Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea.
Chem Biol Interact. 2013 Aug 25;204(3):144-52. doi: 10.1016/j.cbi.2013.05.009. Epub 2013 May 24.
Quercetin and its derivatives have antioxidant and anti-inflammatory effects. Nevertheless, in human keratinocytes, compared to the reports on other toxic insults, researches on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis that may be involved in skin diseases are rare. Furthermore, the effect of quercetin-3-O-(2"-galloyl)-α-l-rhamnopyranoside (QGR), a new quercetin derivative, on TRAIL-induced apoptosis in keratinocytes has not been studied. In this respect, we investigated the effect of QGR on TRAIL-induced apoptosis in human keratinocytes. TRAIL triggers apoptosis by inducing a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels, increase in Bax and VDAC1 levels, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases (-8, -9 and -3), cleavage of PARP-1, and an increase in the tumor suppressor p53 levels. Treatment with QGR prevented TRAIL-induced apoptosis-related protein activation, formation of reactive oxygen species, nuclear damage, and cell death. In contrast, quercetin induces cytotoxicity and had an additive effect on TRAIL-induced apoptosis-related protein activation and cell death. These results suggest that the QGR, unlike quercetin, may reduce TRAIL-induced apoptosis in human keratinocytes by suppressing the activation of the caspase-8- and Bid-pathways and the mitochondria-mediated cell death pathway, which is associated with the formation of reactive oxygen species. These data suggest that QGR could be effective in the prevention of TRAIL-induced apoptosis-mediated skin diseases.
槲皮素及其衍生物具有抗氧化和抗炎作用。然而,在人类角质形成细胞中,与其他毒性损伤的报告相比,关于肿瘤坏死因子相关凋亡诱导配体(TRAIL)诱导凋亡的研究很少,这种凋亡可能与皮肤疾病有关。此外,尚未研究新的槲皮素衍生物槲皮素-3-O-(2”-没食子酰基)-α-L-鼠李吡喃糖苷(QGR)对角质形成细胞中 TRAIL 诱导的凋亡的影响。在这方面,我们研究了 QGR 对人角质形成细胞中 TRAIL 诱导的凋亡的影响。TRAIL 通过诱导 Bid、Bcl-2、Bcl-xL 和 survivin 蛋白水平降低、Bax 和 VDAC1 水平升高、线粒体跨膜电位丧失、细胞色素 c 释放、caspase(-8、-9 和 -3)激活、PARP-1 裂解以及肿瘤抑制因子 p53 水平升高来触发细胞凋亡。QGR 处理可防止 TRAIL 诱导的凋亡相关蛋白激活、活性氧形成、核损伤和细胞死亡。相比之下,槲皮素诱导细胞毒性,并对 TRAIL 诱导的凋亡相关蛋白激活和细胞死亡具有附加作用。这些结果表明,与槲皮素不同,QGR 可能通过抑制 caspase-8 和 Bid 通路以及线粒体介导的细胞死亡通路的激活来减少人角质形成细胞中 TRAIL 诱导的凋亡,这与活性氧的形成有关。这些数据表明,QGR 可有效预防 TRAIL 诱导的凋亡介导的皮肤疾病。