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Tetrahydroxy stilbene glycoside alleviated inflammatory damage by mitophagy via AMPK related PINK1/Parkin signaling pathway

发布时间:1697698547 人气: 来源:

期刊名:Biochemical Pharmacology

发表日期: 27 April 2020

文章地址https://doi.org/10.1016/j.bcp.2020.113997

Abstract

Alzheimer’s disease (AD) is an irreversible neurodegenerative brain disorder with complex pathogenesis. The fibrillar peptide β-amyloid (Aβ) has a chief function in the pathogenesis of AD. Emerging evidence has indicated that there is a tight relationship between inflammation, mitochondrial dysfunction and Aβ formation. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. Recent research corroborated the beneficial roles of TSG in alleviating the learning and memory of AD models. Unfortunately, the underlying mechanism of TSG remains poorly elucidated. The purpose of the present study was to investigate the effects of TSG on LPS/ATP and Aβ25-35-induced inflammation in microglia and neurons and its underlying molecular mechanisms. Our results found that treatment with TSG significantly attenuated the secretion of inflammatory cytokines, reduced NLRP3 inflammasome, and regulated mitophagy. TSG efficiently alleviated LPS-induced inflammatory response by inhibiting the NLRP3 signaling pathway both in microglia and neuron. Meanwhile, TSG promoted autophagy involved in the AMPK/PINK1/Parkin signaling pathway, which may contribute to the protective activity. Additional mechanistic investigations to evaluate the dependence of the neuroprotective role of TSG on PINK1 revealed that a lack of PINK1 inhibited autophagy, especially mitophagy in microglia. Importantly, knockdown of PINK1 or Parkin by siRNA or CRISPR/Cas9 system abolished the protective effects of TSG. In conclusion, these phenomena suggested that TSG prevented LPS/ATP and Aβ-induced inflammation via AMPK/PINK1/Parkin-dependent enhancement of mitophagy. We found the neuroprotective effect of TSG, suggesting it may be beneficial for AD prevention and treatment by suppressing the activation of inflammation.

Section snippets

Used reagents

TSG, molecular weight of 406 (purity > 98%), was purchased from Chengdu Pufei De Biotech Co., Ltd (Sichuan, China). LPS was purchased from Sigma (CA, USA). Dulbecco’s modified Eagle’s medium (DMEM) and fetal bovine serum (FBS) were obtained from Gibco, Thermo Fisher Scientific (NY, USA). Rapamycin (Rapa) or chloroquine (CQ) was purchased from Sigma Aldrich, St Louis, MO, USA. MitoBright Red was purchased from Dojindo (Tokyo, Japan)

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