Protection against indomethacin-induced loss of intestinal epithelial barrier function by a quercetin oxidation metabolite present in onion peel: In vitro and in vivo studies

Oxidative stress is directly implicated in the loss of intestinal epithelial barrier function (IEBF) induced by non-steroidal anti-inflammatory drugs (NSAIDs). Previous studies by our research team demonstrated that 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone (BZF), a quercetin oxidation metabolite that naturally occurs in onion peels, exhibits an antioxidant potency notably higher than quercetin. Thus, we assessed the potential of BZF and a BZF-rich onion peel aqueous extract (OAE) to protect against the loss of IEBF in Caco-2 cell monolayers and in rats exposed to indomethacin. In vitro , pure BZF and OAE standardized in BZF (100 nM), protected against the drop in transepithelial electrical resistance by 70 - 73%. Likewise, it prevented the increase in fluorescein-isothiocyanate labelled dextran (FITC-dextran) paracellular transport by 74% and oxidative stress by 84 - 86%. In vivo , BZF, given orally at a dose 80 mu g/Kg bw as OAE, totally abolished a 30-fold increase in FITC-dextran serum concentration induced by indomethacin. This effect was dose-dependent and largely conserved (85%) when OAE was given 180-min prior to indomethacin. The IEBF-protective effect of OAE was accompanied by a full prevention of the NF- K B activation, and the increases in interleukine-8 secretion and myeloperoxidase activity induced by indomethacin. The protection was also associated with a 21-fold increase in Nrf2, and a 7-fold and 9-fold increase in heme oxygenase-1 and NAD(P)H-quinone oxidoreductase 1, respectively. The IEBF-protecting effect of OAE involves, most likely, its dual capacity to activate Nrf2 while inhibiting NF- K B activation. The extremely low doses of BZF needed to promote such actions warrants extending its IEBF-protective effects to other NSAIDs. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

The quercetin oxidation metabolite 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone (BZF) and its rich onion peel aqueous extract (OAE) can protect against the loss of intestinal epithelial barrier function (IEBF) induced by NSAIDs. The protective effect may involve the dual capacity of activating Nrf2 while inhibiting NF- K B activation.