Host cell cAMP-Epac-Rap1b pathway inhibition by hawthorn extract as a potential target against Trypanosoma cruzi infection
Although the two drugs currently available for the treatment of Chagas disease, Benznidazole and Nifurtimox, have proven to be effective in the acute phase of the disease, the 60–90-day treatment leads to high toxicity and unwanted side effects, presenting, in addition, a low efficacy in the chronic...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1301862/full |
| _version_ | 1797394736521150464 |
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| author | Gabriel Ferri Gabriel Ferri Lucía R. Fernández Lucía R. Fernández Lucía R. Fernández Guillermo Di Mario Guillermo Di Mario Daniel Musikant Daniel Musikant Jorge A. Palermo Jorge A. Palermo Martin M. Edreira Martin M. Edreira Martin M. Edreira |
| author_facet | Gabriel Ferri Gabriel Ferri Lucía R. Fernández Lucía R. Fernández Lucía R. Fernández Guillermo Di Mario Guillermo Di Mario Daniel Musikant Daniel Musikant Jorge A. Palermo Jorge A. Palermo Martin M. Edreira Martin M. Edreira Martin M. Edreira |
| author_sort | Gabriel Ferri |
| collection | DOAJ |
| description | Although the two drugs currently available for the treatment of Chagas disease, Benznidazole and Nifurtimox, have proven to be effective in the acute phase of the disease, the 60–90-day treatment leads to high toxicity and unwanted side effects, presenting, in addition, a low efficacy in the chronic phase of the disease. For this reason, new therapies that are more effective are needed. In this regard, we have recently shown that the inhibition of the Epac-Rap1b pathway suppressed the cAMP-mediated host cell invasion by Trypanosoma cruzi. Interestingly, it has been described that vitexin, a natural flavone that protects against ischemia–reperfusion damage, acts by inhibiting the expression of Epac and Rap1 proteins. Vitexin can be found in plants of the genus Crataegus spp., traditionally known as hawthorn, which are of great interest considering their highly documented use as cardio-protectors. Pre-treating cells with an extract of Crataegus oxyacantha produced levels of T. cruzi invasion comparable to the ones observed for the commercially available Epac1-specific inhibitor, ESI-09. In addition, extract-treated cells exhibited a decrease in the activation of Rap1b, suggesting that the effects of the extract would be mediated by the inhibition of the cAMP-Epac-Rap1 signaling pathway. Using HPLC-HRMS2, we could confirm the presence of vitexin, and other flavones that could act as inhibitors of Epac/Rap1b, in the extracts of C. oxyacantha. Most significantly, when cells were treated with the extract of C. oxyacantha in conjunction with Nifurtimox, an increased modulation of invasion was observed. |
| first_indexed | 2024-03-09T00:24:47Z |
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| id | doaj.art-f0e04c9fb45346558fe3a9da3b49adb0 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-03-09T00:24:47Z |
| publishDate | 2023-12-01 |
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| series | Frontiers in Microbiology |
| spelling | doaj.art-f0e04c9fb45346558fe3a9da3b49adb02023-12-12T04:51:01ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2023-12-011410.3389/fmicb.2023.13018621301862Host cell cAMP-Epac-Rap1b pathway inhibition by hawthorn extract as a potential target against Trypanosoma cruzi infectionGabriel Ferri0Gabriel Ferri1Lucía R. Fernández2Lucía R. Fernández3Lucía R. Fernández4Guillermo Di Mario5Guillermo Di Mario6Daniel Musikant7Daniel Musikant8Jorge A. Palermo9Jorge A. Palermo10Martin M. Edreira11Martin M. Edreira12Martin M. Edreira13CONICET-Universidad de Buenos Aires, IQUIBICEN, Ciudad de Buenos Aires, ArgentinaLaboratorio de Biología Molecular de Trypanosomas, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos, Ciudad de Buenos Aires, ArgentinaLaboratorio de Biología Molecular de Trypanosomas, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos, Ciudad de Buenos Aires, ArgentinaDepartamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, ArgentinaUnidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (UMYMFOR), CONICET-Universidad de Buenos Aires, Buenos