem, Saki and Zhang, Qingzhi and Botting, Nigel P. and Cassidy, Aedín and Kay, Colin D.}, year={2015}, month={Apr}, pages={1095–1106} }
 @article{anthocyanins and their physiologically relevant metabolites alter the expression of il-6 and vcam-1 in cd40l and oxidized ldl challenged vascular endothelial cells_2015, volume={59}, number={6}, journal={Molecular nutrition & food research}, year={2015}, pages={1095–1106} }
 @article{di gesso_kerr_zhang_raheem_yalamanchili_o'hagan_kay_o'connell_2015, title={Flavonoid metabolites reduce tumor necrosis factor-α secretion to a greater extent than their precursor compounds in human THP-1 monocytes}, volume={59}, ISSN={1613-4125}, url={http://dx.doi.org/10.1002/mnfr.201400799}, DOI={10.1002/mnfr.201400799}, abstractNote={ScopeFlavonoids are generally studied in vitro, in isolation, and as unmetabolized precursor structures. However, in the habitual diet, multiple flavonoids are consumed together and found present in the circulation as complex mixtures of metabolites. Using a unique study design, we investigated the potential for singular or additive anti‐inflammatory effects of flavonoid metabolites relative to their precursor structures.}, number={6}, journal={Molecular Nutrition & Food Research}, publisher={Wiley}, author={di Gesso, Jessica L. and Kerr, Jason S. and Zhang, Qingzhi and Raheem, Saki and Yalamanchili, Sai Krishna and O'Hagan, David and Kay, Colin D. and O'Connell, Maria A.}, year={2015}, month={May}, pages={1143–1154} }
 @article{orange juice--derived flavanone and phenolic metabolites do not acutely affect cardiovascular risk biomarkers: a randomized, placebo-controlled, crossover trial in men at moderate risk of cardiovascular disease--_2015, volume={101}, number={5}, journal={The American journal of clinical nutrition}, publisher={Oxford University Press}, year={2015}, pages={931–938} }
 @article{edwards_czank_woodward_cassidy_kay_2015, title={Phenolic Metabolites of Anthocyanins Modulate Mechanisms of Endothelial Function}, volume={63}, ISSN={0021-8561 1520-5118}, url={http://dx.doi.org/10.1021/JF5041993}, DOI={10.1021/JF5041993}, abstractNote={Anthocyanins are reported to have vascular bioactivity, however their mechanisms of action are largely unknown. Evidence suggests that anthocyanins modulate endothelial function, potentially by increasing nitric oxide (NO) synthesis, or enhancing NO bioavailability. This study compared the activity of cyanidin-3-glucoside, its degradation product protocatechuic acid, and phase II metabolite, vanillic acid. Production of NO and superoxide and expression of endothelial NO synthase (eNOS), NADPH oxidase (NOX), and heme oxygenase-1 (HO-1) were established in human vascular cell models. Nitric oxide levels were not modulated by the treatments, although eNOS was upregulated by cyanidin-3-glucoside, and superoxide production was decreased by both phenolic acids. Vanillic acid upregulated p22(phox) mRNA but did not alter NOX protein expression, although trends were observed for p47(phox) downregulation and HO-1 upregulation. Anthocyanin metabolites may therefore modulate vascular reactivity by inducing HO-1 and modulating NOX activity, resulting in reduced superoxide production and improved NO bioavailability.}, number={9}, journal={Journal of Agricultural and Food Chemistry}, publisher={American Chemical Society (ACS)}, author={Edwards, Michael and Czank, Charles and Woodward, Gary M. and Cassidy, Aedín and Kay, Colin D.}, year={2015}, month={Mar}, pages={2423–2431} }
 @article{kay_2015, title={Rethinking paradigms for studying mechanisms of action of plant bioactives}, volume={40}, ISSN={1471-9827}, url={http://dx.doi.org/10.1111/nbu.12178}, DOI={10.1111/nbu.12178}, abstractNote={Abstract}, number={4}, journal={Nutrition Bulletin}, publisher={Wiley}, author={Kay, C. D.}, year={2015}, month={Nov}, pages={335–339} }
 @inproceedings{davidson_jupp_de ferrars_kay_culley_norton_driscoll_vincent_donell_bao_2015, title={Sulfurophane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo}, volume={96}, number={2}, booktitle={International Journal of Experimental Pathology}, author={Davidson, R. and Jupp, O. and de Ferrars, R. and Kay, C. and Culley, K. and Norton, R. and Driscoll, C. and Vincent, T. and Donell, S. and Bao, Y.}, year={2015}, pages={A24} }
 @article{kay_de gesso_warner_amin_de ferrars_edwards_zang_o'hagan_o'connell_2015, title={The bioactivity of flavonoids is likely the result of cumulative low exposure to a variety of structurally similar phenolic metabolites}, volume={29}, url={https://doi.org/10.1096/fasebj.29.1_supplement.118.4}, DOI={10.1096/fasebj.29.1_supplement.118.4}, abstractNote={Activities of 21 flavonoid metabolites were investigated relative to their unmetabolized structures, utilizing 20 assays of vascular reactivity, inflammation and cellular adhesion, in endothelial (HUVEC), smooth muscle (AVSMC) and monocyte (THP‐1) cells, at physiologically relevant concentrations (0.1‐10µM). Unmetabolized flavonoids were generally less active than their phenolic metabolites. In vascular screens no metabolites altered expression of endothelin‐1 or nitric oxide, 3 metabolites induced eNOS, 2metabolites reduced angiotensin‐II induced superoxide, no metabolites induced NOX or p47phox, 1 metabolite upregulated p22phox and 3 metabolites induced HO‐1. In vascular inflammation and adhesion screens in HUVEC, 10, 9 and 6 metabolites reduced IL‐6 following CD40L, oxLDL or TNF‐α stimulation, respectively. 10 and 6 metabolites reduced sVCAM‐1 following CD40L or TNF‐α stimulation, respectively. 2 metabolites attenuated IL‐1β‐stimulated phosphorylation of NF‐κB p65, 1 metabolite induced Nrf2. In monocyte activity assays, 5 metabolites reduced LPS‐induced TNF‐α, 1 metabolite induced IL1B, no metabolites were active on HO‐1, tissue factor, NFkB or nfKB. The evidence suggests that bioactivity of flavonoids in vivo results from low exposure to a variety of structurally similar metabolites modifying inflammation and cellular adhesion pathways.}, number={Supplement 1}, journal={The FASEB Journal}, author={Kay, Colin and de Gesso, Jessica and Warner, Emily and Amin, Hiren and de Ferrars, Rachel and Edwards, Michael and Zang, Qing and O'Hagan, David and O'Connell, Maria}, year={2015}, pages={118.4} }
 @article{holligan_west_gebauer_kay_kris-etherton_2014, title={A moderate-fat diet containing pistachios improves emerging markers of cardiometabolic syndrome in healthy adults with elevated LDL levels}, volume={112}, ISSN={0007-1145 1475-2662}, url={http://dx.doi.org/10.1017/S0007114514001561}, DOI={10.1017/S0007114514001561}, abstractNote={A randomised, cross-over, controlled-feeding study was conducted to evaluate the cholesterol-lowering effects of diets containing pistachios as a strategy for increasing total fat (TF) levelsv. a control (step I) lower-fat diet.Ex vivotechniques were used to evaluate the effects of pistachio consumption on lipoprotein subclasses and functionality in individuals (n28) with elevated LDL levels ( ≥ 2·86 mmol/l). The following test diets (SFA approximately 8 % and cholesterol < 300 mg/d) were used: a control diet (25 % TF); a diet comprising one serving of pistachios per d (1PD; 30 % TF); a diet comprising two servings of pistachios per d (2PD; 34 % TF). A significant decrease in small and dense LDL (sdLDL) levels was observed following the 2PD dietary treatmentv.the 1PD dietary treatment (P= 0·03) and following the 2PD dietary treatmentv.the control treatment (P= 0·001). Furthermore, reductions in sdLDL levels were correlated with reductions in TAG levels (r0·424,P= 0·025) following the 2PD dietary treatmentv.the control treatment. In addition, inclusion of pistachios increased the levels of functional α-1 (P= 0·073) and α-2 (P= 0·056) HDL particles. However, ATP-binding cassette transporter A1-mediated serum cholesterol efflux capacity (P= 0·016) and global serum cholesterol efflux capacity (P= 0·076) were only improved following the 2PD dietary treatmentv.the 1PD dietary treatment when baseline C-reactive protein status was low ( < 103μg/l). Moreover, a significant decrease in the TAG:HDL ratio was observed following the 2PD dietary treatmentv.the control treatment (P= 0·036). There was a significant increase in β-sitosterol levels (P< 0·0001) with the inclusion of pistachios, confirming adherence to the study protocol. In conclusion, the inclusion of pistachios in a moderate-fat diet favourably affects the cardiometabolic profile in individuals with an increased risk of CVD.}, number={5}, journal={British Journal of Nutrition}, publisher={Cambridge University Press (CUP)}, author={Holligan, Simone D. and West, Sheila G. and Gebauer, Sarah K. and Kay, Colin D. and Kris-Etherton, Penny M.}, year={2014}, month={Jul}, pages={744–752} }
 @article{de ferrars_czank_saha_needs_zhang_raheem_botting_kroon_kay_2014, title={Methods for Isolating, Identifying, and Quantifying Anthocyanin Metabolites in Clinical Samples}, volume={86}, ISSN={0003-2700 1520-6882}, url={http://dx.doi.org/10.1021/AC500565A}, DOI={10.1021/AC500565A}, abstractNote={The metabolic fate of anthocyanins until recently was relatively unknown, primarily as a result of their instability at physiological pH and a lack of published methods for isolating and identifying their metabolites from biological samples. The aim of the present work was to establish methods for the extraction and quantification of anthocyanin metabolites present in urine, serum, and fecal samples. 35 commercial and 10 synthetic analytes, including both known and predicted human and microbial metabolites of anthocyanins, were obtained as reference standards. HPLC and MS/MS conditions were optimized for organic modifier, ionic modifier, mobile phase gradient, flow rate, column type, MS source, and compound dependent parameters. The impact of sorbent, solvent, acid, preservative, elution, and evaporation on solid phase extraction (SPE) efficiency was also explored. The HPLC-MS/MS method validation demonstrated acceptable linearity (R(2), 0.997 ± 0.002) and sensitivity (limits of detection (LODs): urine, 100 ± 375 nM; serum, 104 ± 358 nM; feces 138 ± 344 nM), and the final SPE methods provided recoveries of 88.3 ± 17.8% for urine, 86.5 ± 11.1% for serum, and 80.6 ± 20.9% for feces. The final methods were applied to clinical samples derived from an anthocyanin intervention study, where 36 of the 45 modeled metabolites were detected within urine, plasma, or fecal samples. The described methods provide suitable versatility for the identification and quantification of an extensive series of anthocyanin metabolites for use in future clinical studies exploring absorption, distribution, metabolism, and elimination.}, number={20}, journal={Analytical Chemistry}, publisher={American Chemical Society (ACS)}, author={de Ferrars, Rachel M. and Czank, Charles and Saha, Shikha and Needs, Paul W. and Zhang, Qingzhi and Raheem, K. Saki and Botting, Nigel P. and Kroon, Paul A. and Kay, Colin D.}, year={2014}, month={Oct}, pages={10052–10058} }
