Physalin B reduces Aβ secretion through down-regulation of BACE1 expression by activating FoxO1 and inhibiting STAT3 phosphorylation

Zhang, Wei; Bai, Shanshan; Zhang, Qi; Shi, Ruihan; Wang, He-Cheng; Liu, You-Cai; Wu, Ying; Yao, Zhaoyang; Sun, Yi; Wang, Mingyong

doi:10.1016/s1875-5364(21)60090-0

Cited by 13 publications

(9 citation statements)

References 39 publications

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“…A FOXO1 mutant that lacks DNA-binding activity can regulate target gene expression ( Ramaswamy et al., 2002 ). In addition, FOXO1 can regulate target gene transcription through direct interaction with other transcription factors, such as STAT3 ( Yang et al., 2009 ; Oh et al., 2012 ; Ma et al., 2015 ; Zhang et al., 2021 ). STAT3 is a critical transcription factor in inflammatory responses and induces the expression of a large array of inflammatory mediators ( Hillmer et al., 2016 ).…”

Section: Discussionmentioning

confidence: 99%

FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter

Huang²,

Zhu³

et al. 2022

Front. Cell. Infect. Microbiol.

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Integrin β6 (ITGB6), an epithelial-specific receptor, is downregulated in the gingival epithelium of periodontitis and is associated with inflammation response and periodontitis development. However, the transcriptional regulatory mechanism of ITGB6 downregulation in the human gingival epithelium remains unclear. Fibroblast-stimulating lipopeptide-1 (FSL-1), an oral biofilm component, promotes an epithelial cell-driven proinflammatory response in periodontitis partially by suppressing ITGB6 expression. The aim of the current study was to investigate the transcriptional regulatory mechanism of ITGB6 inhibition by FSL-1 in human epithelial cells (HaCaT and primary human gingival epithelial cells), and to delineate the transcriptional mechanism of ITGB6 suppression in periodontitis. We found that FSL-1 inhibited ITGB6 transcription through increasing forkhead box protein O1 (FOXO1) expression and inhibiting signal transducer and activator of transcription 3 (STAT3) activation. Furthermore, FOXO1 bound to STAT3 directly, leading to decreased STAT3 phosphorylation induced by FSL-1. Consequently, the binding of phosphorylated STAT3 to the ITGB6 promoter was decreased, and ITGB6 transcription was therefore downregulated following FSL-1 stimulation. The reciprocal action of STAT3 and FOXO1 on ITGB6 downregulation was also confirmed by the immunostaining of the inflammatory epithelium associated with periodontitis. Our findings suggest that the interaction of FOXO1–STAT3 may be a useful signal target for the treatment of periodontitis.

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Section: Discussionmentioning

confidence: 99%

FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter

Huang²,

Zhu³

et al. 2022

Front. Cell. Infect. Microbiol.

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“… 11 , 12 , 13 FoxO1 is expressed in different brain regions, especially in the hippocampus. 14 In our previous study, FoxO1 levels were found to be significantly lower in the cortical tissue of 6‐month‐old APP/presenilin 1 (PS1) transgenic mice compared to wild‐type mice. Overexpression of FoxO1 in an AD cell model effectively reduces the levels of Aβ and Tau phosphorylation.…”

Section: Introductionmentioning

confidence: 92%

In silico and in vitro analyses of a novel FoxO1 agonist reducing Aβ levels via downregulation of BACE1

Wang

Meng

et al. 2023

CNS Neurosci Ther

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AimsFoxO1 is an important target in the treatment of Alzheimer's disease (AD). However, FoxO1‐specific agonists and their effects on AD have not yet been reported. This study aimed to identify small molecules that upregulate the activity of FoxO1 to attenuate the symptoms of AD.MethodsFoxO1 agonists were identified by in silico screening and molecular dynamics simulation. Western blotting and reverse transcription‐quantitative polymerase chain reaction assays were used to assess protein and gene expression levels of P21, BIM, and PPARγ downstream of FoxO1 in SH‐SY5Y cells, respectively. Western blotting and enzyme‐linked immunoassays were performed to explore the effect of FoxO1 agonists on APP metabolism.ResultsN‐(3‐methylisothiazol‐5‐yl)‐2‐(2‐oxobenzo[d]oxazol‐3(2H)‐yl) acetamide (compound D) had the highest affinity for FoxO1. Compound D activated FoxO1 and regulated the expression of its downstream target genes, P21, BIM, and PPARγ. In SH‐SY5Y cells treated with compound D, BACE1 expression levels were downregulated, and the levels of Aβ1‐40 and Aβ1‐42 were also reduced.ConclusionsWe present a novel small‐molecule FoxO1 agonist with good anti‐AD effects. This study highlights a promising strategy for new drug discovery for AD.

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“…19 In terms of user comfort, floor-type fan coil air conditioning systems can improve indoor thermal comfort in cultural heritage buildings. 20 Intelligent control strategies and equipment can effectively improve the comfort of courtyards during winter. 21 The application of adaptive building facades can improve the health of occupants, 22 and microclimate analysis methods can optimize the living conditions of historical buildings and also protect displayed artworks.…”

Section: Functional Adaptation Of Cultural Heritage In Built Environm...mentioning

confidence: 99%

The adaptation of cultural heritage in built environments

Wang,

He,

Xue

et al. 2023

Indoor and Built Environment

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Physalin B reduces Aβ secretion through down-regulation of BACE1 expression by activating FoxO1 and inhibiting STAT3 phosphorylation

Cited by 13 publications

References 39 publications

FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter

FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter

In silico and in vitro analyses of a novel FoxO1 agonist reducing Aβ levels via downregulation of BACE1

The adaptation of cultural heritage in built environments

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