AnThocyanin and polyphenol bioactives for Health Enhancement through Nutritional Advancement (ATHENA)

Lead Research Organisation: Quadram Institute Bioscience
Department Name: Contracts

Abstract

Anthocyanins are the highly coloured flavonoids that are responsible for the red to dark purple colours of many fruits and vegetables including strawberries, blueberries, blackcurrants and aubergines. Data from epidemiological studies show that there is an inverse relationship between consumption of anthocyanins and risk of disease, particularly cardiovascular diseases (CVD). However, there is a lack of data from high quality randomised controlled trials which are required to establish if anthocyanin consumption causes reductions in CVD risk.

The aim of this project is to undertake a highly controlled dietary intervention to assess whether increased anthocyanin consumption reduces CVD risk. This will be achieved using ‘purple tomatoes’ that express high levels of anthocyanins in the tomato fruit and standard red tomatoes that are replete of anthocyanins. Volunteers will be recruited via the local hospital general surgery department; they will be patients who have been referred to have varicose veins surgically removed. They will be randomised to either the treatment or control group and asked to consume 4 portions of tomato soup per week for about 6 weeks. Before and after the intervention, samples of blood and urine will be collected and various measurements will be made of CVD risk factors such as blood pressure and plasma cholesterol, and of other biomarkers associated with CVD risk. In addition, venous tissue will be collected. Non-targeted transcriptomic analyses will be performed using white blood cell fractions and the venous tissue to identify novel markers of exposure / effect, and to guide research into the underlying mechanisms.

It is expected that the data from this research will establish whether or not anthocyanins, in the context of a complex food matrix, can cause reductions in CVD risk, and will identify potential mechanisms underlying the observed effects.
 
Description 1. By undertaking extensive analyses of the nutrients and non-nutrient 'bioactives' in a whole range of different types of tomatoes including genetically modified purple tomatoes, we have shown that major difference between GM tomatoes producing anthocyanins and the red anthocyanin-free tomatoes is the presence of the anthocyanins in the purple tomatoes. These data were used to support a safety assessment of the purple tomatoes for human consumption.

2. We have shown that by supplementing mouse diets with tomatoes expressing different types of polyphenols, some polyphenols cause reductions in atherosclerotic plaque size compared to red tomatoes whereas other polyphenols are not effective.

3. We have identified a mechanism that plausibly explains how the polyphenols in the diet cause the changes in cholesterol and the reductions in plaques. We have shown that specific metabolites produced by the gut microflora alter important regulatory molecules that control cholesterol metabolism.
Exploitation Route Our research has demonstrated that switching on the production of specific classes of polyphenols in red tomatoes can improve the health benefits of the tomatoes. Specifically, we have shown that the tomatoes expressing resveratrol or a mixture of anthocyanins and flavanols reduce the growth of atherosclerotic plaque in an animal model of human atherosclerosis.
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://www.athena-flora.eu/
 
Description 1. The significant research and associated public engagement and media activities around anthocyanins in foods and colour up your plate has increased public awareness of anthocyanins as health-promoting dietary components. PE and media activities that contributed to this impact included appearances of the lead researcher on national TV (e.g. with Angela Rippon on the BBC programme 'How to stay young' in 2016) and the series of 'Heroes of Food Research' events led by the PI in Norwich in 2015-2016. 2. Our research with genetically modified tomatoes with much higher levels of existing polyphenols or that expressed novel polyphenols that were developed by the John Innes Centre has had an impact on the debate about whether or not GMOs can be beneficial and whether or not they are safe. The plans to undertake a first-in-humans tolerability trial with the purple tomatoes was discussed in the UK House of Lords. 3. By successfully completing a risk assessment and obtaining ethical approval to undertake a first in humans dose escalation tolerability trial, we have potentially changed the GM landscape in the UK and possibly Europe.
First Year Of Impact 2015
Sector Agriculture, Food and Drink,Education,Environment,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic,Policy & public services

 
Description Impact on sustainability, shelf-life and nutritional value by vertically farmed leafy greens via a new local supply chain
Amount € 729,415 (EUR)
Organisation European Union 
Sector Public
Country European Union (EU)
Start 01/2020 
End 12/2020
 
Description Anthocyanin-rich food colorants from Brazilian berries 
Organisation Brazilian Agricultural Research Corporation
Country Brazil 
Sector Public 
PI Contribution The IFR team trained a Brazilian researcher in mammalian cell culture so they could establish a cell culture facility in the EMBRAPA Food Technogy Unit back in Rio. We also trained the researcher in use of HPLC linked to a triple quadruple mass spectrometer for analysis and structural identification of anthocyanins and other phenolics in plant extracts. We also applied NMR analysis and identified two as yet unreported anthocyanins in Jabuticaba.
Collaborator Contribution Provision of three anthocyanin-rich fruit skin powders that can be used as food colourants.
Impact Research presented at the 1st International Conference on Food Bioactives and Health held in Norwich in September 2016. A review of bioactives in Brazilian fruits and their potential health benefits is being drafted for submission to the Trends in Food Science and Technology journal.
Start Year 2016
 
