Resveratrol Inhibits Paraquat-Induced Oxidative Stress and Fibrogenic Response by Activating the Nuclear Factor Erythroid 2-Related Factor 2 Pathway

Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia 26505, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 04/2012; 342(1):81-90. DOI: 10.1124/jpet.112.194142
Source: PubMed


Nuclear factor erythroid 2-related factor 2 (Nrf2) is an antioxidant-activated transcription factor that recently emerged as a critical regulator of cellular defense against oxidative and inflammatory lesions. Resveratrol (Res) is a natural phytoalexin that exhibits multiple therapeutic potentials, including antioxidative and anti-inflammatory effects in animals. Paraquat (PQ) is the second most widely used herbicide worldwide, but it selectively accumulates in human lungs to cause oxidative injury and fibrosis with high mortality. Here, we analyzed the molecular mechanism of the fibrogenic response to PQ and its inhibition by Res and Nrf2. PQ dose-dependently caused toxicity in normal human bronchial epithelial cells (BEAS-2B), resulting in mitochondrial damage, oxidative stress, and cell death. Res at 10 μM markedly inhibited PQ toxicity. PQ at 10 μM stimulated production of inflammatory and profibrogenic factors (tumor necrosis factor α, interleukin 6, and transforming growth factor β1) and induced the transformation of normal human lung fibroblasts (WI38-VA13) to myofibroblasts; both effects were inhibited by Res. Res strongly activated the Nrf2 signaling pathway and induced antioxidant response element-dependent cytoprotective genes. On the other hand, knockout or knockdown of Nrf2 markedly increased PQ-induced cytotoxicity, cytokine production, and myofibroblast transformation and abolished protection by Res. The findings demonstrate that Res attenuates PQ-induced reactive oxygen species production, inflammation, and fibrotic reactions by activating Nrf2 signaling. The study reveals a new pathway for molecular intervention against pulmonary oxidative injury and fibrosis.

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    • "The growth of human population and increasing activities associated with agriculture, urbanization and industrialization have resulted in a staggering release of anthropogenic sources, including pesticides. Paraquat (1,1ʹ-dimethyl-4-4ʹ-bipyridinium dichloride) is the second widely used herbicide in the world for controlling weeds[1]. It is also used as a defoliant and desiccant to aid in the harvesting of cotton, beans, soybeans, potatoes, sunflowers, and sugarcane[2]. "
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    ABSTRACT: Objective: To investigate the physiological effects of paraquat in African freshwater catfish Clarias gariepinus. Methods: Two sublethal test concentrations of paraquat (1.37 and 2.75 mg/L) were chosen based on the 96 h LC50 value (27.46 mg/L). Some experimental fish were exposed to these concentrations and control group for 15 d. Peripheral blood samplings were taken at intervals for assessment of haematological and biochemical parameters. Results: Exposure to paraquat affected behaviour and morphology of Clarias gariepinus. There were significant decreases (P<0.05) in the mean values of hemoglobin, red blood cells, packed cell volume, cellular hemoglobin, and cellular hemoglobin concentration. The levels of white blood cells, glucose, aspartate aminotransferase, and alanine aminotransferase significantly increased (P<0.05) while protein levels declined. However, no definite pattern of changes was observed in the number and type of leucocytes. Conclusions: The results of the present study indicate that paraquat is toxic and has the potential to impair on the physiological activities in African catfish Clarias gariepinus. The use of paraquat should be strongly controlled and carefully monitored to avoid the possible damage done to the environment.
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    • "In addition, inflammatory response is the initial and main mechanism of tissue injury after paraquat poisoning [10] . C-reactive protein (CRP) is an acute-phase protein that has been evaluated extensively in the critical illness [11] . "
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    ABSTRACT: To investigate the prognostic value of plasma C-reactive protein (CRP) level in patients with paraquat poisoning.
    Asian Pacific Journal of Tropical Biomedicine 07/2015; 72. DOI:10.1016/j.apjtb.2015.06.011
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    ABSTRACT: Oxidative stress can result in insulin resistance, a primary cause of type-2 diabetes. Methylglyoxal (MG), a highly reactive dicarbonyl metabolite generated during glucose metabolism, has also been confirmed to cause pancreatic injury and induce inflammation, thereby resulting in insulin resistance. Recently, resveratrol has been reported to exert antioxidant properties, protecting cells from the generation of reactive oxygen species (ROS). The aim of this study was to evaluate resveratrol activation of nuclear factor erythroid 2-related factor 2 (Nrf2) to attenuate MG-induced insulin resistance in Hep G2 cells. Therefore, the molecular signaling events affecting resveratrol-mediated heme oxygenase-1 (HO-1) and glyoxalase expression levels were further investigated in this study. Our findings indicated that resveratrol activated the extracellular signal-regulated kinase (ERK) pathway but not the p38 or c-Jun N-terminal kinase (JNK) pathways, subsequently leading to Nrf2 nuclear translocation and elevation of HO-1 and glyoxalase expression levels. Moreover, resveratrol significantly elevated glucose uptake and protected against MG-induced insulin resistance in Hep G2 cells. In contrast, depletion of Nrf2 by small interfering RNA (si-RNA) resulted in the abrogation of HO-1 and glyoxalase expression in the MG-treated resveratrol group in Hep G2 cells. Administration of an appropriate chemopreventive agent, such as resveratrol, may be an alternative strategy for protecting against MG-induced diabetes.
    Journal of Agricultural and Food Chemistry 08/2012; 60(36):9180-7. DOI:10.1021/jf302831d · 2.91 Impact Factor
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