A carbazole derivative protects cells against endoplasmic reticulum (ER) stress and glutathione depletion.
A carbazole derivative protects cells against endoplasmic reticulum (ER) stress and glutathione depletion.
复制标题
DOI：
10.1254/jphs.08136fp
复制
发表时间：
2008
影响因子：
3.5
通讯作者：
Hikari Miura;K. Takano;Y. Kitao;S. Hibino;T. Choshi;R. Murakami;Hiroto Suzuki;M. Yamada;
中科院分区：
文献类型：
--
作者：
Hikari Miura;K. Takano;Y. Kitao;S. Hibino;T. Choshi;R. Murakami;Hiroto Suzuki;M. Yamada;
细胞内应激如氧化应激和内质网（ER）应激水平的提高与包括脑缺血和神经变性在内的各种神经病理学病症有关。在寻找调节ER应激和ER应激诱导的细胞死亡的化合物的过程中，我们鉴定了咔唑衍生物16- 1,4 [9-（3-氰基苄基）-1，4-二甲基咔唑]，其保护免受ER应激和谷胱甘肽耗竭。16-14在F9 Herp KO细胞和PC 12细胞中抑制衣霉素（Tm）诱导的细胞死亡，并且其对ER应激的调节与未折叠蛋白应答（UPR）信号传导水平的降低相关。由荧光ER驻留蛋白GFP-KDEL的过表达引起的ER应激也被16-14减弱，而不改变GFP-KDEL的表达水平。16-14还防止了由丁硫酰亚胺亚砜（BSO）引起的谷胱甘肽减少诱导的细胞死亡，但不太可能是通过其抗氧化活性。进一步的分析显示，16-14抑制细胞内Ca（2+）响应毒胡萝卜素（Tg）的增加。这些结果表明，16-14可能通过维持细胞内Ca（2+）稳态来保护细胞免受不同的应激。[补充图1：仅可在http：//dx.doi.org/10.1254/jphs.08136FP获得]。
Enhanced levels of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress are implicated in various neuropathological conditions including brain ischemia and neurodegeneration. During a search for compounds that regulate ER stress and ER stress-induced cell death, we identified a carbazole derivative 16-14 [9-(3-cyanobenzyl)-1,4-dimethylcarbazole] that protected against both ER stress and glutathione depletion. 16-14 suppressed tunicamycin (Tm)-induced cell death in both F9 Herp KO cells and PC12 cells, and its regulation of ER stress was associated with reduced levels of unfolded protein response (UPR) signaling. ER stress caused by overexpression of a fluorescent ER-resident protein, GFP-KDEL, was also attenuated by 16-14 without altering the expression levels of GFP-KDEL. 16-14 also prevented glutathione depletion-induced cell death caused by buthionine sulfoximine (BSO), but not likely via its anti-oxidative activity. Further analysis revealed that 16-14 suppressed increases in intracellular Ca(2+) in response to thapsigargin (Tg). These results suggest that 16-14 may protect cells against different stresses via the maintenance of intracellular Ca(2+) homeostasis. [Supplementary Fig. 1: available only at http://dx.doi.org/10.1254/jphs.08136FP].