Description Bespoke synthesis of polyphenol human metabolites 
Organisation University of Barcelona
Country Spain 
Sector Academic/University 
PI Contribution We used synthetic organic chemistry routes to make phase-2 conjugates of various dietary flavonoids and phenolic acids and supplied these to various collaborators for testing of biological activity. These compounds are not available commercially and for many of them they are unique to our lab.
Collaborator Contribution Partners have used these physiologically relevant metabolites to test their biological activity using in vitro models such as cultured mammalian cell models, etc... They have also used them as authentic standards to facilitate identification and quantification of metabolites in human and animal tissues including blood, urine and faeces.
Impact Petri N, Tannergen C, Holst B, Mellon FA, Bao Y, Plumb GW, Bacon J, O'Leary KA, Kroon PA, Knutson L, Forsell P, Eriksson T, Lennernas H & Williamson G (2003) "Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejenum in vivo". Drug Metab Disposition 31, 805-813.Nemeth K, Plumb GW, Berrin J-G, Juge N, Jacob R, Naim HY, Williamson G, Swallow DM, Kroon PA (2003) "Deglycosylation by small intestinal epithelial cell ? glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur J Nutr 42, 29-42.Kroon PA, Clifford MN, Crozier A, Day AJ, Donovan JL, Manach C & Williamson G (2004). How should we assess the effects of exposure to dietary polyphenols in vitro? Am J Clin Nutr 80, 15-21. Dupont MS, Day AJ, Bennett RN, Mellon FA & Kroon PA (2004) "Absorption of kaempferol-3-glucuronide from endive in humans". Eur J Clin Nutr 58, 947-954. Needs PW, Kroon PA (2006) Convenient syntheses of metabolically important quercetin glucuronides and sulfates. Tetrahedron 62, 6862-6868. Davis BD, Needs PW, Kroon PA & Brodbelt (2006) Identification of isomeric flavonoid glucuronides in urine and plasma by metal complexation and liquid chromatography/tandem mass spectrometry. J Mass Spectrom 41, 911-920. Tribolo S, Lodi F, Connor C, Suri S, Wilson V, Taylor M, Needs PW, Kroon PA, Hughes DA (2008). Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells. Atherosclerosis 197, 50-56. Loke WM, Proudfoot JM, Stewart S, McKinley AJ, Needs PW, Kroon PA, Hodgson JM & Croft KD (2008). Metabolic transformation has a profound effect on anti-inflammatory activity of flavonoids such as quercetin: Lack of association between antioxidant and lipoxygenase inhibitory activity. Biochem Pharmacol 75, 1045-1053. Loke WM, Proudfoot JM, Stewart S, McKinley AJ, Needs PW, Kroon PA, Hodgson JM & Croft KD (2008). Quercetin and its in vivo metabolites inhibit neutrophil-mediated low-density lipoprotein oxidation. J Agric Food Chem 56, 3609-3615. Hollands W, Brett GM, Radreau P, Saha S, Teucher B, Bennett, RN & Kroon PA (2008). Processing blackcurrants dramatically reduces the content and does not enhance the urinary yield of anthocyanins in human subjects. Food Chem 108, 869-878. Suri S, Taylor MA, Verity A, Tribolo S, Kroon PA, Hughes DA, Wilson VG (2008). A comparative study of the effects of quercetin and its glucuronide and sulphate metabolites on human neutrophil function in vitro. Biochem Pharmacol 76, 645-673. Barrington R, Williamson G, Bennett RN, Davis BD, Brodbelt JS, Kroon PA (2009). Absorption, conjugation and efflux of the flavonoids, kaempferol and galangin, using the intestinal CaCo-2/TC7 cell model. J Functional Foods 1, 74-97. Brett GM, Hollands W, Needs PW, Teucher B, Dainty JR, Bennett RN, Davis BD, Brodbelt JS & Kroon PA (2009). Absorption, metabolism and excretion of flavanones from single portions of orange fruit and juice and effects of anthropometric variables and contraceptive pill use on flavanone excretion. Br J Nutr 101, 664-675. http://journals.cambridge.org/repo_A44rP6ra (Personal author link) Winterbone MS, Tribolo S, Needs PW, Kroon PA & Hughes DA (2009). Physiologically relevant metabolites of quercetin have no effect on adhesion molecule or chemokine expression in human vascular smooth muscle cells. Atherosclerosis 202, 431-438. Kay CD, Kroon PA, Cassidy A (2009). The bioactivity of dietary anthocyanins is likely to be mediated by their degradation products. Mol Nutr Food Res 53 Suppl 1:S92-101. Lodi F, Jiménez R, Moreno L, Kroon PA, Needs PW, Hughes DA, Santos-Buelga C, González-Paramás A, Cogolludo A, Duarte J, Perez-Vizcaino F (2009). Glucuronidated and sulfated metabolites of the flavonoid quercetin prevent endothelial dysfunction but lack direct vasodilator effects in rat aorta. Atherosclerosis 204, 34-39. Radreau P, Rhodes JD, Mithen RF, Kroon PA, Sanderson J (2009) Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells. Exp Eye Res 89, 995-1002. Curtis PJ, Kroon PA, Hollands WJ, Walls R, Jenkins G, Kay CD, Cassidy A (2009). Cardiovascular disease risk biomarkers and liver function are not altered following twelve week ingestion of an elderberry extract rich in anthocyanins. J Nutr 139, 2266-2271. Soler A, Romero MP, Saha S, Furniss CSM, Kroon PA, Motilva MJ (2010). Digestion stability and evaluation of the metabolism and transport of olive oil phenols in human small intestinal epithelial Caco2/TC7 cell line. Food Chem, 119, 703-714. Suri S, Liu XH, Rayment S, Hughes DA, Kroon PA, Needs PW, Taylor MA, Tribolo S, Wilson VG (2010). Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery. Br J Pharmacol 159, 566-575. Bartholomé R, Haenen G, Hollman PCH, Bast A, Dagnelie PC, Roos D, Keijer J, Kroon PA, Needs PW, Arts ICW (2010). Deconjugation kinetics of glucuronidated phase-II flavonoid metabolites by ß-glucuronidase from neutrophils. Drug Metab Pharmacokinet 25, 379-387. Pereira-Caro G, Mateos R, Saha S, Madrona A, Espartero JL, Bravo L, Kroon PA (2010). Trans-epithelial transport and metabolism of new lipopohilic ether derivatives of hydroxytyrosol by enterocyte-like CaCo-2/TC7 cells. J Agric Food Chem 58, 11501-11509. Al-Shalmani S, Suri S, Hughes DA, Kroon PA, Needs PW, Taylor MA, Tribolo S, Wilson VG (2011). Quercetin and its principal metabolites, but not myricetin, oppose LPS-induced hyporesponsiveness of the porcine isolated coronary artery. Br J Pharmacol 162, 1485-1497. Curtis PJ, Sampson M, Potter J, Dhatariya K, Kroon PA, Cassidy A (2012). Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a one year double-blind randomized controlled trial. Diabetes Care 35, 226-232. Saha S, Hollands W, Needs PW, Ostertag LM, de Roos B, Duthie GG, Kroon PA (2012). Human O-sulfated metabolites of (-)-epicatechin and methyl-(-)-epicatechin are poor substrates for commercial aryl-sulfatases: Implications for studies concerned with quantifying epicatechin bioavailability. Pharmacol Res 65, 592-602. Lodi F, Tribolo S, Winterbone MS, Needs PW, Hughes DA, Kroon PA (2012). Human quercetin conjugated metabolites attenuate TNF-a-induced changes in vasomodulatory molecules in a HUASMCs/HUVECs co-culture model. Planta Med 78, 1571-1573. Hollands WJ, Hart D, Dainty JR, Hasselwander O, Tiihonen K, Wood R, Kroon PA (2013). Bioavailability of epicatechin and effects on nitric oxide metabolites of an apple flavanol-rich extract supplemented beverage compared to a whole apple puree: a randomized, placebo controlled, crossover trial. Mol Nutr Food Res 57, 1209-1217. Tribolo S, Lodi F, Winterbone MS, Saha S, Needs PW, Suri S, Taylor MA, Wilson VG, Walls R, Cassidy A, Hughes DA, Kroon PA (2013). Human metabolic transformation of quercetin blocks its capacity to decrease eNOS expression and endothelin-1 secretion by human endothelial cells. J Agric Food Chem 61, 8589-8596. Czank C, Cassidy A, Zhang Q, Morrison DJ, Preston T, Kroon PA, Botting NP, Kay CD (2013). Human metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: a 13C-tracer study. Am J Clin Nutr 97, 995-1003. Konic-Ristic A, Srdic-Rajica T, Kardum N, Kroon PA, Hollands WJ, Hayran O, Boyko N, Jorjadze M, Glibetic M (2013). Effects of bioactive-rich extracts of pomegranate, persimmon, nettle, dill, kale and Sideritis and isolated bioactives on arachidonic acid induced markers of platelet activation and platelet-leucocyte aggregation. J Sci Food Agric 93, 3581-3587. De Ferrars RM, Czank C, Zhang Q, Botting NP, Kroon PA, Cassidy A, Kay CD (2014). The pharmacokinetics of anthocyanins and their metabolites in humans. Br J Pharmacol 171, 3268-3282. De Ferrars R, Czank C, Saha S, Needs PW, Zhang Q, Raheem KS, Kroon PA, Kay CD (2014). Methods for isolating, identifying and quantifying anthocyanin metabolites in clinical samples. Anal Chem 86, 10052-10058. Danesi F, Kroon PA, Saha S, de Biase D, D'Antuono LF, Bordoni A (2014). Mixed pro- and anti-oxidative effects of pomegranate polyphenols in cultured cells. Int J Mol Sci 15, 19458-19471. Barrington RD, Needs PW, Williamson G, Kroon PA. MK571 inhibits phase-2 conjugation of flavonols by Caco-2/TC7 cells, but does not specifically inhibit their apical efflux. Biochem Pharmacol 95, 193-200. Cerezo AB, Winterbone MS, Moyle CW, Needs PW, Kroon PA (2015). Molecular structure-function relationship of dietary polyphenols for inhibiting VEGF-induced VEGFR-2 activity. Mol Nutr Food Res. 59, 2119-2131. doi: 10.1002/mnfr.201500407. Gornas P, Redenkovs V, Pugacheva I, Soliven A, Needs PW, Kroon PA (2016). Varied composition of tocochromanols in different types of bran: Rye, wheat, oat, spelt, buckwheat, corn and rice. Int J Food Properties 19, 1757-1764. Dower JI, Geleijnse JM, Kroon PA, Philo M, Mensink M, Kromhout D, Hollman PCH (2016). Does epicatechin contribute to the acute vascular function effects of dark chocolate? A randomised, crossover study. Mol Nutr Food Res 60, 2379-2386. Poór M, Boda G, Needs PW, Kroon PA, Lemli B, Bencsik T (2017). Interaction of quercetin and its metabolites with warfarin: displacement of warfarin from serum albumin and inhibition of CYP2C9 enzyme. Biomed Pharmacol 88, 574-581. Hollands WJ*, Voorspoels S*, Jacobs G, Aaby K, Meisland A, Garcia-Villalbad R, Tomas-Barberan F, Piskula MJ, Mawson D, Vovk I, Needs PW and Kroon PA (2017). Development, validation and evaluation of an analytical method for the determination of monomeric and oligomeric procyanidins in apple extracts. J Chromatogr A 1495, 46-56. Van Rymenant E, Grootaert C, Beerens K, Needs P, Kroon P, Kerimi A, Williamson G, García Villalba R, González-Sarrías A, Tomas-Barberan F, Van Camp J, Van de Voorde J. Vasorelaxant activity of twenty-one physiologically relevant (poly)phenolic metabolites on isolated mouse arteries. Mol Nutr Food Res 13, 4331-4335. Perez-Moral N, Saha S, Philo M, Hart DJ, Winterbone MS, Hollands WJ, Spurr M, Bows J, vander Velpen V, Kroon PA*, Curtis PJC (2018) Comparative bio-accessibility, bioavailability and bioequivalence of quercetin, apigenin, glucoraphanin and carotenoids from freeze-dried vegetables incorporated into a baked snack versus minimally processed vegetables: Evidence from in vitro models and a human bioavailability study. J Func Food 48, 410-419. Poor M, Boda G, Kunsagi-Mate S, Needs PW, Kroon PA, Lemli B (2018). Fluorescence spectroscopic evaluation of the interactions of quercetin, isorhamnetin, and quercetin-3 '-sulfate with different albumins. J Luminescence 194, 156-163. Wu Q, Kroon PA, Shao HJ, Needs PW, Yang XB (2018). Differential effects of quercetin and two of its derivatives, isorhamnetin and isorhamnetin-3-glucuronide, in inhibiting the proliferation of human breast cancer MCF-7 cells. J Agric Food Chem 66, 7181-7189. Wu Q, Needs PW, Lu YL, Kroon PA, Ren DY, Yang XB (2018). Different antitumor effects of quercetin, quercetin-3'-sulfate and quercetin-3-glucuronide in human breast cancer MCF-7 cells. Food Func 9, 1736-1746.
Start Year 2010
 
