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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

Grant number: 13/20810-7
Support Opportunities:Regular Research Grants
Duration: March 01, 2014 - August 31, 2016
Field of knowledge:Health Sciences - Pharmacy - Medicines Analysis and Control
Principal Investigator:Yara Maria Lucisano Valim
Grantee:Yara Maria Lucisano Valim
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated researchers: Adriana Balbina Paoliello Paschoalato ; Ana Paula Landi Librandi ; Larissa Fávaro Marchi


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)

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Scientific publications (6)
(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)
FIGUEIREDO-RINHEL, ANDREA S. G.; DE MELO, LAMARTINE L.; BORTOT, LEANDRO O.; SANTOS, EVERTON O. L.; ANDRADE, MICASSIO F.; AZZOLINI, ANA ELISA C. S.; KABEYA, LUCIANA M.; CALIRI, ANTONIO; BASTOS, JAIRO K.; LUCISANO-VALIM, YARA MARIA. Baccharis dracunculifolia DC (Asteraceae) selectively modulates the effector functions of human neutrophils. Journal of Pharmacy and Pharmacology, v. 69, n. 12, p. 1829-1845, . (12/23541-4, 10/19504-0, 13/20810-7, 13/00927-7)
PAOLIELLO-PASCHOALATO, ADRIANA BALBINA; MARCHI, LARISSA FAVARO; DE ANDRADE, MICASSIO FERNANDES; KABEYA, LUCIANA MARIKO; DONADI, EDUARDO ANTONIO; LUCISANO-VALIM, YARA MARIA. Fc gamma and Complement Receptors and Complement Proteins in Neutrophil Activation in Rheumatoid Arthritis: Contribution to Pathogenesis and Progression and Modulation by Natural Products. Evidence-based Complementary and Alternative Medicine, . (12/23541-4, 07/00840-8, 13/20810-7, 07/02487-3)
ALBIERO, LUCINEIA REUSE; DE ANDRADE, MICASSIO FERNANDES; MARCHI, LARISSA FAVARO; LANDI-LIBRANDI, ANA PAULA; GARCIA DE FIGUEIREDO-RINHEL, ANDREA SILVA; CARVALHO, CAMILA ANDRESSA; KABEYA, LUCIANA MARIKO; RIBEIRO DE OLIVEIRA, RENE DONIZETI; CALEIRO SEIXAS AZZOLINI, ANA ELISA; PUPO, MONICA TALLARICO; et al. Immunomodulating action of the 3-phenylcoumarin derivative 6,7-dihydroxy-3-[3 `,4 `-methylenedioxyphenyl]-coumarin in neutrophils from patients with rheumatoid arthritis and in rats with acute joint inflammation. Inflammation Research, v. 69, n. 1, . (12/23541-4, 13/21331-5, 13/20810-7)
GARCIA DE FIGUEIREDO-RINHEL, ANDREA SILVA; DE ANDRADE, MICASSIO FERNANDES; LANDI-LIBRANDI, ANA PAULA; CALEIRO SEIXAS AZZOLINI, ANA ELISA; KABEYA, LUCIANA MARIKO; BASTOS, JAIRO KENUPP; LUCISANO-VALIM, YARA MARIA. Incorporation of Baccharis dracunculifolia DC (Asteraceae) leaf extract into phosphatidylcholine-cholesterol liposomes improves its anti-inflammatory effect in vivo. NATURAL PRODUCT RESEARCH, v. 33, n. 17, p. 2521-2525, . (12/23541-4, 10/19504-0, 13/20810-7, 13/00927-7)
MARCHI, LARISSA F.; PAOLIELLO-PASCHOALATO, ADRIANA B.; OLIVEIRA, RENE D. R.; AZZOLINI, ANA ELISA C. S.; KABEYA, LUCIANA M.; DONADI, EDUARDO A.; LUCISANO-VALIM, YARA MARIA. Activation status of peripheral blood neutrophils and the complement system in adult rheumatoid arthritis patients undergoing combined therapy with infliximab and methotrexate. RHEUMATOLOGY INTERNATIONAL, v. 38, n. 6, p. 1043-1052, . (13/20810-7)
ANDRADE, MICASSIO F.; KABEYA, LUCIANA M.; BORTOT, LEANDRO O.; DOS SANTOS, GABRIELA B.; SANTOS, EVERTON O. L.; ALBIERO, LUCINEIA R.; FIGUEIREDO-RINHEL, ANDREA S. G.; CARVALHO, CAMILA A.; AZZOLINI, ANA ELISA C. S.; CALIRI, ANTONIO; et al. The 3-phenylcoumarin derivative 6,7-dihydroxy-3-[3 `,4 `-methylenedioxyphenyl]-coumarin downmodulates the Fc gamma R- and CR-mediated oxidative metabolism and elastase release in human neutrophils: Possible mechanisms underlying inhibition of the formation and release of neutrophil extracellular traps. Free Radical Biology and Medicine, v. 115, p. 421-435, . (13/20810-7, 13/00927-7, 10/19504-0, 12/23541-4)

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