Abstract
Agrimonolide and desmethylagrimonolide are the main bioactive polyphenols in agrimony with well-documented antioxidant, anti-diabetic, and anti-inflammatory potential. We report here for the first time that agrimonolide and desmethylagrimonolide stimulate the expression of phase II detoxifying enzymes through the Nrf2-dependent signaling pathway. Agrimonolide and desmethylagrimonolide also possess considerable protective activity from oxidative DNA damage. In order to explore the cytoprotective potential of agrimonolide and desmethylagrimonolide on oxidative stress in liver, we developed an oxidative stress model in HepG2 cells, and check the hypothesis whether Nrf2 pathway is involved. Western blotting and luciferase assay revealed that exposure of HepG2 cells to agrimonolide or desmethylagrimonolide leads to increased heme oxygenase-1 (HO-1) expression by activating ARE through induction of Nrf2 and suppression of Kelch-like ECH-associated protein 1 (Keap1). Moreover, agrimonolide and desmethylagrimonolide also activated ERK signaling pathways and significantly attenuated individual p38 MAPK expression, subsequently leading to Nrf2 nuclear translocation. In conclusion, our results indicated that transcriptional activation of Nrf2/ARE is critical in agrimonolide and desmethylagrimonolide-mediated HO-1 induction, which can be regulated partially by the blockade of p38 MAPK signaling pathway and inhibiting nuclear translocation of Nrf2.
Highlights
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are involved in a spectrum of physiological and pathological processes (Medzhitov, 2008)
We demonstrated that AM and DM, which were isolated from A. pilosa, possessed significant antioxidant properties
The main function of superoxide dismutase (SOD) is pivotal in ROS release during oxidative stress by ischemia-reperfusion injury, in the myocardium as a part of heart attack
Summary
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are involved in a spectrum of physiological and pathological processes (Medzhitov, 2008). Low physiological levels of ROS regulate cellular signal transduction and play an important role in normal cell proliferation (Scandalios, 2002). Similar to the regulation of protein function by phosphorylation, oxidation of cysteine residues by ROS results in conformational, structural, and direct catalytic consequences on the targeted signaling proteins (Cross and Templeton, 2006). Oxidative stress occurs when this critical balance is disrupted due to excess of ROS, antioxidants depletion, or both. The major sources of endogenous ROS are hydrogen peroxide and superoxide anion, which are generated by the production of cellular metabolism such as mitochondrial respiration (Waris and Ahsan, 2006). Unstable mitochondrial membrane potential and redox transitions can occur as a result of diverse pathological states such as ischemia/reperfusion injury and toxin exposure, and can have negative consequences for mitochondrial integrity and cellular survival (Zorov et al, 2006). Hydrogen peroxide may be converted into water by the enzymes catalase or glutathione peroxidase (Apel and Hirt, 2004)
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