title: Identification of natural products with neuronal and metabolic benefits through autophagy induction.
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.
authors: a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.|b Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University , Changchun, Jilin , China.
authors: Yuying
authors: Y
authors: Fan
authors: a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.|c Key Laboratory of Industrial Microbiology , Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology , Tianjin , China.
authors: Nan
authors: N
authors: Wang
authors: a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.
authors: Altea
authors: A
authors: Rocchi
authors: a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.
authors: Weiran
authors: W
authors: Zhang
authors: a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.
authors: Robert
authors: R
authors: Vassar
authors: b Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University , Changchun, Jilin , China.
authors: Yifa
authors: Y
authors: Zhou
authors: a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.
authors: Congcong
authors: C
authors: He
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D001688:Biological Products / Q000032:analysis / Q000302:isolation & purification*; D002470:Cell Survival; D003071:Cognition; D003213:Conditioning, Psychological; D004195:Disease Models, Animal; D005239:Fear; D006027:Glycosides / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D007333:Insulin Resistance; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D064209:Phytochemicals / Q000032:analysis / Q000302:isolation & purification*; D051381:Rats; D013256:Steroids / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D001688:Biological Products; D006027:Glycosides; D064209:Phytochemicals; D013256:Steroids; D058570:TOR Serine-Threonine Kinases
keywords: AMPK; Alzheimer's disease; amyloid; autophagy induction; ginsenoside; glycoconjugate; insulin resistance; medicinal plant; phytochemical