 @article{davidson_jupp_de ferrars_kay_culley_norton_driscoll_vincent_donell_bao_et al._2014, title={Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo}, volume={22}, ISSN={1063-4584}, url={http://dx.doi.org/10.1016/j.joca.2014.02.597}, DOI={10.1016/j.joca.2014.02.597}, abstractNote={Purpose: Nutrition impacts directly on ageing and obesity, both of which are major risk factors for osteoarthritis. Sulforaphane (SFN) is an isothiocyanate derived from brassicas, particularly broccoli, and has been reported to regulate signalling pathways relevant to chronic diseases. Our study investigated whether sulforaphane can abrogate cartilage destruction in laboratory models of osteoarthritis and examined mechanism of action in chondrocytes. Methods: The impact of SFN treatment on gene expression, signalling through transcription factors nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and nuclear factor kappaB (NFκB), and histone acetylation were examined in chondrocytes. The intracellular concentrations of SFN and SFN metabolites were quantified in chondrocytes and used to inform transcription factor binding assays. The bovine nasal cartilage explant model (BNC) and destabilisation of medial meniscus (DMM) murine model of osteoarthritis were used to study chondroprotection by SFN. Results: SFN inhibited cytokine-induced metalloproteinase expression in primary human articular chondrocytes (HACs) and in fibroblast-like synovial cells (FLS). SFN can act independently of the Nrf2 transcription factor and histone deacetylase activity in HACs, but does mediate prolonged activation of Jun kinase (JNK) and p38 MAP kinase. SFN attenuates NF-κB signalling through at least inhibition of DNA binding in HACs with attenuation of expression of several NF-κB dependent genes. SFN abrogates cytokine-induced destruction of bovine nasal cartilage at the level of both proteoglycan and collagen breakdown (10μM compared to cytokines alone). It also decreases arthritis score in the DMM murine model of osteoarthritis (3μmol daily dose SFN in diet versus control chow). Conclusions: SFN, at levels which can be obtained through a broccoli-rich diet, inhibits the expression of key metalloproteinases implicated in osteoarthritis independently of Nrf2 and blocks inflammation at the level of NF-κB to protect against cartilage destruction in vitro and in vivo. Ongoing studies in man will ascertain the potential of this compound in human osteoarthritis.}, journal={Osteoarthritis and Cartilage}, publisher={Elsevier BV}, author={Davidson, R.K. and Jupp, O. and de Ferrars, R. and Kay, C.D. and Culley, K.L. and Norton, R. and Driscoll, C. and Vincent, T.L. and Donell, S.T. and Bao, Y. and et al.}, year={2014}, month={Apr}, pages={S322–S323} }
 @article{de ferrars_czank_zhang_botting_kroon_cassidy_kay_2014, title={The pharmacokinetics of anthocyanins and their metabolites in humans}, volume={171}, number={13}, journal={British journal of pharmacology}, author={De Ferrars, RM and Czank, C and Zhang, Q and Botting, NP and Kroon, PA and Cassidy, A and Kay, CD}, year={2014}, pages={3268–3282} }
 @article{holligan_west_gebauer_kay_kris-etherton_2013, title={A moderate-fat diet with pistachios lowers small-dense LDL and improves markers of insulin sensitivity in subjects with moderately-elevated cholesterol Levels}, publisher={Federation of American Societies for Experimental Biology}, author={Holligan, Simone and West, Sheila G and Gebauer, Sarah K and Kay, Colin D and Kris-Etherton, Penny M}, year={2013} }
 @article{kay_botting_cassidy_czank_de ferrars_kroon_morrison_preston_zang_2013, title={Absorption, distribution, metabolism and elimination of a stable isotope-labelled anthocyanin in humans}, volume={27}, number={Supplement 1}, journal={FASEB Journal}, publisher={Federation of American Societies for Experimental Biology}, author={Kay, Colin D. and Botting, Nigel P. and Cassidy, Aedin and Czank, Charles and de Ferrars, Rachel and Kroon, Paul A. and Morrison, Douglas J. and Preston, Tom and Zang, Qingzhi}, year={2013}, month={Apr}, pages={125.6} }
 @article{kay_cassidy_2013, title={Encyclopedia of Human Nutrition: Phytochemicals: Classification and Occurrence}, publisher={Academic Press}, author={Kay, Colin and Cassidy, Aedin}, year={2013} }
 @article{human metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: a 13c-tracer study--_2013, volume={97}, number={5}, journal={The American of Clinical Nutrition}, publisher={Oxford University Press}, year={2013}, pages={995–1003} }
 @article{di gesso_kerr_yalamanchili_cassidy_botting_o’hagan_zhang_raheen_kay_o’connell_2013, place={London, England}, title={Metabolism of dietary flavonoids alters their effect on tumor necrosis factor-α}, volume={63}, ISSN={1043-4666}, url={http://dx.doi.org/10.1016/J.CYTO.2013.06.071}, DOI={10.1016/J.CYTO.2013.06.071}, abstractNote={Flavonoids are polyphenolic secondary metabolites formed by many plants including fruits and vegetables, and are therefore commonly consumed in the diet. Epidemiological evidence suggests that consuming a diet high in fruits and vegetables is positively correlated with a lower incidence of cardiovascular disease (CVD). It has long been hypothesised that flavonoids are central to these beneficial effects, however the exact mechanisms of action remain unclear. Upon consumption of a parent flavonoid, degradation and metabolism occur within the body. We hypothesise that the metabolites are responsible for the health benefits as opposed to their parent compounds. Here 6 parent flavonoids, 4 B-ring degradation products and 10 conjugated flavonoid metabolites were screened for ability to reduce lipopolysaccharide-induced tumour necrosis factor-α (TNF-α) secretion in a human monocytic cell line (THP-1). Physiologically relevant levels of treatments (0.1–10 μM) were pre-incubated in the culture model for 30 min prior to LPS stimulation. These concentrations were not cytotoxic as established using the WST-1 assay. Quercetin, epicatechin and cyanidin-3-glucoside form a common degradation product, protocatechuic acid (PCA), following ingestion. PCA can be metabolised by the liver to form glucuronide and sulfate conjugates. PCA-3-sulfate significantly decreased (38.7%, p < 0.05) TNF-α protein secretion compared to control. This reduction was greater than was elicited by treatment with quercetin (25.6%), epicatechin (21.3%), cyanidin-3-glucoside (13.7%) or PCA (22.1%). Furthermore, sulfation at carbon-3 gave rise to a greater reduction in TNF-α than sulfation at carbon-4 (9.6%) or by glucuronidation at either of these two sites (19.9%, 10.3% respectively). Intriguingly these protein data are not corroborated at the mRNA level, suggesting the treatments are having a post-translational effect. In conclusion, metabolism of parent flavonoids may increase their anti-inflammatory bioactivity. The possibile post-translational effects of flavonoids on TNF-α are currently the focus of our research.}, number={3}, journal={Cytokine}, publisher={Elsevier BV}, author={di Gesso, J.L. and Kerr, J.S. and Yalamanchili, S.K. and Cassidy, A. and Botting, N.P. and O’Hagan, D. and Zhang, Q. and Raheen, S. and Kay, C.D. and O’Connell, M.A.}, year={2013}, month={Sep}, pages={259} }
 @article{de ferrars_cassidy_curtis_kay_2013, title={Phenolic metabolites of anthocyanins following a dietary intervention study in post-menopausal women}, volume={58}, ISSN={1613-4125}, url={http://dx.doi.org/10.1002/mnfr.201300322}, DOI={10.1002/mnfr.201300322}, abstractNote={ScopeNumerous studies feeding anthocyanin‐rich foods report limited bioavailability of the parent anthocyanins. The present study explores the identity and concentration of the phenolic metabolites of anthocyanins in humans.}, number={3}, journal={Molecular Nutrition & Food Research}, publisher={Wiley}, author={de Ferrars, Rachel M. and Cassidy, Aedín and Curtis, Peter and Kay, Colin D.}, year={2013}, month={Oct}, pages={490–502} }
 @inbook{miller_putnam_edwards_woodward_kay_2013, title={Potential Health Benefits of Blackcurrants}, ISBN={9781118635551 9780470674970}, url={http://dx.doi.org/10.1002/9781118635551.ch10}, DOI={10.1002/9781118635551.ch10}, abstractNote={This chapter focuses on the activities of blackcurrants, blackcurrant extracts and anthocyanins (either extracted and purified from blackcurrants or synthetically derived) that are present in significant quantities in blackcurrants. Numerous other berry species have been explored for their health effects, including blueberries, blackberries, elderberries, chokeberries, strawberries and raspberries, to name a few. The chapter highlights a few commonly consumed species. The anthocyanins found in abundance in blackcurrants are the main focus of the chapter (delphinidin-3-O-glucoside, delphinidin-3-O-rutinoside, cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside). First, the chapter talks about occurrence of anthocyanins in the diet. Second, it explains classification, structural property, stability, metabolism and bioavailability of anthocyanins. Finally, the chapter talks about bioactivity of anthocyanins and metabolites.}, booktitle={Bioactives in Fruit}, publisher={John Wiley & Sons, Ltd}, author={Miller, Rosalind and Putnam, Sophie and Edwards, Michael and Woodward, Gary and Kay, Colin}, year={2013}, month={Jun}, pages={215–250} }
 @inbook{miller_putnam_edwards_woodward_kay_2013, place={New York}, title={Potential Health Benefits of Blackcurrants}, ISBN={9780470674970 9781118635551}, DOI={https://doi.org/10.1002/9781118635551.ch10}, abstractNote={This chapter focuses on the activities of blackcurrants, blackcurrant extracts and anthocyanins (either extracted and purified from blackcurrants or synthetically derived) that are present in significant quantities in blackcurrants. Numerous other berry species have been explored for their health effects, including blueberries, blackberries, elderberries, chokeberries, strawberries and raspberries, to name a few. The chapter highlights a few commonly consumed species. The anthocyanins found in abundance in blackcurrants are the main focus of the chapter (delphinidin-3-O-glucoside, delphinidin-3-O-rutinoside, cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside). First, the chapter talks about occurrence of anthocyanins in the diet. Second, it explains classification, structural property, stability, metabolism and bioavailability of anthocyanins. Finally, the chapter talks about bioactivity of anthocyanins and metabolites.}, booktitle={Bioactives in fruit: health benefits and functional foods}, publisher={John Wiley & Sons}, author={Miller, Rosalind and Putnam, Sophie and Edwards, Michael and Woodward, Gary and Kay, Colin}, editor={Skinner, Margot and Hunter, DeniseEditors}, year={2013}, pages={215–250} }
