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Identification of a novel BACE1 inhibitor, timosaponin A-III, for treatment of Alzheimer's disease by a cell extraction and chemogenomics target knowledgebase-guided method.
Wang, Hai-Qiao; Liu, Min; Wang, Liang; Lan, Fen; Zhang, Yi-Han; Xia, Jin-Er; Xu, Zhen-Dong; Zhang, Hai.
Afiliação
  • Wang HQ; Department of Traditional Chinese Medicine, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201112, China.
  • Liu M; Department of Pharmacy, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
  • Wang L; Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
  • Lan F; Department of Pharmacy, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
  • Zhang YH; Department of Pharmacy, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
  • Xia JE; Department of Pharmacy, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
  • Xu ZD; Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China. Electronic address: btxzd123@126.com.
  • Zhang H; Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China. Electronic address: zhxdks2005@126.com.
Phytomedicine ; 75: 153244, 2020 May 24.
Article em En | MEDLINE | ID: mdl-32502824
ABSTRACT

BACKGROUND:

Rhizoma Anemarrhenae (RA) has been conventionally used for treatment of Alzheimer's disease (AD) in Traditional Chinese Medicine, and thus, the active components from RA can be screened.

PURPOSE:

This research aimed to identify the active components of RA and their targets and further clarify the molecular mechanisms underlying its anti-AD activity.

METHODS:

First, the potential active compounds from RA were screened by neurocyte extraction and micro-dialysis methods. Second, the potential targets were predicted by a chemogenomics target knowledgebase and further explored by surface plasmon resonance and enzyme activity assays. Third, the pharmacological effects were evaluated by employing APP/PS1 transgenic mice and SH-SY5Y-APP cells. ELISAs and Western blot analyses were used to evaluate the expression of key molecules in the amyloidogenic and NMDAR/ERK pathways.

RESULTS:

Timosaponin A-III (TA-III) was screened and identified as a potential active component for the anti-AD activity, and BACE1 was proven to be a potential high-affinity target. Enzyme kinetic analysis showed that TA-III had strong noncompetitive inhibitory activity against BACE1. The in vitro and in vivo assays indicated that TA-III had pharmacological effects through improving memory impairment, reducing Aß aggregation via the amyloidogenic pathway and preventing neuronal impairment through downregulating the NMDAR/ERK signaling pathway.

CONCLUSION:

TA-III targets BACE1 to reduce Aß aggregation through down-regulating the NMDAR/ERK pathway for treating AD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Diagnostic_studies Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Diagnostic_studies Idioma: En Ano de publicação: 2020 Tipo de documento: Article