Resveratrol Inhibits Paraquat-Induced Oxidative Stress and Fibrogenic Response by Activating the Nuclear Factor Erythroid 2-Related Factor 2 Pathway
ABSTRACT 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.
Carcinogenesis 11/2014; · 5.27 Impact Factor
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ABSTRACT: Resveratrol, a natural polyphenolic molecule with several biological activities, is a well recognized anti-oxidant, anti-aging and cancer chemopreventive agent. Moreover, resveratrol anti-inflammatory and antifibrotic properties have been demonstrated both in vitro and in different animal models of inflammatory pathologies, including bowel and liver diseases. We review the evidence of resveratrol protective role in respiratory diseases such as acute lung injury, asthma, chronic obstructive pulmonary disease and lung fibrosis. We conclude that resveratrol and its derivatives may act as a therapeutic agents in respiratory diseases and pertinent clinical trials should be performed.Histology and histopathology 12/2014; · 2.24 Impact Factor
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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.