 @article{davidson_jupp_de ferrars_kay_culley_norton_driscoll_vincent_donell_bao_et al._2013, title={Sulforaphane Represses Matrix-Degrading Proteases and Protects Cartilage From Destruction In Vitro and In Vivo}, volume={65}, ISSN={0004-3591}, url={http://dx.doi.org/10.1002/ART.38133}, DOI={10.1002/ART.38133}, abstractNote={ObjectiveSulforaphane (SFN) has been reported to regulate signaling pathways relevant to chronic diseases. The aim of this study was to investigate the impact of SFN treatment on signaling pathways in chondrocytes and to determine whether sulforaphane could block cartilage destruction in osteoarthritis.}, number={12}, journal={Arthritis & Rheumatism}, publisher={Wiley}, author={Davidson, Rose K. and Jupp, Orla and de Ferrars, Rachel and Kay, Colin D. and Culley, Kirsty L. and Norton, Rosemary and Driscoll, Clare and Vincent, Tonia L. and Donell, Simon T. and Bao, Yongping and et al.}, year={2013}, month={Nov}, pages={3130–3140} }
 @article{davidson_jupp_de ferrars_kay_culley_norton_driscoll_vincent_donell_bao_et al._2013, title={Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo}, volume={21}, ISSN={1063-4584}, url={http://dx.doi.org/10.1016/J.JOCA.2013.02.450}, DOI={10.1016/J.JOCA.2013.02.450}, abstractNote={Purpose: Broccoli is rich in glucoraphanin (a glucosinolate). When broccoli is cut or chewed, glucoraphanin is converted by an enzyme, myrosinase, to sulforaphane (an isothiocyanate). Similar compounds are derived from other cruciferous vegetables and these compounds are therefore accessible via the diet. Sulforaphane (SFN) has been reported to regulate signalling pathways relevant to chronic diseases. Our study investigated whether sulforaphane can abrogate cartilage destruction in osteoarthritis and examined mechanism of action in chondrocytes. Methods: The bovine nasal cartilage explant model (BNC) and destabilisation of medial meniscus (DMM) murine model of osteoarthritis were used to study chondroprotection by SFN. Histone acetylation, gene expression, transcription factors nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and nuclear factor kappaB (NF-κB) signalling were examined. Results: SFN abrogates cytokine-induced destruction of bovine nasal cartilage at the level of both proteoglycan and collagen breakdown (10μM compared to cytokines alone). It also decreases arthritis score in the DMM murine model of osteoarthritis (3μmol daily dose SFN in diet versus control chow). SFN inhibited cytokine-induced metalloproteinase expression in primary human articular chondrocytes (HACs) and in fibroblast-like synovial cells (FLS). SFN acts independently of the Nrf2 transcription factor and histone deacetylase activity in HACs, but does mediate prolonged activation of Jun kinase (JNK) and p38 MAP kinase. SFN attenuates NF-κB signalling through at least inhibition of DNA binding in HACs with attenuation of expression of several NF-κB dependent genes. Conclusions: SFN, at levels which can be obtained through a high broccoli diet, inhibits the expression of key metalloproteinases implicated in osteoarthritis independently of Nrf2 and blocks inflammation at the level of NF-κB to protect against cartilage destruction in vitro and in vivo. Future studies in man will ascertain the potential of this compound in human osteoarthritis.}, journal={Osteoarthritis and Cartilage}, publisher={Elsevier BV}, author={Davidson, R.K. and Jupp, O. and de Ferrars, R. and Kay, C.D. and Culley, K.L. and Norton, R. and Driscoll, C. and Vincent, T.L. and Donell, S.T. and Bao, Y. and et al.}, year={2013}, month={Apr}, pages={S217–S218} }
 @article{de ferrars_cassidy_curtis_raheem_zhang_kay_2013, title={The metabolic fate of anthocyanins in humans}, volume={27}, DOI={10.1096/fasebj.27.1_supplement.125.7}, abstractNote={High intakes of anthocyanins (ACN) have been linked to decreased cardiovascular disease risk. However, due to their apparent low bioavailability, it has been postulated that phenolic degradation products of ACNs may be responsible for their bioactivity. We examined the metabolic fate of ACNs following a single dose and short‐term (12 wk) exposure to an elderberry extract, to establish the differential effects of acute v short‐term exposure on metabolism. Biological samples from a 12 wk intervention study (n=15 postmenopausal women, 500 mg/day elderberry ACNs) were analysed for ACN metabolites using HPLC‐MS/MS. 29 metabolites were identified in urine (12 ACN and 17 phenolic metabolites) and 21 in plasma (4 ACN and 17 phenolic metabolites). ACNs reached concentrations of 0.55±0.05 μM/mM creatinine in urine after 3h and 0.034 μM in plasma after 2h. The phenolic degradation products and their metabolites reached concentrations of 31.15±2.37 μM/mM creatinine in urine after 3h and 1.24 μM in plasma after 2h. The profile of metabolites was not significantly different after 12 wks of intake. These results indicate that ACNs are extensively metabolised in vivo, with little suggestion of plasma accumulation following repeated exposure. The reported bioactivity of ACN most likely relates to the high concentrations of circulating phenolic metabolites. Research support: Norwich Medical School, University of East Anglia.}, number={Supplement 1}, journal={FASEB Journal}, publisher={Federation of American Societies for Experimental Biology}, author={de Ferrars, Rachel Margaret and Cassidy, Aedin and Curtis, Peter and Raheem, Kalowole Saki and Zhang, Qingzhi and Kay, Colin D.}, year={2013}, pages={125.7} }
 @article{edwards_czank_cassidy_kay_2013, title={Vascular bioactivity of anthocyanin degradants: inhibition of endothelial superoxide production}, volume={72}, ISSN={0029-6651 1475-2719}, url={http://dx.doi.org/10.1017/S002966511300253X}, DOI={10.1017/S002966511300253X}, abstractNote={Anthocyanins, a sub-class of the flavonoid family of phenolic phytochemicals, are reported to have significant vasoprotective activity, but their low bioavailability suggests bioactivity may be mediated by their degradation products or metabolites. The present study aimed to investigate the vascular bioactivity of selected anthocyanins and phenolic degradants, and elucidate their potential molecular mechanisms of action. Bioactivity was assessed by screening for the modulation of superoxide-generating NADPH oxidase (NOX) and endothelial nitric oxide synthase (eNOS) activity in human umbilical vein endothelial cells. Angiotensin II (Ang II)-stimulated superoxide production was quantified by reduction of ferricytochrome c, based on previously reported methods, and commercially available kits were used to quantify eNOS expression (Quantikine, R&D Systems, UK) and nitric oxide (NO) production (Nitrite/Nitrate Assay, Cayman Chemical Company, USA). Angiotensin IIor tumour necrosis factor-alpha (TNF-a)-stimulated expression of NOX isoform/subunit mRNA and/or protein was assessed by reverse transcription – quantitative polymerase chain reaction and immunoblotting. Superoxide production was significantly decreased (P<0.05; ANOVA with Tukey post-hoc; n = 3) by the anthocyanins peonidin-3glucoside, petunidin-3-glucoside and malvidin-3-glucoside; and the anthocyanin phenolic degradants protocatechuic acid, vanillic acid, and syringic acid. Cyanidin-3-glucoside, peonidin-3-glucoside, and petunidin-3-glucoside also significantly upregulated eNOS (P<0.05; n = 3), whereas the anthocyanin degradants had no effect. Based upon these bioactivity data, the phenolic degradant vanillic acid was selected to explore molecular mechanisms potentially underlying the observed bioactivity. Here, vanillic acid (at 0.1–10mM) did not significantly (P>0.05) modulate mRNA levels of the NOX4 isoform (Figure 1A) or the associated integral membrane protein p22 (Figure 1B); nor did vanillic acid significantly affect protein levels of the NOX2 & 4 isoforms (data not shown) or p47, a key NOX2 subunit (Figure 1C). Trends were observed towards an upregulation of p22 mRNA (P = 0.12 at 1mM), and a decrease in p47 protein (P = 0.27 at 10mM).}, number={OCE4}, journal={Proceedings of the Nutrition Society}, publisher={Cambridge University Press (CUP)}, author={Edwards, M. and Czank, C. and Cassidy, A. and Kay, C. D.}, year={2013} }
 @article{cassidy_rimm_o'reilly_logroscino_kay_chiuve_rexrode_2012, title={Dietary Flavonoids and Risk of Stroke in Women}, volume={43}, ISSN={0039-2499 1524-4628}, url={http://dx.doi.org/10.1161/strokeaha.111.637835}, DOI={10.1161/strokeaha.111.637835}, abstractNote={
            Background and Purpose—
            To date, few studies have examined associations between the wide range of flavonoid subclasses and risk of ischemic, hemorrhagic, and total stroke.
          }, number={4}, journal={Stroke}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Cassidy, Aedín and Rimm, Eric B. and O'Reilly, Éilis J. and Logroscino, Giancarlo and Kay, Colin and Chiuve, Stephanie E. and Rexrode, Kathryn M.}, year={2012}, month={Apr}, pages={946–951} }
 @article{dietary flavonoids and risk of stroke in women_2012, journal={Stroke}, publisher={American Heart Association, Inc.}, year={2012}, pages={STROKEAHA-111} }
 @article{west_gebauer_kay_bagshaw_savastano_diefenbach_kris-etherton_2012, title={Diets Containing Pistachios Reduce Systolic Blood Pressure and Peripheral Vascular Responses to Stress in Adults With Dyslipidemia}, volume={60}, ISSN={0194-911X 1524-4563}, url={http://dx.doi.org/10.1161/hypertensionaha.111.182147}, DOI={10.1161/hypertensionaha.111.182147}, abstractNote={
            Nut consumption reduces cardiovascular risk, and reductions in blood pressure and peripheral vascular resistance may be important mediators of this relationship. We evaluated effects of pistachios on flow-mediated dilation and blood pressure response to acute stress. Twenty-eight adults with dyslipidemia completed a randomized, crossover, controlled-feeding study. All of the meals were provided and calories were controlled. After 2 weeks on a typical Western diet (35% total fat and 11% saturated fat), test diets were presented in counterbalanced order for 4 weeks each, a low-fat control diet (25% total fat and 8% saturated fat), a diet containing 10% of energy from pistachios (on average, 1 serving per day; 30% total fat and 8% saturated fat), and a diet containing 20% of energy from pistachios (on average, 2 servings per day, 34% total fat and 8% saturated fat). None of the resting hemodynamic measures significantly differed from pretreatment values. When resting and stress levels were included in the repeated-measures analysis, average reductions in systolic blood pressure were greater after the diet containing 1 serving per day versus 2 servings per day of pistachios (mean change in systolic blood pressure, −4.8 vs −2.4 mm Hg, respectively;
            P
            <0.05). After the higher dose, there were significant reductions in peripheral resistance (−62.1 dyne·s×cm
            −5
            ) and heart rate (−3 bpm) versus the control diet (
            P
            <0.0001). These changes were partially offset by increases in cardiac output. There was no effect of diet on fasting flow-mediated dilation. Reductions in peripheral vascular constriction and the resulting decrease in hemodynamic load may be important contributors to lower risk in nut consumers.
