title: Suppression in PHLPP2 induction by morin promotes Nrf2-regulated cellular defenses against oxidative injury to primary rat hepatocytes.
abstract: Recent advances indicate a possible role of phytochemicals as modulatory factors in signaling pathways. We have previously demonstrated PHLPP2-mediated suppression of Nrf2 responses during oxidant attack. The present study was designed to explore Nrf2-potentiating mechanism of morin, a flavonol, via its possible role in intervening PHLPP2-regulated Akt/GSK3β/Fyn kinase axis. Efficacy of morin was evaluated against oxidative stress-mediated damage to primary hepatocytes by tert-butyl hydroperoxide (tBHP) and acetaminophen. The anti-cytotoxic effects of morin were found to be a consequence of fortification of Nrf2-regulated antioxidant defenses since morin failed to sustain activities of redox enzyme in Nrf2 silenced hepatocytes. Morin promoted Nrf2 stability and its nuclear retention by possibly modulating PHLPP2 activity which subdues cellular Nrf2 responses by activating Fyn kinase. Pull-down assay using morin-conjugated beads indicated the binding affinity of morin towards PHLPP2. Molecular docking also revealed the propensity of morin to occupy the active site of PHLPP2 enzyme. Thus, dietary phytochemical morin was observed to counteract oxidant-induced hepatocellular damage by promoting Nrf2-regulated transcriptional induction. The findings support the novel role of morin in potentiating Nrf2 responses by limiting PHLPP2 and hence Fyn kinase activation. Therefore, morin may be exploited in developing novel therapeutic strategy aimed at enhancing Nrf2 responses.
authors.affiliation: Herbal Research Laboratory, Food Drug and Chemical Toxicology Group, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Post Box No. 80, M.G. Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research, CSIR-IITR campus, Lucknow, India.
authors.forename: Fatima
authors.initials: F
authors.lastname: Rizvi
authors.affiliation: Herbal Research Laboratory, Food Drug and Chemical Toxicology Group, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Post Box No. 80, M.G. Marg, Lucknow 226001, Uttar Pradesh, India.
authors.forename: Alpana
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Molecular and Structural Biology Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, Uttar Pradesh, India.
authors.forename: Shagun
authors.initials: S
authors.lastname: Krishna
authors.affiliation: Molecular and Structural Biology Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, Uttar Pradesh, India.
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
authors.affiliation: Herbal Research Laboratory, Food Drug and Chemical Toxicology Group, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Post Box No. 80, M.G. Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research, CSIR-IITR campus, Lucknow, India. Electronic address: pkakkar@iitr.res.in.
authors.forename: Poonam
authors.initials: P
authors.lastname: Kakkar
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D020134:Catalytic Domain; D002478:Cells, Cultured; D019610:Cytoprotection; D004353:Drug Evaluation, Preclinical; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D062105:Molecular Docking Simulation; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D061251:Primary Cell Culture; D011485:Protein Binding; D055550:Protein Stability; D017208:Rats, Wistar; D015533:Transcriptional Activation; D047309:Flavones
chemical_list: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D005419:Flavonoids; D051267:NF-E2-Related Factor 2; D010749:Phosphoprotein Phosphatases; C495637:Nfe2l2 protein, rat; C008548:morin; D047309:Flavones; C541124:PHLPP2 protein, rat
keywords: Flavonoid; Fyn kinase; Nrf2; Oxidative stress; PHLPP2