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©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
Sex-specific effects of Eugenia punicifolia extract on gastric ulcer healing in rats
Larissa Lucena Périco, Vinícius Peixoto Rodrigues, Rie Ohara, Gabriela Bueno, Vânia Vasti Alfieri Nunes, Raquel Cássia dos Santos, Ana Carolina Lima Camargo, Luis Antônio Justulin Júnior, Sérgio Faloni de Andrade, Viviane Miranda Bispo Steimbach, Luísa Mota da Silva, Lúcia Regina Machado da Rocha, Wagner Vilegas, Catarina dos Santos, Clélia Akiko Hiruma-Lima
Larissa Lucena Périco, Vinícius Peixoto Rodrigues, Rie Ohara, Gabriela Bueno, Vânia Vasti Alfieri Nunes, Lúcia Regina Machado da Rocha, Clélia Akiko Hiruma-Lima, Department of Physiology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil
Raquel Cássia dos Santos, Laboratory of Bioactive Compounds, São Francisco University, Bragança Paulista 12916-900, São Paulo, Brazil
Ana Carolina Lima Camargo, Luis Antônio Justulin Júnior, Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil
Sérgio Faloni de Andrade, Viviane Miranda Bispo Steimbach, Luísa Mota da Silva, Programa de Pós-graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí - UNIVALI, Itajaí 88302-901, Santa Catarina, Brazil
Wagner Vilegas, Coastal Campus of São Vicente, São Paulo State University (UNESP), São Vicente 11330-900, São Paulo, Brazil
Catarina dos Santos, Department of Biological Science, Faculty of Sciences and Languages, São Paulo State University (UNESP), Assis 19806-900, São Paulo, Brazil
Author contributions: Périco LL, Rodrigues VP, Ohara R, Bueno G, Santos RC, Camargo AC, Justulin LA, de Andrade SF, Steimbach VM, da Silva LM performed most of the experiments; Nunes VV and dos Santos C prepared the extract of Eugenia punicifolia; Périco LL, dos Santos RC, da Rocha LR, Vilegas W and Hiruma-Lima CA, contributed to the conception, design and coordinated the study; Périco LL, Rodrigues VP, Ohara R, da Rocha LR and Hiruma-Lima CA participated in writing the manuscript; all authors approved the final version of the article to be published.
Supported by the São Paulo Research Foundation (FAPESP), No. 2015/14797-3 to Pé rico LL and No. 2009/52237-9 to Laboratory of Biological Assays with Natural Products.
Institutional animal care and use committee statement: All the experimental practices related to animal care and use agreed with the protocols approved by the Ethics Committee on the Use of Animals of the Institute of Biosciences, UNESP, Botucatu, São Paulo, Brazil (No. 675-CEUA).
Conflict-of-interest statement: The authors declare that they have no commercial, personal, political, intellectual, or religious interests related to the work presented herein.
Data sharing statement: All data are available from the corresponding author upon reasonable request.
ARRIVE guidelines statement: The ARRIVE Guidelines have been adopted.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Clélia Akiko Hiruma-Lima, PhD, Adjunct Professor, Department of Physiology, Institute of Biosciences, Botucatu 18618-970, São Paulo, Brazil. clelia.hiruma@unesp.br
Telephone: +55-14-38800312 Fax: +55-14-3815-3744
Received: June 13, 2018
Peer-review started: June 13, 2018
First decision: July 4, 2018
Revised: July 11, 2018
Accepted: August 1, 2018
Article in press: August 1, 2018
Published online: October 14, 2018
AIM
To evaluate the sex-specific effects of a hydroalcoholic extract from Eugenia punicifolia (HEEP) leaves on gastric ulcer healing.
METHODS
In this rat study involving males, intact (cycling) females, and ovariectomized females, gastric ulcers were induced using acetic acid. A vehicle, lansoprazole, or HEEP was administered for 14 d after ulcer induction. Body weight was monitored throughout the treatment period. At the end of treatment, the rats were euthanized and the following in vivo and in vitro investigations were performed: macroscopic examination of the lesion area and organ weights, biochemical analysis, zymography, and evaluation of protein expression levels. Additionally, the concentration-dependent effect of HEEP was evaluated in terms of subacute toxicity and cytotoxicity.
RESULTS
Compared to the vehicle, HEEP demonstrated a great healing capacity by substantially reducing the ulcerative lesion area in males (52.44%), intact females (85.22%), and ovariectomized females (65.47%), confirming that HEEP accelerates the healing of acetic acid-induced gastric lesions and suggesting that this effect is modulated by female sex hormones. The antiulcer effect of HEEP was mediated by prostaglandin E2 only in male rats. Overall, the beneficial effect of HEEP was the highest in intact females. Notably, HEEP promoted the expression of vascular endothelial growth factor (intact vs ovariectomized females) and decreased the expression of Caspase-8 and Bcl-2 (intact female vs male or ovariectomized female). Additionally, HEEP enhanced fibroblast proliferation and migration into a wounded area in vitro, confirming its healing effect. Finally, no sign of subacute toxicity or cytotoxicity of HEEP was observed.
CONCLUSION
In gastric ulcers, HEEP-induced healing (modulated by female sex hormones; in males, mediated by prostaglandin) involves extracellular matrix remodeling, with gastric mucosa cell proliferation and migration.
Core tip: Gastric ulcers, which occur due to an imbalance between protective and aggressive agents at the gastric mucosa surface, is a chronic disease that affects millions worldwide and has high rates of relapse. The conventional treatment for gastric ulcers is associated with several side effects and poor healing of the gastric mucosa. Eugenia punicifolia is a medicinal plant used to treat inflammation and wounds. The present study in rats with gastric ulcers confirms the healing effect of Eugenia punicifolia extract and clarifies its differential effect in males and females. These findings are useful for developing novel and safe therapies for gastric ulcers.
