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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

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Abstract

Objective

To examine whether free (3-PD-5free) and/or liposomal (3-PD-5lipo) 6,7-dihydroxy-3-[3′,4′-methylenedioxyphenyl]-coumarin (3-PD-5) (1) modulate the effector functions of neutrophils from patients with rheumatoid arthritis under remission (i-RA) and with active disease (a-RA), in vitro; and (2) exert anti-inflammatory effect in a rat model of zymosan-induced acute joint inflammation.

Methods and results

Incorporation of 3-PD-5 into unilamellar liposomes of soya phosphatidylcholine and cholesterol was efficient (57.5 ± 7.9%) and yielded vesicles with low diameter (133.7 ± 18.4 nm), polydispersity index (0.39 ± 0.06), and zeta potential (− 1.22 ± 0.34 mV). 3-PD-5free (1 µM) and 3-PD-5lipo (3 µM) equally suppressed elastase release and reactive oxygen species generation in neutrophils from healthy subjects and i-RA and a-RA patients, stimulated with immune complexes. 3-PD-5free (20 µM) suppressed the release of neutrophil extracellular traps and chemotaxis in vitro, without clear signs of cytotoxicity. 3-PD-5lipo (1.5 mg/kg, i.p.) diminished joint edema and synovial infiltration of total leukocytes and neutrophils, without changing the synovial levels of TNF-α, IL-1β, and IL-6.

Conclusion

Altogether, the results reported herein indicate that 3-PD-5 is a promising modulator of the early stages of acute joint inflammation that can help to diminish not only excessive neutrophil infiltration in the synovia but also neutrophil activation and its outcomes in RA patients.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

a-RA:

Active rheumatoid arthritis

BTL1:

Leukotriene B4 receptor

CL:

Chemiluminescence

CXCL8:

Interleukin 8

CXCR1:

CXCL8 receptor type 1

CXCR2:

CXCL8 receptor type 2

DAPI:

4′,6-Diamidino-2-phenylindole dihydrochloride

DMSO:

Dimethyl sulfoxide

DPI:

Diphenyleneiodonium chloride

FITC:

Fluorescein isothiocyanate

HBSS:

Hank’s balanced saline solution

HBSS-gel:

Hank’s balanced saline solution supplemented with gelatin

IC:

Immune complex

i-RA:

Inactive rheumatoid arthritis

i-IC:

Immobilized immune complexes

IL-1β:

Interleukin 1β

IL-6:

Interleukin 6

LTB4 :

Leukotriene B4

MFI:

Median fluorescence intensity

MPO:

Myeloperoxidase

NETs:

Neutrophil extracellular traps

OVA:

Ovalbumin

PBS:

Phosphate-buffered saline

3-PD-5:

6,7-Dihydroxy-3-[3′,4′-methylenedioxyphenyl]-coumarin

3-PD-5free :

Free form of 3-PD-5

3-PD-5lipo :

Liposomal form of 3-PD-5

p-IC:

Precipitated immune complexes

p-ICops:

Precipitated immune complexes opsonized with human serum

PE:

Phycoerythrin

RA:

Rheumatoid arthritis

ROS:

Reactive oxygen species

TNF-α:

Tumor necrosis factor α

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Acknowledgments

The authors thank Dr. Adriana Balbina Paoliello-Paschoalato, Dr. Marcelo Dias Baruffi and Dr. Alexandre Kanashiro for scientific discussions, and Mr. Alcides Silva Pereira and Mrs. Nadir Mazzucato from the School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil, for their helpful technical assistance.

Funding

This study was supported by the Brazilian funding agencies São Paulo Research Foundation (FAPESP, grants 2010/19504-0, 2012/23541-4, 2013/20810-7, and 2013/21331-5) and National Council for Scientific and Technological Development (CNPq, grants 482015/2012-8, 308111/2013-3, and 130209/2015-5).

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Author notes

  1. Lucinéia Reuse Albiero

    Present address: Federal University of Mato Grosso, Sinop, MT, Brazil

  2. Micássio Fernandes de Andrade

    Present address: School of Health Sciences, The State University of Rio Grande do Norte, Mossoró, RN, Brazil

  3. Lucinéia Reuse Albiero and Micássio Fernandes de Andrade have contributed equally to this study.

Authors and Affiliations

  1. Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil

    Lucinéia Reuse Albiero & Micássio Fernandes de Andrade

  2. Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Avenida do Café s/n, Ribeirão Preto, SP, 14040-903, Brazil

    Larissa Fávaro Marchi, Ana Paula Landi-Librandi, Andréa Silva Garcia de Figueiredo-Rinhel, Camila Andressa Carvalho, Luciana Mariko Kabeya, Ana Elisa Caleiro Seixas Azzolini & Yara Maria Lucisano-Valim

  3. Division of Rheumatology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil

    Renê Donizeti Ribeiro de Oliveira

  4. Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Avenida do Café s/n, Ribeirão Preto, SP, 14040-903, Brazil

    Mônica Tallarico Pupo & Flávio da Silva Emery

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Contributions

LRA, MFA, LFM, and YMLV conceived the study; LRA, MFA, LFM, and AECS designed the experiments; RDRO selected the patients and determined their clinical parameters; LRA and LFM selected the healthy volunteers; LRA, MFA, CAC, and AECS performed the in vitro experiments; MFA, APLL, ASGFR, and AECS performed the in vivo experiments; LRA, MFA, LFM, LMK, AECS, and YMLV analyzed the data and discussed the results; MTP and FSE synthesized the 3-phenylcoumarin derivative and discussed the results; LRA, MFA, and LMK wrote the manuscript; and YMLV searched for funding and supervised the study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Lucinéia Reuse Albiero, Micássio Fernandes de Andrade or Yara Maria Lucisano-Valim.

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Conflict of interest

The authors declare that there are no conflicts of interest.

Ethics approval and consent to participate

All procedures performed in studies involving human participants complied with the ethical standards established by the Resolution 466/2012 of the Brazilian National Health Council, and with the 1964 Helsinki declaration and its later amendments. The Human Research Ethics Committee from the Ribeirão Preto Medical School Hospital and from the School of Pharmaceutical Sciences of Ribeirão Preto, both at the University of São Paulo, Ribeirão Preto, SP, Brazil, approved the study protocol (CEP/HCRP n. 15038/2015). All the participants signed an informed consent form to participate in this study. All procedures performed in studies involving animals complied with the ethical standards of The Animal Care Committee from the University of São Paulo, Brazil, which approved the study protocol (CEUA n. 15.1.1163.60.0).

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Albiero, L.R., de Andrade, M.F., Marchi, L.F. 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. Inflamm. Res. 69, 115–130 (2020). https://doi.org/10.1007/s00011-019-01298-w

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