Abstract
A natural alkynol group-substituted thiophene, 2-(penta-1,3-diynyl)-5-(3,4-dihydroxybut-1-ynyl)-thiophene (PDDYT), was isolated from the roots of Echinops grijsii Hance. It possessed potent NAD(P)H: quinone oxidoreductase1 (NQO1) inducing activity and could activate Keap1-Nrf2 pathway effectively in murine hepatoma Hepa 1c1c7 cells. Further investigations indicated that the activation of Keap1-Nrf2 pathway by PDDYT might be attributed to the activation of Akt and depleting the cellular glutathione (GSH).
Highlights
NAD(P)H: quinone oxidoreductase1 (NQO1) is a phase 2 detoxifying enzyme that can convert toxic quinones to hydroquinones and deactivate radicals and electrophiles known to lead to tumorigenesis in normal cellular processes [1,2]
The results indicated that after the treatment with various concentrations of PDDYT for 24 h, the NQO1 expression increased markedly in a dose-dependent manner and the maximum level was 3.31 ± 0.07fold of control at 40 μM (Figures 2a and b). 4'-Bromoflavone was tested as the positive control and its
We investigated the alternation of Nrf2 expression involved in the NQO1 inducing activity of PDDYT
Summary
NAD(P)H: quinone oxidoreductase (NQO1) is a phase 2 detoxifying enzyme that can convert toxic quinones to hydroquinones and deactivate radicals and electrophiles known to lead to tumorigenesis in normal cellular processes [1,2]. The expression of NQO1 is regulated by the Keap1-Nrf. The Keap1-Nrf complex will dissociate, resulting in the transportation of Nrf into the nucleus, where it binds to the antioxidant response element (ARE) regions of detoxification genes and accelerates the expressions of phase 2 detoxifying enzymes [4,5,6]. We demonstrated that PDDYT possessed potent NQO1 inducing activity and could effectively activate the Keap1-Nrf pathway. The compound could lead to a time-dependent up-regulation of the Ser-473 phosphorylation of Akt. The compound could lead to a time-dependent up-regulation of the Ser-473 phosphorylation of Akt Both the above phenomena might be the mechanisms of action of PDDYT involved in its activation of the Keap1-Nrf pathway. We hope our experimental results can provide a more molecular-theoretical basis for the possible application of PDDYT in the future
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