Induction of Nrf2/ARE-mediated cytoprotective genes by red ginseng oil through ASK1–MKK4/7–JNK and p38 MAPK signaling pathways in HepG2 cells

Abstract

BackgroundThe induction of cellular defensive genes such as phase II detoxifying and antioxidant enzymes is a highly effective strategy for protection against carcinogenesis as well as slowing cancer development. Transcription factor Nrf2 (nuclear factor E2-related factor 2) is responsible for activation of phase II enzymes induced by natural chemopreventive compounds.MethodsRed ginseng oil (RGO) was extracted using a supercritical CO2 extraction system and chemical profile of RGO was investigated by GC/MS. Effects of RGO on regulation of the Nrf2/antioxidant response element (ARE) pathway were determined by ARE–luciferase assay, western blotting, and confocal microscopy.ResultsThe predominant components of RGO were 9,12-octadecadienoic acid (31.48%), bicyclo[10.1.0]tridec-1-ene (22.54%), and 22,23-dihydrostigmasterol (16.90%). RGO treatment significantly increased nuclear translocation of Nrf2 as well as ARE reporter gene activity, leading to upregulation of heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1. Phosphorylation of the upstream kinases such as apoptosis signal-regulating kinase (ASK)1, mitogen-activated protein kinase (MAPK) kinase (MKK)4/7, c-Jun N-terminal kinase (JNK), and p38 MAPK were enhanced by treatment with RGO. In addition, RGO-mediated Nrf2 expression and nuclear translocation was attenuated by JNK inhibitor SP600125 and p38 MAPK inhibitor SB202190.ConclusionRGO could be used as a potential chemopreventive agent, possibly by induction of Nrf2/ARE-mediated phase II enzymes via ASK1–MKK4/7–JNK and p38 MAPK signaling pathways.

Matrine‐Type Alkaloids Inhibit Advanced Glycation End Products Induced Reactive Oxygen Species‐Mediated Apoptosis of Aortic Endothelial Cells In Vivo and In Vitro by Targeting MKK3 and p38MAPK Signaling

“…The ARE‐luciferase activity assay was performed in accord with descriptions in previous studies 13. Briefly, after being washed by PBS, RAECs were lysed by reporter lysis buffer (Promega, Fitchburg, WI).…”

“…The ARE-luciferase reporter was constructed according to the description of previous studies 13 and accomplished by GenePharma. The pTI-ARE-luciferase contains a single copy of ARE of 41-base-pair length (5 0 -TAGCTTGGAAATGACATTGC-TAATGGTGACAAAGCAACTTT-3 0 ) and a minimal TATA-Inr promoter.…”

“…Kelch‐like ECH‐associated protein 1 (Keap1) binds to Nrf2 to maintain static status of Nrf2 12. When encountering harmful stimuli, Nrf2 dissociates from Keap1 and further translocates to the nucleus to trigger the transcriptions of antioxidant enzymes genes by binding with ARE, which locates in the promoter region of these genes 13. The activation of Nrf2/ARE signaling is regulated by the upstream kinases.…”

Biological Evaluation of a New Lignan from the Roots of Rice (Oryza sativa)

“…Considering the traditional medicinal efficacy of O. sativa and its importance as a food crop, [2] compound 1 was tested for cytotoxic activity by determining whether it exhibited inhibitory effects on human breast cancer cell lines (MDA-MB-231). [21][22][23][24] Figure 3B). The increasing prevalence of diabetes has increased interest in the identification of active ingredients that regulate blood sugar.…”

The neuroprotective activities of natural products through the Nrf2 upregulation

“…Others act on the nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) pathway and exhibit their potential preventive and therapeutic effects by activation of Nrf2 and subsequently antioxidant enzymes such as heme oxygenase 1 (HO‐1; Iranshahi, Iranshahi, Abtahi, & Karimi, ). Paeonia lactiflora (Ma et al, ), Panax ginseng (Bak et al, ), and Coffea arabica (Cavin et al, ) are examples of such herbs. Apigenin (a flavonoid in some Apiaceae herbs; Sang et al, ), galangin (found in some Zingiberaceae rhizomes; Huang et al, ), glycybridin A & G ( Glycyrrhiza glabra ; K. Li et al, ), lycopene (Hedayati et al, ), and cyanidin (an anthocyanin found in different berry fruits; De Pascual‐Teresa, ) are a few examples of natural substances that have been reported to interact with Nrf2, potentially presenting health promoting properties.…”