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Wnt/β-Catenin Signaling in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (25 July 2023) | Viewed by 6826

Special Issue Editor


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Guest Editor
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
Interests: clinical biochemistry; inflammation; oxidative stress; neurodegeneration; natural compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Wnts are a family of proteins that modulate cellular processes such as proliferation, differentiation, and migration. This family includes 19 members of secreted lipid-modified signaling mediators. Currently, three Wnt signaling pathways have been identified; the canonical Wnt/β-catenin pathway is the best-studied and appears to be involved in the pathophysiology of various CNS disorders. In this pathway, Wnt ligands bind to the cysteine-rich domain frizzled (FZ) receptors which in turn activate several intracellular signaling cascades. At the intracellular level, Wnt/FZ requires the intracellular β-catenin protein, whose levels remain low by the action of a so-called destruction complex. Wnt signaling activation leads to the dissociation of the β-catenin destruction complex; as a consequence, β-catenin accumulates in the cytoplasm and translocates to the nucleus, finally inducing the expression of Wnt target genes. The deregulation of Wnt/β-catenin signaling often leads to various serious diseases, including cancer and non-cancer diseases. Although many articles have reviewed Wnt/β-catenin from various aspects, a systematic review encompassing the origin, composition, function, and pre-clinical and clinical trials of the Wnt/β-catenin signaling pathway in tumors and diseases is lacking. 

This Special Issue will focus on the role of Wnt/β-Catenin signaling as a promising therapeutic target for health and disease. The Special Issue will feature original in vivo and in vitro reviews and studies providing evidence of the welfare effects of novel compounds with no side effects.

Dr. Rosalba Siracusa
Guest Editor

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Keywords

  • acute disease
  • chronic disease
  • inflammation
  • natural compounds
  • small molecules

Published Papers (3 papers)

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Research

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20 pages, 3902 KiB  
Article
The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway
by Danilo Predes, Lorena A. Maia, Isadora Matias, Hannah Paola Mota Araujo, Carolina Soares, Fernanda G. Q. Barros-Aragão, Luiz F. S. Oliveira, Renata R. Reis, Nathalia G. Amado, Alessandro B. C. Simas, Fabio A. Mendes, Flávia C. A. Gomes, Claudia P. Figueiredo and Jose G. Abreu
Int. J. Mol. Sci. 2022, 23(20), 12078; https://doi.org/10.3390/ijms232012078 - 11 Oct 2022
Cited by 2 | Viewed by 2036
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Wnt/β-Catenin Signaling in Health and Disease)
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17 pages, 2396 KiB  
Article
6-Bromoindirubin-3′-Oxime Regulates Colony Formation, Apoptosis, and Odonto/Osteogenic Differentiation in Human Dental Pulp Stem Cells
by Chatvadee Kornsuthisopon, Sunisa Rochanavibhata, Nunthawan Nowwarote, Kevin A. Tompkins, Waleerat Sukarawan and Thanaphum Osathanon
Int. J. Mol. Sci. 2022, 23(15), 8676; https://doi.org/10.3390/ijms23158676 - 04 Aug 2022
Cited by 3 | Viewed by 2006
Abstract
6-bromoindirubin-3′-oxime (BIO) is a candidate small molecule that effectively modulates Wnt signalling owing to its stable property. The present study investigated the influence of BIO on the odonto/osteogenic differentiation of human dental pulp stem cells (hDPSCs). hDPSCs were treated with 200, 400, or [...] Read more.
6-bromoindirubin-3′-oxime (BIO) is a candidate small molecule that effectively modulates Wnt signalling owing to its stable property. The present study investigated the influence of BIO on the odonto/osteogenic differentiation of human dental pulp stem cells (hDPSCs). hDPSCs were treated with 200, 400, or 800 nM BIO, and the effects on hDPSC responses and osteogenic differentiation were assessed. BIO-mediated Wnt activation was confirmed by β-catenin nuclear translocation detected by immunofluorescence staining. BIO attenuated colony formation and cell migration determined by in vitro wound-healing assay. BIO increased early apoptotic cell population evaluated using flow cytometry. For osteogenic induction, BIO promoted alkaline phosphatase (ALP) activity and mineralisation in a dose-dependent manner. ALP, RUNX2, OCN, OSX, ANKH, DMP1, and DSPP mRNA expression were significantly upregulated. The OPG/RANKL expression ratio was also increased. Further, BIO attenuated adipogenic differentiation as demonstrated by decreased lipid accumulation and adipogenic-related gene expression. Bioinformatic analysis of RNA sequencing data from the BIO-treated hDPSCs revealed that BIO modulated pathways related to autophagy and actin cytoskeleton regulation. These findings demonstrated that BIO treatment promoted hDPSC osteogenic differentiation. Therefore, this small molecule is a strong candidate as a bioactive molecule to enhance dentin repair. Full article
(This article belongs to the Special Issue Wnt/β-Catenin Signaling in Health and Disease)
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Review

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27 pages, 2334 KiB  
Review
The Roles of Secreted Wnt Ligands in Cancer
by Johannes Werner, Kim E. Boonekamp, Tianzuo Zhan and Michael Boutros
Int. J. Mol. Sci. 2023, 24(6), 5349; https://doi.org/10.3390/ijms24065349 - 10 Mar 2023
Cited by 6 | Viewed by 2094
Abstract
Wnt ligands are secreted signaling proteins that display a wide range of biological effects. They play key roles in stimulating Wnt signaling pathways to facilitate processes such as tissue homeostasis and regeneration. Dysregulation of Wnt signaling is a hallmark of many cancers and [...] Read more.
Wnt ligands are secreted signaling proteins that display a wide range of biological effects. They play key roles in stimulating Wnt signaling pathways to facilitate processes such as tissue homeostasis and regeneration. Dysregulation of Wnt signaling is a hallmark of many cancers and genetic alterations in various Wnt signaling components, which result in ligand-independent or ligand-dependent hyperactivation of the pathway that have been identified. Recently, research is focusing on the impact of Wnt signaling on the interaction between tumor cells and their micro-environment. This Wnt-mediated crosstalk can act either in a tumor promoting or suppressing fashion. In this review, we comprehensively outline the function of Wnt ligands in different tumor entities and their impact on key phenotypes, including cancer stemness, drug resistance, metastasis, and immune evasion. Lastly, we elaborate approaches to target Wnt ligands in cancer therapy. Full article
(This article belongs to the Special Issue Wnt/β-Catenin Signaling in Health and Disease)
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