4-Methylesculetin, a natural coumarin with intestinal anti-inflammatory activity, elicits a glutathione antioxidant response by different mechanisms

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Autor(es): dc.contributorUniversidade Estadual Paulista (Unesp)-
Autor(es): dc.creatorTanimoto, Alexandre [UNESP]-
Autor(es): dc.creatorWitaicenis, Aline [UNESP]-
Autor(es): dc.creatorCaruso, Ícaro P. [UNESP]-
Autor(es): dc.creatorPiva, Hémily M.R. [UNESP]-
Autor(es): dc.creatorAraujo, Gabriela C. [UNESP]-
Autor(es): dc.creatorMoraes, Fábio R. [UNESP]-
Autor(es): dc.creatorFossey, Marcelo C. [UNESP]-
Autor(es): dc.creatorCornélio, Marinonio L. [UNESP]-
Autor(es): dc.creatorSouza, Fátima P. [UNESP]-
Autor(es): dc.creatorDi Stasi, Luiz C. [UNESP]-
Data de aceite: dc.date.accessioned2022-02-22T00:27:49Z-
Data de disponibilização: dc.date.available2022-02-22T00:27:49Z-
Data de envio: dc.date.issued2020-12-11-
Data de envio: dc.date.issued2020-12-11-
Data de envio: dc.date.issued2020-01-04-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1016/j.cbi.2019.108876-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/199607-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/199607-
Descrição: dc.description4-methylesculetin (4 ME) is a natural antioxidant coumarin with protective effects on the intestinal inflammation, in which oxidative stress plays a key role in its aetiology and pathophysiology. Based on this, we examined the antioxidant molecular mechanisms involved in the intestinal anti-inflammatory activity of the 4 ME. For this purpose, we investigated the effects of the 4 ME on the modulation of gene expression and antioxidant-related enzyme activities in TNBS model of intestinal inflammation as well as the molecular interaction between 4 ME and glutathione reductase. Our results showed that 4 ME modulated glutathione-related enzymes, mainly increasing glutathione reductase activity. These effects were related to upregulation of glutathione reductase and Nrf2 gene expression. Fluorescence and nuclear magnetic resonance data showed that interaction between 4 ME and glutathione reductase is collisional, hydrophobic and spontaneous, in which C4 methyl group is the second epitope most buried into glutathione reductase. Molecular modelling calculation showed Lys70-B, Arg81-A, Glu381-B, Asp443-A, Ser444-A, Glu447-B and Ser475-A participated in electrostatic interaction, Lys70-B, Glu381-B and Arg81-A acted in the hydrophobic interactions and Trp73, Phe377 and Ala446 are responsible for the hydrogen bonds. Based on this, our results showed 4 ME acted by different mechanisms to control oxidative stress induced by intestinal damage, controlling the imbalance between myeloperoxidase activity and glutathione production, upregulating the glutathione S-transferase and glutathione reductase activities, preventing the Nrf2 and glutathione gene expression downregulation with consequent glutathione maintenance. Finally, 4 ME interacted at molecular level with glutathione reductase, stabilizing its enzymatic activity and reducing oxidative stress to take place in intestinal inflammatory process.-
Descrição: dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)-
Descrição: dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)-
Descrição: dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)-
Descrição: dc.descriptionLaboratory of Phytomedicines Pharmacology and Biotechnology (PhytoPharmaTech) Department of Pharmacology Institute of Biosciences UNESP São Paulo State University, Botucatu-
Descrição: dc.descriptionMulti-user Biomolecular Innovation Center (CMIB) Department de Physics Institute of Biosciences Letters e Exact Sciences (IBILCE) UNESP São Paulo State University, Rua Cristovão Colombo, 2265, Jardim Nazareth, São José do Rio Preto-
Descrição: dc.descriptionLaboratory of Phytomedicines Pharmacology and Biotechnology (PhytoPharmaTech) Department of Pharmacology Institute of Biosciences UNESP São Paulo State University, Botucatu-
Descrição: dc.descriptionMulti-user Biomolecular Innovation Center (CMIB) Department de Physics Institute of Biosciences Letters e Exact Sciences (IBILCE) UNESP São Paulo State University, Rua Cristovão Colombo, 2265, Jardim Nazareth, São José do Rio Preto-
Descrição: dc.descriptionFAPESP: 2015/15267-8-
Idioma: dc.languageen-
Relação: dc.relationChemico-Biological Interactions-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subject4-Methylesculetin-
Palavras-chave: dc.subjectGlutathione-
Palavras-chave: dc.subjectGlutathione reductase-
Palavras-chave: dc.subjectGlutathione-related enzymes-
Palavras-chave: dc.subjectInflammatory bowel disease-
Palavras-chave: dc.subjectNrf2-
Título: dc.title4-Methylesculetin, a natural coumarin with intestinal anti-inflammatory activity, elicits a glutathione antioxidant response by different mechanisms-
Tipo de arquivo: dc.typelivro digital-
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