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; 89. DOI:10.1016/j.neuint.2015.07.017 · 3.09 Impact Factor
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    • "Of importance, in PC12 cells, several groups have found that treatment of PC12 cells with b-amyloid or gallic acid causes activation of JNK pathway and cell death, which is effectively blocked by resveratrol (Jang and Surh 2003; Kang et al. 2009). In addition, pre-treatment with resveratrol inhibits H 2 O 2 induced PC12 cell death by up-regulation of heme oxyge- nase-1 (HO-1), which is via activation of Erk1/2 and Akt signaling (Chen et al. 2005). In this study, we found that resveratrol inhibited Cd-induced phosphorylation of JNK, Erk1/2, and p38, including protein expression and phosphorylation of c-Jun, the substrate of JNK, in PC12 cells and primary neurons. "
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    ABSTRACT: Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative disorders. Resveratrol, a natural product, has been found to exert neuroprotective effects. However, little is known regarding the effect of resveratrol on Cd-evoked neurotoxicity. Here we show that resveratrol effectively reversed Cd-elicited cell viability reduction, morphological change, nuclear fragmentation and condensation, as well as activation of caspase-3 in neuronal cells, implying neuroprotection against Cd-poisoning by resveratrol. Further research revealed that both c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases 1/2 (Erk1/2) were involved in the inhibitory effect of resveratrol on Cd-induced cell death, as selective inhibitors of Erk1/2 (U0126) and JNK (SP600125), or overexpression of dominant negative mitogen-activated protein kinase kinase 1 (MKK1) or dominant negative c-Jun potentiated resveratrol's prevention of Cd-induced phosphorylation of JNK and Erk1/2, as well as cell death in neuronal cells. Interestingly, resveratrol potently rescued the cells from Cd-induced suppression of protein phosphatases 2A (PP2A) and 5 (PP5) activity. Overexpression of PP2A or PP5 strengthened the inhibitory effects of resveratrol on Cd-induced activation of Erk1/2 and/or JNK, as well as cell death. The results indicate that resveratrol prevents Cd-induced activation of Erk1/2 and JNK pathways and neuronal cell death in part via activating PP2A and PP5. Our findings strongly support the notion that resveratrol may serve as a potential therapeutic agent in the prevention of Cd-induced neurodegenerative diseases. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2015; 135(3). DOI:10.1111/jnc.13233 · 4.28 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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