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All Studies   Meta Analysis    Recent:   

The flavonoid quercetin decreases ACE2 and TMPRSS2 expression but not SARS‐CoV‐2 infection in cultured human lung cells

Houghton et al., BioFactors, doi:10.1002/biof.2084
Jun 2024  
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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. c19early.org
In Vitro study showing that quercetin acutely decreases expression of ACE2 and TMPRSS2 mRNA and protein in Calu-3 lung epithelial cells cultured at an air-liquid interface. Longer-term lower dose treatment decreased TMPRSS2 but not ACE2 expression. Similar downregulation of ACE2 and TMPRSS2 mRNA by quercetin was seen in human primary bronchial epithelial cells. However, despite decreasing expression of these SARS-CoV-2 host entry proteins by up to 50%, quercetin pre-treatment or co-treatment did not affect SARS-CoV-2 infectivity in Calu-3 cells. Authors note that this result is contrary to known antiviral properties for other viruses and that efficacy was seen for SARS-CoV-2 in1. Many other in vitro studies show either direct antiviral efficacy for SARS-CoV-2 or efficacy against secondary effects2-11 although authors do not reference these studies.
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,4,12,13,23,25,30,38,39,41,42,52,53, MproB,2,12,14,16,19,20,22,24,25,30,34,36-38,42,43,45,53,54, RNA-dependent RNA polymeraseC,12,32, PLproD,37,45, ACE2E,23,24,28,37,41,53, TMPRSS2F,23, helicaseG,29,34, endoribonucleaseH,39, cathepsin LI,26, Wnt-3J,23, FZDK,23, LRP6L,23, ezrinM,40, ADRPN,38, NRP1O,41, EP300P,18, PTGS2Q,24, HSP90AA1R,18,24, matrix metalloproteinase 9S,31, IL-6T,3,35, IL-10U,3, VEGFAV,35, and RELAW,35 proteins. In Vitro studies demonstrate efficacy in Calu-3X,6, A549Y,3, HEK293-ACE2+Z,10, Huh-7AA,4, Caco-2AB,5, Vero E6AC,5,21,42, mTECAD,8, and RAW264.7AE,8 cells. Animal studies demonstrate efficacy in K18-hACE2 miceAF,48, db/db miceAG,8,51, BALB/c miceAH,50, and rats55. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice50.
Houghton et al., 17 Jun 2024, Australia, peer-reviewed, 6 authors. Contact: michael.houghton@monash.edu.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperQuercetinAll
The flavonoid quercetin decreases ACE2 and TMPRSS2 expression but not SARS‐CoV‐2 infection in cultured human lung cells
Michael James Houghton, Eglantine Balland, Matthew James Gartner, Belinda Jane Thomas, Kanta Subbarao, Gary Williamson
BioFactors, doi:10.1002/biof.2084
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2) on host cells, via its spike protein, and transmembrane protease, serine 2 (TMPRSS2) cleaves the spike-ACE2 complex to facilitate virus entry. As rate-limiting steps for virus entry, modulation of ACE2 and/or TMPRSS2 may decrease SARS-CoV-2 infectivity and COVID-19 severity. In silico modeling suggested the natural bioactive flavonoid quercetin can bind to ACE2 and a recent randomized clinical trial demonstrated that oral supplementation with quercetin increased COVID-19 recovery. A range of cultured human cells were assessed for co-expression of ACE2 and TMPRSS2. Immortalized Calu-3 lung cells, cultured and matured at an air-liquid interface (Calu-3-ALIs), were established as the most appropriate. Primary bronchial epithelial cells (PBECs) were obtained from healthy adult males (N = 6) and cultured under submerged conditions to corroborate the outcomes. Upon maturation or reaching 80% confluence, respectively, the Calu-3-ALIs and PBECs were treated with quercetin, and mRNA and protein expression were assessed by droplet digital PCR and ELISA, respectively. SARS-CoV-2 infectivity, and the effects of pre-and co-treatment with Abbreviations: ACE2, angiotensin-converting enzyme 2; ADAM17, a disintegrin and metalloprotease 17; Estradiol, 17β-estradiol; FBS, heatinactivated fetal bovine serum; Pen/Strep, 100 U/mL penicillin and 100 mg/mL streptomycin; TMPRSS2, transmembrane protease, serine 2.
DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. SUPPORTING INFORMATION Additional supporting information can be found online in the Supporting Information section at the end of this article.
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As rate‐limiting steps for virus entry, modulation of ACE2 and/or ' 'TMPRSS2 may decrease SARS‐CoV‐2 infectivity and COVID‐19 severity. In silico modeling ' 'suggested the natural bioactive flavonoid quercetin can bind to ACE2 and a recent randomized ' 'clinical trial demonstrated that oral supplementation with quercetin increased COVID‐19 ' 'recovery. A range of cultured human cells were assessed for co‐expression of ACE2 and ' 'TMPRSS2. Immortalized Calu‐3 lung cells, cultured and matured at an air–liquid interface ' '(Calu‐3‐ALIs), were established as the most appropriate. Primary bronchial epithelial cells ' '(PBECs) were obtained from healthy adult males (<jats:italic>N</jats:italic>\u2009=\u20096) ' 'and cultured under submerged conditions to corroborate the outcomes. Upon maturation or ' 'reaching 80% confluence, respectively, the Calu‐3‐ALIs and PBECs were treated with quercetin, ' 'and mRNA and protein expression were assessed by droplet digital PCR and ELISA, respectively. ' 'SARS‐CoV‐2 infectivity, and the effects of pre‐ and co‐treatment with quercetin, was assessed ' 'by median tissue culture infectious dose assay. Quercetin dose‐dependently decreased ACE2 and ' 'TMPRSS2 mRNA and protein in both Calu‐3‐ALIs and PBECs after 4\u2009h, while TMPRSS2 remained ' 'suppressed in response to prolonged treatment with lower doses (twice daily for 3\u2009days). ' 'Quercetin also acutely decreased ADAM17 mRNA, but not ACE, in Calu‐3‐ALIs, and this warrants ' 'further investigation. Calu‐3‐ALIs, but not PBECs, were successfully infected with ' 'SARS‐CoV‐2; however, quercetin had no antiviral effect, neither directly nor indirectly ' 'through downregulation of ACE2 and TMPRSS2. Calu‐3‐ALIs were reaffirmed to be an optimal cell ' 'model for research into the regulation of ACE2 and TMPRSS2, without the need for prior ' 'genetic modification, and will prove valuable in future coronavirus and respiratory ' 'infectious disease work. 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