Description Bespoke synthesis of polyphenol human metabolites 
Organisation University of Milan
Country Italy 
Sector Academic/University 
PI Contribution We used synthetic organic chemistry routes to make phase-2 conjugates of various dietary flavonoids and phenolic acids and supplied these to various collaborators for testing of biological activity. These compounds are not available commercially and for many of them they are unique to our lab.
Collaborator Contribution Partners have used these physiologically relevant metabolites to test their biological activity using in vitro models such as cultured mammalian cell models, etc... They have also used them as authentic standards to facilitate identification and quantification of metabolites in human and animal tissues including blood, urine and faeces.
Impact Petri N, Tannergen C, Holst B, Mellon FA, Bao Y, Plumb GW, Bacon J, O'Leary KA, Kroon PA, Knutson L, Forsell P, Eriksson T, Lennernas H & Williamson G (2003) "Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejenum in vivo". Drug Metab Disposition 31, 805-813.Nemeth K, Plumb GW, Berrin J-G, Juge N, Jacob R, Naim HY, Williamson G, Swallow DM, Kroon PA (2003) "Deglycosylation by small intestinal epithelial cell ? glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur J Nutr 42, 29-42.Kroon PA, Clifford MN, Crozier A, Day AJ, Donovan JL, Manach C & Williamson G (2004). How should we assess the effects of exposure to dietary polyphenols in vitro? Am J Clin Nutr 80, 15-21. Dupont MS, Day AJ, Bennett RN, Mellon FA & Kroon PA (2004) "Absorption of kaempferol-3-glucuronide from endive in humans". Eur J Clin Nutr 58, 947-954. Needs PW, Kroon PA (2006) Convenient syntheses of metabolically important quercetin glucuronides and sulfates. Tetrahedron 62, 6862-6868. Davis BD, Needs PW, Kroon PA & Brodbelt (2006) Identification of isomeric flavonoid glucuronides in urine and plasma by metal complexation and liquid chromatography/tandem mass spectrometry. J Mass Spectrom 41, 911-920. Tribolo S, Lodi F, Connor C, Suri S, Wilson V, Taylor M, Needs PW, Kroon PA, Hughes DA (2008). Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells. Atherosclerosis 197, 50-56. Loke WM, Proudfoot JM, Stewart S, McKinley AJ, Needs PW, Kroon PA, Hodgson JM & Croft KD (2008). Metabolic transformation has a profound effect on anti-inflammatory activity of flavonoids such as quercetin: Lack of association between antioxidant and lipoxygenase inhibitory activity. Biochem Pharmacol 75, 1045-1053. Loke WM, Proudfoot JM, Stewart S, McKinley AJ, Needs PW, Kroon PA, Hodgson JM & Croft KD (2008). Quercetin and its in vivo metabolites inhibit neutrophil-mediated low-density lipoprotein oxidation. J Agric Food Chem 56, 3609-3615. Hollands W, Brett GM, Radreau P, Saha S, Teucher B, Bennett, RN & Kroon PA (2008). Processing blackcurrants dramatically reduces the content and does not enhance the urinary yield of anthocyanins in human subjects. Food Chem 108, 869-878. Suri S, Taylor MA, Verity A, Tribolo S, Kroon PA, Hughes DA, Wilson VG (2008). A comparative study of the effects of quercetin and its glucuronide and sulphate metabolites on human neutrophil function in vitro. Biochem Pharmacol 76, 645-673. Barrington R, Williamson G, Bennett RN, Davis BD, Brodbelt JS, Kroon PA (2009). Absorption, conjugation and efflux of the flavonoids, kaempferol and galangin, using the intestinal CaCo-2/TC7 cell model. J Functional Foods 1, 74-97. Brett GM, Hollands W, Needs PW, Teucher B, Dainty JR, Bennett RN, Davis BD, Brodbelt JS & Kroon PA (2009). Absorption, metabolism and excretion of flavanones from single portions of orange fruit and juice and effects of anthropometric variables and contraceptive pill use on flavanone excretion. Br J Nutr 101, 664-675. http://journals.cambridge.org/repo_A44rP6ra (Personal author link) Winterbone MS, Tribolo S, Needs PW, Kroon PA & Hughes DA (2009). Physiologically relevant metabolites of quercetin have no effect on adhesion molecule or chemokine expression in human vascular smooth muscle cells. Atherosclerosis 202, 431-438. Kay CD, Kroon PA, Cassidy A (2009). The bioactivity of dietary anthocyanins is likely to be mediated by their degradation products. Mol Nutr Food Res 53 Suppl 1:S92-101. Lodi F, Jiménez R, Moreno L, Kroon PA, Needs PW, Hughes DA, Santos-Buelga C, González-Paramás A, Cogolludo A, Duarte J, Perez-Vizcaino F (2009). Glucuronidated and sulfated metabolites of the flavonoid quercetin prevent endothelial dysfunction but lack direct vasodilator effects in rat aorta. Atherosclerosis 204, 34-39. Radreau P, Rhodes JD, Mithen RF, Kroon PA, Sanderson J (2009) Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells. Exp Eye Res 89, 995-1002. Curtis PJ, Kroon PA, Hollands WJ, Walls R, Jenkins G, Kay CD, Cassidy A (2009). Cardiovascular disease risk biomarkers and liver function are not altered following twelve week ingestion of an elderberry extract rich in anthocyanins. J Nutr 139, 2266-2271. Soler A, Romero MP, Saha S, Furniss CSM, Kroon PA, Motilva MJ (2010). Digestion stability and evaluation of the metabolism and transport of olive oil phenols in human small intestinal epithelial Caco2/TC7 cell line. Food Chem, 119, 703-714. Suri S, Liu XH, Rayment S, Hughes DA, Kroon PA, Needs PW, Taylor MA, Tribolo S, Wilson VG (2010). Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery. Br J Pharmacol 159, 566-575. Bartholomé R, Haenen G, Hollman PCH, Bast A, Dagnelie PC, Roos D, Keijer J, Kroon PA, Needs PW, Arts ICW (2010). Deconjugation kinetics of glucuronidated phase-II flavonoid metabolites by ß-glucuronidase from neutrophils. Drug Metab Pharmacokinet 25, 379-387. Pereira-Caro G, Mateos R, Saha S, Madrona A, Espartero JL, Bravo L, Kroon PA (2010). Trans-epithelial transport and metabolism of new lipopohilic ether derivatives of hydroxytyrosol by enterocyte-like CaCo-2/TC7 cells. J Agric Food Chem 58, 11501-11509. Al-Shalmani S, Suri S, Hughes DA, Kroon PA, Needs PW, Taylor MA, Tribolo S, Wilson VG (2011). Quercetin and its principal metabolites, but not myricetin, oppose LPS-induced hyporesponsiveness of the porcine isolated coronary artery. Br J Pharmacol 162, 1485-1497. Curtis PJ, Sampson M, Potter J, Dhatariya K, Kroon PA, Cassidy A (2012). Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a one year double-blind randomized controlled trial. Diabetes Care 35, 226-232. Saha S, Hollands W, Needs PW, Ostertag LM, de Roos B, Duthie GG, Kroon PA (2012). Human O-sulfated metabolites of (-)-epicatechin and methyl-(-)-epicatechin are poor substrates for commercial aryl-sulfatases: Implications for studies concerned with quantifying epicatechin bioavailability. Pharmacol Res 65, 592-602. Lodi F, Tribolo S, Winterbone MS, Needs PW, Hughes DA, Kroon PA (2012). Human quercetin conjugated metabolites attenuate TNF-a-induced changes in vasomodulatory molecules in a HUASMCs/HUVECs co-culture model. Planta Med 78, 1571-1573. Hollands WJ, Hart D, Dainty JR, Hasselwander O, Tiihonen K, Wood R, Kroon PA (2013). Bioavailability of epicatechin and effects on nitric oxide metabolites of an apple flavanol-rich extract supplemented beverage compared to a whole apple puree: a randomized, placebo controlled, crossover trial. Mol Nutr Food Res 57, 1209-1217. Tribolo S, Lodi F, Winterbone MS, Saha S, Needs PW, Suri S, Taylor MA, Wilson VG, Walls R, Cassidy A, Hughes DA, Kroon PA (2013). Human metabolic transformation of quercetin blocks its capacity to decrease eNOS expression and endothelin-1 secretion by human endothelial cells. J Agric Food Chem 61, 8589-8596. Czank C, Cassidy A, Zhang Q, Morrison DJ, Preston T, Kroon PA, Botting NP, Kay CD (2013). Human metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: a 13C-tracer study. Am J Clin Nutr 97, 995-1003. Konic-Ristic A, Srdic-Rajica T, Kardum N, Kroon PA, Hollands WJ, Hayran O, Boyko N, Jorjadze M, Glibetic M (2013). Effects of bioactive-rich extracts of pomegranate, persimmon, nettle, dill, kale and Sideritis and isolated bioactives on arachidonic acid induced markers of platelet activation and platelet-leucocyte aggregation. J Sci Food Agric 93, 3581-3587. De Ferrars RM, Czank C, Zhang Q, Botting NP, Kroon PA, Cassidy A, Kay CD (2014). The pharmacokinetics of anthocyanins and their metabolites in humans. Br J Pharmacol 171, 3268-3282. De Ferrars R, Czank C, Saha S, Needs PW, Zhang Q, Raheem KS, Kroon PA, Kay CD (2014). Methods for isolating, identifying and quantifying anthocyanin metabolites in clinical samples. Anal Chem 86, 10052-10058. Danesi F, Kroon PA, Saha S, de Biase D, D'Antuono LF, Bordoni A (2014). Mixed pro- and anti-oxidative effects of pomegranate polyphenols in cultured cells. Int J Mol Sci 15, 19458-19471. Barrington RD, Needs PW, Williamson G, Kroon PA. MK571 inhibits phase-2 conjugation of flavonols by Caco-2/TC7 cells, but does not specifically inhibit their apical efflux. Biochem Pharmacol 95, 193-200. Cerezo AB, Winterbone MS, Moyle CW, Needs PW, Kroon PA (2015). Molecular structure-function relationship of dietary polyphenols for inhibiting VEGF-induced VEGFR-2 activity. Mol Nutr Food Res. 59, 2119-2131. doi: 10.1002/mnfr.201500407. Gornas P, Redenkovs V, Pugacheva I, Soliven A, Needs PW, Kroon PA (2016). Varied composition of tocochromanols in different types of bran: Rye, wheat, oat, spelt, buckwheat, corn and rice. Int J Food Properties 19, 1757-1764. Dower JI, Geleijnse JM, Kroon PA, Philo M, Mensink M, Kromhout D, Hollman PCH (2016). Does epicatechin contribute to the acute vascular function effects of dark chocolate? A randomised, crossover study. Mol Nutr Food Res 60, 2379-2386. Poór M, Boda G, Needs PW, Kroon PA, Lemli B, Bencsik T (2017). Interaction of quercetin and its metabolites with warfarin: displacement of warfarin from serum albumin and inhibition of CYP2C9 enzyme. Biomed Pharmacol 88, 574-581. Hollands WJ*, Voorspoels S*, Jacobs G, Aaby K, Meisland A, Garcia-Villalbad R, Tomas-Barberan F, Piskula MJ, Mawson D, Vovk I, Needs PW and Kroon PA (2017). Development, validation and evaluation of an analytical method for the determination of monomeric and oligomeric procyanidins in apple extracts. J Chromatogr A 1495, 46-56. Van Rymenant E, Grootaert C, Beerens K, Needs P, Kroon P, Kerimi A, Williamson G, García Villalba R, González-Sarrías A, Tomas-Barberan F, Van Camp J, Van de Voorde J. Vasorelaxant activity of twenty-one physiologically relevant (poly)phenolic metabolites on isolated mouse arteries. Mol Nutr Food Res 13, 4331-4335. Perez-Moral N, Saha S, Philo M, Hart DJ, Winterbone MS, Hollands WJ, Spurr M, Bows J, vander Velpen V, Kroon PA*, Curtis PJC (2018) Comparative bio-accessibility, bioavailability and bioequivalence of quercetin, apigenin, glucoraphanin and carotenoids from freeze-dried vegetables incorporated into a baked snack versus minimally processed vegetables: Evidence from in vitro models and a human bioavailability study. J Func Food 48, 410-419. Poor M, Boda G, Kunsagi-Mate S, Needs PW, Kroon PA, Lemli B (2018). Fluorescence spectroscopic evaluation of the interactions of quercetin, isorhamnetin, and quercetin-3 '-sulfate with different albumins. J Luminescence 194, 156-163. Wu Q, Kroon PA, Shao HJ, Needs PW, Yang XB (2018). Differential effects of quercetin and two of its derivatives, isorhamnetin and isorhamnetin-3-glucuronide, in inhibiting the proliferation of human breast cancer MCF-7 cells. J Agric Food Chem 66, 7181-7189. Wu Q, Needs PW, Lu YL, Kroon PA, Ren DY, Yang XB (2018). Different antitumor effects of quercetin, quercetin-3'-sulfate and quercetin-3-glucuronide in human breast cancer MCF-7 cells. Food Func 9, 1736-1746.
Start Year 2010
 
