Flavonolignan 2,3-dehydrosilydianin activates Nrf2 and upregulates NAD(P)H:quinone oxidoreductase 1 in Hepa1c1c7 cells

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 48 h of exposure, 2,3-dehydrosilydianin at concentrations of 25 μM 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.

2,3-Dehydroderivatives of Silymarin Flavonolignans: Prospective Natural Compounds for the Prevention of Chronic Diseases

“…While silybin A, silybin B and silychristin A were quite weak chelators, 2,3-dehydrosilybin was found to be a potent iron and copper chelating agent [10]. Moreover, 2,3-dehydrosilydianin (but not silybin, silychristin, silydianin, 2,3-dehydrosilybin, or 2,3-dehydrosilychristin) was found to activate Nrf2 and upregulate NAD(P)H:quinone oxidoreductase 1 in Hepa1c1c7 cells [11]. 2,3-Dehydrosilybin and its gallates were also more efficient inhibitors of angiogenesis that silybin and silybin derived gallates [12,13].…”

Flavolignans from Silymarin as Nrf2 Bioactivators and Their Therapeutic Applications

“…In current investigations, SM and its flavolignans have shown to activate Nrf2 (Table 1). The research of Roubalová et al [151] found that, after h of exposure of the main Silybum marianum flavolingnans and their 2,3-dehydroderivatives, 25 µM and 50 µM of 2,3-dehydrosolydianin significantly increased the activation of Nrf2 and the expression of the Nqo1 gene, 1.6-and 2.3-fold, respectively, as well as of the target genes Hem oxygenase1 (Hmox-1), gammaglutamyl-cystein ligase modifier subunit (Gclm), and gamma glutamyl-cystein ligase catalytic subunit (Gclc) by 2.2-fold, 1.5-fold, and 1-3-fold, respectively, but only at a concentration of 50 µM against the control in murine Hepatoma Hepa1c1c7 cells. In addition, the concentration of NOQ1 and GCLM proteins also increased at 50 µM, whereas the levels of HMOX1 and GCLC did not change significantly.…”

Mitigative Effects of Alpha-lipoic Acid on the Toxicity of Dimethoate in Male Rats

“…Blood urea nitrogen (BUN) was measured using a commercial kit (BUN II reagent kit; Wako Pure Chemical Industries). [16] Biochemical estimation of serum lipid profile Triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol concentrations were evaluated enzymatically using assay kits (Sigma Chemical Co, St Louis, MO, USA). Very low-density lipoprotein (VLDL)-cholesterol was calculated as triglycerides and LDL-cholester-ol was calculated by the equation LDL-cholesterol=Total serum cholesterol -(HDL+VlDl).…”