Sengupta Bidisha, Sahihi Mehdi, Dehkhodaei Monireh, Kelly Darrian, Arany Istvan
Department of Chemistry, Tougaloo College, Tougaloo, Mississippi, United States of America.
Department of Chemistry, University of Isfahan, Isfahan, Iran.
PLoS One. 2017 Jun 22;12(6):e0179777. doi: 10.1371/journal.pone.0179777. eCollection 2017.
Plant flavonoids are well known as antioxidants against oxidative stress induced by exposure to external pollutants. Nicotine (NIC) is one of those agents which increases renal oxidative stress, an important factor in the pathogenesis of renal epithelial injury in smokers. Although several studies had been conducted on flavonoids and oxidative stress, the mechanism of the protective pathways are not fully understood. Here, we present studies on antioxidant properties of two mono-hydroxyflavone isomers, 3-hydroxyflanove (3HF)- and 7-hydroxyflavone (7HF), against nicotine-associated oxidative stress and injury in cultured renal proximal tubule cells and correlate their antioxidant properties with their chemical structure. Our data clearly demonstrates, for the first time, that while both 3HF and 7HF protect renal cells from NIC-associated cytotoxicity, the mechanism of their action is different: 3HF elicits protective activity via the PKA/CREB/MnSOD pathway while 7HF does so via the ERK/Nrf2/HO-1 pathway. Molecular docking and dynamics simulations with two major signaling pathway proteins showed significant differences in the binding energies of 3HF (-5.67 and -7.39 kcal.mol-1) compared to 7HF (-5.41 and -8.55 kcal.mol-1) in the matrices of CREB and Keap1-Nrf2 proteins respectively, which corroborate with the observed differences in their protective properties in the renal cells. The implications of this novel explorative study is likely to promote the understanding of the mechanisms of the antioxidative functions of different flavones.
植物黄酮类化合物作为对抗因暴露于外部污染物而诱导的氧化应激的抗氧化剂而广为人知。尼古丁（NIC）是增加肾脏氧化应激的因素之一，而氧化应激是吸烟者肾上皮损伤发病机制中的一个重要因素。尽管已经对黄酮类化合物和氧化应激进行了多项研究，但保护途径的机制尚未完全了解。在此，我们展示了关于两种单羟基黄酮异构体，即3-羟基黄酮（3HF）和7-羟基黄酮（7HF），对培养的肾近端小管细胞中尼古丁相关氧化应激和损伤的抗氧化特性的研究，并将它们的抗氧化特性与其化学结构相关联。我们的数据首次清楚地表明，虽然3HF和7HF都能保护肾细胞免受NIC相关的细胞毒性，但它们的作用机制不同：3HF通过PKA/CREB/MnSOD途径引发保护活性，而7HF则通过ERK/Nrf2/HO-1途径发挥作用。与两种主要信号通路蛋白的分子对接和动力学模拟显示，在CREB和Keap1-Nrf2蛋白矩阵中，3HF（-5.67和-7.39 kcal.mol-1）与7HF（-5.41和-8.55 kcal.mol-1）的结合能存在显著差异，这与它们在肾细胞中观察到的保护特性差异相符。这项新颖的探索性研究的意义可能会促进对不同黄酮抗氧化功能机制的理解。
