Induction of sulfiredoxin expression and reduction of peroxiredoxin hyperoxidation by the neuroprotective Nrf2 activator 3H-1,2-dithiole-3-thione.
Induction of sulfiredoxin expression and reduction of peroxiredoxin hyperoxidation by the neuroprotective Nrf2 activator 3H-1,2-dithiole-3-thione.
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DOI：
10.1111/j.1471-4159.2008.05648.x
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发表时间：
2008-10
影响因子：
4.7
通讯作者：
Hardingham GE
中科院分区：
文献类型：
--
作者：
Soriano FX;Léveillé F;Papadia S;Higgins LG;Varley J;Baxter P;Hayes JD;Hardingham GE
过氧化物还毒素是基于半胱氨酸的抗氧化酶的一个重要家族，在几种神经变性模型中发挥神经保护作用。然而，在氧化应激下，它们很容易因活性位点半胱氨酸残基的高氧化而失活。我们发现，在皮质神经元中，化学预防诱导剂3h -1,2-二硫基-3-硫酮（D3T）可以激活转录因子Nrf2，抑制氧化损伤后失活的、高氧化的过氧化物还原素的形成，并保护神经元免受氧化应激。在神经元和神经胶质细胞中，Nrf2的表达和化学预防性Nrf2激活剂（包括D3T和萝卜硫素）的处理上调了硫氧还蛋白，硫氧还蛋白是一种负责还原高氧化过氧还蛋白的酶。硫氧还蛋白表达的诱导是由Nrf2介导的，通过其启动子中的顺式抗氧化反应元件（ARE）起作用。Srxn1中的ARE元件包含一个嵌入的AP-1位点，该位点通过突触活动指导Srxn1的诱导。因此，神经元中Nrf2活性的升高可防止过氧化物还氧蛋白的过度氧化，并诱导了are基因家族的新成员，其酶还原高氧化过氧化物还氧蛋白的功能可能有助于Nrf2激活剂的神经保护作用。
Peroxiredoxins are an important family of cysteine-based antioxidant enzymes that exert a neuroprotective effect in several models of neurodegeneration. However, under oxidative stress they are vulnerable to inactivation through hyperoxidation of their active site cysteine residues. We show that in cortical neurons, the chemopreventive inducer 3H-1,2-dithiole-3-thione (D3T), that activates the transcription factor Nrf2, inhibits the formation of inactivated, hyperoxidized peroxiredoxins following oxidative trauma, and protects neurons against oxidative stress. In both neurons and glia, Nrf2 expression and treatment with chemopreventive Nrf2 activators, including D3T and sulforaphane, up-regulates sulfiredoxin, an enzyme responsible for reducing hyperoxidized peroxiredoxins. Induction of sulfiredoxin expression is mediated by Nrf2, acting via a cis-acting antioxidant response element (ARE) in its promoter. The ARE element in Srxn1 contains an embedded AP-1 site which directs induction of Srxn1 by synaptic activity. Thus, raising Nrf2 activity in neurons prevents peroxiredoxin hyperoxidation and induces a new member of the ARE-gene family, whose enzymatic function of reducing hyperoxidized peroxiredoxins may contribute to the neuroprotective effects of Nrf2 activators.
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