Chemical inducers of heat shock proteins derived from medicinal plants and cytoprotective genes response
Chemical inducers of heat shock proteins derived from medicinal plants and cytoprotective genes response
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DOI：
10.3109/02656736.2011.627408
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发表时间：
2012-01-01
影响因子：
3.1
通讯作者：
Kadowaki, Makoto
中科院分区：
文献类型：
--
作者：
Ahmed, Kanwal;Furusawa, Yukihiro;Kadowaki, Makoto
环境压力会导致损伤，从而激活任何有机体的适应性反应。细胞的应激反应是基于细胞保护蛋白的诱导，即所谓的应激或热休克蛋白(HSPs)。众所周知，热休克蛋白作为分子伴侣参与了许多疾病的治疗。因此，在本研究中，我们在从药用植物中分离的化合物中寻找无毒的伴侣诱导剂。用免疫印迹法筛选了80个化合物在人淋巴瘤U937细胞中的Hsp70诱导活性。有5个化合物对HSP70有明显的上调作用，其中紫草素的作用最强。紫草素能在0.1mM诱导HSP70，3h后不激活热休克转录因子1(HSF-1)。它还会诱导产生大量的活性氧物种。利用全球范围的基因芯片和计算基因表达分析工具研究了紫草素响应基因的表达水平。观察到核因子红系相关因子2(NRF2，NFEL2L2)介导的氧化应激反应显著增加，导致HSP激活。基因芯片分析结果通过实时荧光定量聚合酶链式反应得到进一步验证。总之，紫草素诱导HSP70的详细机制还不完全清楚，Nrf2及其靶基因可能参与了U937细胞HSP70的上调。
Environmental stress induces damage that activates an adaptive response in any organism. The cellular stress response is based on the induction of cytoprotective proteins, the so-called stress or heat shock proteins (HSPs). HSPs are known to function as molecular chaperones which are involved in the therapeutic approach of many diseases. Therefore in the current study we searched nontoxic chaperone inducers in chemical compounds isolated from medicinal plants. Screening of 80 compounds for their Hsp70-inducing activity in human lymphoma U937 cells was performed by western blotting. Five compounds showed significant Hsp70 up-regulation among them shikonin was most potent. Shikonin was able to induce Hsp70 at 0.1 mu M after 3 h without activation of heat shock transcription factor 1 (HSF-1). It also induces significant reactive oxygen species generation. The expression level of genes responsive to shikonin was studied using global-scale microarrays and computational gene expression analysis tools. Significant increase in the nuclear factor erythroid 2-related factor 2 (Nrf2, NFEL2L2) -mediated oxidative stress response was observed that leads to the activation of HSP. The results of gene chip analysis were further confirmed by real-time qPCR assay. In short, the detailed mechanisms of Hsp70 induction by shikonin is not fully understood, Nrf2 and its target genes might be involved in the Hsp70 up-regulation in U937 cells.