Description Bespoke synthesis of polyphenol human metabolites 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution We used synthetic organic chemistry routes to make phase-2 conjugates of various dietary flavonoids and phenolic acids and supplied these to various collaborators for testing of biological activity. These compounds are not available commercially and for many of them they are unique to our lab.
Collaborator Contribution Partners have used these physiologically relevant metabolites to test their biological activity using in vitro models such as cultured mammalian cell models, etc... They have also used them as authentic standards to facilitate identification and quantification of metabolites in human and animal tissues including blood, urine and faeces.
Impact Petri N, Tannergen C, Holst B, Mellon FA, Bao Y, Plumb GW, Bacon J, O'Leary KA, Kroon PA, Knutson L, Forsell P, Eriksson T, Lennernas H & Williamson G (2003) "Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejenum in vivo". Drug Metab Disposition 31, 805-813.Nemeth K, Plumb GW, Berrin J-G, Juge N, Jacob R, Naim HY, Williamson G, Swallow DM, Kroon PA (2003) "Deglycosylation by small intestinal epithelial cell ? glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur J Nutr 42, 29-42.Kroon PA, Clifford MN, Crozier A, Day AJ, Donovan JL, Manach C & Williamson G (2004). How should we assess the effects of exposure to dietary polyphenols in vitro? Am J Clin Nutr 80, 15-21. Dupont MS, Day AJ, Bennett RN, Mellon FA & Kroon PA (2004) "Absorption of kaempferol-3-glucuronide from endive in humans". Eur J Clin Nutr 58, 947-954. Needs PW, Kroon PA (2006) Convenient syntheses of metabolically important quercetin glucuronides and sulfates. Tetrahedron 62, 6862-6868. Davis BD, Needs PW, Kroon PA & Brodbelt (2006) Identification of isomeric flavonoid glucuronides in urine and plasma by metal complexation and liquid chromatography/tandem mass spectrometry. J Mass Spectrom 41, 911-920. Tribolo S, Lodi F, Connor C, Suri S, Wilson V, Taylor M, Needs PW, Kroon PA, Hughes DA (2008). Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells. Atherosclerosis 197, 50-56. Loke WM, Proudfoot JM, Stewart S, McKinley AJ, Needs PW, Kroon PA, Hodgson JM & Croft KD (2008). Metabolic transformation has a profound effect on anti-inflammatory activity of flavonoids such as quercetin: Lack of association between antioxidant and lipoxygenase inhibitory activity. Biochem Pharmacol 75, 1045-1053. Loke WM, Proudfoot JM, Stewart S, McKinley AJ, Needs PW, Kroon PA, Hodgson JM & Croft KD (2008). Quercetin and its in vivo metabolites inhibit neutrophil-mediated low-density lipoprotein oxidation. J Agric Food Chem 56, 3609-3615. Hollands W, Brett GM, Radreau P, Saha S, Teucher B, Bennett, RN & Kroon PA (2008). Processing blackcurrants dramatically reduces the content and does not enhance the urinary yield of anthocyanins in human subjects. Food Chem 108, 869-878. Suri S, Taylor MA, Verity A, Tribolo S, Kroon PA, Hughes DA, Wilson VG (2008). A comparative study of the effects of quercetin and its glucuronide and sulphate metabolites on human neutrophil function in vitro. Biochem Pharmacol 76, 645-673. Barrington R, Williamson G, Bennett RN, Davis BD, Brodbelt JS, Kroon PA (2009). Absorption, conjugation and efflux of the flavonoids, kaempferol and galangin, using the intestinal CaCo-2/TC7 cell model. J Functional Foods 1, 74-97. Brett GM, Hollands W, Needs PW, Teucher B, Dainty JR, Bennett RN, Davis BD, Brodbelt JS & Kroon PA (2009). Absorption, metabolism and excretion of flavanones from single portions of orange fruit and juice and effects of anthropometric variables and contraceptive pill use on flavanone excretion. Br J Nutr 101, 664-675. http://journals.cambridge.org/repo_A44rP6ra (Personal author link) Winterbone MS, Tribolo S, Needs PW, Kroon PA & Hughes DA (2009). Physiologically relevant metabolites of quercetin have no effect on adhesion molecule or chemokine expression in human vascular smooth muscle cells. Atherosclerosis 202, 431-438. Kay CD, Kroon PA, Cassidy A (2009). The bioactivity of dietary anthocyanins is likely to be mediated by their degradation products. Mol Nutr Food Res 53 Suppl 1:S92-101. Lodi F, Jiménez R, Moreno L, Kroon PA, Needs PW, Hughes DA, Santos-Buelga C, González-Paramás A, Cogolludo A, Duarte J, Perez-Vizcaino F (2009). Glucuronidated and sulfated metabolites of the flavonoid quercetin prevent endothelial dysfunction but lack direct vasodilator effects in rat aorta. Atherosclerosis 204, 34-39. Radreau P, Rhodes JD, Mithen RF, Kroon PA, Sanderson J (2009) Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells. Exp Eye Res 89, 995-1002. Curtis PJ, Kroon PA, Hollands WJ, Walls R, Jenkins G, Kay CD, Cassidy A (2009). Cardiovascular disease risk biomarkers and liver function are not altered following twelve week ingestion of an elderberry extract rich in anthocyanins. J Nutr 139, 2266-2271. Soler A, Romero MP, Saha S, Furniss CSM, Kroon PA, Motilva MJ (2010). Digestion stability and evaluation of the metabolism and transport of olive oil phenols in human small intestinal epithelial Caco2/TC7 cell line. Food Chem, 119, 703-714. Suri S, Liu XH, Rayment S, Hughes DA, Kroon PA, Needs PW, Taylor MA, Tribolo S, Wilson VG (2010). Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery. Br J Pharmacol 159, 566-575. Bartholomé R, Haenen G, Hollman PCH, Bast A, Dagnelie PC, Roos D, Keijer J, Kroon PA, Needs PW, Arts ICW (2010). Deconjugation kinetics of glucuronidated phase-II flavonoid metabolites by ß-glucuronidase from neutrophils. Drug Metab Pharmacokinet 25, 379-387. Pereira-Caro G, Mateos R, Saha S, Madrona A, Espartero JL, Bravo L, Kroon PA (2010). Trans-epithelial transport and metabolism of new lipopohilic ether derivatives of hydroxytyrosol by enterocyte-like CaCo-2/TC7 cells. J Agric Food Chem 58, 11501-11509. Al-Shalmani S, Suri S, Hughes DA, Kroon PA, Needs PW, Taylor MA, Tribolo S, Wilson VG (2011). Quercetin and its principal metabolites, but not myricetin, oppose LPS-induced hyporesponsiveness of the porcine isolated coronary artery. Br J Pharmacol 162, 1485-1497. Curtis PJ, Sampson M, Potter J, Dhatariya K, Kroon PA, Cassidy A (2012). Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a one year double-blind randomized controlled trial. Diabetes Care 35, 226-232. Saha S, Hollands W, Needs PW, Ostertag LM, de Roos B, Duthie GG, Kroon PA (2012). Human O-sulfated metabolites of (-)-epicatechin and methyl-(-)-epicatechin are poor substrates for commercial aryl-sulfatases: Implications for studies concerned with quantifying epicatechin bioavailability. Pharmacol Res 65, 592-602. Lodi F, Tribolo S, Winterbone MS, Needs PW, Hughes DA, Kroon PA (2012). Human quercetin conjugated metabolites attenuate TNF-a-induced changes in vasomodulatory molecules in a HUASMCs/HUVECs co-culture model. Planta Med 78, 1571-1573. Hollands WJ, Hart D, Dainty JR, Hasselwander O, Tiihonen K, Wood R, Kroon PA (2013). Bioavailability of epicatechin and effects on nitric oxide metabolites of an apple flavanol-rich extract supplemented beverage compared to a whole apple puree: a randomized, placebo controlled, crossover trial. Mol Nutr Food Res 57, 1209-1217. Tribolo S, Lodi F, Winterbone MS, Saha S, Needs PW, Suri S, Taylor MA, Wilson VG, Walls R, Cassidy A, Hughes DA, Kroon PA (2013). Human metabolic transformation of quercetin blocks its capacity to decrease eNOS expression and endothelin-1 secretion by human endothelial cells. J Agric Food Chem 61, 8589-8596. Czank C, Cassidy A, Zhang Q, Morrison DJ, Preston T, Kroon PA, Botting NP, Kay CD (2013). Human metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: a 13C-tracer study. Am J Clin Nutr 97, 995-1003. Konic-Ristic A, Srdic-Rajica T, Kardum N, Kroon PA, Hollands WJ, Hayran O, Boyko N, Jorjadze M, Glibetic M (2013). Effects of bioactive-rich extracts of pomegranate, persimmon, nettle, dill, kale and Sideritis and isolated bioactives on arachidonic acid induced markers of platelet activation and platelet-leucocyte aggregation. J Sci Food Agric 93, 3581-3587. De Ferrars RM, Czank C, Zhang Q, Botting NP, Kroon PA, Cassidy A, Kay CD (2014). The pharmacokinetics of anthocyanins and their metabolites in humans. Br J Pharmacol 171, 3268-3282. De Ferrars R, Czank C, Saha S, Needs PW, Zhang Q, Raheem KS, Kroon PA, Kay CD (2014). Methods for isolating, identifying and quantifying anthocyanin metabolites in clinical samples. Anal Chem 86, 10052-10058. Danesi F, Kroon PA, Saha S, de Biase D, D'Antuono LF, Bordoni A (2014). Mixed pro- and anti-oxidative effects of pomegranate polyphenols in cultured cells. Int J Mol Sci 15, 19458-19471. Barrington RD, Needs PW, Williamson G, Kroon PA. MK571 inhibits phase-2 conjugation of flavonols by Caco-2/TC7 cells, but does not specifically inhibit their apical efflux. Biochem Pharmacol 95, 193-200. Cerezo AB, Winterbone MS, Moyle CW, Needs PW, Kroon PA (2015). Molecular structure-function relationship of dietary polyphenols for inhibiting VEGF-induced VEGFR-2 activity. Mol Nutr Food Res. 59, 2119-2131. doi: 10.1002/mnfr.201500407. Gornas P, Redenkovs V, Pugacheva I, Soliven A, Needs PW, Kroon PA (2016). Varied composition of tocochromanols in different types of bran: Rye, wheat, oat, spelt, buckwheat, corn and rice. Int J Food Properties 19, 1757-1764. Dower JI, Geleijnse JM, Kroon PA, Philo M, Mensink M, Kromhout D, Hollman PCH (2016). Does epicatechin contribute to the acute vascular function effects of dark chocolate? A randomised, crossover study. Mol Nutr Food Res 60, 2379-2386. Poór M, Boda G, Needs PW, Kroon PA, Lemli B, Bencsik T (2017). Interaction of quercetin and its metabolites with warfarin: displacement of warfarin from serum albumin and inhibition of CYP2C9 enzyme. Biomed Pharmacol 88, 574-581. Hollands WJ*, Voorspoels S*, Jacobs G, Aaby K, Meisland A, Garcia-Villalbad R, Tomas-Barberan F, Piskula MJ, Mawson D, Vovk I, Needs PW and Kroon PA (2017). Development, validation and evaluation of an analytical method for the determination of monomeric and oligomeric procyanidins in apple extracts. J Chromatogr A 1495, 46-56. Van Rymenant E, Grootaert C, Beerens K, Needs P, Kroon P, Kerimi A, Williamson G, García Villalba R, González-Sarrías A, Tomas-Barberan F, Van Camp J, Van de Voorde J. Vasorelaxant activity of twenty-one physiologically relevant (poly)phenolic metabolites on isolated mouse arteries. Mol Nutr Food Res 13, 4331-4335. Perez-Moral N, Saha S, Philo M, Hart DJ, Winterbone MS, Hollands WJ, Spurr M, Bows J, vander Velpen V, Kroon PA*, Curtis PJC (2018) Comparative bio-accessibility, bioavailability and bioequivalence of quercetin, apigenin, glucoraphanin and carotenoids from freeze-dried vegetables incorporated into a baked snack versus minimally processed vegetables: Evidence from in vitro models and a human bioavailability study. J Func Food 48, 410-419. Poor M, Boda G, Kunsagi-Mate S, Needs PW, Kroon PA, Lemli B (2018). Fluorescence spectroscopic evaluation of the interactions of quercetin, isorhamnetin, and quercetin-3 '-sulfate with different albumins. J Luminescence 194, 156-163. Wu Q, Kroon PA, Shao HJ, Needs PW, Yang XB (2018). Differential effects of quercetin and two of its derivatives, isorhamnetin and isorhamnetin-3-glucuronide, in inhibiting the proliferation of human breast cancer MCF-7 cells. J Agric Food Chem 66, 7181-7189. Wu Q, Needs PW, Lu YL, Kroon PA, Ren DY, Yang XB (2018). Different antitumor effects of quercetin, quercetin-3'-sulfate and quercetin-3-glucuronide in human breast cancer MCF-7 cells. Food Func 9, 1736-1746.
Start Year 2010
 