          }, number={1}, journal={Hypertension}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={West, Sheila G. and Gebauer, Sarah K. and Kay, Colin D. and Bagshaw, Deborah M. and Savastano, David M. and Diefenbach, Christopher and Kris-Etherton, Penny M.}, year={2012}, month={Jul}, pages={58–63} }
 @article{amin_czank_cassidy_kay_2012, title={Effect of cyanidin-glucoside and its metabolites on inflammatory biomarkers of vascular function}, volume={71}, ISSN={0029-6651 1475-2719}, url={http://dx.doi.org/10.1017/S0029665112001127}, DOI={10.1017/S0029665112001127}, abstractNote={Diet derived anthocyanins may have vasoprotective properties, however their low bioavailability suggests that their bioactivity is mediated by their degradants and/or metabolites. Endothelial expression of cell adhesion molecules (CAMs) and cytokines can be activated through ligation of CD40L to its receptor or injury to the endothelium by oxidised low-density lipoprotein (oxLDL), and is an initiating step in the pathogenesis of atherosclerosis. The present study aimed to investigate the ability of cyanidin-glucoside (C3G), the most abundant dietary anthocyanin, and its metabolites to modulate the expression of CAMs and cytokines in cultured human umbilical vein endothelial cells (HUVECs) challenged with either CD40L or oxLDL. Compounds selected for bioactivity screening were C3G, its degradant, protocatechuic acid (PCA), and a methylated metabolite of PCA, vanillic acid (VA). HUVEC were treated with either CD40L expressing Jurkat cells (D1.1 cells, 1 · 10 cell/well) or oxLDL (5mg/mL), with or without C3G, PCA or VA at 0.1 to 10mM concentrations for 24 hours. Vascular cell adhesion molecule-1 (VCAM-1) and interleukin-6 (IL6) were then measured by ELISA (table below).}, number={OCE2}, journal={Proceedings of the Nutrition Society}, publisher={Cambridge University Press (CUP)}, author={Amin, H. and Czank, C. and Cassidy, A. and Kay, C. D.}, year={2012} }
 @article{effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials--_2012, volume={95}, number={3}, journal={The American journal of clinical nutrition}, publisher={Oxford University Press}, year={2012}, pages={740–751} }
 @article{west_gebauer_kay_skulas-ray_kris-etherton_2012, title={Effects of pistachios and walnuts on hemodynamic reactivity to stress: Clinical trials in adults with dyslipidemia}, volume={5}, number={12}, journal={Australasian Medical Journal (Online}, author={West, S.G. and Gebauer, S.K. and Kay, C.D. and Skulas-Ray, A.C. and Kris-Etherton, P.M.}, year={2012}, pages={676} }
 @article{zhang_raheem_botting_slawin_kay_o'hagan_2012, title={Flavonoid metabolism: the synthesis of phenolic glucuronides and sulfates as candidate metabolites for bioactivity studies of dietary flavonoids}, volume={68}, ISSN={0040-4020}, url={http://dx.doi.org/10.1016/j.tet.2012.03.100}, DOI={10.1016/j.tet.2012.03.100}, abstractNote={Epidemiological studies indicate that flavonoid intake is inversely associated with the risk of coronary heart disease, yet the mechanisms responsible for their bioactivity are still a matter of debate. Based on the rapid and extensive metabolism of most flavonoids, their health effects most likely result from the biological activity of their metabolites. However, a lack of commercially available compounds/standards has prevented the study of metabolite bioactivity and resulted in a focus on non-physiologically relevant precursor/parent structures. This paper details the synthesis of a series of phenolic glucuronide 1a–e and sulfate 2a–e derivates as candidate metabolites for use as reference compounds in metabolic profiling studies and for the exploration of flavonoid bioactivity.}, number={22}, journal={Tetrahedron}, publisher={Elsevier BV}, author={Zhang, Qingzhi and Raheem, K. Saki and Botting, Nigel P. and Slawin, Alexandra M.Z. and Kay, Colin D. and O'Hagan, David}, year={2012}, month={Jun}, pages={4194–4201} }
 @article{jennings_welch_fairweather-tait_kay_minihane_chowienczyk_jiang_cecelja_spector_macgregor_et al._2012, title={Higher anthocyanin intake is associated with lower arterial stiffness and central blood pressure in women--}, volume={96}, number={4}, journal={The American journal of clinical nutrition}, publisher={Oxford University Press}, author={Jennings, Amy and Welch, Ailsa A and Fairweather-Tait, Sue J and Kay, Colin and Minihane, Anne-Marie and Chowienczyk, Phil and Jiang, Benyu and Cecelja, Marina and Spector, Tim and Macgregor, Alex and et al.}, year={2012}, pages={781–788} }
 @article{de ferrars_cassidy_curtis_czank_zhang_kalowole_botting_kay_2012, title={Investigating the bioavailability of anthocyanin metabolites}, volume={71}, ISSN={0029-6651 1475-2719}, url={http://dx.doi.org/10.1017/S0029665112001231}, DOI={10.1017/S0029665112001231}, abstractNote={Anthocyanins (ACN) are a sub-class of flavonoids, found within many red berries and vegetables and have been linked to a decrease in cardiovascular disease (CVD) risk factors. However, bioavailability studies have consistently reported extremely low recoveries (<0.1% of administered dose) within biological fluids. ACN rapidly degrade into their phenolic acid and aldehyde constituents at neutral pH) and may be further metabolised, forming many possible methyl, glucuronide, sulfate and glutathione conjugates. This work focuses on identifying these unknown ACN metabolites. Previously published solid phase extraction (SPE) methods were optimised to obtain high extraction efficiencies for an extensive range (n = 51) of putative metabolites in urine (84.4% 19.4) and serum (84.5% 15.9) samples. High performance liquid chromatography (HPLC-UVvis) and mass spectrometry (MS) conditions were also optimised. Clinical samples from a 12-week anthocyanin intervention where 52 postmenopausal females were fed 500 mg/day elderberry extract were analysed for the presence of anthocyanin metabolites. To date, we have identified nine metabolites (Fig. 1). In addition, post bolus samples indicate an increased excretion of a number of currently unidentified metabolites relative to baseline values (data not shown), which are the focus of future investigation.}, number={OCE2}, journal={Proceedings of the Nutrition Society}, publisher={Cambridge University Press (CUP)}, author={de Ferrars, R. and Cassidy, A. and Curtis, P. and Czank, C. and Zhang, Q. and Kalowole, K. and Botting, N. and Kay, C. D.}, year={2012} }
 @article{kay_hooper_kroon_rimm_cassidy_2012, title={Relative impact of flavonoid composition, dose and structure on vascular function: A systematic review of randomised controlled trials of flavonoid-rich food products}, volume={56}, ISSN={1613-4125}, url={http://dx.doi.org/10.1002/mnfr.201200363}, DOI={10.1002/mnfr.201200363}, abstractNote={ScopePrevious systematic reviews suggest beneficial effects of flavonoids on biomarkers of cardiovascular disease (CVD) risk, but have overlooked the impact of dose response or food complexity. The aim of the present study was to examine the relative impact of composition, flavonoid structure and dose.}, number={11}, journal={Molecular Nutrition & Food Research}, publisher={Wiley}, author={Kay, Colin D. and Hooper, Lee and Kroon, Paul A. and Rimm, Eric B. and Cassidy, Aedín}, year={2012}, month={Sep}, pages={1605–1616} }
 @article{relative impact of flavonoid composition, dose and structure on vascular function: a systematic review of randomised controlled trials of flavonoid-rich food products_2012, volume={56}, number={11}, journal={Molecular nutrition & food research}, year={2012}, pages={1605–1616} }
 @article{zhang_botting_kay_2012, place={MA,USA}, title={Synthesis of [6, 8, 10, 3’, 5’-C-13 (5)]-cyanidin-3-glucoside, for human in vivo metabolism studies}, volume={55}, number={3}, journal={Journal of Labelled Compounds & Radiopharmaceuticals}, publisher={Wiley-Blackwell}, author={Zhang, Qingzhi and Botting, Nigel P. and Kay, Colin}, year={2012}, month={Mar}, pages={131–132} }
 @article{czank_de ferrars_amin_kroon_zhang_kalowole_botting_cassidy_kay_2012, title={The impact of human metabolism on the bioactivity of anthocyanins}, volume={71}, ISSN={0029-6651 1475-2719}, url={http://dx.doi.org/10.1017/S0029665112002388}, DOI={10.1017/S0029665112002388}, abstractNote={of 0.66 0.41 m M. We explored the bioactivity ofthese metabolites on vascular health by measuring the effects on mediators of nitric oxide bioavailability including endothelial nitric oxidesynthase (eNOS), NADPH oxidase (NOX4) and superoxide. Protein expression of eNOS was measured by ELISA and NOX4 by westernblotting, while superoxide was measured indirectly via ferrocytochrome C oxidation (A}, number={OCE2}, journal={Proceedings of the Nutrition Society}, publisher={Cambridge University Press (CUP)}, author={Czank, C. and De Ferrars, R. and Amin, H. and Kroon, P. A. and Zhang, Q. and Kalowole, K. and Botting, N. and Cassidy, A. and Kay, C. D.}, year={2012} }
 @article{edwards_czank_cassidy_kay_2012, title={Vascular bioactivity of anthocyanins and phenolic acid degradants: modulation of superoxide and nitric oxide}, volume={71}, ISSN={0029-6651 1475-2719}, url={http://dx.doi.org/10.1017/s0029665112001164}, DOI={10.1017/s0029665112001164}, abstractNote={Anthocyanins, a sub-class of the flavonoid family of phenolic phytochemicals, may have significant vasoprotective activity, but their low bioavailability suggests bioactivity could be mediated by degradation products or metabolites. The present study aimed to investigate vascular bioactivity of selected anthocyanins and phenolic degradants, and potential synergy between flavonoids and ascorbic acid. Bioactivity was assessed by human umbilical vein endothelial cell (HUVEC) superoxide production and expression of NAD(P)H oxidase (NOX), and production of nitric oxide (NO) and expression of endothelial NO synthase (eNOS). Cell viability was measured by the WST-1 assay (Roche Applied Science, UK), and superoxide production assessed based on previously reported methods. Briefly, HUVECs were incubated with 0.1mM angiotensin II (Ang II), with or without treatment compounds (0.1–10mM), for 6 h and superoxide production quantified by reduction of ferricytochrome c. NOX expression was investigated by immunoblotting, and commercially available kits were used to quantify nitric oxide (NO) production (Nitrite/Nitrate Assay, Cayman Chemical Company, USA) and eNOS expression (Quantikine, R&D Systems, UK). Cell viability was not affected (P>0.05) by any treatment at 10mM (data not shown). Superoxide production (as tabulated below) was significantly decreased (P<0.05) by the anthocyanins peonidinand malvidin-glucoside; and the anthocyanin phenolic degradants protocatechuic acid, vanillic acid, and syringic acid. Superoxide was also significantly decreased by protocatechuic acid in combination with two flavonoids, epicatechin and quercetin, and ascorbic acid; although to a lesser extent than with protocatechuic acid alone.}, number={OCE2}, journal={Proceedings of the Nutrition Society}, publisher={Cambridge University Press (CUP)}, author={Edwards, M. and Czank, C. and Cassidy, A. and Kay, C. D.}, year={2012} }
