靶向自噬发现胡椒石油醚部位具有抗衰老和抗阿尔茨海默病作用。
Targeting autophagy to discover the Piper wallichii petroleum ether fraction exhibiting antiaging and anti-Alzheimer's disease effects in Caenorhabditis elegans.
机构信息
Department of Pharmacy, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Gui Yang, China; Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Key Laboratory of Medical Electrophysiology of Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.
Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Key Laboratory of Medical Electrophysiology of Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.
出版信息
Phytomedicine. 2023 Aug;117:154916. doi: 10.1016/j.phymed.2023.154916. Epub 2023 Jun 3.
BACKGROUND
With population aging, the incidence of aging-related Alzheimer's disease (AD) is increasing, accompanied by decreased autophagy activity. At present, Caenorhabditis elegans (C. elegans) is widely employed to evaluate autophagy and in research on aging and aging-related diseases in vivo. To discover autophagy activators from natural medicines and investigate their therapeutic potential in antiaging and anti-AD effects, multiple C. elegans models related to autophagy, aging, and AD were used.
METHOD
In this study, we employed the DA2123 and BC12921 strains to discover potential autophagy inducers using a self-established natural medicine library. The antiaging effect was evaluated by determining the lifespan, motor ability, pumping rate, lipofuscin accumulation of worms, and resistance ability of worms under various stresses. In addition, the anti-AD effect was examined by detecting the paralysis rate, food-sensing behavior, and amyloid-β and Tau pathology in C. elegans. Moreover, RNAi technology was used to knock down the genes related to autophagy induction.
RESULTS
We discovered that Piper wallichii extract (PE) and the petroleum ether fraction (PPF) activated autophagy in C. elegans, as evidenced by increased GFP-tagged LGG-1 foci and decreased GFP-p62 expression. In addition, PPF extended the lifespan and enhanced the healthspan of worms by increasing body bends and pumping rates, decreasing lipofuscin accumulation, and increasing resistance to oxidative, heat, and pathogenic stress. Moreover, PPF exhibited an anti-AD effect by decreasing the paralysis rate, improving the pumping rate and slowing rate, and alleviating Aβ and Tau pathology in AD worms. However, the feeding of RNAi bacteria targeting unc-51, bec-1, lgg-1, and vps-34 abolished the antiaging and anti-AD effects of PPF.
CONCLUSION
Piper wallichii may be a promising drug for antiaging and anti-AD. More future studies are also needed to identify autophagy inducers in Piper wallichii and clarify their molecular mechanisms.
背景
随着人口老龄化，与年龄相关的阿尔茨海默病（AD）的发病率正在增加，同时自噬活性下降。目前，秀丽隐杆线虫（C. elegans）被广泛用于评估自噬，并在体内研究衰老和与衰老相关的疾病。为了从天然药物中发现自噬激活剂，并研究其在抗衰老和抗 AD 作用中的治疗潜力，使用了多种与自噬、衰老和 AD 相关的 C. elegans 模型。
方法
在这项研究中，我们使用 DA2123 和 BC12921 品系，使用我们自行建立的天然药物文库来发现潜在的自噬诱导剂。通过确定寿命、运动能力、泵速、线虫脂褐素积累和各种应激下的抗性能力来评估抗衰老作用。此外，通过检测线虫的麻痹率、食物感知行为以及淀粉样β和 Tau 病理学来检测抗 AD 作用。此外，还使用 RNAi 技术敲低与自噬诱导相关的基因。
结果
我们发现胡椒提取物（PE）和石油醚馏分（PPF）激活了线虫的自噬，这表现为 GFP 标记的 LGG-1 焦点增加和 GFP-p62 表达减少。此外，PPF 通过增加体弯曲和泵速、减少脂褐素积累以及提高对氧化、热和致病应激的抗性，延长了线虫的寿命并增强了它们的健康寿命。此外，PPF 通过降低麻痹率、提高泵速和减速率以及减轻 AD 线虫中的 Aβ 和 Tau 病理学，表现出抗 AD 作用。然而，喂食靶向 unc-51、bec-1、lgg-1 和 vps-34 的 RNAi 细菌会消除 PPF 的抗衰老和抗 AD 作用。
结论
胡椒可能是一种有前途的抗衰老和抗 AD 药物。还需要更多的未来研究来鉴定胡椒中的自噬诱导剂并阐明其分子机制。
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