Common Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells

Warner, E.F., Zhang, Q., Raheem, S., O’Hagan, D., O’Connell, M.A. and Kay, C.D. 2016. Common Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells. Journal of Nutrition. 146 (3), pp. 465-473. doi:10.3945/jn.115.217943

TitleCommon Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells
AuthorsWarner, E.F.
Zhang, Q.
Raheem, S.
O’Hagan, D.
O’Connell, M.A.
Kay, C.D.
Abstract

Background: Flavonoids have been implicated in the prevention of cardiovascular disease; however, their mechanisms of action have yet to be elucidated, possibly because most previous in vitro studies have used supraphysiological concentrations of unmetabolized flavonoids, overlooking their more bioavailable phenolic metabolites.

Objective: We aimed to explore the effects of phenolic metabolites and their precursor flavonoids at physiologically achievable concentrations, in isolation and combination, on soluble vascular cellular adhesion molecule-1 (sVCAM-1).

Method: Fourteen phenolic acid metabolites and 6 flavonoids were screened at 1 μM for their relative effects on sVCAM-1 secretion by human umbilical vein endothelial cells stimulated with tumor necrosis factor alpha (TNF-α). The active metabolites were further studied for their response at different concentrations (0.01 μM–100 μM), structure-activity relationships, and effect on vascular cellular adhesion molecule (VCAM)-1 mRNA expression. In addition, the additive activity of the metabolites and flavonoids was investigated by screening 25 unique mixtures at cumulative equimolar concentrations of 1 μM.

Results: Of the 20 compounds screened at 1 μM, inhibition of sVCAM-1 secretion was elicited by 4 phenolic metabolites, of which protocatechuic acid (PCA) was the most active (−17.2%, P = 0.05). Investigations into their responses at different concentrations showed that PCA significantly reduced sVCAM-1 15.2–36.5% between 1 and 100 μM, protocatechuic acid-3-sulfate and isovanillic acid reduced sVCAM-1 levels 12.2–54.7% between 10 and 100 μM, and protocatechuic acid-4-sulfate and isovanillic acid-3-glucuronide reduced sVCAM-1 secretion 27.6% and 42.8%, respectively, only at 100 μM. PCA demonstrated the strongest protein response and was therefore explored for its effect on VCAM-1 mRNA, where 78.4% inhibition was observed only after treatment with 100 μM PCA. Mixtures of the metabolites showed no activity toward sVCAM-1, suggesting no additive activity at 1 μM.

Conclusions: The present findings suggest that metabolism of flavonoids increases their vascular efficacy, resulting in a diversity of structures of varying bioactivity in human endothelial cells.

JournalJournal of Nutrition
Journal citation146 (3), pp. 465-473
ISSN0022-3166
Year2016
PublisherAmerican Society for Nutrition
Accepted author manuscript
Digital Object Identifier (DOI)doi:10.3945/jn.115.217943
Publication dates
Published03 Feb 2016

Related outputs

Glutamate mediated metabolic neutralization mitigates propionate toxicity in intracellular Mycobacterium tuberculosis
Lee, J.J., Lim, J., Gao, S., Lawson, C.P., Odell, M., Raheem, S., Woo, J., Kang, S-H., Kang, S-S., Jeon, B-Y. and Eoh, H. 2018. Glutamate mediated metabolic neutralization mitigates propionate toxicity in intracellular Mycobacterium tuberculosis. Scientific Reports. 8. doi:10.1038/s41598-018-26950-z

Signatures of anthocyanin metabolites identified in humans inhibit biomarkers of vascular inflammation in human endothelial cells
Warner, E.F., Smith, M.J., Zhang, Q., Raheem, S., O’Hagan, D., O'Connell, M.A. and Kay, C.D. 2017. Signatures of anthocyanin metabolites identified in humans inhibit biomarkers of vascular inflammation in human endothelial cells. Molecular Nutrition & Food Research. 61 (9), p. 1600053. doi:10.1002/mnfr.201700053

Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance
Warhurst, D., Craig, J.C. and Raheem, S. 2016. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance. PLoS ONE. 11 (8), p. e0160091. doi:10.1371/journal.pone.0160091

Effects of Fluconazole on the Metabolomic Profile of Candida albicans
Katragkou, A., Alexander, E.L., Eoh, H., Raheem, S., Roilides, E. and Walsh, T.J. 2016. Effects of Fluconazole on the Metabolomic Profile of Candida albicans. Journal of Antimicrobial Chemotherapy. 71 (3), pp. 635-640. doi:10.1093/jac/dkv381

Flavonoid metabolites reduce tumor necrosis factor-α secretion to a greater extent than their precursor compounds in human THP-1 monocytes.
di Gesso, J.L., Kerr, J.S., Zhang, Q., Raheem, S., Yalamanchili, S.K., O’Hagan, D., Kay, C.D. and O'Connell, M.A. 2015. Flavonoid metabolites reduce tumor necrosis factor-α secretion to a greater extent than their precursor compounds in human THP-1 monocytes. Molecular Nutrition & Food Research. 59 (6), pp. 1143-1154. doi:10.1002/mnfr.201400799

Anthocyanins and their physiologically relevant metabolites alter the expression of IL-6 and VCAM-1 in CD40L and oxidized LDL challenged vascular endothelial cells
Amin, H.P., Czank, C., Raheem, S., Zhang, Q., Botting, N.P., Cassidy, A. and Kay, C.D. 2015. Anthocyanins and their physiologically relevant metabolites alter the expression of IL-6 and VCAM-1 in CD40L and oxidized LDL challenged vascular endothelial cells. Molecular Nutrition & Food Research. 59 (6), pp. 1095-1106. doi:10.1002/mnfr.201400803

Methods for Isolating, Identifying, and Quantifying Anthocyanin Metabolites in Clinical Samples
de Ferrars, R.M., Czank, C., Saha, S., Needs, P.W., Zhang, Q., Raheem, S., Botting, N.P., Kroon, P.A. and Kay, C.D. 2014. Methods for Isolating, Identifying, and Quantifying Anthocyanin Metabolites in Clinical Samples. Analytical Chemistry. 86 (20), pp. 10052-10058. doi:10.1021/ac500565a

Flavonoid metabolism: the synthesis of phenolic glucuronides and sulfates as candidate metabolites for bioactivity studies of dietary flavonoids
Zhang, Q., Raheem, S., Botting, N.P., Slawin, A.M.Z., Kay, C.D. and O’Hagan, D. 2012. Flavonoid metabolism: the synthesis of phenolic glucuronides and sulfates as candidate metabolites for bioactivity studies of dietary flavonoids. Tetrahedron. 68, pp. 4194-4201. doi:10.1016/j.tet.2012.03.100

Total synthesis of 3,5-O-dicaffeoylquinic acid and its derivatives
Raheem, S., Botting, Nigel P., Williamson, G. and Barron, D. 2011. Total synthesis of 3,5-O-dicaffeoylquinic acid and its derivatives. Tetrahedron Letters. 52 (52), p. 7175. doi:10.1016/j.tetlet.2011.10.127

Permalink - https://westminsterresearch.westminster.ac.uk/item/9v8z2/common-phenolic-metabolites-of-flavonoids-but-not-their-unmetabolized-precursors-reduce-the-secretion-of-vascular-cellular-adhesion-molecules-by-human-endothelial-cells


Share this
Tweet
Email

Usage statistics

12 total views
54 total downloads
1 views this month
3 downloads this month
These values are for the period from September 2nd 2018, when this repository was created

Export as