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Smokeless tobacco induces toxicity and apoptosis in neuronal cells: a mechanistic evaluation.
Free Radical Research ( IF 3.3 ) Pub Date : 2020-08-26 , DOI: 10.1080/10715762.2020.1805446
Sushobhan Biswas 1 , Hrishita Das 2 , Ujjal Das 1 , Aaveri Sengupta 1 , Rakhi Dey Sharma 3 , Subhas Chandra Biswas 2 , Sanjit Dey 1
Affiliation  

Smokeless tobacco (SLT) or chewing tobacco has been a highly addictive practice in India across ages, posing major threat to the systemic health and possibly neurodegeneration. Earlier studies showed components of SLT could be harmful to neuronal health. However, mechanism of SLT in neurodegeneration remained unexplored. This study investigated the detrimental role of SLT on differentiated neuronal cell lines, PC12 and SH-SY5Y by using graded doses of water soluble lyophilised SLT. Reduced cell viability, compromised mitochondrial structure and functions were observed when neuronal cell lines were treated with SLT (6 mg/mL) for 24 h. There was reduction of oxidative phosphorylation and aerobic glycolysis as determined by diminution of ATP production (2.5X) and basal respiration (1.9X). Mitochondrial membrane potential was dropped by 3.5 times. Bid, a pro-apoptotic Bcl-2 family protein, has imperative role in regulating mitochondrial outer membrane permeabilization and subsequent cytochrome c release leading to apoptosis. This article for the first time indicated the involvement of Bid in SLT mediated neurotoxicity and possibly neurodegeneration. SLT treatment enhanced expression of cleaved-Bid in time dependent manner. The involvement of Bid was further confirmed by using Bid specific shRNA which reversed the effects of SLT and conferred significant protection from apoptosis up to 72 h. Thus, our results clearly indicated that SLT induced neuronal cell death occurred via production of ROS, alteration of mitochondrial morphology, membrane potential and oxidative phosphorylation, inactivation of survival pathway and activation of apoptotic markers mediated by Bid. Therefore, Bid could be a potential future therapeutic target for SLT induced neurodegeneration.



中文翻译:

无烟烟草在神经元细胞中诱导毒性和凋亡:一种机械评估。

多年来,无烟烟草(SLT)或咀嚼烟草在印度一直是一种高度成瘾的行为,对系统健康和可能的神经变性构成了重大威胁。早期研究表明,SLT的成分可能对神经元健康有害。然而,SLT在神经退行性疾病中的机制尚待探索。这项研究使用分级剂量的水溶性冻干SLT来研究SLT对分化的神经元细胞系PC12和SH-SY5Y的有害作用。当用SLT(6 mg / mL)处理神经元细胞系24小时时,观察到细胞活力降低,线粒体结构和功能受损。通过减少ATP的产生(2.5倍)和基础呼吸(1.9倍)可以确定氧化磷酸化和有氧糖酵解的减少。线粒体膜电位下降了3.5倍。出价,c释放导致凋亡。这篇文章首次表明Bid参与了SLT介导的神经毒性和可能的​​神经变性。SLT处理以时间依赖的方式增强了裂解出价的表达。通过使用Bid特异的shRNA进一步证实了Bid的参与,该shRNA逆转了SLT的作用,并提供了长达72 h的细胞凋亡保护。因此,我们的结果清楚地表明,SLT诱导的神经元细胞死亡是通过产生ROS,线粒体形态改变,膜电位和氧化磷酸化,存活途径失活以及Bid介导的凋亡标志物活化而发生的。因此,出价可能是SLT诱导的神经变性的潜在未来治疗靶标。

更新日期:2020-09-21
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