Urolithin A conjugation with NSAIDs inhibits its glucuronidation and maintains improvement of Caco-2 monolayers' barrier function.

Autor: Korczak M; Microbiota Lab, Medical University of Warsaw, Warsaw, Poland., Roszkowski P; Faculty of Chemistry, University of Warsaw, Warsaw, Poland., Skowrońska W; Department of Pharmaceutical Biology, Medical University of Warsaw, Warsaw, Poland., Żołdak KM; Microbiota Lab, Medical University of Warsaw, Warsaw, Poland., Popowski D; Microbiota Lab, Medical University of Warsaw, Warsaw, Poland; Department of Food Safety and Chemical Analysis, Prof. Wacław Dąbrowski Institute of Agricultural and Food Biotechnology - State Research Institute, Warsaw, Poland., Granica S; Department of Pharmaceutical Biology, Medical University of Warsaw, Warsaw, Poland., Piwowarski JP; Microbiota Lab, Medical University of Warsaw, Warsaw, Poland. Electronic address: jakub.piwowarski@wum.edu.pl.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Dec 31; Vol. 169, pp. 115932. Date of Electronic Publication: 2023 Nov 24.
DOI: 10.1016/j.biopha.2023.115932
Abstrakt: Urolithin A (UA) is an ellagitannin-derived postbiotic metabolite which emerged as a promising health-boosting agent, promoting mitophagy, improving skeletal muscle function, and suppressing the inflammatory response. However, phase II intestinal metabolism severely limits its biopotency, leading to the formation of nonactive glucuronides. To address this constraint, a set of new UA derivatives (UADs), conjugated with nonsteroidal anti-inflammatory drugs (NSAIDs), was synthesized. The bioavailability and inhibitory activity of UADs against UA-glucuronidation were evaluated using differentiated Caco-2 cell monolayers. Parallelly, after the administration of tested substances, the transepithelial electrical resistance (TEER) of the cell monolayers was continuously monitored using the CellZscope device. Though investigated UADs did not penetrate Caco-2 monolayers, all of them significantly suppressed the glucuronidation rate of UA, while conjugates with diclofenac increased the concentration of free molecule on the basolateral side. Moreover, esters of UA with diclofenac (DicloUA) and aspirin (AspUA) positively influenced cell membrane integrity. Western blot analysis revealed that some UADs, including DicloUA, increased the expression of pore-sealing tight junction proteins and decreased the level of pore-forming claudin-2, which may contribute to their beneficial activity towards the barrier function. To provide comprehensive insight into the mechanism of action of DicloUA, Caco-2 cells were subjected to transcriptomic analysis. Next-generation sequencing (NGS) uncovered substantial changes in the expression of genes involved, for instance, in multivesicular body organization and zinc ion homeostasis. The results presented in this study offer new perspectives on the beneficial effects of modifying UA's structure on its intestinal metabolism and bioactivity in vitro.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: