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      Moringin activates Wnt canonical pathway by inhibiting GSK3β in a mouse model of experimental autoimmune encephalomyelitis

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          Abstract

          Aberrant canonical Wnt–β-catenin signaling has been reported in multiple sclerosis (MS), although the results are controversial. The present study aimed to examine the role of the Wnt–β-catenin pathway in experimental MS and also to test moringin (4-[α-L-rhamnopyranosyloxy]-benzyl isothiocyanate), resulting from exogenous myrosinase hydrolysis of the natural phytochemical glucomoringin 4(α-L-rhamnosyloxy)-benzyl glucosinolate as a modulator of neuroinflammation via the β-catenin–PPARγ axis. Experimental autoimmune encephalomyelitis (EAE), the most common model of MS, was induced in C57BL/6 mice by immunization with MOG 35–55. Released moringin (10 mg/kg glucomoringin +5 μL myrosinase/mouse) was administered daily for 1 week before EAE induction and continued until mice were killed on day 28 after EAE induction. Our results clearly showed that the Wnt–β-catenin pathway was downregulated in the EAE model, whereas moringin pretreatment was able to avert this. Moringin pretreatment normalizes the aberrant Wnt–β-catenin pathway, resulting in GSK3β inhibition and β-catenin upregulation, which regulates T-cell activation (CD4 and FoxP3), suppresses the main inflammatory mediators (IL-1β, IL-6, and COX2), through activation of PPARγ. In addition, moringin attenuates apoptosis by reducing the expression of the Fas ligand and cleaved caspase 9, and in parallel increases antioxidant Nrf2 expression in EAE mice. Taken together, our results provide an interesting discovery in identifying moringin as a modulator of the Wnt–β-catenin signaling cascade and as a new potential therapeutic target for MS treatment.

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          Most cited references 47

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          Multiple Sclerosis

          New England Journal of Medicine, 343(13), 938-952
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            Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors.

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              Autoimmune T cell responses in the central nervous system.

              Autoreactive T cell responses have a crucial role in central nervous system (CNS) diseases such as multiple sclerosis. Recent data indicate that CNS autoimmunity can be mediated by two distinct lineages of CD4+ T cells that are defined by the production of either interferon-gamma or interleukin-17. The activity of these CD4+ T cell subsets within the CNS influences the pathology and clinical course of disease. New animal models show that myelin-specific CD8+ T cells can also mediate CNS autoimmunity. This Review focuses on recent progress in delineating the pathogenic mechanisms, regulation and interplay between these different T cell subsets in CNS autoimmunity.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                04 October 2016
                : 10
                : 3291-3304
                Affiliations
                [1 ]IRCCS Centre Neurolesi “Bonino-Pulejo”, Messina, Italy
                [2 ]Council for Agricultural Research and Economics, Research Centre for Industrial Crops (CREA-CIN), Bologna, Italy
                Author notes
                Correspondence: Emanuela Mazzon, IRCCS Centre Neurolesi “Bonino-Pulejo”, SS113 Via Provinciale Palermo, Contrada Casazza, Messina 98124, Italy, Tel +39 090 6012 8708, Fax +39 090 6012 8850, Email emazzon.irccs@ 123456gmail.com
                Article
                dddt-10-3291
                10.2147/DDDT.S110514
                5063603
                © 2016 Giacoppo et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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