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Quercetin and Baicalein Act as Potent Antiamyloidogenic and Fibril Destabilizing Agents for SOD1 Fibrils.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-03-25 , DOI: 10.1021/acschemneuro.9b00677 Nidhi K Bhatia 1 , Priya Modi 1 , Shilpa Sharma 1 , Shashank Deep 1
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-03-25 , DOI: 10.1021/acschemneuro.9b00677 Nidhi K Bhatia 1 , Priya Modi 1 , Shilpa Sharma 1 , Shashank Deep 1
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has been associated with the deposition of aggregates of superoxide dismutase 1 (SOD1). Effective therapeutics against SOD1 fibrillation is still an area of active research. Herein, we demonstrate the potential of two naturally occurring flavonoids (quercetin and baicalein) to inhibit fibrillation of wild-type SOD1 with the aid of a series of biophysical techniques. Our seeding experiments reveal that both of these flavonoids significantly affect the fibril elongation. Interestingly, our ThT binding assay, TEM, and SDS-PAGE experiments suggest that these flavonoids also disintegrate the fibrils into shorter fragments but do not completely depolymerize them into monomers. Binding parameters obtained from the analysis of UV−vis spectra suggest that these flavonoids bind moderately to native SOD1 dimer and have different binding sites. Docking of these flavonoids with a non-native monomer, non-native trimer, and oligomer derived from the 11-residue segment of SOD1 indicates that both quercetin and baicalein can bind to these species and thus can arrest the elongation of fibrils by blocking the fibrillar core regions on the intermediate species formed during aggregation of SOD1. MTT assay data revealed that both the flavonoids reduced the cytotoxicity of SOD1 fibrils. Experimental data also show the antiamyloidogenic potential of both flavonoids against A4V SOD1 mutant fibrillation. Thus, our findings may provide a direction for designing effective therapeutic agents against ALS which can act as promising antiamyloidogenic and fibril destabilizing agents.
中文翻译：
槲皮素和黄ical素充当SOD1原纤维的有效抗淀粉样蛋白生成剂和原纤维去稳定剂。
肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，与超氧化物歧化酶1（SOD1）的聚集物沉积有关。对抗SOD1颤动的有效疗法仍然是活跃的研究领域。在本文中，我们通过一系列生物物理技术证明了两种天然类黄酮（槲皮素和黄ical素）抑制野生型SOD1的原纤维形成的潜力。我们的播种实验表明，这两种类黄酮均会显着影响原纤维的伸长。有趣的是，我们的ThT结合测定，TEM和SDS-PAGE实验表明，这些类黄酮还可以将原纤维分解为较短的片段，但不会完全解聚为单体。从紫外可见光谱分析获得的结合参数表明，这些类黄酮与天然SOD1二聚体适度结合，并具有不同的结合位点。这些类黄酮与非天然单体，非天然三聚体和衍生自SOD1 11残基片段的低聚物对接，表明槲皮素和黄ical素均可与这些物种结合，因此可通过阻断原纤维来阻止原纤维的伸长。 SOD1聚集过程中形成的中间物种上的核心区域。MTT分析数据表明，这两种类黄酮均降低了SOD1原纤维的细胞毒性。实验数据还显示，两种类黄酮均具有抗A4V SOD1突变型原纤维形成的抗淀粉样蛋白作用。从而，
更新日期：2020-04-23
中文翻译：
槲皮素和黄ical素充当SOD1原纤维的有效抗淀粉样蛋白生成剂和原纤维去稳定剂。
肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，与超氧化物歧化酶1（SOD1）的聚集物沉积有关。对抗SOD1颤动的有效疗法仍然是活跃的研究领域。在本文中，我们通过一系列生物物理技术证明了两种天然类黄酮（槲皮素和黄ical素）抑制野生型SOD1的原纤维形成的潜力。我们的播种实验表明，这两种类黄酮均会显着影响原纤维的伸长。有趣的是，我们的ThT结合测定，TEM和SDS-PAGE实验表明，这些类黄酮还可以将原纤维分解为较短的片段，但不会完全解聚为单体。从紫外可见光谱分析获得的结合参数表明，这些类黄酮与天然SOD1二聚体适度结合，并具有不同的结合位点。这些类黄酮与非天然单体，非天然三聚体和衍生自SOD1 11残基片段的低聚物对接，表明槲皮素和黄ical素均可与这些物种结合，因此可通过阻断原纤维来阻止原纤维的伸长。 SOD1聚集过程中形成的中间物种上的核心区域。MTT分析数据表明，这两种类黄酮均降低了SOD1原纤维的细胞毒性。实验数据还显示，两种类黄酮均具有抗A4V SOD1突变型原纤维形成的抗淀粉样蛋白作用。从而，
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