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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
ARTICLE HIGHLIGHTS
Research background
Gastric ulcers refer to acid injury in the digestive tract, resulting in a mucosal break that reaches to the submucosal layer. Acid peptic disorders are very common in the United States, with four million individuals (new cases and recurrences) affected per year. This disease occurs more often in men than in women, but these sex differences are less pronounced after the age of 45 years, probably because there is an increased incidence of ulcers in menopausal women.
Research motivation
The conventional treatment of gastric ulcers is based on the inhibition of gastric acid secretion. However, this therapy is associated with several side effects and poor quality of ulcer healing. Therefore, alternative therapies are desirable. We investigated the effects of extracts from the leaves of E. punicifolia (HEEP), which is a medicinal plant popularly used to treat inflammation and wounds.
Research objectives
We evaluated the sex-specific effects of HEEP in the healing of gastric ulcers induced by acetic acid in rats.
Research methods
We used a rat model of acetic acid-induced gastric ulcers to evaluate the healing effect of HEEP. We measured prostaglandin levels, analyzed the extracellular matrix by zymography, evaluated the quality of ulcer healing by western blot, and assessed the healing activity by scratch assay. Subacute toxicity (in vivo) and cytotoxicity (in vitro) were also investigated.
Research results
HEEP demonstrated a high healing capacity, with substantial reduction of lesion area in all groups studied (males, intact females, ovariectomized females). HEEP accelerated the healing of gastric lesions, and this effect was modulated by female sex hormones. The curative role of HEEP is due to an increase in PGE2 (only in males), as well as an inhibition (MMP-9) and maintenance (MMP-2) of the extracellular matrix in the gastric mucosa. The HEEP healing properties were also confirmed by the enhancement of proliferation and coverage of scratched wounds in a fibroblast monolayer (in vitro). No sign of toxicity was observed in this study.
Research conclusions
This was the first study to prove the healing activity of HEEP in acetic acid-induced gastric ulcers for both sexes (males vs females) and irrespective of hormonal status (cycling vs ovariectomized females). This effect is modulated by female sex hormones. The curative effect of HEEP is also mediated by prostaglandin, the remodeling of the extracellular matrix, and both cell proliferation and migration in the gastric mucosa. Additionally, HEEP does not cause subacute toxicity or cytotoxicity.
Research perspectives
The present findings support the popular use of E. punicifolia in the treatment of gastrointestinal ulcers, and contribute to the search for new therapies for diseases of the gastrointestinal tract.
