Ayoub Iriny M, Eldahshan Omayma A, Roxo Mariana, Zhang Shaoxiong, Wink Michael, Singab Abdel Nasser B
Pharmacognosy Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Centre for Drug Discovery Research and Development, Ain Shams University, Cairo, Egypt.
Arch Pharm (Weinheim). 2024 Dec;357(12):e2400464. doi: 10.1002/ardp.202400464. Epub 2024 Oct 3.
The leaf extract of Alnus rugosa (AR) together with the isolated compound baicalein 5,6-dimethyl ether (BME) were investigated for their antioxidant, radical scavenging, antiaging, and neuroprotective properties using the Caenorhabditis elegans model. The stress resistance and antiaging potential of AR and BME were assessed in wild-type N2 and transgenic C. elegans strains CF1553, TJ356, and BA17. Transgenic CL4176 expressing the human amyloid-beta peptide (Aβ) was used as a model for Aβ toxicity, whereas transgenic AM141 expressing polyQ aggregates was employed as a model for Huntington's disease. An in silico molecular docking study using Discovery Studio 4.5 was performed to elucidate the putative binding mode of BME to the active sites of Daf-2 protein, involved in longevity and oxidative stress resistance in C. elegans. BME and AR significantly delayed the appearance of oxidative stress markers in wild-type N2 and transgenic strains TJ356 and CF1553, affecting the DAF-16/FOXO transcription factor subcellular distribution and inducing expression of the sod-3 antioxidative gene. Pretreatment with AR significantly reduced the aging marker lipofuscin accumulation in BA17 worms, its effect was greater than that of epigallocatechin gallate, suggesting a potential antiaging effect. Neuroprotective effects of AR and BME were confirmed in AM141 transgenic worms, inducing a significant reduction in the score of polyQ40::GFP aggregates. Moreover, BME (25 µg/mL) resulted in a significant delay in Aβ-induced paralysis in CL4176 worms. In silico molecular modeling revealed that BME exhibited good fitting scores within the active sites of the Daf-2 protein. AR and BME exert beneficial effects in the modulation of age-related markers and attenuation of neurotoxicity in neurodegenerative disorders. Hence, AR and BME could be recognized as promising antioxidant and neuroprotective natural drug candidates that could be included in neuro-nutraceuticals.
利用秀丽隐杆线虫模型，对糙皮桦（AR）叶提取物以及分离出的化合物黄芩素5,6 - 二甲醚（BME）的抗氧化、自由基清除、抗衰老和神经保护特性进行了研究。在野生型N2和转基因秀丽隐杆线虫菌株CF1553、TJ356和BA17中评估了AR和BME的抗应激和抗衰老潜力。表达人淀粉样β肽（Aβ）的转基因CL4176用作Aβ毒性模型，而表达多聚谷氨酰胺聚集体的转基因AM141用作亨廷顿舞蹈病模型。使用Discovery Studio 4.5进行了计算机分子对接研究，以阐明BME与秀丽隐杆线虫中参与寿命和抗氧化应激的Daf - 2蛋白活性位点的假定结合模式。BME和AR显著延迟了野生型N2以及转基因菌株TJ356和CF1553中氧化应激标志物的出现，影响DAF - 16/FOXO转录因子的亚细胞分布并诱导sod - 3抗氧化基因的表达。用AR预处理可显著减少BA17蠕虫中衰老标志物脂褐素的积累，其效果大于表没食子儿茶素没食子酸酯，表明具有潜在的抗衰老作用。在AM141转基因蠕虫中证实了AR和BME的神经保护作用，可使多聚谷氨酰胺40::GFP聚集体的评分显著降低。此外，BME（25μg/mL）可显著延迟CL4176蠕虫中Aβ诱导的麻痹。计算机分子建模显示，BME在Daf - 2蛋白的活性位点内表现出良好的拟合分数。AR和BME在调节与年龄相关的标志物以及减轻神经退行性疾病中的神经毒性方面发挥有益作用。因此，AR和BME可被认为是有前景的抗氧化和神经保护天然药物候选物，可纳入神经营养保健品中。
