Toxic Effects of Mildly Elevated Homocysteine Concentrations in Neuronal-Like Cells |
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Authors: | M. Currò A. Gugliandolo C. Gangemi R. Risitano R. Ientile D. Caccamo |
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Affiliation: | 1. Department of Biomedical Sciences and Morphofunctional Imaging, Polyclinic University of Messina, Via C. Valeria, 98125, Messina, Italy 2. Department of Clinical and Experimental Medicine, Polyclinic University of Messina, Messina, Italy
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Abstract: | Epidemiological and experimental evidence indicated that hyperhomocysteinemia is associated with neurodegeneration. However, homocysteine neurotoxic effects have been so far investigated mostly by employing homocysteine concentrations (≥100 µM) much higher than homocysteine mean plasma levels (20 µM) observed in patients with neurodegenerative disorders. While evaluating the effects of a prolonged exposure to ~20 µM homocysteine in neuronal-like differentiated SH-SY5Y cells, we observed a 35 % loss of cell viability and a four-fold increase in reactive oxygen species levels in cells incubated with homocysteine for five days compared with controls. Moreover, homocysteine increased by 30 % and around two-fold, respectively, the Comet-positive cell number and DNA damage indexes (tail length, T-DNA, olive tail moment) compared with controls. Cell response to homocysteine-induced DNA damage involved the up-regulation of Bax and, at a greater extent, Bcl-2, but not caspase-3, in association with a p53-independent increase of p21 levels; concomitantly, also p16 levels were increased. When looking at time-dependent changes in cyclin expression, we found that a significant up-regulation of cyclins D1, A1, E1, but not B1, concomitant with p21 down-regulation, occurred in cells incubated with homocysteine for three days. However, in line with the observed increase of p21 and p16 levels, a five days incubation with homocysteine induced cyclin down-regulation accompanied by a strong reduction of phosphorylated pRB amounts. These results suggest that, when prolonged, the exposure of neuronal-like cells to mildly elevated homocysteine concentrations triggers oxidative and genotoxic stress involving an early induction of cyclins, that is late repressed by G1-S check-point regulators. |
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