Systematic study of the molecular mechanisms involved in the inhibition of the oxidative metabolism of the stimulated neutrophils by the Baccharis dracunculifolia, 3-phenylcoumarin derivatives and 3,5,7-triidroxiflavonaimplications on the RA therapeutics

Abstract

Neutrophils are part of the innate immune system and play a crucial role in the first line of defense against microorganisms. The activation of these cells triggers the processes of phagocytosis, degranulation and activation of oxidative metabolism, acting jointly, to the death of pathogens. Then, these cells undergo apoptosis, a process essential for controlling and ending of inflammatory response. However, in some inflammatory pathologies involving the reactions of type III hypersensitivity, there are intense recruitment and activation of neutrophils, leading to massive release of toxic granule contents and of oxidant species capable of damaging the tissue. Therefore, modulation of these processes by natural substances is a potential therapeutic target for inflammatory diseases such as rheumatoid arthritis. In this context, the plant extract of Baccharis dracunculifolia, the 3-phenylcoumarin derivative of 6,7- dihydroxy -[3 ', 4'- methylenedioxyphenyl ]- coumarin and the flavonoid 3,5,7 - triidroxiflavone have shown promise as modulators of neutrophil oxidative metabolism, and in recent years, the research with these substances has been intensified in our laboratory. Thus, the objective of this project is to continue the evaluation of inhibitory effect of these substances on various effector functions of neutrophils, expanding this study by investigating the molecular mechanisms of action related to these compounds. In addition, we will also evaluate the therapeutic applicability using nanocarriers of natural substances, already defined in the laboratory, in an animal model of rheumatoid arthritis. Moreover, after the establishment of action of these compounds in the experimental model, it will be assessed their effects on the neutrophils from patients with rheumatoid arthritis. These studies will provide input for a possible therapeutic alternative in inflammatory processes triggered by accentuated participation of neutrophils. (AU)