Molecular mechanisms underlying cochlear degeneration in the tubby mouse and the therapeutic effect of sulforaphane.
Molecular mechanisms underlying cochlear degeneration in the tubby mouse and the therapeutic effect of sulforaphane.
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DOI：
10.1016/j.neuint.2008.08.013
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发表时间：
2009-03
影响因子：
4.2
通讯作者：
Cao, Wei
中科院分区：
文献类型：
--
作者：
Kong, Li;Chen, Guang-Di;Zhou, Xiaohong;McGinnis, James F.;Li, Feng;Cao, Wei
关键词：
与在人类中观察到的Usher综合征一样，Tubby小鼠的两种主要表型是进行性听力损失和视网膜变性。然而，盆相关耳蜗变性的机制仍不清楚。细胞中的还原/氧化（氧化还原）失衡与多种疾病有关。本研究检测了细胞中重要的氧化还原系统硫氧还蛋白（Trx）和Trx还原酶（TrxR）以及Trx/TrxR相关的上下游蛋白在tubby小鼠耳蜗中的表达。本报告还研究了萝卜硫素（SF）对耳蜗变性的治疗作用，这表明我们以前的报告中对tub相关的视网膜变性有保护作用。结果表明，tub突变可显著抑制Trx和TrxR的表达。调节Trx和TrxR等表达的转录因子Nrf 2（NFE 2相关因子2）的表达水平也在tubby小鼠耳蜗中受到抑制。此外，在tubby小鼠耳蜗中观察到活化的细胞外信号调节激酶（p-ERK）水平降低。相比之下，caspase-3的表达和活性增强，在tubby小鼠，表明凋亡细胞死亡。耳蜗中的管相关分子改变通过SF的长期治疗来预防。因此，SF治疗显著延迟了与耳蜗变性相关的耳蜗变性。其他未知的蛋白质可能有助于tubby相关的变性，因为Nrf 2调节除了Trx/TrxR之外的许多其他抗氧化剂，并且萝卜硫素虽然完全阻止了Nrf 2和Trx/TrxR的改变，但并不能完全阻止耳蜗变性。
As with Usher syndrome observed in humans, the two main phenotypes of the tubby mouse are progressive hearing loss and retinal degeneration. Yet, the mechanism underlying the tub-related cochlear degeneration is still unclear. The reduction/oxidation (redox) imbalance in the cell is related to many kinds of diseases. This study examined expressions of thioredoxin (Trx) and Trx reductase (TrxR), an important redox system in the cell, and the related upstream and downstream proteins of the Trx/TrxR in the tubby mouse cochlea. This report also examined the therapeutic effect of sulforaphane (SF) on the cochlear degeneration, which showed a protective effect on the tub-related retinal degeneration in our previous report. The results showed that the tub-mutation resulted in a significant suppression of Trx and TrxR expressions. Expression level of Nrf2 (NFE2 related factor 2), a transcription factor that regulates expression of Trx and TrxR and others, was also suppressed in the tubby mouse cochlea. Furthermore, a lowered level of activated extracellular signal-regulated kinase (p-ERK) was observed in the tubby mouse cochlea. In contrast, caspase-3 expression and activity were enhanced in the tubby mouse, suggesting apoptotic cell death. The tub-related molecular alterations in the cochlea were prevented by chronic treatment with SF. As a result, the SF-treatment significantly delayed the tub-related cochlear degeneration. Other unknown proteins may contribute to tubby-related degeneration because Nrf2 regulates many other antioxidants besides Trx/TrxR and sulforaphane did not prevent cochlear degeneration completely although it completely prevented alterations of Nrf2 and Trx/TrxR.
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DOI：
10.1073/pnas.90.7.2965
发表时间：
1993-04-01
影响因子：
11.1
作者：
PRESTERA, T;HOLTZCLAW, WD;TALALAY, P
通讯作者：
TALALAY, P
影响因子：
6.2
作者：
Li, C;Tang, YH;Cao, W
通讯作者：
Cao, W
影响因子：
1.7
作者：
OHLEMILLER, KK;HUGHES, RM;SILVERMAN, MS
通讯作者：
SILVERMAN, MS
影响因子：
4.8
作者：
Papaiahgari, S;Kleeberger, SR;Reddy, SP
通讯作者：
Reddy, SP
影响因子：
2.8
作者：
Rao, DB;Moore, DR;Fechter, LD
通讯作者：
Fechter, LD