 @article{zhang_botting_kay_2011, title={A gram scale synthesis of a multi-13 C-labelled anthocyanin,[6, 8, 10, 3′, 5′-13 C 5] cyanidin-3-glucoside, for use in oral tracer studies in humans}, volume={47}, number={38}, journal={Chemical Communications}, publisher={Royal Society of Chemistry}, author={Zhang, Qingzhi and Botting, Nigel P and Kay, Colin}, year={2011}, pages={10596–10598} }
 @article{zhang_botting_kay_2011, title={A gram scale synthesis of a multi-13C-labelled anthocyanin, [6,8,10,3′,5′-13C5]cyanidin-3-glucoside, for use in oral tracer studies in humans}, volume={47}, ISSN={1359-7345 1364-548X}, url={http://dx.doi.org/10.1039/c1cc14323a}, DOI={10.1039/c1cc14323a}, abstractNote={The major dietary anthocyanin, cyanidin-3-glucoside, was prepared on a 4 g scale from three units of diethyl [2-(13)C]malonate and one unit of [1,3-(13)C(2)]acetone, such that five isotope locations were distributed throughout the molecule to provide a penta-(13)C(5)-labelled anthocyanin, [6,8,10,3',5'-(13)C(5)]cyanidin-3-glucoside chloride, for use in human stable-isotope tracer studies.}, number={38}, journal={Chemical Communications}, publisher={Royal Society of Chemistry (RSC)}, author={Zhang, Qingzhi and Botting, Nigel P. and Kay, Colin}, year={2011}, pages={10596} }
 @article{woodward_cassidy_kay_2011, title={A potential mechanism of action of dietary anthocyanins: modulation of endothelial superoxide production by phenolic acid metabolites}, volume={70}, ISSN={0029-6651 1475-2719}, url={http://dx.doi.org/10.1017/s0029665111002837}, DOI={10.1017/s0029665111002837}, abstractNote={It has long been thought that diets rich in anthocyanins confer protection against the oxidative progression of CVD. Although inflammatory cell superoxide production is believed to be a major contributor to oxidative-induced vascular dysfunction, recent studies have suggested the contribution of vascular superoxide production resulting from multi-component NADPH oxidases (NOX) within endothelial cells. To this end, the present study aimed to assess the structure-activity relationships of anthocyanin derived degradation products and metabolites in the modulation of angiotensin II (Ang II) induced superoxide release from intact endothelial cells. Direct Fe/ion reducing capacity and inhibition of xanthine oxidase were also investigated. Initially, several conjugated anthocyanin-derived phenolic acid metabolites were chemically synthesised and characterised by LC/MS and H NMR. To assess the modulation of Ang II-induced superoxide production, confluent HUVECs were exposed to physiological concentrations of treatment compounds and the reduction of cytochrome c was measured at 550 nm. Superoxide generation was determined using co-incubations in the presence of superoxide dismutase. NOX expression was confirmed by Western blot and qRT-PCR analysis. Fe/ion reducing capacity was assessed from the direct reduction of cytochrome c and the inhibition of superoxide production by xanthine/xanthine oxidase was assessed spectrophotometrically following incubations in the presence of xanthine, ferricytochrome c and the treatment compounds. Significance of triplicate experiments was determined (one-way ANOVA with Tukey post-hoc tests) against control or basal conditions (P<0.05) and data expressed as % of controls mean (SD). Here we present evidence that anthocyanins and their metabolites attenuate Ang II-induced endothelial superoxide production and that the cellular activity of anthocyanins was enhanced following degradation and metabolism to phenolic acid metabolites. Specifically, at concentrations of 0.1 and 1mM, respectively, the glucuronide conjugate of 4-hydroxybenzoic acid [27.9 (SD 8.4) and 97.2 (SD 15.3)% inhibition] showed a greater effect on Ang II-induced superoxide release than its precursors 4-hydroxybezoic acid (33.2 (SD 23.3) and 71.4 SD 16.2)% inhibition) and pelargonidin-3-glucoside [21.0 (SD 24.7) and 22.7 (SD 18.8)% inhibition]. Similarly, cyanidin-3-glucoside and protocatechuic acid did not appear to attenuate superoxide production at physiological concentrations, although both the glucuronide [87.9 (SD 4.1) and 1.4 (SD 18.9)% inhibition] and methyl (0.5 (SD 17.7) and 67.6 (SD 26.3)% inhibition] conjugates of protocatechuic acid demonstrated significant inhibitory effects. Thus, the ability of phenolic acids to inhibit superoxide release appeared to be inversely associated with the number of aryl hydroxyls (flOH = ›bioactivity), which was in express opposition to their antioxidant potential (›OH = ›antioxidant potential), as established via Fe/ion reduction and xanthane oxidase inhibition assays. Based on this dichotomy, it is likely that the biological effects of anthocyanins on the vasculature, at physiologically relevant concentrations, are mediated by their phenolic acid degradation products and metabolites.}, number={OCE4}, journal={Proceedings of the Nutrition Society}, publisher={Cambridge University Press (CUP)}, author={Woodward, G. M. and Cassidy, A. and Kay, C. D.}, year={2011} }
 @article{woodward_needs_kay_2011, title={Anthocyanin-derived phenolic acids form glucuronides following simulated gastrointestinal digestion and microsomal glucuronidation}, volume={55}, number={3}, journal={Molecular nutrition & food research}, publisher={WILEY-VCH Verlag Weinheim}, author={Woodward, Gary M and Needs, Paul W and Kay, Colin D}, year={2011}, pages={378–386} }
 @article{woodward_mccarthy_pham-thanh_kay_2011, title={Anthocyanins Remain Stable during Commercial Blackcurrant Juice Processing}, volume={76}, ISSN={0022-1147}, url={http://dx.doi.org/10.1111/j.1750-3841.2011.02263.x}, DOI={10.1111/j.1750-3841.2011.02263.x}, abstractNote={Abstract:  It remains important to establish the stability of anthocyanins throughout commercial processing in order to maintain the bioactivity of the processed food/s. The present study aimed to assess the recovery and formation of anthocyanins and their free phenolic acid degradation products during the commercial processing of blackcurrant juice concentrate. A bench‐scale processing model was also established to allow for alteration of predefined parameters to identify where commercial processes could be modified to influence anthocyanin yield. No significant loss in anthocyanins was observed throughout the commercial processing of blackcurrants, from whole berry through milling, to pectin hydrolysis and sodium bisulphite addition (P ≥ 0.7). No significant loss in anthocyanins was observed following the subsequent processing of pressed juice, through pasteurization, decantation, filtration, and concentration (P ≥ 0.9). Similarly, the bench‐scale model showed no significant losses in anthocyanin content except during pasteurization (22%± 0.7%, P < 0.001). In the full‐factorial Design of Experiment model analysis, only sodium bisulphite concentration had an impact on anthocyanin recovery, which resulted in an increase (23% to 27%; P < 0.001) in final anthocyanin concentration. No phenolic degradation products (free protocatechuic acid or gallic acid derived from cyanidin and delphinin species, respectively) were identified in any processed sample when compared to authentic analytical standards, analyzed by ultra‐performance liquid chromatography DAD.}, number={6}, journal={Journal of Food Science}, publisher={Wiley}, author={Woodward, Gary M. and McCarthy, Danielle and Pham-Thanh, Danh and Kay, Colin D.}, year={2011}, month={Jul}, pages={S408–S414} }
 @inproceedings{holligan_gebauer_west_kay_kris-etherton_2011, title={Effects of pistachios on emerging CVD risk factors in moderately hypercholesterolemic individuals}, volume={25}, DOI={10.1096/fasebj.25.1_supplement.971.21}, abstractNote={Pistachios are a known source of several cardioprotective, bioactive components. A randomized, crossover, controlled feeding study was conducted to determine their dose‐related effects on emerging CVD risk factors in persons (N=28) with moderately elevated LDL‐C levels (≥ 2.86 mmol/L). Three test diets (2100 kcal/d; SFA ~ 8%; cholesterol < 300mg/dl) of either a low‐fat, control diet (CON; 25% total fat); a low‐dose diet (1 PD) with 32–63 g/d pistachios (CON + 10% energy from pistachios, 30% total fat); or a high‐dose diet (2 PD) with 63–126 g/d pistachios (CON + 20% energy from pistachios, 34% total fat) were evaluated. We report a significant difference (P < 0.05) in small‐dense LDL levels (sdLDL) between the 2 PD (34.96 ± 1.74 mg/dl) and the CON diet (44.10 ± 2.58 mg/dl) with no significant difference between the 1 PD (42.37 ± 3.29 mg/dl) and CON diet or between the 1 PD and 2 PD diets. No significant effects on Lipoprotein (a) or HDL subpopulations were detected. Similar, significant decreases in LDL‐C for both the 1PD and 2PD versus CON were seen but differences in sdLDL are important since this is a strong predictor of CVD risk status. These results support the use of 63–126 g/d of pistachios in a cholesterol‐lowering diet due to their effects on LDL‐C and sdLDL levels.}, number={S1}, booktitle={The FASEB Journal}, author={Holligan, Simone and Gebauer, Sarah and West, Sheila and Kay, Colin D. and Kris-Etherton, Penny}, year={2011}, pages={971.21} }
 @article{njike_faridi_shuval_dutta_kay_west_kris-etherton_katz_2011, title={Effects of sugar-sweetened and sugar-free cocoa on endothelial function in overweight adults}, volume={149}, ISSN={0167-5273}, url={http://dx.doi.org/10.1016/j.ijcard.2009.12.010}, DOI={10.1016/j.ijcard.2009.12.010}, abstractNote={<h2>Abstract</h2><h3>Background</h3> Studies of cocoa suggest an array of cardiovascular benefits; however, the effects of daily intake of sugar-free and sugar-sweetened cocoa beverages on endothelial function (EF) have yet to be established. <h3>Methods</h3> 44 adults (BMI 25–35kg/m<sup>2</sup>) participated in a randomized, controlled, crossover trial. Participants were randomly assigned to a treatment sequence: sugar-free cocoa beverage, sugar-sweetened cocoa beverage, and sugar-sweetened cocoa-free placebo. Treatments were administered daily for 6weeks, with a 4-week washout period. <h3>Results</h3> Cocoa ingestion improved EF measured as flow-mediated dilation (FMD) compared to placebo (sugar-free cocoa: change, 2.4% [95% CI, 1.5 to 3.2] vs. −0.8% [95% CI, −1.9 to 0.3]; difference, 3.2% [95% CI, 1.8 to 4.6]; <i>p</i><0.001 and sugar-sweetened cocoa: change, 1.5% [95% CI, 0.6 to 2.4] vs. −0.8% [95% CI, −1.9 to 0.3]; difference, 2.3% [95% CI, 0.9 to 3.7]; <i>p=</i>0.002). The magnitude of improvement in FMD after consumption of sugar-free versus sugar-sweetened cocoa was greater, but not significantly. Other biomarkers of cardiac risk did not change appreciably from baseline. BMI remained stable throughout the study. <h3>Conclusions</h3> Daily cocoa ingestion improves EF independently of other biomarkers of cardiac risk, and does not cause weight gain. Sugar-free preparations may further augment endothelial function.}, number={1}, journal={International Journal of Cardiology}, publisher={Elsevier BV}, author={Njike, Valentine Yanchou and Faridi, Zubaida and Shuval, Kerem and Dutta, Suparna and Kay, Colin D. and West, Sheila G. and Kris-Etherton, Penny M. and Katz, David L.}, year={2011}, month={May}, pages={83–88} }
