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Lower Concentrations of Blueberry Polyphenolic-Rich Extract Differentially Alter HepG2 Cell Proliferation and Expression of Genes Related to Cell-Cycle, Oxidation and Epigenetic Machinery

Farideh Shafiee-Kermani, Michael A Grusak, Sally J Gustafson, Mary Ann Lila and Mihai Niculescu

 In vitro cancer models have been used to study the effect of relatively high concentrations (>200 μg/ml) of phenolic plant extracts upon cell proliferation. In this study we report that the treatment of human hepatocarcinoma, HepG2, cells with lower concentrations of blueberry phenolic extract (6.5-100 μg/mL) for 96 h induced a non-linear response in cell proliferation, with a significant peak at 25 μg/mL and lower proliferation observed at higher concentrations, while no differences in apoptosis were present across groups. Flow cytometry analysis indicated a reduction of almost 19% of cells in S-phase for 25 μg/mL, as compared to control, while, no changes were observed for other concentrations. The percent of cells in G2/M phase was reduced at 50 μg/ml, while all other concentrations increased the percent of cells in G0/G1 phase. Gene expression analysis revealed concentration-specific changes for several genes involved in cell-cycle regulation (cyclin D1, cyclin-dependent kinase inhibitor 1A, and proliferating cell nuclear antigen, PCNA), antioxidant metabolism (glutamate-cysteine ligase catalytic subunit and glutathione reductase), and epigenetic machinery related to cell-cycle progression (DNA-methyltransferase 1, DNA-methyltransferase 3a, and Sirtuin 1). Neither the generation of reactive oxygen species (ROS) nor the intracellular redox status was affected by any treatment. Taken together, these data indicated that lower concentrations of blueberry phenolic extracts induce differential effects upon cell proliferation and the expression of genes involved in cell-cycle progression and epigenetic machinery in HepG2 cells. These findings provide insight into the molecular mechanisms associated with concentration-specific alterations induced by blueberry polyphenols upon cell growth and proliferation in these cells.