Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy.
Proteomics. 2010 Apr;10(8):1645-57. doi: 10.1002/pmic.200900579.
Unconjugated bilirubin (UCB) is a powerful antioxidant and a modulator of cell growth through the interaction with several signal transduction pathways. Although newborns develop a physiological jaundice, in case of severe hyperbilirubinemia UCB may become neurotoxic causing severe long-term neuronal damages, also known as bilirubin encephalopathy. To investigate the mechanisms of UCB-induced neuronal toxicity, we used the human neuroblastoma cell line SH-SY5Y as an in vitro model system. We verified that UCB caused cell death, in part due to oxidative stress, which leads to DNA damage and cell growth reduction. The mechanisms of cytotoxicity and cell adaptation to UCB were studied through a proteomic approach that identified differentially expressed proteins involved in cell proliferation, intracellular trafficking, protein degradation and oxidative stress response. In particular, the results indicated that cells exposed to UCB undertake an adaptive response that involves DJ-1, a multifunctional neuroprotective protein, crucial for cellular oxidative stress homeostasis. This study sheds light on the mechanisms of bilirubin-induced neurotoxicity and might help to design a strategy to prevent or ameliorate the neuronal damages leading to bilirubin encephalopathy.
未结合胆红素（UCB）是一种强大的抗氧化剂，通过与几种信号转导途径相互作用来调节细胞生长。虽然新生儿会出现生理性黄疸，但在严重高胆红素血症的情况下，UCB 可能会变得神经毒性，导致严重的长期神经元损伤，也称为胆红素脑病。为了研究 UCB 诱导的神经元毒性的机制，我们使用人神经母细胞瘤细胞系 SH-SY5Y 作为体外模型系统。我们验证了 UCB 会导致细胞死亡，部分原因是氧化应激，这会导致 DNA 损伤和细胞生长减少。通过蛋白质组学方法研究了细胞毒性和细胞对 UCB 的适应机制，该方法鉴定了涉及细胞增殖、细胞内运输、蛋白质降解和氧化应激反应的差异表达蛋白。特别是，结果表明，暴露于 UCB 的细胞会进行适应性反应，涉及多功能神经保护蛋白 DJ-1，该蛋白对于细胞氧化应激稳态至关重要。这项研究阐明了胆红素诱导的神经毒性的机制，并可能有助于设计预防或改善导致胆红素脑病的神经元损伤的策略。