 @inbook{cassidy_kay_2011, title={Phytochemicals}, ISBN={9781444327779 9781405168083}, url={http://dx.doi.org/10.1002/9781444327779.ch14}, DOI={10.1002/9781444327779.ch14}, abstractNote={Chapter 14 Phytochemicals Professor Aedín Cassidy, Professor Aedín Cassidy University of East Anglia, UKSearch for more papers by this authorDr Colin D Kay, Dr Colin D Kay University of East Anglia, UKSearch for more papers by this author Professor Aedín Cassidy, Professor Aedín Cassidy University of East Anglia, UKSearch for more papers by this authorDr Colin D Kay, Dr Colin D Kay University of East Anglia, UKSearch for more papers by this author Book Editor(s):Dr Susan A Lanham-New, Dr Susan A Lanham-New University of Surrey, UKSearch for more papers by this authorProfessor Ian A Macdonald, Professor Ian A Macdonald University of Nottingham, UKSearch for more papers by this authorAssociate Professor Helen M Roche, Associate Professor Helen M Roche University College Dublin, IrelandSearch for more papers by this author First published: 19 November 2010 https://doi.org/10.1002/9781444327779.ch14 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onEmailFacebookTwitterLinkedInRedditWechat Summary This chapter contains sections titled: Introduction Historical perspective The phenolic phytochemicals Carotenoids Phytosterols Sulphur-containing compounds: sulphides and glucosinolates Phytochemical toxicity Perspectives on the future Future work Further reading FURTHER READING Chun OK, Chung SJ, Song WO, Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr 2007; 137(5): 1244–1252. 10.1093/jn/137.5.1244 CASPubMedWeb of Science®Google Scholar D'Archivio M et al. Polyphenols, dietary sources and bioavailability. Ann Ist Super Sanita 2007; 43(4): 348–361. CASPubMedGoogle Scholar Erdman JW Jr et al. Flavonoids and heart health: Proceedings of the ILSI North America Flavonoids Workshop, May 31–June 1, 2005, Washington, DC. J Nutr 2007; 137(3): 718S–737S. 10.1093/jn/137.3.718S CASPubMedWeb of Science®Google Scholar Holst B, Williamson G. Nutrients and phytochemicals: from bioavailability to bioefficacy beyond antioxidants. Curr Opin Biotechnol 2008; 19(2): 73–82. 10.1016/j.copbio.2008.03.003 CASPubMedWeb of Science®Google Scholar Hooper L et al. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2008; 88(1): 38–50. 10.1093/ajcn/88.1.38 CASPubMedWeb of Science®Google Scholar Manach C et al. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 2005; 81(1 Suppl): 230S–242S. 10.1093/ajcn/81.1.230S CASPubMedWeb of Science®Google Scholar Milner JA. Preclinical perspectives on garlic and cancer. J Nutr 2006; 136 (3 Suppl): 827S–831S. CASPubMedWeb of Science®Google Scholar Rao AV, Rao LG. Carotenoids and human health. Pharmacol Res 2007; 55(3): 207–16. 10.1016/j.phrs.2007.01.012 CASPubMedWeb of Science®Google Scholar Rasmussen SE et al. Dietary proanthocyanidins: occurrence, dietary intake, bioavailability, and protection against cardiovascular disease. Mol Nutr Food Res 2005; 49(2): 159–174. 10.1002/mnfr.200400082 CASPubMedWeb of Science®Google Scholar Scalbert A., Williamson G. Dietary intake and bioavailability of polyphenols. J Nutr 2000; 130 (8S Suppl): 2073S–2085S. 10.1093/jn/130.8.2073S CASPubMedWeb of Science®Google Scholar USDA. USDA Database for the Flavonoid Content of Selected Foods – Release 2.1. 2007 [cited May 20, 2009]; Available from: http://www.nal.usda.gov/fnic/foodcomp/Data/ Flav/Flav02-1.pdf. Google Scholar Williamson G, Manach C. Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies. Am J Clin Nutr 2005; 81(1 Suppl): 243S–255S. CASPubMedWeb of Science®Google Scholar Yang CS et al. Bioavailability issues in studying the health effects of plant polyphenolic compounds. Mol Nutr Food Res 2008; 52 Suppl 1: S139–S151. 10.1002/mnfr.200700234 PubMedWeb of Science®Google Scholar Nutrition and Metabolism, Second Edition ReferencesRelatedInformation}, booktitle={Nutrition and Metabolism}, publisher={Wiley-Blackwell}, author={Cassidy, Aedín and Kay, Colin D}, year={2011}, month={Mar}, pages={339–352} }
 @article{cassidy_kay_rimm_2011, title={Reply to C Drossard et al}, volume={93}, DOI={10.3945/ajcn.110.010744}, number={4}, journal={The American Journal of Clinical Nutrition}, author={Cassidy, Aedın and Kay, Colin and Rimm, Eric B.}, year={2011}, month={Feb}, pages={866–867} }
 @article{woodward_needs_kay_2010, title={Anthocyanin-derived phenolic acids form glucuronides following simulated gastrointestinal digestion and microsomal glucuronidation}, volume={55}, ISSN={1613-4125}, url={http://dx.doi.org/10.1002/mnfr.201000355}, DOI={10.1002/mnfr.201000355}, abstractNote={Abstract}, number={3}, journal={Molecular Nutrition & Food Research}, publisher={Wiley}, author={Woodward, Gary M. and Needs, Paul W. and Kay, Colin D.}, year={2010}, month={Oct}, pages={378–386} }
 @article{woodward_cassidy_kroon_kay_2010, title={Anthocyanins form potentially-bioactive phenolic degradation products under simulated physiological conditions}, volume={69}, ISSN={0029-6651 1475-2719}, url={http://dx.doi.org/10.1017/s0029665109992163}, DOI={10.1017/s0029665109992163}, abstractNote={An abstract is not available for this content. As you have access to this content, full HTML content is provided on this page. A PDF of this content is also available in through the ‘Save PDF’ action button.}, number={OCE1}, journal={Proceedings of the Nutrition Society}, publisher={Cambridge University Press (CUP)}, author={Woodward, G. M. and Cassidy, A. and Kroon, P. A. and Kay, C. D.}, year={2010} }
 @article{curtis_kroon_hollands_walls_kay_jenkins_cassidy_2010, title={CVD risk biomarkers and liver and kidney function are not modified following 12-week ingestion of an elderberry extract rich in anthocyanins}, volume={69}, ISSN={0029-6651 1475-2719}, url={http://dx.doi.org/10.1017/s0029665109992813}, DOI={10.1017/s0029665109992813}, abstractNote={The intake of anthocyanins, a subclass of flavonoids that confers the red, blue and purple colours to plant-based foods such as berries, apples and blackcurrants (Ribes nigrum), has been shown in epidemiological studies to be negatively correlated with CVD risk. In vitro, anthocyanins also exhibit activities in keeping with a protective effect, such as reduced immune cell-activated radical, cytokine and adhesion molecule production and reduced NO activity. However, to date there is limited evidence on the effects of consumption of physiologically-relevant doses of anthocyanins on biomarkers of CVD risk and safety biomarkers. In this randomised parallel placebo-controlled study the effect of 12 weeks of consumption of 500 mg anthocyanins (present predominantly in the cyanidin glycoside form; from elderberry (Sambucus nigra))/d, on biomarkers of CVD risk and liver and kidney function was examined in fifty-two healthy women (anthocyanins, n 26; placebo, n 26). Eligible participants were post-menopausal women (no menstruation for ‡ 12 months) under 70 years of age, not taking hormone-replacement therapy (HRT) for ‡ 6 months and with BMI between 20 kg/m and 32 kg/m. Fasting blood samples were collected at baseline and 12 weeks and used to assess a series of vascular biomarkers and liver and kidney function, as indicated in the Table. In addition, platelet reactivity was assessed at 0 and 2 h at both baseline and end of the study.}, number={OCE1}, journal={Proceedings of the Nutrition Society}, publisher={Cambridge University Press (CUP)}, author={Curtis, P. J. and Kroon, P. A. and Hollands, W. J. and Walls, R. and Kay, C. D. and Jenkins, G. and Cassidy, A.}, year={2010} }
 @article{habitual intake of flavonoid subclasses and incident hypertension in adults--_2010, volume={93}, number={2}, journal={The American journal of clinical nutrition}, publisher={Oxford University Press}, year={2010}, pages={338–347} }
 @article{kay_gebauer_west_kris-etherton_2010, title={Pistachios increase serum antioxidants and lower serum oxidized-LDL in hypercholesterolemic adults}, volume={140}, number={6}, journal={The Journal of nutrition}, publisher={Oxford University Press}, author={Kay, Colin D and Gebauer, Sarah K and West, Sheila G and Kris-Etherton, Penny M}, year={2010}, pages={1093–1098} }
 @article{kay_2010, title={The future of flavonoid research}, volume={104}, ISSN={0007-1145 1475-2662}, url={http://dx.doi.org/10.1017/S000711451000396X}, DOI={10.1017/S000711451000396X}, abstractNote={There are insufficient data to provide conclusive evidence on the health effects of most flavonoid subclasses. Future research of polyphenol bioactivity requires a more complete understanding of their intake, bioavailability and metabolism. The following summarises the limitations of polyphenol research as described across various reviews throughout the literature and presents the key requirements for future research. These include establishing the effects of processing, bioavailability and metabolism, developing physiologically appropriate in vitro models, standard methods of analysis and appropriate clinical biomarkers. The future of flavonoid research will undoubtedly depend upon the resolve of these issues, and although the field has shown continuous progress for many years, progress will likely slow if these challenges are not met.}, number={S3}, journal={British Journal of Nutrition}, publisher={Cambridge University Press (CUP)}, author={Kay, Colin D.}, year={2010}, month={Oct}, pages={S91–S95} }