Aires, ArgentinaCONICET-Universidad de Buenos Aires, IQUIBICEN, Ciudad de Buenos Aires, ArgentinaLaboratorio de Biología Molecular de Trypanosomas, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos, Ciudad de Buenos Aires, ArgentinaCONICET-Universidad de Buenos Aires, IQUIBICEN, Ciudad de Buenos Aires, ArgentinaLaboratorio de Biología Molecular de Trypanosomas, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos, Ciudad de Buenos Aires, ArgentinaDepartamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, ArgentinaUnidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (UMYMFOR), CONICET-Universidad de Buenos Aires, Buenos Aires, ArgentinaCONICET-Universidad de Buenos Aires, IQUIBICEN, Ciudad de Buenos Aires, ArgentinaLaboratorio de Biología Molecular de Trypanosomas, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos, Ciudad de Buenos Aires, ArgentinaDepartment of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United StatesAlthough the two drugs currently available for the treatment of Chagas disease, Benznidazole and Nifurtimox, have proven to be effective in the acute phase of the disease, the 60–90-day treatment leads to high toxicity and unwanted side effects, presenting, in addition, a low efficacy in the chronic phase of the disease. For this reason, new therapies that are more effective are needed. In this regard, we have recently shown that the inhibition of the Epac-Rap1b pathway suppressed the cAMP-mediated host cell invasion by Trypanosoma cruzi. Interestingly, it has been described that vitexin, a natural flavone that protects against ischemia–reperfusion damage, acts by inhibiting the expression of Epac and Rap1 proteins. Vitexin can be found in plants of the genus Crataegus spp., traditionally known as hawthorn, which are of great interest considering their highly documented use as cardio-protectors. Pre-treating cells with an extract of Crataegus oxyacantha produced levels of T. cruzi invasion comparable to the ones observed for the commercially available Epac1-specific inhibitor, ESI-09. In addition, extract-treated cells exhibited a decrease in the activation of Rap1b, suggesting that the effects of the extract would be mediated by the inhibition of the cAMP-Epac-Rap1 signaling pathway. Using HPLC-HRMS2, we could confirm the presence of vitexin, and other flavones that could act as inhibitors of Epac/Rap1b, in the extracts of C. oxyacantha. Most significantly, when cells were treated with the extract of C. oxyacantha in conjunction with Nifurtimox, an increased modulation of invasion was observed.https://www.frontiersin.org/articles/10.3389/fmicb.2023.1301862/fullTrypanosoma cruzicAMP signalingEPACRap1bhawthornCrataegus |
| spellingShingle | Gabriel Ferri Gabriel Ferri Lucía R. Fernández Lucía R. Fernández Lucía R. Fernández Guillermo Di Mario Guillermo Di Mario Daniel Musikant Daniel Musikant Jorge A. Palermo Jorge A. Palermo Martin M. Edreira Martin M. Edreira Martin M. Edreira Host cell cAMP-Epac-Rap1b pathway inhibition by hawthorn extract as a potential target against Trypanosoma cruzi infection Frontiers in Microbiology Trypanosoma cruzi cAMP signaling EPAC Rap1b hawthorn Crataegus |
| title | Host cell cAMP-Epac-Rap1b pathway inhibition by hawthorn extract as a potential target against Trypanosoma cruzi infection |
| title_full | Host cell cAMP-Epac-Rap1b pathway inhibition by hawthorn extract as a potential target against Trypanosoma cruzi infection |
| title_fullStr | Host cell cAMP-Epac-Rap1b pathway inhibition by hawthorn extract as a potential target against Trypanosoma cruzi infection |
| title_full_unstemmed | Host cell cAMP-Epac-Rap1b pathway inhibition by hawthorn extract as a potential target against Trypanosoma cruzi infection |
| title_short | Host cell cAMP-Epac-Rap1b pathway inhibition by hawthorn extract as a potential target against Trypanosoma cruzi infection |
| title_sort | host cell camp epac rap1b pathway inhibition by hawthorn extract as a potential target against trypanosoma cruzi infection |
| topic | Trypanosoma cruzi cAMP signaling EPAC Rap1b hawthorn Crataegus |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1301862/full |
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