Roubalová Lenka, Dinkova-Kostova Albena T, Biedermann David, Křen Vladimír, Ulrichová Jitka, Vrba Jiří
Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic.
Jacqui Wood Cancer Centre, Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, Scotland, UK.
Fitoterapia. 2017 Jun;119:115-120. doi: 10.1016/j.fitote.2017.04.012. Epub 2017 Apr 24.
Silybum marianum (milk thistle) is a medicinal plant used for the treatment of various liver disorders. This study examined whether the main flavonolignans from S. marianum (i.e. silybin, silychristin, silydianin) and their 2,3-dehydro derivatives (i.e. 2,3-dehydrosilybin, 2,3-dehydrosilychristin, 2,3-dehydrosilydianin) activate the Nrf2 pathway, which regulates the expression of genes encoding many cytoprotective enzymes, including NAD(P)H:quinone oxidoreductase 1 (NQO1). After 48h of exposure, 2,3-dehydrosilydianin at concentrations of 25μM and higher significantly elevated the activity of NQO1 in murine hepatoma Hepa1c1c7 cells. In contrast, other tested compounds at non-cytotoxic concentrations had a mild or negligible effect on the NQO1 activity. Using a luciferase reporter assay, 2,3-dehydrosilydianin was found to significantly activate transcription via the antioxidant response element in stably transfected human AREc32 reporter cells. Moreover, 2,3-dehydrosilydianin caused the accumulation of Nrf2 and significantly induced the expression of the Nqo1 gene at both the mRNA and protein levels in Hepa1c1c7 cells. We found that 2,3-dehydrosilydianin also increased to some extent the expression of other Nrf2 target genes, namely of the heme oxygenase-1 gene (Hmox1) and the glutamate-cysteine ligase modifier subunit gene (Gclm). We conclude that 2,3-dehydrosilydianin activates Nrf2 and induces Nrf2-mediated gene expression in Hepa1c1c7 cells.
水飞蓟（奶蓟）是一种用于治疗各种肝脏疾病的药用植物。本研究检测了水飞蓟中的主要黄酮木脂素（即水飞蓟宾、水飞蓟素、水飞蓟宁）及其2,3 -脱氢衍生物（即2,3 -脱氢水飞蓟宾、2,3 -脱氢水飞蓟素、2,3 -脱氢水飞蓟宁）是否能激活Nrf2信号通路，该通路可调节许多细胞保护酶编码基因的表达，包括NAD(P)H：醌氧化还原酶1（NQO1）。暴露48小时后，浓度为25μM及以上的2,3 -脱氢水飞蓟宁显著提高了小鼠肝癌Hepa1c1c7细胞中NQO1的活性。相比之下，其他非细胞毒性浓度的受试化合物对NQO1活性的影响轻微或可忽略不计。通过荧光素酶报告基因检测，发现2,3 -脱氢水飞蓟宁在稳定转染的人AREc32报告细胞中通过抗氧化反应元件显著激活转录。此外，2,3 -脱氢水飞蓟宁导致Nrf2积累，并在Hepa1c1c7细胞的mRNA和蛋白质水平上显著诱导Nqo1基因的表达。我们发现2,3 -脱氢水飞蓟宁在一定程度上还增加了其他Nrf2靶基因的表达，即血红素加氧酶-1基因（Hmox1）和谷氨酸-半胱氨酸连接酶调节亚基基因（Gclm）。我们得出结论，2,3 -脱氢水飞蓟宁在Hepa1c1c7细胞中激活Nrf2并诱导Nrf2介导的基因表达。