Description Bespoke synthesis of polyphenol human metabolites 
Organisation University of Perth
Country Australia 
Sector Academic/University 
PI Contribution We used synthetic organic chemistry routes to make phase-2 conjugates of various dietary flavonoids and phenolic acids and supplied these to various collaborators for testing of biological activity. These compounds are not available commercially and for many of them they are unique to our lab.
Collaborator Contribution Partners have used these physiologically relevant metabolites to test their biological activity using in vitro models such as cultured mammalian cell models, etc... They have also used them as authentic standards to facilitate identification and quantification of metabolites in human and animal tissues including blood, urine and faeces.
Impact Petri N, Tannergen C, Holst B, Mellon FA, Bao Y, Plumb GW, Bacon J, O'Leary KA, Kroon PA, Knutson L, Forsell P, Eriksson T, Lennernas H & Williamson G (2003) "Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejenum in vivo". Drug Metab Disposition 31, 805-813.Nemeth K, Plumb GW, Berrin J-G, Juge N, Jacob R, Naim HY, Williamson G, Swallow DM, Kroon PA (2003) "Deglycosylation by small intestinal epithelial cell ? glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur J Nutr 42, 29-42.Kroon PA, Clifford MN, Crozier A, Day AJ, Donovan JL, Manach C & Williamson G (2004). How should we assess the effects of exposure to dietary polyphenols in vitro? Am J Clin Nutr 80, 15-21. Dupont MS, Day AJ, Bennett RN, Mellon FA & Kroon PA (2004) "Absorption of kaempferol-3-glucuronide from endive in humans". Eur J Clin Nutr 58, 947-954. Needs PW, Kroon PA (2006) Convenient syntheses of metabolically important quercetin glucuronides and sulfates. Tetrahedron 62, 6862-6868. Davis BD, Needs PW, Kroon PA & Brodbelt (2006) Identification of isomeric flavonoid glucuronides in urine and plasma by metal complexation and liquid chromatography/tandem mass spectrometry. J Mass Spectrom 41, 911-920. Tribolo S, Lodi F, Connor C, Suri S, Wilson V, Taylor M, Needs PW, Kroon PA, Hughes DA (2008). Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells. Atherosclerosis 197, 50-56. Loke WM, Proudfoot JM, Stewart S, McKinley AJ, Needs PW, Kroon PA, Hodgson JM & Croft KD (2008). Metabolic transformation has a profound effect on anti-inflammatory activity of flavonoids such as quercetin: Lack of association between antioxidant and lipoxygenase inhibitory activity. Biochem Pharmacol 75, 1045-1053. Loke WM, Proudfoot JM, Stewart S, McKinley AJ, Needs PW, Kroon PA, Hodgson JM & Croft KD (2008). Quercetin and its in vivo metabolites inhibit neutrophil-mediated low-density lipoprotein oxidation. J Agric Food Chem 56, 3609-3615. Hollands W, Brett GM, Radreau P, Saha S, Teucher B, Bennett, RN & Kroon PA (2008). Processing blackcurrants dramatically reduces the content and does not enhance the urinary yield of anthocyanins in human subjects. Food Chem 108, 869-878. Suri S, Taylor MA, Verity A, Tribolo S, Kroon PA, Hughes DA, Wilson VG (2008). A comparative study of the effects of quercetin and its glucuronide and sulphate metabolites on human neutrophil function in vitro. Biochem Pharmacol 76, 645-673. Barrington R, Williamson G, Bennett RN, Davis BD, Brodbelt JS, Kroon PA (2009). Absorption, conjugation and efflux of the flavonoids, kaempferol and galangin, using the intestinal CaCo-2/TC7 cell model. J Functional Foods 1, 74-97. Brett GM, Hollands W, Needs PW, Teucher B, Dainty JR, Bennett RN, Davis BD, Brodbelt JS & Kroon PA (2009). Absorption, metabolism and excretion of flavanones from single portions of orange fruit and juice and effects of anthropometric variables and contraceptive pill use on flavanone excretion. Br J Nutr 101, 664-675. http://journals.cambridge.org/repo_A44rP6ra (Personal author link) Winterbone MS, Tribolo S, Needs PW, Kroon PA & Hughes DA (2009). Physiologically relevant metabolites of quercetin have no effect on adhesion molecule or chemokine expression in human vascular smooth muscle cells. Atherosclerosis 202, 431-438. Kay CD, Kroon PA, Cassidy A (2009). The bioactivity of dietary anthocyanins is likely to be mediated by their degradation products. Mol Nutr Food Res 53 Suppl 1:S92-101. Lodi F, Jiménez R, Moreno L, Kroon PA, Needs PW, Hughes DA, Santos-Buelga C, González-Paramás A, Cogolludo A, Duarte J, Perez-Vizcaino F (2009). Glucuronidated and sulfated metabolites of the flavonoid quercetin prevent endothelial dysfunction but lack direct vasodilator effects in rat aorta. Atherosclerosis 204, 34-39. Radreau P, Rhodes JD, Mithen RF, Kroon PA, Sanderson J (2009) Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells. Exp Eye Res 89, 995-1002. Curtis PJ, Kroon PA, Hollands WJ, Walls R, Jenkins G, Kay CD, Cassidy A (2009). Cardiovascular disease risk biomarkers and liver function are not altered following twelve week ingestion of an elderberry extract rich in anthocyanins. J Nutr 139, 2266-2271. Soler A, Romero MP, Saha S, Furniss CSM, Kroon PA, Motilva MJ (2010). Digestion stability and evaluation of the metabolism and transport of olive oil phenols in human small intestinal epithelial Caco2/TC7 cell line. Food Chem, 119, 703-714. Suri S, Liu XH, Rayment S, Hughes DA, Kroon PA, Needs PW, Taylor MA, Tribolo S, Wilson VG (2010). Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery. Br J Pharmacol 159, 566-575. Bartholomé R, Haenen G, Hollman PCH, Bast A, Dagnelie PC, Roos D, Keijer J, Kroon PA, Needs PW, Arts ICW (2010). Deconjugation kinetics of glucuronidated phase-II flavonoid metabolites by ß-glucuronidase from neutrophils. Drug Metab Pharmacokinet 25, 379-387. Pereira-Caro G, Mateos R, Saha S, Madrona A, Espartero JL, Bravo L, Kroon PA (2010). Trans-epithelial transport and metabolism of new lipopohilic ether derivatives of hydroxytyrosol by enterocyte-like CaCo-2/TC7 cells. J Agric Food Chem 58, 11501-11509. Al-Shalmani S, Suri S, Hughes DA, Kroon PA, Needs PW, Taylor MA, Tribolo S, Wilson VG (2011). Quercetin and its principal metabolites, but not myricetin, oppose LPS-induced hyporesponsiveness of the porcine isolated coronary artery. Br J Pharmacol 162, 1485-1497. Curtis PJ, Sampson M, Potter J, Dhatariya K, Kroon PA, Cassidy A (2012). Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a one year double-blind randomized controlled trial. Diabetes Care 35, 226-232. Saha S, Hollands W, Needs PW, Ostertag LM, de Roos B, Duthie GG, Kroon PA (2012). Human O-sulfated metabolites of (-)-epicatechin and methyl-(-)-epicatechin are poor substrates for commercial aryl-sulfatases: Implications for studies concerned with quantifying epicatechin bioavailability. Pharmacol Res 65, 592-602. Lodi F, Tribolo S, Winterbone MS, Needs PW, Hughes DA, Kroon PA (2012). Human quercetin conjugated metabolites attenuate TNF-a-induced changes in vasomodulatory molecules in a HUASMCs/HUVECs co-culture model. Planta Med 78, 1571-1573. Hollands WJ, Hart D, Dainty JR, Hasselwander O, Tiihonen K, Wood R, Kroon PA (2013). Bioavailability of epicatechin and effects on nitric oxide metabolites of an apple flavanol-rich extract supplemented beverage compared to a whole apple puree: a randomized, placebo controlled, crossover trial. Mol Nutr Food Res 57, 1209-1217. Tribolo S, Lodi F, Winterbone MS, Saha S, Needs PW, Suri S, Taylor MA, Wilson VG, Walls R, Cassidy A, Hughes DA, Kroon PA (2013). Human metabolic transformation of quercetin blocks its capacity to decrease eNOS expression and endothelin-1 secretion by human endothelial cells. J Agric Food Chem 61, 8589-8596. Czank C, Cassidy A, Zhang Q, Morrison DJ, Preston T, Kroon PA, Botting NP, Kay CD (2013). Human metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: a 13C-tracer study. Am J Clin Nutr 97, 995-1003. Konic-Ristic A, Srdic-Rajica T, Kardum N, Kroon PA, Hollands WJ, Hayran O, Boyko N, Jorjadze M, Glibetic M (2013). Effects of bioactive-rich extracts of pomegranate, persimmon, nettle, dill, kale and Sideritis and isolated bioactives on arachidonic acid induced markers of platelet activation and platelet-leucocyte aggregation. J Sci Food Agric 93, 3581-3587. De Ferrars RM, Czank C, Zhang Q, Botting NP, Kroon PA, Cassidy A, Kay CD (2014). The pharmacokinetics of anthocyanins and their metabolites in humans. Br J Pharmacol 171, 3268-3282. De Ferrars R, Czank C, Saha S, Needs PW, Zhang Q, Raheem KS, Kroon PA, Kay CD (2014). Methods for isolating, identifying and quantifying anthocyanin metabolites in clinical samples. Anal Chem 86, 10052-10058. Danesi F, Kroon PA, Saha S, de Biase D, D'Antuono LF, Bordoni A (2014). Mixed pro- and anti-oxidative effects of pomegranate polyphenols in cultured cells. Int J Mol Sci 15, 19458-19471. Barrington RD, Needs PW, Williamson G, Kroon PA. MK571 inhibits phase-2 conjugation of flavonols by Caco-2/TC7 cells, but does not specifically inhibit their apical efflux. Biochem Pharmacol 95, 193-200. Cerezo AB, Winterbone MS, Moyle CW, Needs PW, Kroon PA (2015). Molecular structure-function relationship of dietary polyphenols for inhibiting VEGF-induced VEGFR-2 activity. Mol Nutr Food Res. 59, 2119-2131. doi: 10.1002/mnfr.201500407. Gornas P, Redenkovs V, Pugacheva I, Soliven A, Needs PW, Kroon PA (2016). Varied composition of tocochromanols in different types of bran: Rye, wheat, oat, spelt, buckwheat, corn and rice. Int J Food Properties 19, 1757-1764. Dower JI, Geleijnse JM, Kroon PA, Philo M, Mensink M, Kromhout D, Hollman PCH (2016). Does epicatechin contribute to the acute vascular function effects of dark chocolate? A randomised, crossover study. Mol Nutr Food Res 60, 2379-2386. Poór M, Boda G, Needs PW, Kroon PA, Lemli B, Bencsik T (2017). Interaction of quercetin and its metabolites with warfarin: displacement of warfarin from serum albumin and inhibition of CYP2C9 enzyme. Biomed Pharmacol 88, 574-581. Hollands WJ*, Voorspoels S*, Jacobs G, Aaby K, Meisland A, Garcia-Villalbad R, Tomas-Barberan F, Piskula MJ, Mawson D, Vovk I, Needs PW and Kroon PA (2017). Development, validation and evaluation of an analytical method for the determination of monomeric and oligomeric procyanidins in apple extracts. J Chromatogr A 1495, 46-56. Van Rymenant E, Grootaert C, Beerens K, Needs P, Kroon P, Kerimi A, Williamson G, García Villalba R, González-Sarrías A, Tomas-Barberan F, Van Camp J, Van de Voorde J. Vasorelaxant activity of twenty-one physiologically relevant (poly)phenolic metabolites on isolated mouse arteries. Mol Nutr Food Res 13, 4331-4335. Perez-Moral N, Saha S, Philo M, Hart DJ, Winterbone MS, Hollands WJ, Spurr M, Bows J, vander Velpen V, Kroon PA*, Curtis PJC (2018) Comparative bio-accessibility, bioavailability and bioequivalence of quercetin, apigenin, glucoraphanin and carotenoids from freeze-dried vegetables incorporated into a baked snack versus minimally processed vegetables: Evidence from in vitro models and a human bioavailability study. J Func Food 48, 410-419. Poor M, Boda G, Kunsagi-Mate S, Needs PW, Kroon PA, Lemli B (2018). Fluorescence spectroscopic evaluation of the interactions of quercetin, isorhamnetin, and quercetin-3 '-sulfate with different albumins. J Luminescence 194, 156-163. Wu Q, Kroon PA, Shao HJ, Needs PW, Yang XB (2018). Differential effects of quercetin and two of its derivatives, isorhamnetin and isorhamnetin-3-glucuronide, in inhibiting the proliferation of human breast cancer MCF-7 cells. J Agric Food Chem 66, 7181-7189. Wu Q, Needs PW, Lu YL, Kroon PA, Ren DY, Yang XB (2018). Different antitumor effects of quercetin, quercetin-3'-sulfate and quercetin-3-glucuronide in human breast cancer MCF-7 cells. Food Func 9, 1736-1746.
Start Year 2010
 
