Icariside II Enhances Nrf2 Nuclear Translocation to Upregulate Phase II Detoxifying Enzyme Expression Coupled with the ERK, Akt and JNK Signaling Pathways

Abstract

In the present study, the potent inducers of phase II detoxifying and antioxidant stress responsive to icariside II was investigated. First, a dose of 0–10 µM icariside II showed no significantly cytotoxicity on HepG2 cells by MTT assays and icariside II could enhance cellular GSH levels by ELISA assay. Then, the potential roles of ERK, Akt and JNK in the regulation of icariside II-induced Nrf2-dependent ARE transcriptional activity as well as ARE-mediated endogenous HO-1 and glutathione GST protein expression in HepG2 cells were estimated. Icariside II activated the nuclear translocation of Nrf2 and the up-regulated expression of Nrf2-related antioxidant protein OH-1 and GST were evaluated by Western blotting. Then the phosphorylation levels of ERK1/2, Akt and JNK1/2 were further examined by Western blotting assays. Results showed that icariside II significantly increased the phosphorylation levels of ERK1/2, Akt and JNK1/2. Furthermore, icariside II-induced ARE transcriptional activity was attenuated by the inhibition of ERK, Akt and JNK signaling using biochemical inhibitors. These results suggest that the Nrf2/ARE pathway plays an important role in the regulation of icariside-mediated antioxidant effects in HepG2 cells.

Green Tea Polyphenol EGCG Attenuates MDSCs-mediated Immunosuppression through Canonical and Non-Canonical Pathways in a 4T1 Murine Breast Cancer Model

“…Since EGCG was able to inhibit the activation of NF-κB signal pathway ( Figure 6I), its down-regulation on the expression of cytokines, especially for IL-6, IL-10, TGF-β and GM-CSF was further validated in MDSCs accordingly ( Figure 6J-M). In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-related antioxidant protein OH-1 play a crucial role in defensing cellular stress [33], and endogenous antioxidant enzymes, such as catalase (CAT), superoxide dismutase (SOD) and glutathione-S-transferase (GST) [34]. However, no significant differences in these genes in EGCG treatment groups were observed when compared to the control group ( Figure S2).…”

Sulodexide up-regulates glutathione S-transferase P1 by enhancing Nrf2 expression and translocation in human umbilical vein endothelial cells injured by oxygen glucose deprivation

“…Antioxidant response element (ARE) is a cis-acting sequence located in promoter regions of genes encoding phase II enzymes. The activation of gene transcription via the ARE is regulated by nuclear factor-erythroid 2-related factor (Nrf2) signaling [7]. In an inactive state, Nrf2 is retained in the cytoplasm by binding to Kelch-like ECH-associated protein (Keap1).…”

Coroglaucigenin enhances the radiosensitivity of human lung cancer cells through Nrf2/ROS pathway

“…A number of studies have found that overexpression of antioxidant enzyme occurs in cancer resistance to radiation therapy, whereas blocking these antioxidant defenses can enhance radiation sensitivity [5–9]. Nuclear factor-erythroid 2-related factor-2 (Nrf2), a redox sensitive transcription factor, regulates the expression of several detoxifying enzymes, such as heme oxygenase-1 (HO-1), and nicotinamide adenine dinucleotide phosphate (reduced) (NADPH): quinone oxidoreductase-1 (NQO-1), through binding to antioxidant response element (ARE) within gene promoters [9, 10]. Ionizing radiation (IR) causes DNA nucleotide modifications, single and double strand DNA breaks (SSBs and DSBs), both directly and indirectly via formation of free radicals and ROS.…”