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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Tanimoto, Alexandre [1] ; Witaicenis, Aline [1] ; Caruso, Icaro P. [2] ; Piva, Hemily M. R. [2] ; Araujo, Gabriela C. [2] ; Moraes, Fabio R. [2] ; Fossey, Marcelo C. [2] ; Cornelio, Marinonio L. [2] ; Souza, Fatima P. [2] ; Di Stasi, Luiz C. [1]
Total Authors: 10
Affiliation:
[1] Sao Paulo State Univ, Inst Biosci, Dept Pharmacol, UNESP, Lab Phytomed Pharmacol & Biotechnol PhytoPharmaTe, BR-18618689 Botucatu, SP - Brazil
[2] Sao Paulo State Univ, UNESP, Inst Biosci Letters & Exact Sci IBILCE, Multiuser Biomol Innovat Ctr CMIB, Dept Phys, Rua Cristovao Colombo 2265, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: Chemico-Biological Interactions; v. 315, JAN 5 2020.
Web of Science Citations: 0
Abstract

4-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, G1u381-B, Asp443-A, Ser444-A, G1u447-B and Ser475-A participated in electrostatic interaction, Lys70-B, G1u381-B and Arg81-A acted in the hydrophobic interactions and Trp73, Phe377 and A1a446 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. (AU)

FAPESP's process: 15/15267-8 - Inflammatory bowel disease (IBD): novel approaches for diagnosis and gut microbiota modulation in ulcerative colitis patients
Grantee:Luiz Claudio Di Stasi
Support Opportunities: Research Projects - Thematic Grants