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Quercetin improves and protects Calu-3 airway epithelial barrier function

DiGuilio et al., Frontiers in Cell and Developmental Biology, doi:10.3389/fcell.2023.1271201
Nov 2023  
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Quercetin for COVID-19
23rd treatment shown to reduce risk in July 2021
*, now with p = 0.0031 from 11 studies.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,400+ studies for 79 treatments.
In Vitro analysis of quercetin on airway epithelial barrier function using the Calu-3 cell culture model. Results show that quercetin increases transepithelial electrical resistance and decreases transepithelial leaks, indicating improved barrier function. These effects are concentration-dependent and show a biphasic time course. Quercetin also alters tight junctional protein composition, partially inhibits cell replication, and decreases linear junctional density, contributing to improved barrier function. Furthermore, quercetin effectively reduces barrier compromise caused by the pro-inflammatory cytokine TNF-α, partly due to its action in reducing TNF-α-induced ERK 1/2 phosphorylation and altering the tight junctional complex. The study suggests quercetin’s potential in airway diseases involving barrier compromise, like COVID-19, due to its capability to improve epithelial barrier function and protect against inflammatory cytokines.
Bioavailability. Quercetin has low bioavailability and studies typically use advanced formulations to improve bioavailability which may be required to reach therapeutic concentrations.
58 preclinical studies support the efficacy of quercetin for COVID-19:
In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeA,1,2,14,16,17,22,30,31,33,34,51,52, MproB,1,3,5,7,9,10,12,15,16,22,26,28-30,34,35,37,52,53, RNA-dependent RNA polymeraseC,1,24, PLproD,29,37, ACE2E,14,15,20,29,33,52, TMPRSS2F,14, helicaseG,21,26, endoribonucleaseH,31, cathepsin LI,18, Wnt-3J,14, FZDK,14, LRP6L,14, ezrinM,32, ADRPN,30, NRP1O,33, EP300P,8, PTGS2Q,15, HSP90AA1R,8,15, matrix metalloproteinase 9S,23, IL-6T,13,27, IL-10U,13, VEGFAV,27, and RELAW,27 proteins. In Vitro studies demonstrate efficacy in Calu-3X,40, A549Y,13, HEK293-ACE2+Z,47, Huh-7AA,17, Caco-2AB,39, Vero E6AC,11,34,39, mTECAD,42, and RAW264.7AE,42 cells. Animal studies demonstrate efficacy in K18-hACE2 miceAF,44, db/db miceAG,42,50, BALB/c miceAH,49, and rats54. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice49.
DiGuilio et al., 23 Nov 2023, peer-reviewed, 8 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperQuercetinAll
Quercetin improves and protects Calu-3 airway epithelial barrier function
K M Diguilio, E Rybakovsky, M C Valenzano, H H Nguyen, E A Del Rio, E Newberry, R Spadea, J M Mullin
Frontiers in Cell and Developmental Biology, doi:10.3389/fcell.2023.1271201
Introduction: In light of the impact of airway barrier leaks in COVID-19 and the significance of vitamin D in COVID-19 outcomes, including airway barrier protection, we investigated whether the very common dietary flavonoid quercetin could also be efficacious in supporting airway barrier function. Methods: To address this question, we utilized the widely used airway epithelial cell culture model, Calu-3. Results: We observed that treating Calu-3 cell layers with quercetin increased transepithelial electrical resistance while simultaneously reducing transepithelial leaks of 14C-D-mannitol (Jm) and 14C-inulin. The effects of quercetin were concentration-dependent and exhibited a biphasic time course. These effects of quercetin occurred with changes in tight junctional protein composition as well as a partial inhibition of cell replication that resulted in decreased linear junctional density. Both of these effects potentially contribute to improved barrier function. Quercetin was equally effective in reducing the barrier compromise caused by the pro-inflammatory cytokine TNF-α, an action that seemed to derive, in part, from reducing the elevation of ERK 1/2 caused by TNF-α. Discussion: Quercetin improved Calu-3 barrier function and reduced TNF-α-induced barrier compromise, mediated in part by changes in the tight junctional complex.
Data availability statement The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation. Ethics statement Ethical approval was not required for the studies on humans in accordance with the local legislation and institutional requirements because only commercially available established cell lines were used. Author contributions KD: writing-original draft, writing-review and editing, and investigation. ER: investigation and writing-review and editing. MV: investigation and writing-review and editing. HN: investigation and writing-review and editing. ED: investigation and writing-review and editing. EN: investigation and writing-review and editing. RS: investigation and writing-review and editing. JM: writing-review and editing, conceptualization, supervision, and writing-original draft. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Supplementary material The Supplementary Material for this article can be..
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