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Flavanone glycosides inhibit β-site amyloid precursor protein cleaving enzyme 1 and cholinesterase and reduce Aβ aggregation in the amyloidogenic pathway.

Author(s): Ali MY, Jannat S, Edraki N, Das S, Chang WK, Kim HC, Park SK, Chang MS

Chem Biol Interact. 2019 Jun 10;: Authors: Ali MY, Jannat S, Edraki N, Das S, Chang WK, Kim HC, Park SK, Chang MS

Article GUID: 31194956
Didymin, a dietary citrus flavonoid exhibits anti-diabetic complications and promotes glucose uptake through the activation of PI3K/Akt signaling pathway in insulin-resistant HepG2 cells.

Author(s): Ali MY, Zaib S, Rahman MM, Jannat S, Iqbal J, Park SK, Chang MS

Chem Biol Interact. 2019 May 25;305:180-194 Authors: Ali MY, Zaib S, Rahman MM, Jannat S, Iqbal J, Park SK, Chang MS

Article GUID: 30928401
Title:Flavanone glycosides inhibit β-site amyloid precursor protein cleaving enzyme 1 and cholinesterase and reduce Aβ aggregation in the amyloidogenic pathway.
Authors:Ali MY,  Jannat S,  Edraki N,  Das S,  Chang WK,  Kim HC,  Park SK,  Chang MS
Link:https://www.ncbi.nlm.nih.gov/pubmed/31194956?dopt=Abstract
DOI:10.1016/j.cbi.2019.06.020
Category:Chem Biol Interact
PMID:31194956
Dept Affiliation: BIOLOGY
1 Department of Korean Medicine, Graduate School, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea; Department of Chemistry and Biochemistry, Faculty of Arts and Science, Concordia University, 7141, Sherbrooke St. W, Montreal, Quebec, Canada; Department of Biology, Faculty of Arts and Science, Concordia University, 7141, Sherbrooke St. W, Montreal, Quebec, Canada; Centre for Structural and Functional Genomic, Dept. of Biology, Faculty of Arts and Science, Concordia University, 7141, Sherbrooke St. W, Montreal, QC, Canada.
2 Department of Biochemistry and Molecular Biology, University of Calgary, T2N 1N4, Alberta, Canada.
3 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
4 Department of Microbiology, University of Calcutta, 35 Ballygunge, Kolkata, 700 019, India.
5 Department of Korean Medicine, Graduate School, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
6 Department of Korean Medicine, Graduate School, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea. Electronic address: mschang@khu.ac.kr.

Description:

Flavanone glycosides inhibit ß-site amyloid precursor protein cleaving enzyme 1 and cholinesterase and reduce Aß aggregation in the amyloidogenic pathway.

Chem Biol Interact. 2019 Jun 10;:

Authors: Ali MY, Jannat S, Edraki N, Das S, Chang WK, Kim HC, Park SK, Chang MS

Abstract

Alzheimer's disease (AD) is a slow but progressive neurodegenerative disease. One of the pathological hallmarks of AD is the progressive accumulation of ß-amyloid (Aß) in the form of senile plaques, and Aß insult to neuronal cells has been identified as one of the major causes of AD onset. In the present study, we investigated the anti-AD potential of four flavonoids, naringenin, didymin, prunin, and poncirin, by evaluating their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). All four flavonoids displayed promising inhibitory activity against AChE, BChE, and BACE1. Structure-activity relationships suggested that glycosylation of naringenin at sugar moieties, and at different positions of the glycosidic linkage, might be closely associated with anti-AD potential. Kinetic and docking studies showed the lowest binding energy and highest affinity for the mixed, competitive, and non-competitive type inhibitors didymin, prunin, and poncirin. Hydrophobic interactions and the number of hydrogen bonds determined the strength of the protein-inhibitor interaction. We also examined the neuroprotective mechanisms by which flavonoids act against Aß25-35-induced toxicity in PC12?cells. Exposure of PC12?cells to 10?µM?Aß25-35 for 24?h resulted in a significant decrease in cell viability. In addition, pretreatment of PC12?cells with different concentrations of flavonoids for 1?h significantly reversed the effects of Aß. Furthermore, treatment with the most active flavonoid, didymin, significantly reduced BACE1, APPsß, and C99 expression levels in a dose-dependent manner, without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Together, our results indicate that flavonoids, and in particular didymin, exhibit inhibitory activity in vitro, and may be useful in the development of therapeutic modalities for the treatment of AD.

PMID: 31194956 [PubMed - as supplied by publisher]