Inhibition of VEGF signalling by dietary polyphenols as a plausible mechanism for their health benefits

Lead Research Organisation: Quadram Institute Bioscience
Department Name: Contracts

Abstract

Cardiovascular diseases (CVD) are the single biggest cause of death worldwide and are particularly prevalent in westernised populations including Europe. Epidemiological evidence indicates that consumption of flavonoid-rich diets is associated with reduced CVD risk. In addition, recent systematic reviews of data from high quality clinical trials have shown that consumption of certain flavonoids and flavonoid-rich foods significantly reduce CVD risk. There is huge potential for the development and marketing of flavonoid-rich foods that reduce CVD risk, and EFSA is reviewing hundreds of dossiers of evidence in support of such health claims. But, there is an almost complete lack of evidence of the mechanisms involved in vivo. This is largely because the majority of existing proposed mechanisms have not been shown to occur at the sub-micromolar concentrations observed in blood and tissues, and do not take account of extensive human metabolism of ingested flavonoids. The host research team have recently discovered that certain polyphenols that are present in red wine, strawberries and cocoa potently inhibit vascular endothelial growth factor (VEGF) signalling in vascular endothelial cells at sub-micromolar concentrations. Because VEGF is pro-atherosclerotic, inhibition of VEGF signalling is a plausible mechanism to explain flavonoid-induced reductions in CVD risk.
The objectives of this project are to:
(i) determine the molecular basis of the inhibition of VEGF signalling by dietary polyphenols,
(ii) examine the effect of human metabolism of polyphenols on the efficacy of VEGF signalling inhibition, and
(iii) develop and validate an in vitro cellular model, involving intestinal metabolism and absorption processes, suitable for assessing the potential impact of ingested polyphenols on VEGF signalling.
The project will provide a molecular understanding of a plausible mechanism by which dietary flavonoids can reduce CVD risk.
 
Description The main objectives were to investigate which types of dietary polyphenols were effective inhibitors of VEGF signalling and which were not, establish how the normal changes in the polyphenol structure that occur during absorption and human metabolism affected their ability to inhibit VEGF signalling, and to develop a new in vitro model that incorporates human metabolism in assessments of VEGF inhibition.

The main findings were:
(1) Of 60 polyphenols tested, only a limited number (about 5) were considered potent inhibitors of VEGF signalling (i.e. were effective at low physiologically-relevant concentrations). This shows there is considerable specificity for the polyphenol. The most potent polyphenols were from green tea, apples, red wine, pomegranates and chocolate, and they could inhibit 50% of the VEGFR2 activation activity at concentrations below 1 micromolar which is in the physiological range.

(2) Phase-2 metabolism, which is a normal bodily process whereby small sugars or sulphate groups are added to xenobiotics to make them more soluble and tagged for excretion via the kidneys and liver, had a negative effect on the VEGF inhibitory activity of the polyphenols. However, some polyphenols like EGCG from green tea are not phase-2 metabolised and so they would still function as effective inhibitors of VEGF.

(3) We successfully developed a co-culture model involving CaCo2 cells that were a model of small intestinal epithelial cells which effectively metabolised the polyphenols, and human umbilical vein endothelial cells which are a model of the vascular endothelium, and used this to explore the effects of metabolism on VEGF-inhibitory activity.
Exploitation Route Now that we know which polyphenols are effective, we and others can focus future research to demonstrate their efficacy on these and not on potentially ineffective polyphenols. We have already worked with an SME and developed some protection of the intellectual property in this area. It is expected that this company and others will seek to develop products that are based on inhibition of VEGF signalling and angiogenesis.

Our in vitro model has significant potential utility in future research, because it is suitable for studies of polyphenol efficacy using a whole range of endothelial-relevant biomarkers, not just VEGF signalling.

If this early stage basic research can be translated into study outcomes that demonstrate beneficial effects in animal models or human subjects, then the public could be informed of the most suitable and effective dietary sources of these polyphenols and be advised to consume suitable quantities to achieve the health benefit(s).
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description By demonstrating which polyphenols are effective and which are not, we have created a rationale for focussing future research and development in this area. Developing and evaluating polyphenols as inhibitors of VEGF signalling is a key component of a 28-partner EU collaborative project coordinated by Kroon which includes 15 SMEs from across Europe. Some of these are interested in exploiting the VEGF-inhibitory properties of certain polyphenols, and there is already a patent submitted by one of the partners (revenue agreement with IFR, Kroon is an inventor).
First Year Of Impact 2012
Sector Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
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