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α-红没药醇对 Aβ诱导的 PC12 细胞神经毒性的抗淀粉样变性和抗细胞凋亡作用。

Anti-amyloidogenic and anti-apoptotic effect of α-bisabolol against Aβ induced neurotoxicity in PC12 cells.

机构信息

Department of Biotechnology, Alagappa University, Karaikudi 630003, Tamil Nadu, India.

Computer Aided Drug Design and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi 630003, Tamil Nadu, India.

出版信息

Eur J Med Chem. 2018 Jan 1;143:1196-1207. doi: 10.1016/j.ejmech.2017.10.017. Epub 2017 Oct 10.

Abstract

Alzheimer's disease (AD) is a life-threatening neurodegenerative disorder leading to dementia, with a progressive decline in memory and other thinking skills of elderly populace. Of the multiple etiological factors of AD, the accumulation of senile plaques (SPs) particularly as Aβ oligomers correlates with the relentlessness cognitive impairment in AD patients and play a vital role in AD pathology. Since natural essential oil constituents have successfully served as a source of drugs for AD treatment, the present study aims at the in vitro and in silico investigation of anti-amyloidogenic potential and anti-apoptotic property of the α-bisabolol against Aβ induced neurotoxicity in PC12 cells. Treatment with α-bisabolol (5 μg/ml) after 24 h incubation with Aβ reduced the aggregation propensity of Aβ (p < 0.05), as observed by the reduced fluorescence intensity of thioflavin T (ThT). Confocal laser scanning microscopy (CLSM) analysis, Transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopic analysis and molecular dynamics simulation study also substantiated the Aβ fibril formation hampering ability of α-bisabolol even after 9 days of incubations. The results of antiaggregation and disaggregation assay showed an increase in fluorescence intensity in Aβ treated group, whereas the co-treatment of α-bisabolol (5 μg/ml) with Aβ showed an extensive decrease in the fluorescence intensity, which suggests that α-bisabolol prevents the oligomers formation as well as disaggregates the matured fibrils. FACS analysis of the cells revealed the competency of α-bisabolol in rescuing the PC12 cells from Aβ induced neurotoxicity and chromosomal damage and clonogenic assay proved its ability to retain the colony survival of cells. Overall, the anti-amyloidogenic and anti-apoptotic effect of α-bisabolol proves that it could be used as an excellent therapeutic drug to combat AD.

摘要

阿尔茨海默病(AD)是一种危及生命的神经退行性疾病,导致痴呆,老年人的记忆和其他思维技能逐渐下降。在 AD 的多种病因中,老年斑(SPs)的积累,特别是 Aβ 寡聚体,与 AD 患者的认知障碍的无情进展相关,并在 AD 病理学中发挥重要作用。由于天然精油成分已成功用作 AD 治疗药物的来源,因此本研究旨在通过体外和计算机模拟研究 α- 姜烯醇对 Aβ 诱导的 PC12 细胞神经毒性的抗淀粉样蛋白形成和抗凋亡作用。在用 Aβ 孵育 24 小时后用 α- 姜烯醇(5μg/ml)处理可降低 Aβ 的聚集倾向(p<0.05),这可以通过减少硫黄素 T(ThT)的荧光强度来观察到。共焦激光扫描显微镜(CLSM)分析,透射电子显微镜(TEM),傅立叶变换红外(FTIR)光谱分析和分子动力学模拟研究也证实了 α- 姜烯醇即使在孵育 9 天后也能阻碍 Aβ 纤维形成的能力。抗聚集和去聚集测定的结果显示在用 Aβ 处理的组中荧光强度增加,而在用 Aβ 与 α- 姜烯醇(5μg/ml)共同处理时,荧光强度则广泛降低,这表明 α- 姜烯醇可防止寡聚体形成并使成熟纤维解聚。细胞 FACS 分析显示 α- 姜烯醇有能力使 PC12 细胞从 Aβ 诱导的神经毒性和染色体损伤中恢复,克隆形成测定证明其能够保持细胞的集落存活率。总体而言,α- 姜烯醇的抗淀粉样蛋白形成和抗凋亡作用证明其可作为治疗 AD 的优秀治疗药物。

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