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In vitro evaluation of antioxidant and anti-inflammatory derivatives 3-phenylcoumarins in human neutrophils stimulated and in animal models of arthritis.

Grant number: 12/23541-4
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2013
Effective date (End): May 31, 2016
Field of knowledge:Health Sciences - Pharmacy - Medicines Analysis and Control
Principal Investigator:Yara Maria Lucisano Valim
Grantee:Micássio Fernandes de Andrade
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Neutrophils are part of the innate immune system and play a crucial role in the first line of defense against microorganisms, characterized by the functions to recognize, phagocytose and destroy pathogens. The activation of neutrophils via Fc³ and CR receptors triggers processes of phagocytosis, degranulation and activation of oxidative metabolism, which act together to the death of pathogens. Then, these cells undergo apoptosis, a process essential for terminating the inflammatory response. However, in some inflammatory diseases, such as type hypersensitivity reactions III, occurs intense recruitment and activation of neutrophils, leading to massive release of toxic granule contents and oxidizing species capable of damaging the tissue. Therefore, modulation of these processes by natural substances is numerous potential therapeutic targets for inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus. In this context, 3-phenylcoumarins derivatives have been shown promise as anti-inflammatory drugs and modulators of oxidative metabolism of neutrophils, and the search for this class of substances has intensified in recent years in our laboratory. Thus, this study aims to assess the effect of the 3-phenylcoumarins derivatives in oxidative metabolism of human neutrophils triggered by the activation of Fc³ receptors but also receptors CR, and cooperation between them. Furthermore, it is proposed to evaluate the effects of these derivatives on calcium metabolism and activity and assembly of the enzyme complex NADPH oxidase and signaling pathways that lead to activation of this complex. It is also proposed to assess the anti-inflammatory activity of the 3-phenylcoumarins derivatives through the recruitment of neutrophils and receptor expression. Finally, the substances are encapsulated into liposomes and applied in the animal model of rheumatoid arthritis. These studies will provide input for a possible therapeutic application in inflammatory processes triggered by the deposition of immune complexes (IC).

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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)
PAOLIELLO-PASCHOALATO, A. B.; AZZOLINI, A. E. C. S.; CRUZ, M. F. C.; MARCHI, L. F.; KABEYA, L. M.; DONADI, E. A.; LUCISANO-VALIM, Y. M.. Isolation of healthy individuals' and rheumatoid arthritis patients' peripheral blood neutrophils by the gelatin and Ficoll-Hypaque methods: Comparative efficiency and impact on the neutrophil oxidative metabolism and Fe gamma receptor expression. JOURNAL OF IMMUNOLOGICAL METHODS, v. 412, p. 70-77, . (12/23541-4)
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)
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)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
ANDRADE, Micássio Fernandes de. Study of the immunomodulator effect of the 3-phenylcoumarin derivative 6,7-dihydroxy-3-[3\',4\'-methylenedioxyphenyl]-coumarin in stimulated human neutrophils and in an animal model of zymosan-induced inflammation. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.

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