Please use this identifier to cite or link to this item: https://doi.org/10.1002/cmdc.202200292
Title: Ribisins and Certain Analogues Exert Neuroprotective Effects through Activation of the Keap1-Nrf2-ARE Pathway
Authors: Tan, Shen H
Karuppasamy, Muthukumar
Lan, Ping
Zhang, Yaochun 
Hu, Jiayi
Lai, Xingchen
Lim, Belinda Siok-Cheng
Liu, Weiliang
Chen, Jing
Chew, Eng-Hui 
Banwell, Martin G
Keywords: Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
Anti-oxidant
neuroprotection
Nrf2-binding Kelch domain
ribisins
synthetic analogues
ALZHEIMERS-DISEASE BRAIN
OXIDATIVE STRESS
BENZOFURAN DERIVATIVES
LIPID-PEROXIDATION
KEAP1
NRF2
INDUCTION
STABILIZATION
INDUCERS
QUINONE
Issue Date: 16-Sep-2022
Publisher: WILEY-V C H VERLAG GMBH
Citation: Tan, Shen H, Karuppasamy, Muthukumar, Lan, Ping, Zhang, Yaochun, Hu, Jiayi, Lai, Xingchen, Lim, Belinda Siok-Cheng, Liu, Weiliang, Chen, Jing, Chew, Eng-Hui, Banwell, Martin G (2022-09-16). Ribisins and Certain Analogues Exert Neuroprotective Effects through Activation of the Keap1-Nrf2-ARE Pathway. CHEMMEDCHEM 17 (18). ScholarBank@NUS Repository. https://doi.org/10.1002/cmdc.202200292
Abstract: Oxidative stress contributes to the pathogenesis of various neurodegenerative diseases and induction of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is a validated neuroprotective strategy. Synthetically-derived samples of members of the ribisin class of natural product together with a range of analogues were evaluated for their neuroprotective capacities. Four of the twenty-four compounds tested were found to strongly stimulate antioxidant response element-dependent transcriptional activity in human-derived SH-SY5Y cells. Further, in rat pheochromocytoma PC12 cells and mouse brain cortical cultures these compounds upregulated levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target gene products, namely heme oxygenase (HO-1) and NAD(P)H quinone reductase 1 (NQO1). Functionally speaking, the compounds conferred protection in these cell models challenged with H2O2. In silico molecular modeling suggests that certain of the ribisins can dock in the Nrf2-binding Kelch domain in Keap1, while cysteine labeling by biotinylated iodoacetamide suggest that cysteine residues within Keap1 react with the ribisins. It is thus proposed that the most active compounds exert their neuroprotective activities by targeting Keap1, thereby activating Nrf2 and so increasing transactivation of Nrf2-responsive genes that encode for detoxifying and antioxidant enzymes.
Source Title: CHEMMEDCHEM
URI: https://scholarbank.nus.edu.sg/handle/10635/245074
ISSN: 1860-7179
1860-7187
DOI: 10.1002/cmdc.202200292
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