Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32.
Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32.
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DOI：
10.1038/cddis.2011.76
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发表时间：
2011-08-25
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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听力损失通常是由内耳的机械感觉毛细胞死亡引起的。毛细胞易受衰老、噪音创伤和耳毒性药物（包括氨基糖苷类抗生素和抗衰老剂顺铂）引起的死亡的影响。耳毒性药物每年导致超过50万美国人永久性听力损失。我们以前表明，诱导热休克蛋白（HSP）抑制氨基糖苷类和顺铂诱导的毛细胞死亡的整个器官培养的椭圆囊从成年小鼠。为了开始将这些发现转化为旨在抑制耳毒性药物引起的听力损失的临床治疗，我们现在已经研究了一种药理学HSP诱导剂雷公藤红素。南蛇藤酚诱导的HSPs在胞囊的上调，它提供了显着的保护，对氨基糖苷类药物诱导的毛细胞死亡在体外和体内。此外，雷公藤红素抑制接受全身性氨基糖苷类药物治疗的小鼠的听力损失。我们的数据表明，主要的热休克转录因子HSF-1是不需要雷公藤红素介导的保护。HSP 32（也称为血红素加氧酶-1，HO-1）是雷公藤红素保护作用的主要介质。HSP 32/HO-1抑制促凋亡c-Jun N-末端激酶（JNK）活化和毛细胞死亡。总之，我们的数据表明雷公藤红素通过HSP 32/HO-1诱导抑制氨基糖苷类耳毒性。
Hearing loss is often caused by death of the mechanosensory hair cells of the inner ear. Hair cells are susceptible to death caused by aging, noise trauma, and ototoxic drugs, including the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Ototoxic drugs result in permanent hearing loss for over 500 000 Americans annually. We showed previously that induction of heat shock proteins (HSPs) inhibits both aminoglycoside- and cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. In order to begin to translate these findings into a clinical therapy aimed at inhibiting ototoxic drug-induced hearing loss, we have now examined a pharmacological HSP inducer, celastrol. Celastrol induced upregulation of HSPs in utricles, and it provided significant protection against aminoglycoside-induced hair cell death in vitro and in vivo. Moreover, celastrol inhibited hearing loss in mice receiving systemic aminoglycoside treatment. Our data indicate that the major heat shock transcription factor HSF-1 is not required for celastrol-mediated protection. HSP32 (also called heme oxygenase-1, HO-1) is the primary mediator of the protective effect of celastrol. HSP32/HO-1 inhibits pro-apoptotic c-Jun N-terminal kinase (JNK) activation and hair cell death. Taken together, our data indicate that celastrol inhibits aminoglycoside ototoxicity via HSP32/HO-1 induction.
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影响因子：
2.8
作者：
Sha, SH;Schacht, J
通讯作者：
Schacht, J
DOI：
10.1007/s10162-006-0043-x
发表时间：
2006-09-01
影响因子：
2.4
作者：
Cunningham, Lisa L.;Brandon, Carlene S.
通讯作者：
Brandon, Carlene S.
DOI：
10.1002/neu.20054
发表时间：
2004-11-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
Matsui, JI;Gale, JE;Warchol, ME
通讯作者：
Warchol, ME
影响因子：
4.8
作者：
McMillan, DR;Xiao, XZ;Benjamin, IJ
通讯作者：
Benjamin, IJ
影响因子：
5.3
作者：
Hunt, CR;Dix, DJ;Pandita, TK
通讯作者：
Pandita, TK