| Grant number: | 16/14420-0 |
| Support Opportunities: | Regular Research Grants |
| Start date: | December 01, 2016 |
| End date: | November 30, 2018 |
| Field of knowledge: | Health Sciences - Nutrition |
| Principal Investigator: | Luís Fernando Barbisan |
| Grantee: | Luís Fernando Barbisan |
| Host Institution: | Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil |
| City of the host institution: | Botucatu |
| Associated researchers: | Bruno Cogliati ; Fernando Salvador Moreno |
Abstract
Recently, hepatic fibrosis and carcinogenesis have been linked to altered expression of several miRNAs. In contrast, studies indicate that coffee drinking is associated with a 40% lower risk of developing fibrosis or liver cancer, while decaf drinking is not. Thus, the present project will evaluate whether caffeine alone or associated with trigoneline and/or chlorogenic acid (CGA), abundant compounds in coffee: (A) attenuates fibrosis-associated hepatocarcinogenesis (FAH) in vivo; (B) attenuates the fibrosis in vitro; (C) alters the miRNAs global expression profile and the expression of target genes of differentially expressed miRNAs in the liver. Thus, C3H/He male mice will be submitted to FAH model induced by diethylnitrosamine (DEN) and carbon tetrachloride (CCl4). Moreover, C3A (malignant hepatocytes) and LPS-treated LX-2 (HSC) will be used to perform 3D co-culture. Both mice and 3D co-culture will be exposed to caffeine alone or associated to trigonelline and/or CGA. Co-culture samples will be collected for collagen I determination, hepatocyte and HSCs counting, quantification of pro-inflammatory cytokines (IL-6, TNF-±, TGFb-1, I-17A and IL-23) and gene expression (collagen ±1(I), ±-SMA, TGF²-1, MMP-2, MMP-9, MMP-13 and TIMP-1). Liver samples will be collected for histopathological evaluation (HE), analysis of collagen content (Picro sirius Red) and immunohistochemistry (Ki-67, cleaved caspase-3, CK 8/18, F4/80, desmin and ±-SMA). Other liver samples will be used for global miRNA expression. After identification of differentially expressed miRNAs, bioinformatics prediction of target genes will be performed. The list of predicted genes will be used to evaluate the expression of target mRNAs. Additive or synergistic effects of the coffee compounds are expected and could represent novel therapeutic tools to chronic liver disease-associated Hepatocarcinogenesis. (AU)
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