Abstract
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.
Highlights
Flavonolignans are plant polyphenols with a chemical structure consisting of a flavonoid and a lignan moiety
The study included i) silybin, silychristin and silydianin, isolated from commercially available extract from the fruits of S. marianum [18,23], and ii) 2,3dehydrosilybin, 2,3-dehydrosilychristin and 2,3-dehydrosilydianin, which were prepared by oxidation, by molecular oxygen under basic conditions, of the compounds listed in the first item [11,23]
To identify whether any of the tested compounds stimulate NF-E2 p45-related factor 2 (Nrf2) activity, we evaluated their effect on the activity level of NAD(P) H:quinone oxidoreductase 1 (NQO1) in murine hepatoma Hepa1c1c7 cells, a well-established model for the NQO1 assay [21]
Summary
Flavonolignans are plant polyphenols with a chemical structure consisting of a flavonoid and a lignan (phenylpropanoid) moiety. They are found in some species of the families Asteraceae, Fabaceae, Poaceae, and others [1]. The best known and most studied flavonolignan is silybin [2], which together with silychristin and silydianin (Fig. 1) are major components of silymarin, a standardized extract from the fruits of Silybum marianum (milk thistle; Asteraceae). These flavonolignans originate biosynthetically from the flavanonol taxifolin (2,3-dihydroquercetin) and coniferyl alcohol. Due to the low stereoselectivity of the biosynthetic processes, silybin, silychristin and their 2,3-dehydro derivatives naturally occur as pairs of transconfigured diastereomers/enantiomers, denoted A and B [3]
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