 @article{hanwell_kay_lampe_holub_duncan_2009, title={Acute Fish Oil and Soy Isoflavone Supplementation Increase Postprandial Serum (n-3) Polyunsaturated Fatty Acids and Isoflavones but Do Not Affect Triacylglycerols or Biomarkers of Oxidative Stress in Overweight and Obese Hypertriglyceridemic Men}, volume={139}, ISSN={0022-3166 1541-6100}, url={http://dx.doi.org/10.3945/jn.109.105171}, DOI={10.3945/jn.109.105171}, abstractNote={Chronic consumption of fish and fish oil high in (n-3) PUFA reduces triacylglycerols (TG) but may increase oxidative stress, whereas consumption of soy isoflavones may reduce oxidative stress. Elevated serum TG and oxidative stress are considered cardiovascular disease (CVD) risk factors, but the effects of acute (n-3) PUFA and soy isoflavones on these CVD risk factors are unknown. The purpose of the study was to determine the effects of acutely supplementing a high-fat, high-fructose meal with fish oil and isoflavone placebo (FO) and fish oil placebo and soy isoflavones (ISO). In a randomized, double-blind, placebo-controlled, crossover study, 10 overweight or obese men consumed a high-fat, high-fructose meal with 4 dietary supplement combinations: fish oil placebo and isoflavone placebo (placebo); fish oil and isoflavone placebo (FO); fish oil placebo and isoflavones (ISO); and fish oil and isoflavones (FO + ISO). Serum collected at baseline and at 2, 4, and 6 h postprandially was analyzed for fatty acids, isoflavones, TG, and oxidative stress biomarkers (lipid hydroperoxides, oxidized-LDL, total antioxidant status). FO significantly increased serum (n-3) PUFA and ISO increased serum isoflavones. The study meal significantly increased serum total fatty acids and TG without affecting oxidative stress biomarkers. Serum TG and oxidative stress biomarkers did not differ between treatments. The FO and ISO were bioavailable but did not attenuate the postprandial rise in serum TG. Neither the study meal nor the FO or ISO induced significant changes in oxidative stress biomarkers. The current study adds to a limited literature on the acute effects of FO and ISO interventions on postprandial biomarkers of CVD risk.}, number={6}, journal={The Journal of Nutrition}, publisher={Oxford University Press (OUP)}, author={Hanwell, Heather E. C. and Kay, Colin D. and Lampe, Johanna W. and Holub, Bruce J. and Duncan, Alison M.}, year={2009}, month={Apr}, pages={1128–1134} }
 @article{woodward_kroon_cassidy_kay_2009, title={Anthocyanin Stability and Recovery: Implications for the Analysis of Clinical and Experimental Samples}, volume={57}, ISSN={0021-8561 1520-5118}, url={http://dx.doi.org/10.1021/jf900602b}, DOI={10.1021/jf900602b}, abstractNote={The proportion of ingested anthocyanins to reach the systemic circulation is reported to be a small percentage of their ingested dose. This may be due to physiochemical degradation in vivo or following routine sample treatment. Therefore, this study aimed to quantitatively investigate the effect of anthocyanin structure on their stability under simulated (in vitro) physiological conditions and to assess their degradation and recovery following routine preanalytical sample extraction and storage. It was demonstrated that B-ring hydroxylation mediated the degradation of anthocyanins to their phenolic acid and aldehyde constituents, successful anthocyanin extraction is dependent on both sample preparation technique and anthocyanin structure, and anthocyanins are stable through multiple freeze-thaw cycles. These data indicate that significant portions of ingested anthocyanins are likely to degrade to phenolic acids and aldehyde in vivo. Consequently, these compounds should be the target of future bioavailability and bioactivity studies to establish the true occurrence and impact of anthocyanins on human health.}, number={12}, journal={Journal of Agricultural and Food Chemistry}, publisher={American Chemical Society (ACS)}, author={Woodward, Gary and Kroon, Paul and Cassidy, Aedin and Kay, Colin}, year={2009}, month={Jun}, pages={5271–5278} }
 @article{cardiovascular disease risk biomarkers and liver and kidney function are not altered in postmenopausal women after ingesting an elderberry extract rich in anthocyanins for 12 weeks_2009, volume={139}, number={12}, journal={The Journal of nutrition}, publisher={Oxford University Press}, year={2009}, pages={2266–2271} }
 @article{hanwell_kay_holub_duncan_2009, title={Soy protein isoflavones, serum lipids and markers of oxidation and inflammation}, volume={139}, journal={Journal of Nutrition}, author={Hanwell, C. and Kay, C.D. and Holub, B.J. and Duncan, A.}, year={2009}, pages={1–7} }
 @article{kay_kroon_cassidy_2009, title={The bioactivity of dietary anthocyanins is likely to be mediated by their degradation products}, volume={53}, ISSN={1613-4125}, url={http://dx.doi.org/10.1002/mnfr.200800461}, DOI={10.1002/mnfr.200800461}, abstractNote={Abstract}, number={S1}, journal={Molecular Nutrition & Food Research}, publisher={Wiley}, author={Kay, Colin D. and Kroon, Paul A. and Cassidy, Aedin}, year={2009}, month={May}, pages={S92–S101} }
 @article{mazza_kay_2008, title={Bioactivity, absorption, and metabolism of anthocyanins}, volume={1}, journal={Recent advances in polyphenol research}, publisher={Wiley-Blackwell}, author={Mazza, Giuseppe and Kay, Colin D}, year={2008}, pages={228–262} }
 @article{gebauer_west_kay_alaupovic_bagshaw_kris-etherton_2008, title={Effects of pistachios on cardiovascular disease risk factors and potential mechanisms of action: a dose-response study--}, volume={88}, number={3}, journal={The American journal of clinical nutrition}, publisher={Oxford University Press}, author={Gebauer, Sarah K and West, Sheila G and Kay, Colin D and Alaupovic, Petar and Bagshaw, Deborah and Kris-Etherton, Penny M}, year={2008}, pages={651–659} }
 @article{kay_kroon_cassidy_2008, title={The major intestinal metabolites of anthocyanins are unlikely to be conjugates of their parent compounds but metabolites of their degradation products}, volume={67}, ISSN={0029-6651 1475-2719}, url={http://dx.doi.org/10.1017/s0029665108009828}, DOI={10.1017/s0029665108009828}, abstractNote={) does not appear achievable inhuman subjects. Furthermore, the in vitro mechanistic bioactivity of anthocyanins has been exclusively explored using aglycones andglycoside conjugates, despite a lack of evidence establishing these compounds as the biologically-available forms.As spontaneous degradation of anthocyanins to phenolic acids and aldehydes is reported to occur under experimental}, number={OCE8}, journal={Proceedings of the Nutrition Society}, publisher={Cambridge University Press (CUP)}, author={Kay, Colin and Kroon, Paul and Cassidy, Aedin}, year={2008}, month={May} }
 @inbook{psota_west_kris-etherton_maddox bagshaw_kay_2007, title={Clinical Nutrition Studies}, ISBN={9780849392184 9781420008890}, url={http://dx.doi.org/10.1201/9781420008890.ch41}, DOI={10.1201/9781420008890.ch41}, booktitle={Handbook of Nutrition and Food, Second Edition}, publisher={CRC Press}, author={Psota, Tricia and West, Sheila and Kris-Etherton, Penny and Maddox Bagshaw, Deborah and Kay, Colin}, year={2007}, month={Aug}, pages={693–714} }
 @inproceedings{courtney_kay_lampe_holub_duncan_2007, title={Effect of acute fish oil and soy isoflavone supplementation on postprandial serum triglycerides and biomarkers of oxidative stress in overweight or obese, hypertriglyeridemic men}, volume={21}, DOI={10.1096/fasebj.21.5.A370-d}, abstractNote={Chronic intake of fish and fish oil (FO) high in omega‐3 fatty acids (n‐3PUFA) reduces triglycerides (TG) but increases oxidative stress (OXID), whereas chronic intake of soy isoflavones (ISO) may reduce OXID. Elevated serum TG and OXID are cardiovascular disease (CVD) risk factors, however the effects of acute n‐3PUFA and soy isoflavone supplementation are unknown. Ten overweight or obese males consumed a high‐fat, high‐fructose meal with four supplement combinations (ISOplacebo+FOplacebo; ISOplac+FO; ISO+FOplac; and ISO+FO) in a randomized, double blind, placebo‐controlled, crossover study. Blood was collected at baseline, 2, 4 and 6h post‐meal and analyzed for fatty acids, isoflavones, TG and OXID markers (oxidized‐LDL, lipid hydroperoxides and total antioxidant status). FO treatments significantly increased serum n‐3PUFA and ISO treatments increased serum isoflavones. The study meal significantly increased TG within all treatments but did not significantly affect any OXID biomarkers. There were no significant differences between treatments for TG or OXID. This study adds to limited research on the effects of acute doses of FO and ISO on postprandial biomarkers of CVD risk.}, number={5}, booktitle={The FASEB Journal}, author={Courtney, Heather and Kay, Colin D. and Lampe, Johanna W. and Holub, Bruce J. and Duncan, Alison M.}, year={2007}, month={Apr}, pages={A370} }
 @article{west_kay_gebauer_savastano_diefenbach_kris‐etherton_2007, title={Pistachios Reduce Blood Pressure and Vascular Responses to Acute Stress in Healthy Adults}, volume={21}, ISSN={0892-6638 1530-6860}, url={http://dx.doi.org/10.1096/fasebj.21.5.a696-a}, DOI={10.1096/fasebj.21.5.a696-a}, abstractNote={Exaggerated blood pressure (BP) reactivity to psychological stress is a risk factor for CVD. We designed a randomized, controlled, crossover feeding study to evaluate the effects of pistachios on responses to standardized stressors in 28 hypercholesterolemic adults with normal BP. Subjects were fed 3 isoenergetic diets for 4 wk each after a 2-wk run-in diet (35% total fat, 11% SFA). Diets studied were: a Step-1 diet without pistachios (25% total fat, 8% SFA), Step-1 plus 1.5 oz/d pistachios (1.5oz diet; 30% total fat, 8% SFA) and a similar diet containing 3.0 oz/d pistachios (3oz diet; 34% total fat, 8% SFA). At the end of each diet, BP and total peripheral vascular resistance (TPR) were measured at rest and during a math task and the cold pressor. Both pistachio diets reduced mean systolic BP (P < 0.05), although the magnitude of this effect was larger on the 1.5oz diet (change in SBP = −2.4 vs −4.7 mm Hg). The 3oz diet had larger effects on systemic hemodynamics (see Figure). The 3oz diet significantly reduced TPR and heart rate, and these changes were offset by increases in cardiac output. This shift in systemic hemodynamics would be expected to reduce cardiac workload if maintained long term. Our results suggest a novel dose-dependent mechanism for the cardioprotective effects of pistachios. Supported by: California Pistachio Commission Partial support by: GCRC, PSU (NIH grant M01RR10732) Fellowship support by NSERC}, number={5}, journal={The FASEB Journal}, publisher={Wiley}, author={West, Sheila G. and Kay, Colin D. and Gebauer, Sarah K. and Savastano, David M. and Diefenbach, Chris M. and Kris‐Etherton, Penny M.}, year={2007}, month={Apr} }
 @inbook{gebauer_kay_west_alaupovic_psota_kris-etherton_2007, title={Pistachios beneficially affect multiple lipid and apolipoprotein CVD risk factors}, volume={21}, DOI={10.1096/fasebj.21.5.A695-b}, abstractNote={The beneficial effect of almonds and walnuts on CVD risk has been well studied; however little is known about the effects of pistachios on CVD risk factors. A randomized, crossover design controlled feeding study was conducted to compare the effects of 2 amounts of pistachios on CVD risk factors in 28 hypercholesterolemic adults (M = 10, W = 18; LDL‐C = 133 ± 4.3 mg/dl). Subjects were fed 3 isoenergetic diets for 4 wk each after a 2‐wk run‐in diet (35% total fat, 11% SFA, 8% PUFA, 13% MUFA). Diets included a Step‐I diet without pistachios (25% total fat, 8% SFA, 5% PUFA, 9% MUFA), with 1.5 oz/d pistachios (1.5 oz PD) 10% en; 30% total fat, 8% SFA, 6% PUFA, 12% MUFA), and with 3.0 oz/d pistachios (3.0 oz PD) (20% en; 34% total fat, 8% SFA, 8% PUFA, 15% MUFA). Compared to baseline, there was a reduction in TC (−6.7%, −8.4%), LDL‐C (−8.9%, −11.6%), and non‐HDL‐C (−7.5%, −11.2%) on the 1.5 oz PD and 3.0 oz PD (P's<0.01), respectively. The 3.0 oz PD decreased TC:HDL‐C (P<0.01), LDL‐C:HDL‐C (P<0.05), and non‐HDL‐C:HDL‐C (P<0.01), as well as apoB (P<0.05) and apoB:apoA (P<0.001). There was a significant difference between the 1.5 oz PD and 3.0 PD on the ratios of TC:HDL‐C, LDL‐C:HDL‐C, and non‐HDL‐C:HDL‐C (P's<0.05), indicating that the pistachio‐rich diets improve lipids, lipoproteins, and apolipoproteins in a dose‐dependent manner.}, number={5}, booktitle={The FASEB Journal}, author={Gebauer, Sarah K. and Kay, Colin D. and West, Sheila G. and Alaupovic, Petar and Psota, Tricia L. and Kris-Etherton, Penny M.}, year={2007}, month={Apr}, pages={A695} }
