Trehalose protects against oxidative stress by regulating the Keap1-Nrf2 and autophagy pathways.
Trehalose protects against oxidative stress by regulating the Keap1-Nrf2 and autophagy pathways.
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DOI：
10.1016/j.redox.2017.09.007
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发表时间：
2018-05
期刊：
影响因子：
11.4
通讯作者：
Higami Y
中科院分区：
文献类型：
--
作者：
Mizunoe Y;Kobayashi M;Sudo Y;Watanabe S;Yasukawa H;Natori D;Hoshino A;Negishi A;Okita N;Komatsu M;Higami Y
自噬功能障碍通过降解细胞器和蛋白质来调节细胞内稳态，其与多种疾病如癌症、神经变性和代谢疾病的发病机制相关。海藻糖是一种天然存在的无毒二糖，存在于植物、昆虫、微生物和无脊椎动物中，但不存在于哺乳动物中，据报道其作为雷帕霉素（mTOR）非依赖性自噬诱导剂的机制靶标发挥作用。此外，海藻糖作为一种抗氧化剂的功能，但其潜在的分子机制尚不清楚。在这项研究中，我们发现，海藻糖不仅促进自噬，而且增加p62蛋白的表达，在自噬无关的方式。此外，海藻糖以p62依赖性方式增加核因子（红细胞衍生2）样2（Nrf 2）的核转位，并增强其下游抗氧化因子血红素加氧酶-1（Ho-1）和烟酰胺腺嘌呤二核苷酸磷酸醌脱氢酶1（Nqo 1）的表达。此外，用海藻糖处理显著减少了活性氧的量。总的来说，这些结果表明，海藻糖除了诱导自噬外，还可以作为p62-Keap 1/Nrf 2途径的新型激活剂发挥作用。因此，海藻糖可用于治疗许多涉及氧化应激和自噬功能障碍的慢性疾病。海藻糖的一种新的细胞保护机制被确定。海藻糖激活自噬。海藻糖以不依赖自噬的方式增加p62表达。海藻糖相关的p62上调激活Keap 1-Nrf 2通路。海藻糖通过Nrf 2调节的抗氧化剂基因表达降低氧化应激。
Dysfunction of autophagy, which regulates cellular homeostasis by degrading organelles and proteins, is associated with pathogenesis of various diseases such as cancer, neurodegeneration and metabolic disease. Trehalose, a naturally occurring nontoxic disaccharide found in plants, insects, microorganisms and invertebrates, but not in mammals, was reported to function as a mechanistic target of the rapamycin (mTOR)-independent inducer of autophagy. In addition, trehalose functions as an antioxidant though its underlying molecular mechanisms remain unclear. In this study, we showed that trehalose not only promoted autophagy, but also increased p62 protein expression, in an autophagy-independent manner. In addition, trehalose increased nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in a p62-dependent manner and enhance expression of its downstream antioxidant factors, heme oxygenase-1 (Ho-1) and nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (Nqo1). Moreover, treatment with trehalose significantly reduced amount of reactive oxygen species. Collectively, these results suggested that trehalose can function as a novel activator of the p62–Keap1/Nrf2 pathway, in addition to inducing autophagy. Therefore, trehalose may be useful to treat many chronic diseases involving oxidative stress and dysfunction of autophagy. A novel cellular protective mechanism of trehalose is identified. Trehalose activates autophagy. Trehalose increases p62 expression in an autophagy-independent manner. Trehalose-associated p62 upregulation activates the Keap1–Nrf2 pathway. Trehalose lowers oxidative stress via Nrf2-regulated antioxidant gene expression.
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