Journal
CHEMICO-BIOLOGICAL INTERACTIONS
Volume 315, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2019.108876
Keywords
Glutathione; Inflammatory bowel disease; 4-Methylesculetin; Glutathione reductase; Glutathione-related enzymes; Nrf2
Funding
- Sao Paulo Research Foundation (FAPESP) [2015/15267-8]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - Brasil (CAPES) [001]
- National Council for Scientific and Technological Development (CNPq)
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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.
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