Traditional Chinese medicinal formula Si-Wu-Tang prevents oxidative damage by activating Nrf2-mediated detoxifying/antioxidant genes.
Traditional Chinese medicinal formula Si-Wu-Tang prevents oxidative damage by activating Nrf2-mediated detoxifying/antioxidant genes.
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DOI：
10.1186/2045-3701-4-8
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发表时间：
2014-02-10
影响因子：
7.5
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Liu M;Ravula R;Wang Z;Zuo Z;Chow MS;Thakkar A;Prabhu S;Andresen B;Huang Y
诱导Nrf2介导的解毒/抗氧化基因已被认为是一种有效的癌症化学预防策略。四物汤由赤芍、当归、川芎、地黄四味药组成，是治疗妇科疾病最受欢迎的东方传统药物之一。本研究的目的是在体内外检测SWT对Nrf2通路的影响，并鉴定其活性成分(S)。应用硫代罗丹明B比色法、Annexin-V/碘化丙啶染色和流式细胞术分析了乳腺上皮细胞株MCF-10A经双氧水处理后的细胞存活率和细胞凋亡率。SWT能显著降低H_2O_2诱导的MCF-10A细胞的细胞毒作用和细胞凋亡。用定量RT-PCR、Western Blot和免疫细胞化学方法检测Nrf2和Nrf2调控基因Hmox1和SLC7A11的表达。SWT在MCF10A细胞中强烈诱导受Nrf2调控的基因，并增加Nrf2的核转位。用健康雌性SD大鼠评价SWT的体内药效学作用。连续6天灌胃给予SWT(1,000 mg/kg/d，连续6天)可使肝脏中Nrf2调控基因Hmox1和SLc7A11的表达增加。利用抗氧化剂反应元件-荧光素酶报告基因分析，在SWT产品中已鉴定的9种化合物中，z-甘草内酯被发现是影响Nrf2激活的主要成分。Z-甘草内酯被证实具有高效的诱导Nrf2调控基因和Nrf2核转位的能力。我们的结果表明，SWT及其成分z-甘草内酯能够在体内外激活非肿瘤细胞和器官中的Nrf2途径，提示SWT可能是一种口服有效且无毒的癌症化学预防药物。
Induction of Nrf2-mediated detoxifying/antioxidant genes has been recognized as an effective strategy for cancer chemoprevention. Si-Wu-Tang (SWT), comprising the combination of four herbs, Paeoniae, Angelicae, Chuanxiong and Rehmanniae, is one of the most popular traditional oriental medicines for women’s diseases. The purpose of this study is to determine the effects of SWT on Nrf2 pathway in vitro and in vivo and to identify the active component(s). Cell viability and apoptosis were analyzed in the non-cancerous breast epithelial cell line MCF-10A after H2O2 treatment in the presence or absence of SWT using the Sulphorhodamine B assay, Annexin-V/Propidium iodide staining and flow cytometry. SWT strongly reduced H2O2 -induced cytotoxicity and apoptosis in MCF-10A cells. Expression of Nrf2 and Nrf2-regulated genes HMOX1 (heme oxygenase 1) and SLC7A11 (xCT) was evaluated by quantitative RT-PCR, Western Blot and immunocytochemistry. SWT strongly induced Nrf2-regulated genes at mRNA and protein levels and increased the nuclear translocation of Nrf2 in MCF-10A cells. The in vivo pharmacodynamic effect of SWT was evaluated in healthy female Sprague–Dawley rats. Short-term oral administration of SWT (1,000 mg/kg per day for six consecutive days) to rats resulted in an increased expression of Nrf2-regulated genes Hmox1 and Slc7A11 in the liver detected by quantitative RT-PCR. Among nine compounds that have been identified previously in the SWT products, z-liguistilide was discovered as the main component responsible for the effect of Nrf2 activation using the antioxidant response element-luciferase reporter gene assay. Z-liguistilide was confirmed with a high potency to induce Nrf2-regulated genes and Nrf2 nuclear translocation. Our results demonstrated that SWT and its component z-liguistilide are able to activate the Nrf2 pathway in non-cancerous cells and organs in vitro and in vivo, suggesting that SWT might be an orally effective and nontoxic agent for cancer chemoprevention.
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