Description Novel Anthocyanins from Jabuticaba 
Organisation Brazilian Agricultural Research Corporation
Department Embrapa Agrobiologia
Country Brazil 
Sector Private 
PI Contribution The QIB team used HPLC, LC-MSn and NMR to isolate and determine the structure of anthocyanins in a novel Jabuticaba peel powder to be used as a food colourant and identified novel anthocyanin structures that had not been report previously.
Collaborator Contribution EMBRAPA Food Technology (Rio) provided the novel, patented peel powder and sent a researcher to characterise the anthocyanins as part of the BPA award.
Impact Identification of novel anthocyanins.
Start Year 2016
 
Title First-in-humans dose-escalation tolerability trial for a non-approved genetically modified food plant 
Description Following the completion of a successful risk assessment, we have obtained a favourable opinion by a UK National Research Ethics Committee to undertake the first ever human dietary intervention research trial with a non-approved genetically modified food plant. This work was supported by funding from the EU FP7 programme (FP7-ATHENA) and by a BBSRC through a institute strategic programme grant to the Quadram Institute (formerly the Institute of Food Research). 
Type Preventative Intervention - Nutrition and Chemoprevention
Current Stage Of Development Initial development
Year Development Stage Completed 2017
Development Status Actively seeking support
Impact Following the completion of a successful risk assessment, we have obtained a favourable opinion by a UK National Research Ethics Committee to undertake the first ever human dietary intervention research trial with a non-approved genetically modified food plant. This sets a precedent for the process of obtaining ethical approval for feeding GM foods that have been developed through research but not been through the regulatory approval process. The impact is likely, in time, to be substantial if the public acceptance and commercial interest in improved GM foods is realised. 
 