 @article{kay_gebauer_west_kris-etherton_2007, title={Pistachios reduce serum oxidized LDL and increase serum antioxidant levels}, publisher={Federation of American Societies for Experimental Biology}, author={Kay, Colin D and Gebauer, Sarah K and West, Sheila G and Kris-Etherton, Penny M}, year={2007} }
 @article{kay_2006, title={Aspects of anthocyanin absorption, metabolism and pharmacokinetics in humans}, volume={19}, ISSN={0954-4224 1475-2700}, url={http://dx.doi.org/10.1079/NRR2005116}, DOI={10.1079/NRR2005116}, abstractNote={Abstract}, number={1}, journal={Nutrition Research Reviews}, publisher={Cambridge University Press (CUP)}, author={Kay, Colin D}, year={2006}, month={Jun}, pages={137–146} }
 @article{kay_kris-etherton_west_2006, title={Effects of antioxidant-rich foods on vascular reactivity: Review of the clinical evidence}, volume={8}, ISSN={1523-3804 1534-6242}, url={http://dx.doi.org/10.1007/S11883-006-0027-7}, DOI={10.1007/S11883-006-0027-7}, abstractNote={The foods and nutrients discussed in this paper are components of dietary patterns that have been associated with lower cardiovascular disease risk. The focus of this review is on the effects of antioxidant foods on vascular health and discussion of their potential mechanisms of action. The foods reviewed include fruits and vegetables, red grapes and red wine, tea, cocoa/chocolate, and olive oil. The primary challenge in studying the cardioprotective components of a dietary pattern is in identifying mechanism(s) of action as well as the bioactive nutrients responsible. In selecting papers for this review, we focused on studies of whole foods and beverages that met the following criteria: 1) they are commonly consumed in typical diets, 2) they appear to have direct antioxidant effects, and 3) they have demonstrated effects on endothelial function in several human studies. The evidence presented herein suggests that dietary consumption of fruits and vegetables, red grapes and red wine, tea, chocolate, and olive oil may improve vascular reactivity, in part, by attenuating the adverse effects of oxidation on endothelial function. Additional research is needed to better understand the mechanism(s) by which antioxidant-rich foods and beverages favorably affect endothelial function and the extent to which this reflects direct antioxidant effects.}, number={6}, journal={Current Atherosclerosis Reports}, publisher={Springer Science and Business Media LLC}, author={Kay, Colin D. and Kris-Etherton, Penny M. and West, Sheila G.}, year={2006}, month={Nov}, pages={510–522} }
 @inproceedings{kay_kris-etherton_holub_hecker_west_2006, title={Inflammatory status modifies the actions of n3 fatty acids on vascular function}, volume={20}, DOI={10.1096/fasebj.20.4.A10-b}, abstractNote={We examined the postprandial effects of 3 meals containing unsaturated fatty acids on flow mediated dilation (FMD), serum fatty acids, and inflammatory biomarkers (CRP, Il‐6, TNF‐alpha) in individuals with type 2 diabetes (n=15) at baseline and 4h after the meals. The monounsaturated fatty acid (MUFA) meal contained 50 g fat from high oleic safflower and canola oils. Two additional meals were prepared by replacing 7% to 8% of MUFA with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from fish oil, or alpha‐linolenic acid (ALA) from canola oil. In individuals with elevated baseline CRP, change in FMD after the fish oil meal was positively correlated with change in CRP, such that larger increases in CRP were associated with larger improvements in vascular function. However, during the ALA treatment, this group exhibited an inverse relationship between change in FMD and CRP. For subjects with low fasting CRP, CRP response to the ALA meal was positively correlated with FMD response. Changes in FMD and CRP were unrelated during the MUFA meal. In subjects with elevated baseline CRP, FMD response to the n3 meals was proportional to EPA, DHA, total n3, and the ratio of n3 to omega‐6. FMD response was inversely correlated with the ratio of arachidonic acid (AA) to EPA. In conclusion, the specific effects of n3 fatty acids on vascular function appear to be dependent on background inflammatory status of individuals with type II diabetes.}, number={4}, booktitle={The FASEB Journal}, author={Kay, Colin David and Kris-Etherton, Penny M. and Holub, Bruce J. and Hecker, Kari D. and West, Sheila G.}, year={2006}, month={Mar}, pages={A10} }
 @inbook{holub_kay_2005, title={Anthocyanins and Cancer Prevention}, ISBN={9780849339455 9781420026399}, ISSN={2154-7408}, url={http://dx.doi.org/10.1201/9781420026399.ch20}, DOI={10.1201/9781420026399.ch20}, booktitle={Nutrition and Cancer Prevention}, publisher={CRC Press}, author={Holub, Bruce and Kay, Colin}, year={2005}, month={Sep} }
 @article{kay_mazza_holub_2005, title={Anthocyanins exist in the circulation primarily as metabolites in adult men}, volume={135}, number={11}, journal={The Journal of nutrition}, publisher={Oxford University Press}, author={Kay, Colin D and Mazza, Giuseppe and Holub, Bruce J}, year={2005}, pages={2582–2588} }
 @phdthesis{kay_2004, place={Guelph, Ont.}, title={Analysis of the bioactivity, metabolism, and pharmacokinetics of anthocyanins in humans}, school={University of Guelph}, author={Kay, Colin}, year={2004} }
 @article{kay_mazza_holub_wang_2004, title={Anthocyanin metabolites in human urine and serum}, volume={91}, ISSN={0007-1145 1475-2662}, url={http://dx.doi.org/10.1079/BJN20041126}, DOI={10.1079/BJN20041126}, abstractNote={In the present study we investigated the metabolic conversion of cyanidin glycosides in human subjects using solid-phase extraction, HPLC–diode array detector, MS, GC, and enzymic techniques. Volunteers consumed approximately 20 g chokeberry extract containing 1·3 g cyanidin 3-glycosides (899 mg cyanidin 3-galactoside, 321 mg cyanidin 3-arabinoside, 51 mg cyanidin 3-xyloside and 50 mg cyanidin 3-glucoside). Blood samples were drawn at 0, 0·5, 1, and 2 h post-consumption of the extract. Urine samples were also collected at 0, 4–5, and 22–24 h. We have confirmed that human subjects have the capacity to metabolise cyanidin 3-glycosides, as we observed at least ten individual anthocyanin metabolites in the urine and serum. Average concentrations of anthocyanins and anthocyanin metabolites in the urine reached levels of 17·9 (range 14·9–20·9) μmol/l within 5 h post-consumption and persisted in 24 h urine samples at levels of 12·1 (range 11·1–13·0) nmol/l. In addition, average total levels of anthocyanins and anthocyanin metabolites detected in the serum were observed at 591·7 (range 197·3–986·1) nmol/l within 2 h post-consumption. Cyanidin 3-galactoside accounted for 55·4 % (9·9 (range 7·2–12·6) μmol/l) and 66·0 % (390·6 (range 119·4–661·9) nmol/l) of the detected anthocyanins in the urine and serum samples, respectively. The metabolites were identified as glucuronide conjugates, as well as methylated and oxidised derivatives of cyanidin 3-galactoside and cyanidin glucuronide. Conjugation probably affects the biological activity of anthocyanins and these metabolic products are likely in part responsible for the reported health benefits associated with the consumption of anthocyanins.}, number={6}, journal={British Journal of Nutrition}, publisher={Cambridge University Press (CUP)}, author={Kay, Colin D. and Mazza, G. and Holub, Bruce J. and Wang, Jian}, year={2004}, month={Jun}, pages={933–942} }
 @article{mazza_cacace_kay_2004, title={Methods of analysis for anthocyanins in plants and biological fluids}, volume={87}, number={1}, journal={Journal of AOAC international}, publisher={AOAC International}, author={Mazza, G and Cacace, Juan E and Kay, Colin D}, year={2004}, pages={129–145} }
 @inproceedings{mazza_kay_holub_2003, title={Anthocyanins Absorption and Serum Antioxidant Status in Humans}, booktitle={The 12th World Food Congress}, author={Mazza, Giuseppe and Kay, Colin D. and Holub, Bruce J.}, year={2003} }
 @article{kay_holub_2003, title={The postprandial effects of dietary antioxidants in humans}, volume={5}, number={6}, journal={Current atherosclerosis reports}, publisher={Current Medicine Group}, author={Kay, Colin D and Holub, Bruce J}, year={2003}, pages={452} }
 @article{mazza_kay_cottrell_holub_2002, title={Absorption of anthocyanins from blueberries and serum antioxidant status in human subjects}, volume={50}, number={26}, journal={Journal of agricultural and food chemistry}, publisher={ACS Publications}, author={Mazza, G and Kay, Colin D and Cottrell, Tony and Holub, Bruce J}, year={2002}, pages={7731–7737} }
 @phdthesis{kay_2002, place={Guelph, Ont.}, title={Assessment of the in Vivo Antioxidant Potential of Wild Blueberries in Humans}, school={University of Guelph}, author={Kay, Colin David}, year={2002} }
 @article{kay_holub_2002, title={The effect of wild blueberry (Vaccinium angustifolium) consumption on postprandial serum antioxidant status in human subjects}, volume={88}, number={4}, journal={British Journal of Nutrition}, publisher={Cambridge University Press}, author={Kay, Colin D and Holub, Bruce J}, year={2002}, pages={389–397} }
 @article{hajimahmoodi_oveisi_sadeghi_jannat_hadjibabaie_farahani_akrami_namdar_ader_wessmann_et al._2000, title={Activity and concentration of polyphenolic antioxidants in apple: Effect of cultivar, harvest year and storage condition.}, volume={11}, number={12}, journal={Pakistan Journal of Biological Sciences}, publisher={orgz}, author={Hajimahmoodi, M and Oveisi, MR and Sadeghi, N and Jannat, B and Hadjibabaie, M and Farahani, E and Akrami, MR and Namdar, R and Ader, P and Wessmann, A and et al.}, year={2000}, pages={1056–1067} }
 @book{kesteren_izquierdo_serrano_rodda_lois_revilla_nolte_padilla_rocha_restrepo_1991, place={Quito, Ecuador}, title={Agroindustria rural en Venezuela}, institution={Instituto Latinoamericano de Fomento Agroindustrial}, author={Kesteren, A. and Izquierdo, E. and Serrano, J. and Rodda, A. and Lois, M. and Revilla, C. and Nolte, E. and Padilla, D. and Rocha, J.L. and Restrepo, J.I.}, year={1991} }