Effects of eugenol and dehidrodieugenol isolated from Nectandra leucantha (Lauraceae) treatments in experimental models of acute and chronic lung disease

• Grant number: 18/06088-0
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2018
• End date: February 28, 2021
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Carla Máximo Prado
• Grantee: Carla Máximo Prado
• Host Institution: Instituto de Saúde e Sociedade (ISS). Universidade Federal de São Paulo (UNIFESP). Campus Baixada Santista. Santos , SP, Brazil
• Associated researchers: Clarice Rosa Olivo ; Iolanda de Fátima Lopes Calvo Tibério ; João Henrique Ghilardi Lago ; Lidio Gonçalves Lima Neto ; Wothan Tavares de Lima

Abstract

According to DATASUS data, respiratory diseases, including asthma, emphysema, pneumonia, bronchitis and bronchiolitis, have led to more than 135,000 deaths in 2017. The acute respiratory distress syndrome (ARDS) affects 2% to 26% of all mechanical ventilation hospitalized in intensive care centers is characterized by a diffuse pulmonary inflammatory response that causes acute lung injury (LPA) due to the activation of pro-inflammatory and oxidizing agents from various causes, and has a mortality rate of around 40% despite of studies with new therapeutic and ventilatory strategies. Bronchial asthma, a chronic allergic disease characterized by bronchial hyperresponsiveness, chronic inflammation mainly with a response profile diverted to Th2 and bronchial remodeling with impairment of function, still has a very high morbidity. Still, a portion of the patients present different phenotypes that do not respond to conventional treatment. Pulmonary emphysema, which affects mainly smokers, is the fourth cause of death in the world, and is characterized by the destruction of lung tissue by proteases and oxidants leading to progressive worsening of lung function, which, for the most part, is not reversible with conventional treatments. In common, these diseases have, in addition to pulmonary inflammation, the participation of oxidative stress in their pathophysiology and the lack of a specific and effective treatment for all patients. Our group has sought new therapeutic strategies for these diseases and mainly to understand pathophysiological mechanisms as well as action of new compounds with therapeutic potential. In this sense, eugenol is a substance with anti-inflammatory and antioxidant effects already known, but still controversial, while its dimerized form (dehydrodieugenol), isolated from the vegetal species Nectandra leucantha (Lauraceae), could have a more intense effect in the reduction of inflammation and less toxic. Objective: To evaluate the effects of treatment with eugenol and its dimer (dehydrodieugenol) on changes in pulmonary and histopathological function, characterizing possible mechanisms of action in models of pulmonary inflammatory diseases (model of acute lung injury, experimental asthma with eosinophilic phenotype and phenotype neutrophilic and pulmonary emphysema).Methodology: Mice will be submitted to LPS instillation protocol for induction of LPA, elastase for induction of emphysema and ovalbumin for induction of two different models of asthma. These animals will be treated with eugenol and dehydrodieugenol according to each protocol. Some groups will receive dexamethasone as a positive control of recommended treatment for some of these diseases. In all subprojects will be evaluated the mechanics of the respiratory system, pulmonary inflammation through the bronchoalveolar lavage, the dosage of pro-inflammatory cytokines; the remodeling of the extracellular matrix, oxidative stress and possible signaling pathways such as NF-kB, MAP kinase, JAK-STAT-SOCS and components of the cholinergic anti-inflammatory system. Some in vitro cell culture experiments will be performed to evaluate cytotoxicity and antioxidant capacity of the compounds. Histopathological analysis of the liver of the animals will also be performed to assess toxicity. Statistical analysis will be performed through the SigmaStat program and the tests will be subsequently selected. Due to the constant search for an effective therapeutic measure in the treatment of respiratory diseases and the known anti-inflammatory and antioxidant effect of eugenol and its dimer, animals treated with dehydrodieugenol are expected to show improvement in inflammatory response and pulmonary function and reduction of oxidative stress induced in these models of pulmonary diseases. Additionally, it will be possible to understand some of the mechanisms of action of these compounds. (AU)

Scientific publications

(14)

(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)

STILHANO, ROBERTA SESSA; COSTA, ANGELICA JARDIM; NISHINO, MICHELLE SAYURI; SHAMS, SHAHIN; BARTOLOMEO, CYNTHIA SILVA; BREITHAUPT-FALOPPA, ANA CRISTINA; SILVA, EDUARDO ALEXANDRE; RAMIREZ, ANA LOPEZ; PRADO, CARLA MAXIMO; URESHINO, RODRIGO PORTES. SARS-CoV-2 and the possible connection to ERs, ACE2, and RAGE: Focus on susceptibility factors. FASEB JOURNAL, v. 34, n. 11, p. 14103-14119, NOV 2020. (20/04709-8, 18/16719-8, 18/06088-0, 16/20796-2)

