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Induction of ovarian tumor and influence of melatonin on inflammatory signaling pathway mediated by Toll-like receptor 4 in UChB rats

Abstract

Ovarian cancer has the highest incidence in peri-and post-menopausal women and, due to its late diagnosis and poor prognosis, is the fourth most common cause of cancer death. Ovarian cancer responds initially to chemotherapy agents, reducing the growth of tumor mass, however, many women timely develop chemoresistance linked to the inflammatory process. It is undisputed that the risk factors may present co-carcinogenic effects, such as chronic alcoholism. Interestingly, proinflammatory mechanisms arising from ethanol-induced chemical mediators are similar to those found in ovarian cancer during the chemoresistance process. Since melatonin has immunomodulatory and oncostatic activities, and also seems to alleviate side effects of the disease, especially in hormone-dependent tumors, the study aims to evaluate the effect of ovarian tumor induction and the influence of long-term melatonin on inflammatory process through Toll-like receptor 4 signaling in a model of ethanol-preferring rats (UChB). Thus, the following parameters will be investigated: daily evaluation of the estrous cycle during the trials, frequency and characterization of the types of ovarian tumors by histopathological analysis, mapping and quantification of proteins by proteomic analysis (MALDI-Imaging - matrix-assisted laser desorption/ionization), immunolocalization and quantification of Toll-like receptors (TLR)-4, estradiol receptor (ER)-alpha and ER-beta and immunological factors: nuclear factor kappa beta (NF-kB), inhibitor of NF-kB (IkB), IkB kinase complex (IKKB), myeloid differentiation factor (MyD88), mitogen-associated protein kinase (p38MAPK) and kinase receptor associated interleukin 1 (IRAK-1) by immunohistochemistry and Western blot. Furthermore, it will also be assessed the inflammatory process by obtaining the concentration of pro-inflammatory cytokines: interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha by ELISA in ovarian tissue and the determinations of plasma 17B-estradiol, LH and FSH by radioimmunoassay (RIA). Our results will provide important evidence in clarifying the effects of melatonin during the inflammatory process related to ovarian cancer. (AU)

Scientific publications (7)
(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)
ZONTA, YOHAN RICCI; MARTINEZ, MARCELO; CAMARGO, ISABEL CRISTINA C.; DOMENICONI, RAQUEL F.; LUPI JUNIOR, LUIZ ANTONIO; PINHEIRO, PATRICIA FERNANDA F.; REITER, RUSSEL J.; MARTINEZ, FRANCISCO EDUARDO; CHUFFA, LUIZ GUSTAVO A. Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 18, n. 4 APR 2017. Web of Science Citations: 21.
DE ALMEIDA CHUFFA, LUIZ GUSTAVO; LUPI-JUNIOR, LUIZ ANTONIO; COSTA, ALINE BALANDIS; AMORIM, JOAO PAULO DE ARRUDA; SEIVA, FABIO RODRIGUES FERREIRA. The role of sex hormones and steroid receptors on female reproductive cancers. Steroids, v. 118, p. 93-108, FEB 2017. Web of Science Citations: 51.
CHUFFA, LUIZ GUSTAVO A.; LUPI JUNIOR, LUIZ ANTONIO; SEIVA, FABIO R. F.; MARTINEZ, MARCELO; DOMENICONI, RAQUEL F.; PINHEIRO, PATRICIA FERNANDA F.; DOS SANTOS, LUCILENE D.; MARTINEZ, FRANCISCO EDUARDO. Quantitative Proteomic Profiling Reveals That Diverse Metabolic Pathways Are Influenced by Melatonin in an in Vivo Model of Ovarian Carcinoma. JOURNAL OF PROTEOME RESEARCH, v. 15, n. 10, p. 3872-3882, OCT 2016. Web of Science Citations: 14.
CHUFFA, LUIZ GUSTAVO A.; ALVES, MICHELLY S.; MARTINEZ, MARCELO; CAMARGO, ISABEL CRISTINA C.; PINHEIRO, PATRICIA F. F.; DOMENICONI, RAQUEL F.; JUNIOR, LUIZ ANTONIO L.; MARTINEZ, FRANCISCO EDUARDO. Apoptosis is triggered by melatonin in an in vivo model of ovarian carcinoma. Endocrine-Related Cancer, v. 23, n. 2, p. 65-76, FEB 2016. Web of Science Citations: 23.
CHUFFA, LUIZ GUSTAVO A.; FIORUCI-FONTANELLI, BEATRIZ A.; MENDES, LEONARDO O.; FERREIRA SEIVA, FABIO R.; MARTINEZ, MARCELO; FAVARO, WAGNER J.; DOMENICONI, RAQUEL F.; PINHEIRO, PATRICIA F. F.; DOS SANTOS, LUCILENE DELAZARI; MARTINEZ, FRANCISCO EDUARDO. Melatonin attenuates the TLR4-mediated inflammatory response through MyD88-and TRIF-dependent signaling pathways in an in vivo model of ovarian cancer. BMC CANCER, v. 15, FEB 6 2015. Web of Science Citations: 37.
FERREIRA, GRAZIELLE M.; MARTINEZ, MARCELO; CAMARGO, ISABEL CRISTINA C.; DOMENICONI, RAQUEL F.; MARTINEZ, FRANCISCO EDUARDO; CHUFFA, LUIZ GUSTAVO A. Melatonin Attenuates Her-2, p38 MAPK, p-AKT, and mTOR Levels in Ovarian Carcinoma of Ethanol-Preferring Rats. JOURNAL OF CANCER, v. 5, n. 9, p. 728-735, 2014. Web of Science Citations: 27.
CHUFFA, LUIZ GUSTAVO A.; FIORUCI-FONTANELLI, BEATRIZ A.; MENDES, LEONARDO O.; FAVARO, WAGNER J.; PINHEIRO, PATRICIA FERNANDA F.; MARTINEZ, MARCELO; MARTINEZ, FRANCISCO EDUARDO. Characterization of Chemically Induced Ovarian Carcinomas in an Ethanol-Preferring Rat Model: Influence of Long-Term Melatonin Treatment. PLoS One, v. 8, n. 12 DEC 18 2013. Web of Science Citations: 24.

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