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The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway

The Wnt/β-catenin signaling pathway dictates cell proliferation and differentiation during embryonic development and tissue homeostasis. Its deregulation is associated with many pathological conditions, including neurodegenerative disease, frequently downregulated. The lack of efficient treatment fo...

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Autores principales: Predes, Danilo, Maia, Lorena A., Matias, Isadora, Araujo, Hannah Paola Mota, Soares, Carolina, Barros-Aragão, Fernanda G. Q., Oliveira, Luiz F. S., Reis, Renata R., Amado, Nathalia G., Simas, Alessandro B. C., Mendes, Fabio A., Gomes, Flávia C. A., Figueiredo, Claudia P., Abreu, Jose G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9602613/
https://www.ncbi.nlm.nih.gov/pubmed/36292931
http://dx.doi.org/10.3390/ijms232012078
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author Predes, Danilo
Maia, Lorena A.
Matias, Isadora
Araujo, Hannah Paola Mota
Soares, Carolina
Barros-Aragão, Fernanda G. Q.
Oliveira, Luiz F. S.
Reis, Renata R.
Amado, Nathalia G.
Simas, Alessandro B. C.
Mendes, Fabio A.
Gomes, Flávia C. A.
Figueiredo, Claudia P.
Abreu, Jose G.
author_facet Predes, Danilo
Maia, Lorena A.
Matias, Isadora
Araujo, Hannah Paola Mota
Soares, Carolina
Barros-Aragão, Fernanda G. Q.
Oliveira, Luiz F. S.
Reis, Renata R.
Amado, Nathalia G.
Simas, Alessandro B. C.
Mendes, Fabio A.
Gomes, Flávia C. A.
Figueiredo, Claudia P.
Abreu, Jose G.
author_sort Predes, Danilo
collection PubMed
description The Wnt/β-catenin signaling pathway dictates cell proliferation and differentiation during embryonic development and tissue homeostasis. Its deregulation is associated with many pathological conditions, including neurodegenerative disease, frequently downregulated. The lack of efficient treatment for these diseases, including Alzheimer’s disease (AD), makes Wnt signaling an attractive target for therapies. Interestingly, novel Wnt signaling activating compounds are less frequently described than inhibitors, turning the quest for novel positive modulators even more appealing. In that sense, natural compounds are an outstanding source of potential drug leads. Here, we combine different experimental models, cell-based approaches, neuronal culture assays, and rodent behavior tests with Xenopus laevis phenotypic analysis to characterize quercitrin, a natural compound, as a novel Wnt signaling potentiator. We find that quercitrin potentiates the signaling in a concentration-dependent manner and increases the occurrence of the Xenopus secondary axis phenotype mediated by Xwnt8 injection. Using a GSK3 biosensor, we describe that quercitrin impairs GSK3 activity and increases phosphorylated GSK3β S9 levels. Treatment with XAV939, an inhibitor downstream of GSK3, impairs the quercitrin-mediated effect. Next, we show that quercitrin potentiates the Wnt3a-synaptogenic effect in hippocampal neurons in culture, which is blocked by XAV939. Quercitrin treatment also rescues the hippocampal synapse loss induced by intracerebroventricular injection of amyloid-β oligomers (AβO) in mice. Finally, quercitrin rescues AβO-mediated memory impairment, which is prevented by XAV939. Thus, our study uncovers a novel function for quercitrin as a Wnt/β-catenin signaling potentiator, describes its mechanism of action, and opens new avenues for AD treatments.
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spelling pubmed-96026132022-10-27 The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway Predes, Danilo Maia, Lorena A. Matias, Isadora Araujo, Hannah Paola Mota Soares, Carolina Barros-Aragão, Fernanda G. Q. Oliveira, Luiz F. S. Reis, Renata R. Amado, Nathalia G. Simas, Alessandro B. C. Mendes, Fabio A. Gomes, Flávia C. A. Figueiredo, Claudia P. Abreu, Jose G. Int J Mol Sci Article The Wnt/β-catenin signaling pathway dictates cell proliferation and differentiation during embryonic development and tissue homeostasis. Its deregulation is associated with many pathological conditions, including neurodegenerative disease, frequently downregulated. The lack of efficient treatment for these diseases, including Alzheimer’s disease (AD), makes Wnt signaling an attractive target for therapies. Interestingly, novel Wnt signaling activating compounds are less frequently described than inhibitors, turning the quest for novel positive modulators even more appealing. In that sense, natural compounds are an outstanding source of potential drug leads. Here, we combine different experimental models, cell-based approaches, neuronal culture assays, and rodent behavior tests with Xenopus laevis phenotypic analysis to characterize quercitrin, a natural compound, as a novel Wnt signaling potentiator. We find that quercitrin potentiates the signaling in a concentration-dependent manner and increases the occurrence of the Xenopus secondary axis phenotype mediated by Xwnt8 injection. Using a GSK3 biosensor, we describe that quercitrin impairs GSK3 activity and increases phosphorylated GSK3β S9 levels. Treatment with XAV939, an inhibitor downstream of GSK3, impairs the quercitrin-mediated effect. Next, we show that quercitrin potentiates the Wnt3a-synaptogenic effect in hippocampal neurons in culture, which is blocked by XAV939. Quercitrin treatment also rescues the hippocampal synapse loss induced by intracerebroventricular injection of amyloid-β oligomers (AβO) in mice. Finally, quercitrin rescues AβO-mediated memory impairment, which is prevented by XAV939. Thus, our study uncovers a novel function for quercitrin as a Wnt/β-catenin signaling potentiator, describes its mechanism of action, and opens new avenues for AD treatments. MDPI 2022-10-11 /pmc/articles/PMC9602613/ /pubmed/36292931 http://dx.doi.org/10.3390/ijms232012078 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Predes, Danilo
Maia, Lorena A.
Matias, Isadora
Araujo, Hannah Paola Mota
Soares, Carolina
Barros-Aragão, Fernanda G. Q.
Oliveira, Luiz F. S.
Reis, Renata R.
Amado, Nathalia G.
Simas, Alessandro B. C.
Mendes, Fabio A.
Gomes, Flávia C. A.
Figueiredo, Claudia P.
Abreu, Jose G.
The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway
title The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway
title_full The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway
title_fullStr The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway
title_full_unstemmed The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway
title_short The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway
title_sort flavonol quercitrin hinders gsk3 activity and potentiates the wnt/β-catenin signaling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9602613/
https://www.ncbi.nlm.nih.gov/pubmed/36292931
http://dx.doi.org/10.3390/ijms232012078
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