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Effect of Melatonin on the Phenotype and Function of Neutrophils in Wistar Rats with Walker-256 Tumor.

Grant number: 17/15036-1
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): December 01, 2017
Effective date (End): May 31, 2019
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:José Cipolla Neto
Grantee:Wilson Mitsuo Tatagiba Kuwabara
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:14/50457-0 - Melatonin and the control of energy metabolism: basic, clinical and epidemiological research, AP.TEM


According to the World Health Organization (WHO), cancer is the second leading cause of death in the world. The development of new therapies and the discovery of new molecules capable of fighting cancer are major targets of the 21st century research. Melatonin is at the center of several studies against cancer and has been unveiled as a potent oncotic molecule, acting from the beginning of the neoplastic process until the later stages, such as metastasis. Moreover, melatonin also plays a fundamental role in the immune system regulation. The role of leukocytes in fighting cancer has been gaining so much evidence in recent decades that cancer is already considered a failure of the immune system. Many chemotherapies promote the cessation of tumor cell growth, but at the same time cause a drop in the individual's immunity, especially innate immunity, which often results in failure of therapy and tumor recurrence. In recent years, neutrophils have come to be seen, not only as a cell that acts against invading microorganisms, but also as antigen presenting cells and cells that regulate the microenvironment of solid tumors. Cancer has an important immunosuppressive action on neutrophils, generating a change of "N1" profile (Antitumoral) to a "N2" profile (Pro tumoral), which increases the capacity of the tumor to grow and spread. There are no studies in the literature that address the action of melatonin on the function and inflammatory profile of neutrophils in cancer. Thus, this study aims to assess the immunomodulatory capacity of melatonin, that is, the ability of this molecule to prevent the change of N1/N2 inflammatory phenotype, in neutrophils of rats with Walker-256 tumor. Therefore, pinealectomized and non-pinealectomized rats will receive 10 mg/kg of melatonin orally, solubilized in the water they will ingest at night. A group without supplementation will be used as control. Half of these animals will be inoculated with Walker-256 tumor and half of the groups will be injected with 0.9% saline, as a control of the surgery. The metabolic profile of the experimental groups will be analyzed by GTT, ITT, insulinemia and serum parameters (Total Cholesterol, LDL, HDL and triglycerides). The antitumor action of melatonin will be evaluated by the size, weight and spread of the tumor. The role of melatonin in the change in neutrophil phenotype will first be evaluated by the gene expression (qPCR) of certain surface markers. After detection of the altered genes, the phenotype will be validated by flow cytometry. Finally, neutrophil functions will be evaluated by the production of cytokines by ELISA, production of reactive oxygen species using luminol as a chemiluminescent probe, phagocytic capacity, migratory capacity and cell death by flow cytometry.

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Scientific publications
(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)
TATAGIBA KUWABARA, WILSON MITSUO; ANDRADE-SILVA, JESSICA; BERTAGLIA PEREIRA, JOICE NAIARA; SCIALFA, JULIETA HELENA; CIPOLLA-NETO, JOSE. Neutrophil activation causes tumor regression in Walker 256 tumor-bearing rats. SCIENTIFIC REPORTS, v. 9, . (17/15036-1, 14/50457-0)

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