PONCI, VITOR; SILVA, RAFAEL C.; SANTANA, FERNANDA PAULA R.; GRECCO, SIMONE S.; FORTUNATO, CELIA REGINA M.; OLIVEIRA, MARIA A.; TAVARES-DE-LIMA, WOTHAN; OLIVO, CLARICE R.; CALVO TIBERIO, IOLANDA DE FATIMA L.; GOMES, KAIO S.; et al. Biseugenol Exhibited Anti-Inflammatory and Anti-Asthmatic Effects in an Asthma Mouse Model of Mixed-Granulocytic Asthma. Molecules, v. 25, n. 22, NOV 2020. (18/06088-0, 18/07885-1)

SANTANA, FERNANDA P. R.; RICARDO-DA-SILVA, FERNANDA Y.; FANTOZZI, EVELYN T.; PINHEIRO, NATHALIA M.; TIBERIO, IOLANDA F. L. C.; MOREIRA, LUIZ FELIPE PINHO; PRADO, MARCO ANTONIO M.; PRADO, VANIA F.; TAVARES-DE-LIMA, WOTHAN; PRADO, CARLA MAXIMO; et al. Lung Edema and Mortality Induced by Intestinal Ischemia and Reperfusion Is Regulated by VAChT Levels in Female Mice. Inflammation, v. 44, n. 4, p. 1553-1564, AUG 2021. (14/25689-4, 18/06088-0)

SANTANA, FERNANDA PAULA R.; THEVENARD, FERNANDA; GOMES, KAIO S.; TAGUCHI, LAURA; CAMARA, NIELS OLSEN S.; STILHANO, ROBERTA S.; URESHINO, RODRIGO P.; PRADO, CARLA MAXIMO; LAGO, JOAO HENRIQUE GHILARDI. New perspectives on natural flavonoids on COVID-19-induced lung injuries. Phytotherapy Research, v. 35, n. 9, p. 4988-5006, SEP 2021. (20/01221-4, 18/07885-1, 18/06088-0)

LOURENCO, LUIZ OTAVIO; RIBEIRO, ALESSANDRA MUSSI; QUIRINO DOS SANTOS LOPES, FERNANDA DEGOBBI TENORIO; LOPES CALVO TIBERIO, IOLANDA DE FATIMA; TAVARES-DE-LIMA, WOTHAN; PRADO, CARLA MAXIMO. ifferent Phenotypes in Asthma: Clinical Findings and Experimental Animal Model. CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY, v. 62, n. 1, SI, SEP 2021. (18/06088-0)

BITTENCOURT-MERNAK, I, MARCIA; PINHEIRO, NATHALIA M.; DA SILVA, RAFAEL C.; PONCI, VITOR; BANZATO, ROSANA; PINHEIRO, ARUANA J. M. C. R.; OLIVO, CLARICE R.; TIBERIO, IOLANDA F. L. C.; LIMA NETO, LIDIO G.; SANTANA, FERNANDA P. R.; et al. Effects of Eugenol and Dehydrodieugenol B from Nectandra leucantha against Lipopolysaccharide (LPS)-Induced Experimental Acute Lung Inflammation. Journal of Natural Products, v. 84, n. 8, p. 2282-2294, AUG 27 2021. (18/07885-1, 18/06088-0)

OLIVO, C. R.; CASTRO, T. B. P.; RIANE, A.; REGONHA, T.; RIVERO, D. H. R. F.; VIEIRA, R. P.; SARAIVA-ROMANHOLO, B. M.; LOPES, F. D. T. Q. S.; TIBERIO, I. F. L. C.; MARTINS, M. A.; et al. The effects of exercise training on the lungs and cardiovascular function of animals exposed to diesel exhaust particles and gases. Environmental Research, v. 203, JAN 2022. (18/02537-5, 18/06088-0, 18/01531-3)

SANTANA, FERNANDA P. R.; DA SILVA, RAFAEL C.; PONCI, VITOR; PINHEIRO, ARUANA J. M. C. R.; OLIVO, CLARICE R.; CAPERUTO, LUCIANA C.; ARANTES-COSTA, FERNANDA M.; CLAUDIO, SAMUEL R.; RIBEIRO, DANIEL A.; TIBERIO, IOLANDA F. L. C.; et al. Dehydrodieugenol improved lung inflammation in an asthma model by inhibiting the STAT3/SOCS3 and MAPK pathways. Biochemical Pharmacology, v. 180, OCT 2020. (14/25689-4, 18/06088-0)