Description 'Heroes of Food Research' Public Engagement activity 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The purpose of the set of activities was to engage in a dialogue with members of the public in the region where we recruit participants to partake in dietary intervention studies. The activities included two sessions in Norwich's Forum Library public space where visitors could read about the types of studies that were going on, discuss what was involved when volunteering to participate in a study, ask questions of study PIs and study managers, taste intervention foods, complete a short questionnaire, and sign up for future activities which included an evening session with audience participation and voting and a workshop to gather feedback from potential volunteers. As a result of the activities and the significant feedback from the general public and those who had previously participated in human studies, we completely revamped our institute's Human Studies internet pages, recorded feedback and subsequently changed various features of our adverts that invited people to participate in specific studies, and recruited a significant number of new people to our database of interested volunteers.
Year(s) Of Engagement Activity 2015,2016
URL https://quadram.ac.uk/volunteer/
 
Description Appearance on BBC Programme 'How to Stay Young' with Angela Rippon 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact A Group Leader at the Institute of Food Research (now the Quadram Institute Bioscience) was filmed doing some research with anthocyanin-rich purple potatoes for the BBC programme 'How to stay young' with Angela Rippon and Dr Chris van Tulleken. This was screened nationally in 2016 and was also available on BBC iPlayer. The audience was millions. A number of enquiries from members of the public came to the QIB researcher following the showing of the programme.
Year(s) Of Engagement Activity 2016
URL https://www.bbc.co.uk/programmes/b095gd8f
 
Description Bioavailability 2018 International Conference, 'Understanding the bioavailability of micronutrients and bioactive compounds for improved public health', the 8th in the series of Bioavailability conferences. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Bioavailability 2018 International Conference, 'Understanding the bioavailability of micronutrients and bioactive compounds for improved public health', the 8th in the series of Bioavailability conferences.
Year(s) Of Engagement Activity 2018
 
Description Bioavailability Conference Poster 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I presented a poster on my findings on the urinary metabolites of anthocyanins post dietary intervention. This was seen by numerous different researchers from all over the world.
Year(s) Of Engagement Activity 2018
 
Description International Clinical Trial Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact International Clinical Trial Day
Year(s) Of Engagement Activity 2019