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Study of the paper uric acid and redox modulation on the system cell innate immune microbicide activity

Grant number: 15/21563-9
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): June 01, 2016
Status:Discontinued
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Flavia Carla Meotti
Grantee:Railmara Pereira da Silva
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:11/18106-4 - Oxidation of uric acid by myeloperoxidase in inflammatory processes and the implications for cardiovascular disease, AP.JP
Associated scholarship(s):18/25865-8 - Investigatoin of urate oxidation and urate-derived adducts in plasma albumin in cystic fibrosis and sepsis, BE.EP.DD

Abstract

Uric Acid (UA) is the final product of purine metabolism in humans and accumulates in plasma in the order of hundred micromolar. Because of its ability to donate electrons, uric acid is considered the main antioxidant in this environment. However, uric acid has been described to increase the damage caused by oxidative stress and inactivate enzymes sensible to oxidation. The one electron oxidation of uric acid by peroxidase generates urate free radical, which combines with superoxide to form the oxidant urate hydroperoxide. Our research group demonstrated the formation of this potent oxidizing agent under conditions that mimic the inflammatory oxidative burst. Because of the electrophilic character of urate hydroperoxide and other intermediaries derived from its decomposition (hydroxyisourate), our hypothesis is that the uric acid oxidation and the formation of these compounds could contribute to the microbicidal activity of innate immunity cells. Contrary to our expectations, the microbicidal effect of neutrophils and macrophages against Pseudomonas aeruginosa (PA) was significantly decreased in the presence of uric acid. Furthermore, uric acid significantly decreased the level of interleukin-1² (IL-1²) and tumor necrosis factor ± (TNF-±). Based on this data, the general objective of this project is to understand the mechanisms by which uric acid causes dysfunction in the microbicidal activity of innate immune cells. Since uric acid can act as an anti or pro-oxidant, we will firstly evaluate the redox state of the inflammatory cells challenged with PA in the presence or absence of uric acid. The levels of reduced and oxidized glutathione (GSH and GSSG) will be quantified. We will also quantify the oxidation of uric acid through the formation of allantoin. In addition, we will monitor the formation of urate hydroperoxide by the immune cells. Subsequently, inflammatory and apoptotic signaling pathways sensitive to redox modulation will be monitored, including Nrf2 and NF-kB (Nuclear Factor Kappa B) transcription factors; the signaling pathway of ASK-1 (Apoptosis Signal-regulating Kinase 1) and its downstream cascade proteins: JNK (c-Jun-NH2-terminal) and p38 MAPKs (Mitogen-activated Protein Kinases). We believe that the modulation of these pathways, that are responsive to the redox stress in the cell, could be responsible for alterations of microbicidal response of the immune cells in the presence of uric acid. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CHAUSSE, BRUNO; KAKIMOTO, PAMELA A.; CALDEIRA-DA-SILVA, CAMILLE C.; CHAVES-FILHO, ADRIANO B.; YOSHINAGA, MARCOS Y.; DA SILVA, RAILMARA PEREIRA; MIYAMOTO, SAYURI; KOWALTOWSKI, ALICIA J. Distinct metabolic patterns during microglial remodeling by oleate and palmitate. BIOSCIENCE REPORTS, v. 39, n. 4 APR 30 2019. Web of Science Citations: 0.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.