A formulated red ginseng extract rescues PC12 cells from PCB-induced oxidative cell death through Nrf2-mediated upregulation of heme oxygenase-1 and glutamate cysteine ligase.
Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that display a broad spectrum of biological and toxicological properties. There has been compelling evidence supporting that PCB-induced cytotoxicity is mediated through generation of reactive oxygen species (ROS). Considerable attention has been focused on identifying naturally occurring phytochemicals that are able to scavenge excess ROS, thereby protecting against oxidative cell death. Red ginseng, which has a variety of biological and pharmacological activities including antioxidant, anti-inflammatory, antimutagenic and anticarcinogenic effects, has been used for thousands of years as a general tonic in traditional oriental medicine. In this study, we have investigated the effect of red ginseng extract (RGE) on PCB126-induced oxidative cell death in cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with PCB126 exhibited increased accumulation of intracellular ROS and underwent apoptosis as determined by positive in situ terminal end-labeling (TUNEL staining) and the perturbation of the mitochondrial membrane potential (ΔΨ(m)). RGE treatment attenuated PCB126-induced cytotoxicity, apoptotic features and intracellular ROS accumulation. RGE treatment upregulated heme oxygenase-1 (HO-1) and glutamate cysteine ligase (GCLC) that are key antioxidant enzymes essential for cellular defense against oxidative stress. To elucidate the molecular mechanisms underlying RGE-mediated HO-1 and GCLC induction, we have examined the possible involvement of NF-E2-related factor 2 (Nrf2), a redox-sensitive transcription factor, that plays an important role in the transcriptional regulation of diverse antioxidative genes via interaction with the antioxidant response element (ARE). Treatment of PC12 cells with RGE increased the nuclear translocation, ARE-binding and transcriptional activity of Nrf2. Moreover, U0126 and LY294002, pharmacological inhibitors of MEK1/2 and phosphatidylinositol 3-kinase which are upstream of ERK1/2 and Akt/protein kinase B, respectively attenuated HO-1 and GCLC expression as well as the ARE-driven transcriptional activation of Nrf2. These findings, taken together, suggest that HO-1 and GCLC induction via Nrf2 activation may contribute to cytoprotection exerted by RGE against PCB126-induced oxidative stress.
Park
So-Hyun
SH
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Jang
Jung-Hee
JH
Chen
Chu-Yue
CY
Na
Hye-Kyung
HK
Surh
Young-Joon
YJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D004785:Environmental Pollutants / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D005894:Panax / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
D002070:Butadienes; D002867:Chromones; D004785:Environmental Pollutants; D009025:Morpholines; D051267:NF-E2-Related Factor 2; D009570:Nitriles; D010936:Plant Extracts; D047428:Protein Kinase Inhibitors; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012313:RNA; D011078:Polychlorinated Biphenyls; D051547:Heme Oxygenase-1; D005721:Glutamate-Cysteine Ligase