title: Hormetic effect of panaxatriol saponins confers neuroprotection in PC12 cells and zebrafish through PI3K/AKT/mTOR and AMPK/SIRT1/FOXO3 pathways.
abstract: Hormesis is an adaptive response of living organisms to a moderate stress. However, its biomedical implication and molecular mechanisms remain to be intensively investigated. Panaxatriol saponins (PTS) is the major bioactive components extracted from Panax notoginseng, a widely used herbal medicine for cerebrovascular diseases. This study aims to examine the hormetic and neuroprotective effects of PTS in PC12 cells and zebrafish Parkinson's disease (PD) models. Our results demonstrated that PTS stimulated PC12 cell growth by about 30% at low doses, while PTS at high doses inhibited cell growth, which is a typical hormetic effect. Moreover, we found that low dose PTS pretreatment significantly attenuated 6-OHDA-induced cytotoxicity and up-regulated PI3K/AKT/mTOR cell proliferation pathway and AMPK/SIRT1/FOXO3 cell survival pathway in PC12 cells. These results strongly suggested that neuroprotective effects of PTS may be attributable to the hormetic effect induced by PTS through activating adaptive response-related signaling pathways. Notably, low dose PTS could significantly prevent the 6-OHDA-induced dopaminergic neuron loss and improve the behavior movement deficiency in zebrafish, whereas relative high dose PTS exhibited neural toxicity, further supporting the hormetic and neuroprotective effects of PTS. This study indicates that PTS may have the potential in the development of future therapeutic medicines for PD.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Chuwen
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.|Lee's Pharmaceutical (Hong Kong) Ltd., Shatin, Hong Kong 999077, China.
authors.forename: Shenghui
authors.initials: S
authors.lastname: Chen
authors.affiliation: Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, Shandong Provincial Key Laboratory for Biosensor, Biology Institute of Shandong Academy of Sciences, Jinan 250014, China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Jiaolin
authors.initials: J
authors.lastname: Bao
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Yeer
authors.initials: Y
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Meiwan
authors.initials: M
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Huanxing
authors.initials: H
authors.lastname: Su
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Simon Ming Yuen
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, Shandong Provincial Key Laboratory for Biosensor, Biology Institute of Shandong Academy of Sciences, Jinan 250014, China.
authors.forename: Kechun
authors.initials: K
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Jian-Bo
authors.initials: JB
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors.forename: Chengwei
authors.initials: C
authors.lastname: He
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D000071316:Forkhead Box Protein O3 / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D036145:Ginsenosides / Q000008:administration & dosage* / Q000737:chemistry; D059165:Hormesis / Q000187:drug effects* / Q000235:genetics; D000066829:Neuroprotection / Q000187:drug effects; D016716:PC12 Cells; D053723:Panax notoginseng / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D051381:Rats; D012503:Saponins / Q000008:administration & dosage* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D015027:Zebrafish / Q000235:genetics*
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D000071316:Forkhead Box Protein O3; D036145:Ginsenosides; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D012503:Saponins; D056564:Sirtuin 1; D058570:TOR Serine-Threonine Kinases; C004563:panaxatriol; C488368:Sirt1 protein, rat