PUBLICATION
Shinorine ameliorates chromium induced toxicity in zebrafish hepatocytes through the facultative activation of Nrf2-Keap1-ARE pathway
- Authors
- Shaw, P., Sen, A., Mondal, P., Dey Bhowmik, A., Rath, J., Chattopadhyay, A.
- ID
- ZDB-PUB-201002-95
- Date
- 2020
- Source
- Aquatic toxicology (Amsterdam, Netherlands) 228: 105622 (Journal)
- Registered Authors
- Keywords
- Amelioration, Chromium toxicity, Molecular docking, Nrf2-Keap1, ROS, Shinorine, Zebrafish hepatocytes
- MeSH Terms
-
- Animals
- Cell Survival/drug effects
- Cells, Cultured
- Chromium/toxicity*
- Cyanobacteria/metabolism
- Cyclohexylamines/isolation & purification
- Cyclohexylamines/pharmacology*
- Glycine/analogs & derivatives*
- Glycine/isolation & purification
- Glycine/pharmacology
- Hepatocytes/drug effects*
- Hepatocytes/metabolism
- Hepatocytes/pathology
- Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors*
- Kelch-Like ECH-Associated Protein 1/metabolism
- Molecular Docking Simulation
- NF-E2-Related Factor 2/metabolism*
- Oxidative Stress/drug effects
- Primary Cell Culture
- Signal Transduction
- Water Pollutants, Chemical/toxicity*
- Zebrafish/metabolism*
- PubMed
- 32947073 Full text @ Aquat. Toxicol.
Citation
Shaw, P., Sen, A., Mondal, P., Dey Bhowmik, A., Rath, J., Chattopadhyay, A. (2020) Shinorine ameliorates chromium induced toxicity in zebrafish hepatocytes through the facultative activation of Nrf2-Keap1-ARE pathway. Aquatic toxicology (Amsterdam, Netherlands). 228:105622.
Abstract
Hexavalent chromium, a heavy metal toxicant, abundantly found in the environment showed hepatotoxic potential in zebrafish liver and instigated the Nrf2-Keap1-ARE pathway as a cellular stress response as reported in our previous studies. In the present study we have evaluated the ameliorating effect of shinorine, a mycosporine like amino acid (MAAs) and a mammalian Keap1 antagonist against chromium induced stress in zebrafish hepatocytes. Shinorine was found to be effective in increasing the cell viability of chromium treated hepatocytes through curtailing the cellular ROS content. Trigonelline, an Nrf2 inhibitor was found to reduce the viability of hepatocyte cultures co-exposed to shinorine and chromium. In other words, trigonelline being an Nrf2 blocker neutralised the alleviating effect of shinorine. This indicated that shinorine mediated cyto-protection in Cr [VI]-intoxicated cells is Nrf2 dependent. Further, qRT-PCR analysis revealed comparatively higher expression of nfe2l2 and nqo1 in shinorine + chromium treated hepatocytes than cells exposed to chromium alone indicating a better functioning of Nrf2-Keap1-Nqo1 axis. To further confirm if shinorine can lead to disruption of Nrf2-Keap1 interaction in zebrafish hepatocytes and render cytoprotection to chromium exposure, our in silico analysis through molecular docking revealed that shinorine could bind to the active amino acid residues of the DGR domain, responsible for Nrf2-Keap1 interaction of all the three Keap1s evaluated. This is the first report about shinorine that ameliorates chromium induced toxicity through acting as an Nrf2-Keap1 interaction disruptor. We additionally carried out in-silico pharmacokinetic and ADMET studies to evaluate druglikeness of shinorine whose promising results indicated its potential to be developed as an ideal therapeutic candidate against toxicant induced pathological conditions.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping