Singh Pallavi, Chowdhuri D Kar
Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India.
Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India.
Chemosphere. 2018 Jan;191:302-314. doi: 10.1016/j.chemosphere.2017.10.037. Epub 2017 Oct 7.
Increased oxidative stress is one of the major causes of hexavalent chromium [Cr(VI)], a heavy metal with diverse applications and environmental presence, induced neuronal adversities in exposed organism including Drosophila. Sestrin (sesn), an oxidative stress responsive gene, emerges as a novel player in the management of oxidative stress response. It is reported to be regulated by Target of rapamycin (TOR) and the former regulates autophagy and plays an important role in the prevention of neurodegeneration. Due to limited information regarding the role of sesn in chemical induced cellular adversities, it was hypothesized that modulation of sesn may improve the Cr(VI) induced neuronal adversities in Drosophila. Upon exposure of Cr(VI) (5.0-20.0 μg/ml) to D. melanogaster larvae (w; background control), neuronal cell death was observed at 20.0 μg/ml of Cr(VI) concentration which was found to be reversed by targeted sesn overexpression (Elav-GAL4>UAS-sesn) in those cells of exposed organism by the induction of autophagy concomitant with decreased reactive oxygen species (ROS) level, p-Foxo-, p-JNK- and p-Akt-levels with decreased apoptosis. Conversely, after sesn knockdown (Elav-GAL4>UAS-sesn) in neuronal cells, they become more vulnerable to oxidative stress and apoptosis. Furthermore, knockdown of sesn in neuronal cells of exposed organism resulted in decreased autophagy with increased TOR and p-S6k levels while overexpression of sesn led to their decreased levels suggestive of decreased anabolic and increased catabolic activity in neuronal cells shifting energy towards the augmentation of cellular repair. Taken together, the study suggests therapeutic implications of sesn against chemical induced neuronal adversities in an organism.
氧化应激增加是六价铬[Cr(VI)]诱导暴露生物体（包括果蝇）出现神经元损伤的主要原因之一。六价铬是一种具有多种用途且存在于环境中的重金属。Sestrin（sesn）是一种氧化应激反应基因，已成为氧化应激反应管理中的一个新角色。据报道，它受雷帕霉素靶蛋白（TOR）调控，前者调节自噬，并在预防神经退行性变中起重要作用。由于关于sesn在化学诱导的细胞损伤中的作用的信息有限，因此推测调节sesn可能改善果蝇中六价铬诱导的神经元损伤。将六价铬（5.0 - 20.0μg/ml）暴露于黑腹果蝇幼虫（w；背景对照）后，在六价铬浓度为20.0μg/ml时观察到神经元细胞死亡，而通过在暴露生物体的这些细胞中靶向过表达sesn（Elav - GAL4>UAS - sesn），伴随自噬诱导、活性氧（ROS）水平降低、p - Foxo -、p - JNK - 和p - Akt水平降低以及凋亡减少，这种细胞死亡现象得到逆转。相反，在神经元细胞中敲低sesn（Elav - GAL4>UAS - sesn）后，它们对氧化应激和凋亡变得更加敏感。此外，在暴露生物体的神经元细胞中敲低sesn导致自噬减少，TOR和p - S6k水平升高，而过表达sesn则导致它们的水平降低，这表明神经元细胞中的合成代谢减少，分解代谢活动增加，能量转向增强细胞修复。综上所述，该研究表明sesn对生物体中化学诱导的神经元损伤具有治疗意义。
