Identification of natural products with neuronal and metabolic benefits through autophagy induction
Identification of natural products with neuronal and metabolic benefits through autophagy induction
复制标题
通过自噬诱导鉴定具有神经元和代谢益处的天然产物
DOI：
10.1080/15548627.2016.1240855
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发表时间：
2017-01-01
期刊：
影响因子：
13.3
通讯作者：
He, Congcong
中科院分区：
文献类型：
--
作者：
Fan, Yuying;Wang, Nan;He, Congcong
自噬是一种内务溶酶体降解途径，对细胞存活、稳态和功能至关重要。各种疾病模型表明，自噬的上调可能有助于对抗疾病的发病机制。然而，尽管最近报道了几种合成自噬诱导剂的小分子筛选，但不同结构和功能的天然化学物质尚未包括在合成文库中，并且缺乏对其在自噬中的作用的表征。为了发现新的自噬调节化合物并研究其治疗机制，我们使用分析化学方法从传统疗法中使用的药用植物库中分离天然植物化学物质。从这个中试植物代谢物库中，我们发现了几种新的诱导自噬的植物化学物质，包括Rg2。Rg2是一种类固醇糖苷化学物质，以ampk - ulk1依赖和mtor独立的方式激活自噬。在细胞模型中，Rg2诱导自噬增强了蛋白质聚集体的清除，改善了阿尔茨海默病小鼠模型中的认知行为，并预防高脂肪饮食诱导的胰岛素抵抗。因此，我们从药用植物中发现了一系列诱导自噬的植物化学物质，并发现其中一种化合物Rg2依赖于自噬途径的激活来介导代谢和神经营养作用。这些发现可能有助于解释药用植物如何发挥对代谢疾病的治疗作用。
ABSTRACT Autophagy is a housekeeping lysosomal degradation pathway important for cellular survival, homeostasis and function. Various disease models have shown that upregulation of autophagy may be beneficial to combat disease pathogenesis. However, despite several recently reported small-molecule screens for synthetic autophagy inducers, natural chemicals of diverse structures and functions have not been included in the synthetic libraries, and characterization of their roles in autophagy has been lacking. To discover novel autophagy-regulating compounds and study their therapeutic mechanisms, we used analytic chemistry approaches to isolate natural phytochemicals from a reservoir of medicinal plants used in traditional remedies. From this pilot plant metabolite library, we identified several novel autophagy-inducing phytochemicals, including Rg2. Rg2 is a steroid glycoside chemical that activates autophagy in an AMPK-ULK1-dependent and MTOR-independent manner. Induction of autophagy by Rg2 enhances the clearance of protein aggregates in a cell-based model, improves cognitive behaviors in a mouse model of Alzheimer disease, and prevents high-fat diet-induced insulin resistance. Thus, we discovered a series of autophagy-inducing phytochemicals from medicinal plants, and found that one of the compounds Rg2 mediates metabolic and neurotrophic effects dependent on activation of the autophagy pathway. These findings may help explain how medicinal plants exert the therapeutic functions against metabolic diseases.