A critical examination of human data for the biological activity of quercetin and its phase-2 conjugates

Williamson, Gary; Clifford, Michael N.

doi:10.1080/10408398.2023.2299329

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2024

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Cited by 4 publications

References 253 publications

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Phytomedicine

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Liu,

Huang,

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et al. 2024

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A critical examination of human data for the biological activity of phenolic acids and their phase-2 conjugates derived from dietary (poly)phenols, phenylalanine, tyrosine and catecholamines

Williamson,

Clifford

2024

Critical Reviews in Food Science and Nutrition

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Pirin does not bind to p65 or regulate NFκB-dependent gene expression but does modulate cellular quercetin levels

Meschkewitz,

Lisabeth,

Cab-Gomez

et al. 2024

Preprint

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Pirin is a non-heme iron binding protein with a variety of proposed functions including serving as a co-activator of p65 NFkappaB and quercetinase activity. We report here, failure to confirm pirin's primary proposed mechanism, binding of Fe(III)-pirin and p65. Analytical size exclusion chromatography (SEC) and fluorescence polarization (FP) studies did not detect an interaction. We also found no effects of pirin on TNFalpha-activated p65-regulated gene transcription using mouse embryonic fibroblasts (MEFs) from a pirin knockout mouse and a pirin knockdown NIH3T3 fibroblast cell line. TNFalpha-activated p65 response gene mRNA was neither increased nor decreased in cells with loss of pirin compared to wildtype cells. Furthermore, pirin immunofluorescence in NIH3T3 fibroblasts showed primarily a cytoplasmic localization, not nuclear as in most previous studies. This was confirmed by cell fractionation analysis. Pirin did show colocalization with the endoplasmic reticulum (ER) marker protein disulfide-isomerase (PDI) as well as cyotoplasmic labeling. We confirmed pirin's quercetinase activity in biochemical assays and demonstrated competitive inhibition by the pirin inhibitor CCG-257081. Cellular quercetin levels in cells exposed to quercetin in vitro were increased by knockdown of pirin or by treatment with pirin inhibitors. Since pirin is localized to ER and flavanols are protective of ER stress, we investigated whether pirin knockdown altered ER stress signaling but did not find any effect of pirin knockdown on ER stress response genes. Our results challenge the dominant model of pirin's function (NFkappaB regulation) but confirm its quercetinase activity with implications for the mechanisms of pirin binding small molecules.

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A critical examination of human data for the biological activity of quercetin and its phase-2 conjugates

Cited by 4 publications

References 253 publications

Natural products with anti-tumorigenesis potential targeting macrophage

Natural products with anti-tumorigenesis potential targeting macrophage

A critical examination of human data for the biological activity of phenolic acids and their phase-2 conjugates derived from dietary (poly)phenols, phenylalanine, tyrosine and catecholamines

Pirin does not bind to p65 or regulate NFκB-dependent gene expression but does modulate cellular quercetin levels

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