Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy

Abstract Chagas disease cardiomyopathy is a parasite-driven inflammatory disease to which there are no effective treatments. Here we evaluated the therapeutic potential of N,N-dimethylsphingosine(DMS), which blocks the production of sphingosine-1-phosphate(S1P), a mediator of cellular events during...

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Autores principales:	Juliana Fraga Vasconcelos, Cássio Santana Meira, Daniela Nascimento Silva, Carolina Kymie Vasques Nonaka, Pâmela Santana Daltro, Simone Garcia Macambira, Pablo Daniel Domizi, Valéria Matos Borges, Ricardo Ribeiro-dos-Santos, Bruno Solano de Freitas Souza, Milena Botelho Pereira Soares
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f523be7d2d254deba65b6a98701b6a56
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spelling	oai:doaj.org-article:f523be7d2d254deba65b6a98701b6a562021-12-02T16:06:50ZTherapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy10.1038/s41598-017-06275-z2045-2322https://doaj.org/article/f523be7d2d254deba65b6a98701b6a562017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06275-zhttps://doaj.org/toc/2045-2322Abstract Chagas disease cardiomyopathy is a parasite-driven inflammatory disease to which there are no effective treatments. Here we evaluated the therapeutic potential of N,N-dimethylsphingosine(DMS), which blocks the production of sphingosine-1-phosphate(S1P), a mediator of cellular events during inflammatory responses, in a model of chronic Chagas disease cardiomyopathy. DMS-treated, Trypanosoma cruzi-infected mice had a marked reduction of cardiac inflammation, fibrosis and galectin-3 expression when compared to controls. Serum concentrations of galectin-3, IFNγ and TNFα, as well as cardiac gene expression of inflammatory mediators were reduced after DMS treatment. The gene expression of M1 marker, iNOS, was decreased, while the M2 marker, arginase1, was increased. DMS-treated mice showed an improvement in exercise capacity. Moreover, DMS caused a reduction in parasite load in vivo. DMS inhibited the activation of lymphocytes, and reduced cytokines and NO production in activated macrophage cultures in vitro, while increasing IL-1β production. Analysis by qRT-PCR array showed that DMS treatment modulated inflammasome activation induced by T. cruzi on macrophages. Altogether, our results demonstrate that DMS, through anti-parasitic and immunomodulatory actions, can be beneficial in the treatment of chronic phase of T. cruzi infection and suggest that S1P-activated processes as possible therapeutic targets for the treatment of Chagas disease cardiomyopathy.Juliana Fraga VasconcelosCássio Santana MeiraDaniela Nascimento SilvaCarolina Kymie Vasques NonakaPâmela Santana DaltroSimone Garcia MacambiraPablo Daniel DomiziValéria Matos BorgesRicardo Ribeiro-dos-SantosBruno Solano de Freitas SouzaMilena Botelho Pereira SoaresNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Juliana Fraga Vasconcelos Cássio Santana Meira Daniela Nascimento Silva Carolina Kymie Vasques Nonaka Pâmela Santana Daltro Simone Garcia Macambira Pablo Daniel Domizi Valéria Matos Borges Ricardo Ribeiro-dos-Santos Bruno Solano de Freitas Souza Milena Botelho Pereira Soares Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy
description	Abstract Chagas disease cardiomyopathy is a parasite-driven inflammatory disease to which there are no effective treatments. Here we evaluated the therapeutic potential of N,N-dimethylsphingosine(DMS), which blocks the production of sphingosine-1-phosphate(S1P), a mediator of cellular events during inflammatory responses, in a model of chronic Chagas disease cardiomyopathy. DMS-treated, Trypanosoma cruzi-infected mice had a marked reduction of cardiac inflammation, fibrosis and galectin-3 expression when compared to controls. Serum concentrations of galectin-3, IFNγ and TNFα, as well as cardiac gene expression of inflammatory mediators were reduced after DMS treatment. The gene expression of M1 marker, iNOS, was decreased, while the M2 marker, arginase1, was increased. DMS-treated mice showed an improvement in exercise capacity. Moreover, DMS caused a reduction in parasite load in vivo. DMS inhibited the activation of lymphocytes, and reduced cytokines and NO production in activated macrophage cultures in vitro, while increasing IL-1β production. Analysis by qRT-PCR array showed that DMS treatment modulated inflammasome activation induced by T. cruzi on macrophages. Altogether, our results demonstrate that DMS, through anti-parasitic and immunomodulatory actions, can be beneficial in the treatment of chronic phase of T. cruzi infection and suggest that S1P-activated processes as possible therapeutic targets for the treatment of Chagas disease cardiomyopathy.
format	article
author	Juliana Fraga Vasconcelos Cássio Santana Meira Daniela Nascimento Silva Carolina Kymie Vasques Nonaka Pâmela Santana Daltro Simone Garcia Macambira Pablo Daniel Domizi Valéria Matos Borges Ricardo Ribeiro-dos-Santos Bruno Solano de Freitas Souza Milena Botelho Pereira Soares
author_facet	Juliana Fraga Vasconcelos Cássio Santana Meira Daniela Nascimento Silva Carolina Kymie Vasques Nonaka Pâmela Santana Daltro Simone Garcia Macambira Pablo Daniel Domizi Valéria Matos Borges Ricardo Ribeiro-dos-Santos Bruno Solano de Freitas Souza Milena Botelho Pereira Soares
author_sort	Juliana Fraga Vasconcelos
title	Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy
title_short	Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy
title_full	Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy
title_fullStr	Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy
title_full_unstemmed	Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy
title_sort	therapeutic effects of sphingosine kinase inhibitor n,n-dimethylsphingosine (dms) in experimental chronic chagas disease cardiomyopathy
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f523be7d2d254deba65b6a98701b6a56
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Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy

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