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Effects of zinc deficiency and supplementation on chemically-induced hepatocarcinogenesis in mice

Grant number: 14/01795-0
Support type:Scholarships in Brazil - Master
Effective date (Start): September 01, 2014
Effective date (End): February 29, 2016
Field of knowledge:Health Sciences - Medicine
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Luís Fernando Barbisan
Grantee:Guilherme Ribeiro Romualdo
Home Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil


Hepatocellular Carcinoma (HCC) represents approximately 6% of all incident cases of cancer and it is the third leading cause of cancer death globally. The development of this malignancy involves great complexity in its pathogenesis and highlights the involvement of metals including iron, zinc and copper. Zinc is a metal that, due the diversity of roles it plays in the body has been the subject of studies that define it as a promising agent for cancer prevention. The present project aims to evaluate the effects of different concentrations of zinc on the development of pre-neoplastic and neoplastic lesions in hepatocarcinogenesis model induced by Diethylnitrosamine (DEN) and promoted by sodium Phenobarbital (FB) in Balb/C neonates. Male Balb/C will be initiated with a single dose of Diethylnitrosamine (DEN, 50 mg/kg bw, ip) on postnatal day 15 (15 PND). At 28 PND (weaning), animals will be randomly allocated into three groups and fed diets prepared with different concentrations of zinc: adequate levels (35 mg/kg diet), defficient (3 mg/kg diet) or supplemented (180 mg/kg of feed) and 0.05% sodium phenobarbital (50 g/kg diet) until euthanasia. Animals will be sacrificed at two moments of the experiment, some will be sacrificed at 12 weeks after weaning (n = 10/group) and the remainder at 24 weeks after weaning (n = 10/group). At the necropsy, liver and blood will be collected. Liver samples will be processed for histological procedures (immunohistochemistry and H & E reactions) including determination of incidence and multiplicity of proliferative lesions, cell proliferation (Ki67) and apoptosis indexes, expression of transforming growth factor alpha (TGF-±), p53 and ² - catenin in pre-neoplastic and neoplastic lesions in the liver. Liver samples will be also processed for molecular analysis (Western blotting and zimography for matrix metalloproteinases 2 and 9), biochemical analysis (activity of catalase, SOD and zinc levels) and comet assay. Blood samples will be also collected to determine transaminases (ALT and AST), Alcaline Fosfatase (AF), Gama Glutamil Transferase (GGT) and zinc. (AU)

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)
ROMUALDO, GUILHERME R.; GOTO, RENATA L.; FERNANDES, ANA A. H.; COGLIATI, BRUNO; BARBISAN, LUIS F. Vitamin D-3 supplementation attenuates the early stage of mouse hepatocarcinogenesis promoted by hexachlorobenzene fungicide. Food and Chemical Toxicology, v. 107, n. A, p. 27-36, SEP 2017. Web of Science Citations: 1.
ROMUALDO, GUILHERME RIBEIRO; GOTO, RENATA LEME; HENRIQUE FERNANDES, ANA ANGELICA; COGLIATI, BRUNO; BARBISAN, LUIS FERNANDO. Dietary zinc deficiency predisposes mice to the development of preneoplastic lesions in chemically-induced hepatocarcinogenesis. Food and Chemical Toxicology, v. 96, p. 280-289, OCT 2016. Web of Science Citations: 8.
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
ROMUALDO, Guilherme Ribeiro. Efeitos da deficiência ou suplementação de zinco sobre a hepatocarcinogênese química em camundongos. 2016. Master's Dissertation - Universidade Estadual Paulista "Júlio de Mesquita Filho" Faculdade de Medicina..

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