Department of Food and Nutrition, Seoul National University, San 56-1 Sillim-Dong, Kwanak-Gu, Seoul, 151-742, Korea.
Amino Acids. 2010 Aug;39(3):785-94. doi: 10.1007/s00726-010-0523-5. Epub 2010 Mar 4.
Previously, we reported that isoflavones exert a protective effect against the endoplasmic reticulum (ER) stress-mediated neuronal degeneration, and ER stress-mediated homocysteine toxicity may play an important role in the pathogenesis of neurodegeneration. Therefore, in this study we investigated the effects of isoflavones (genistein and daidzein) against homocysteine-mediated neurotoxicity in SH-SY5Y human neuroblastoma cells. The treatment of cells with either 17beta-estradiol or isoflavones significantly protected the cells against homocysteine-mediated apoptosis. Isoflavones repressed homocysteine-mediated ER stress, reflected in the reduced expression of the immunoglobin heavy chain-binding protein mRNA, spliced X-box-protein-1 mRNA and the phosphorylated form of eukaryotic translation initiation factor 2alpha protein. Homocysteine caused significant increases in intracellular S-adenosylhomocysteine (SAH) and DNA damage. Isoflavones significantly alleviated DNA damage, but did not change SAH levels. Furthermore, the treatment of cells with isoflavones significantly reduced the microtubule-associated protein tau hyperphosphorylation by inactivating glycogen synthase kinase-3beta and activating serine/threonine-protein phosphatase 2A. These results clearly demonstrate that isoflavones alleviate the ER stress- and DNA damage-mediated neurodegeneration caused by homocysteine.
先前，我们报道过异黄酮对内质网（ER）应激介导的神经元变性具有保护作用，而 ER 应激介导的同型半胱氨酸毒性可能在神经变性的发病机制中发挥重要作用。因此，在这项研究中，我们研究了异黄酮（染料木黄酮和大豆苷元）对 SH-SY5Y 人神经母细胞瘤细胞中同型半胱氨酸介导的神经毒性的影响。用 17β-雌二醇或异黄酮处理细胞可显著保护细胞免受同型半胱氨酸介导的凋亡。异黄酮抑制同型半胱氨酸介导的 ER 应激，表现为免疫球蛋白重链结合蛋白 mRNA、剪接 X 盒蛋白-1 mRNA 和真核翻译起始因子 2α蛋白磷酸化形式的表达减少。同型半胱氨酸导致细胞内 S-腺苷同型半胱氨酸（SAH）和 DNA 损伤显著增加。异黄酮显著减轻 DNA 损伤，但不改变 SAH 水平。此外，异黄酮处理细胞可通过使糖原合酶激酶-3β失活和激活丝氨酸/苏氨酸蛋白磷酸酶 2A 显著减轻微管相关蛋白 tau 的过度磷酸化。这些结果清楚地表明，异黄酮可减轻同型半胱氨酸引起的 ER 应激和 DNA 损伤介导的神经变性。
