Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells

National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, Republic of Korea.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 07/2005; 331(4):993-1000. DOI: 10.1016/j.bbrc.2005.03.237
Source: PubMed


Resveratrol (3,4',5-trihydroxy stilbene), a phytoalexin found in the skin and seeds of grapes, has been reported to possess anti-inflammatory, anticarcinogenic, and antioxidant activities. In this work, we assessed the ability of resveratrol to upregulate heme oxygenase-1 (HO-1) gene expression via activation of NF-E2-related factor 2 (Nrf2) in cultured PC12 cells. Nrf2 is a transcription factor involved in the cellular protection against oxidative stress through antioxidant response element (ARE)-directed induction of several phase 2 detoxifying and antioxidant enzymes, such as HO-1. Here, we report that resveratrol induces HO-1 expression via the ARE-mediated transcriptional activation of Nrf2. Moreover, PC12 cells treated with resveratrol exhibited transient activation of Akt/protein kinase B and extracellular signal-regulated protein kinase 1/2 (ERK1/2). LY294002 and U0126, pharmacological inhibitors of phosphatidylinositol 3-kinase and MEK1/2 which are upstream of Akt and ERK1/2, respectively, attenuated resveratrol-induced HO-1 expression and exhibited antioxidant effects. Taken together, the above findings suggest that resveratrol augments cellular antioxidant defense capacity through induction of HO-1 via Nrf2-ARE signaling, thereby protecting PC12 cells from oxidative stress.

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    • "RES can effectively activate the nuclear factor erythroid-related factor 2/antioxidant responsive element (Nrf2/ARE) pathway, a major cellular antioxidant enzyme system (Ungvari et al., 2009, 2007). Studies using an ischemia/reperfusion model (Ren et al., 2011; Sinha et al., 2002) and a neuronal cell-line (PC 12 cells) (Chen et al., 2005) demonstrate that RES treatment attenuates elevation of lipid peroxidation through activation of the Nrf2/ARE pathway, which up-regulates heme-oxygenase 1 (HO1) and superoxide-dismutases (SODs) expression. In an ischemia/reperfusion animal model, the reduction in oxidative stress by RES via Nrf2/ARE activation reduced motor impairment and infarct size (Ren et al., 2011; Sinha et al., 2002). "
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    ABSTRACT: Age is the greatest universal risk factor for neurodegenerative diseases. During aging, these conditions progress from minor loss of function to major disruptions in daily life, loss of independence and ultimately death. Because approximately 25% of the world population is expected to be older than age 65 by 2050, and no treatments exist to halt or reverse ongoing neurodegeneration, the need for effective prevention strategies is more pressing that ever before. A growing body of research supports the role of diet in healthy aging, particularly diets rich in bioactive phytochemical compounds. Recently, stilbenes such as resveratrol (3, 5, 4'-trans-trihydroxystilbene) and its analogue, pterostilbene, have gained a significant amount of attention for their potent antioxidant, anti-inflammatory, and anticarcinogenic properties. However, evidence for the beneficial effects of stilbenes on cerebral function is just beginning to emerge. In this review, we summarize the current knowledge on the role of resveratrol and pterostilbene in improving brain health during aging, with specific focus on antioxidant and anti-inflammatory signaling and behavioral outcomes. Copyright © 2015. Published by Elsevier Ltd.
    Neurochemistry International 07/2015; DOI:10.1016/j.neuint.2015.07.017 · 3.09 Impact Factor
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    • "Although further studies are needed to explore the cytoprotective effects of OPDA in other cell types, it is interesting that OPDA has a unique cytoprotective function in mammals as well as in plants. A variety of plant-derived nutraceuticals have demonstrated cytoprotective activity against oxidative stress through Nrf2 activation in SH-SY5Y or PC12 cells [67] [68] [69] [70] [71] [72]. Additionally, the potential therapeutic value of each of these compounds in neurogenerative diseases has been discussed [73]. "
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    ABSTRACT: Background: Jasmonates are plant lipid-derived oxylipins that act as key signaling compounds when plants are under oxidative stress, but little is known about their functions in mammalian cells. Here we investigated whether jasmonates could protect human neuroblastoma SH-SY5Y cells against oxidative stress-induced toxicity. Methods: The cells were pretreated with individual jasmonates for 24 hand exposed to hydrogen peroxide (H2O2) for 24 h. Before the resulting cytotoxicity, intracellular reactive oxygen species (ROS) levels, and mitochondrial membrane potential were measured. We also measured intracellular glutathione (GSH) levels and investigated changes in the signaling cascade mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) in cells treated with 12-oxo phytodienbic acid (OPDA). Results: Among the jasmonates, only OPDA suppressed H2O2-induced cytotoxicity. OPDA pretreatment also inhibited the H2O2-induced ROS increase and mitochondrial membrane potential decrease. In addition, OPDA induced the nuclear translocation of Nrf2 and increased intracellular GSH level and the expression of the Nrf2-regulated phase II antioxidant enzymes heme oxygenase-1, NADPH quinone oxidoreductase 1, and glutathione reductase. Finally, the cytoprotective effects of OPDA were reduced by siRNA-induced knockdown of Nrf2. Conclusions: These results demonstrated that among jasmonates, only OPDA suppressed oxidative stress-induced death of human neuroblastoma cells, which occurred via activation of the Nrf2 pathway. General significance: Plant-derived oxylipin OPDA may have the potential to provide protection against oxidative stress-related diseases. (C) 2014 The Authors. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - General Subjects 09/2014; 1840(12). DOI:10.1016/j.bbagen.2014.09.003 · 4.38 Impact Factor
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    • "Under normal unstressed conditions, Nrf2 is anchored by Keap 1 (Kelch-like ECH-associating protein 1) in the cytoplasm, which causes polyubiquitination and proteasome mediated degradation . It has also been shown to induce HO1 via Nrf2 and PI3K/AKT pathways and thereby reduce ROS induced oxidative damage in PC 12 cells (Chen et al., 2005). Resveratrol is known to promote HO-1 expression through the activation of Nrf2 in primary neuronal cultures (Table 1L; Zhuang et al., 2003; Figure 2). "
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    ABSTRACT: Alzheimer's disease is a chronic neurodegenerative disorder characterized by a progressive loss of cognitive and behavioral abilities. Extracellular senile plaques and intracellular neurofibrillary tangles are hallmarks of AD. Researchers aim to analyze the molecular mechanisms underlying AD pathogenesis; however, the therapeutic options available to treat this disease are inadequate. In the past few years, several studies have reported interesting insights about the neuroprotective properties of the polyphenolic compound resveratrol (3, 5, 4'-trihydroxy-trans-stilbene) when used with in vitro and in vivo models of AD. The aim of this review is to focus on the neuroprotective and antioxidant effects of resveratrol on AD and its multiple potential mechanisms of action. In addition, because the naturally occurring forms of resveratrol have a very limited half-life in plasma, a description of potential analogs aimed at increasing the bioavailability in plasma is also discussed.
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