RODRIGUES LEMES, ROBERTHA MARIANA; COSTA, ANGELICA JARDIM; BARTOLOMEO, CYNTHIA SILVA; BASSANI, TAYSA BERVIAN; NISHINO, MICHELLE SAYURI; DA SILVA PEREIRA, GUSTAVO JOSE; SMAILI, SORAYA SOUBHI; DE BARROS MACIEL, RUI MONTEIRO; BRACONI, CARLA TORRES; DA CRUZ, EDGAR FERREIRA; et al. 17 beta-estradiol reduces SARS-CoV-2 infection in vitro. PHYSIOLOGICAL REPORTS, v. 9, n. 2, JAN 2021. (16/20796-2, 06/60402-1, 18/06088-0, 20/06153-7, 19/10922-9, 20/04709-8)

SANTANA, FERNANDA P. R.; DA SILVA, RAFAEL C.; GRECCO, SIMONE DOS S.; PINHEIRO, ARUANA J. M. C. R.; CAPERUTO, LUCIANA C.; ARANTES-COSTA, FERNANDA M.; CLAUDIO, SAMUEL R.; YOSHIZAKI, KELLY; MACCHIONE, MARIANGELA; RIBEIRO, DANIEL A.; et al. Inhibition of MAPK and STAT3-SOCS3 by Sakuranetin Attenuated Chronic Allergic Airway Inflammation in Mice. Mediators of Inflammation, v. 2019, SEP 3 2019. (18/06088-0, 14/25689-4)

COSTA, ANGELICA JARDIM; LEMES, ROBERTHA MARIANA RODRIGUES; BARTOLOMEO, CYNTHIA SILVA; NUNES, TAMIRES ALVES; PEREIRA, GABRIELA CRUZ; OLIVEIRA, RAFAELA BRITO; GOMES, ALEXANDRE LOPES; SMAILI, SORAYA SOUBHI; MACIEL, RUI MONTEIRO DE BARROS; NEWSON, LOUISE; et al. Overexpression of estrogen receptor GPER1 and G1 treatment reduces SARS-CoV-2 infection in BEAS-2B bronchial cells. Molecular and Cellular Endocrinology, v. 558, p. 8-pg., 2022-12-01. (20/04709-8, 06/60402-1, 18/06088-0, 20/13480-4, 20/06153-7, 18/02762-9, 16/20796-2, 19/10922-9)

BANZATO, ROSANA; PINHEIRO, NATHALIA M.; OLIVO, CLARICE R.; SANTANA, FERNANDA R.; LOPES, FERNANDA D. T. Q. S.; CAPERUTO, LUCIANA C.; CAMARA, NIELS O.; MARTINS, MILTON A.; TIBERIO, IOLANDA F. L. C.; PRADO, MARCO ANTONIO M.; et al. Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema. SCIENTIFIC REPORTS, v. 11, n. 1, AUG 5 2021. (18/06088-0, 11/15817-7, 18/02537-5, 18/15738-9, 13/02881-4)

SARAIVA-ROMANHOLO, BEATRIZ MANGUEIRA; DE GENARO, ISABELLA SANTOS; DE ALMEIDA, FRANCINE MARIA; FELIX, SORAIA NOGUEIRA; COTTES LOPES, MARINA RIBEIRO; AMORIM, THAIS SANTOS; VIEIRA, RODOLFO PAULA; ARANTES-COSTA, FERNANDA MAGALHAES; MARTINS, MILTON ARRUDA; LOPES CALVO TIBERIO, IOLANDA DE FATIMA; et al. Exposure to Sodium Hypochlorite or Cigarette Smoke Induces Lung Injury and Mechanical Impairment in Wistar Rats. Inflammation, v. 45, n. 4, p. 20-pg., 2022-05-02. (09/53904-9, 18/06088-0)

SEIXAS, MARIA LUIZA G. A.; MITRE, LUCAS PARI; SHAMS, SHAHIN; LANZUOLO, GABRIEL BARBUGIAN; BARTOLOMEO, CYNTHIA SILVA; SILVA, EDUARDO A.; PRADO, CARLA MAXIMO; URESHINO, RODRIGO; STILHANO, ROBERTA SESSA. Unraveling Muscle Impairment Associated With COVID-19 and the Role of 3D Culture in Its Investigation. FRONTIERS IN NUTRITION, v. 9, p. 20-pg., 2022-02-10. (20/04709-8, 18/06088-0, 16/20796-2, 19/10922-9)