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- W2770552203 abstract "Hyperglycemia provokes ROS mediated oxidation of macromolecules resulting in their malfunction. Proteins being one of the abundant cellular macromolecules are prone to oxidation leading to conformational changes, loss of activity and accumulation in ER. Accumulation of misfolded proteins results in ER stress and activates the unfolded protein response (UPR) sensors i.e. PERK, ATF-6 and IRE-1α to enhance the proper protein folding activity. Activation of PERK arrests global protein synthesis by phosphorylating eIF2α at Ser51 which in turn, transcribes ATF4 and CHOP that inhibits anti-apoptotic protein Bcl2 thereby inducing apoptosis (proteotoxic apoptosis) via caspase-3 pathway during sustained ER stress. This study was aimed to assess the effect of a bioflavonoid, morin, to reduce ER stress provoked hepatotoxicity in diabetic male Wistar rats. Earlier we showed that Morin reduces hepatotoxicity by modulating PHLPP2/GSK3β/Nrf2 axis resulting into enhanced antioxidant response. ER stress inhibitory potential of Morin was compared with a known ER stress chemical inhibitor, ISRIB in diabetic rats. Protein disulfide isomerase assay, microsomal GSH/GSSG ratio and total thiol levels indicated that Morin reduced ER stress significantly. Pull down assay established that Morin inhibits PERK activation by interacting with its luminal domain which was further confirmed by molecular docking studies. Further, immunoblotting and immunofluorescence studies showed that Morin reduced UPR sensor activation and down-regulated their target proteins such as IRE-1, ATF6, p-eIF2α, XBP1, Bip, PDI, ATF-4, and CHOP, thereby preventing ER stress significantly. Moreover, histopathological studies confirmed prevention of hepatic injury by Morin. Thus, the study shows that Morin may reduce diabetic hepatotoxicity by attenuating ER stress induced cell death through PERK inactivation." @default.
- W2770552203 created "2017-12-04" @default.
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- W2770552203 date "2017-11-01" @default.
- W2770552203 modified "2023-09-27" @default.
- W2770552203 title "Morin Prevents ER Stress Mediated Hepatotoxicity by Modulating PERK-eIF2α-ATF4 Axis in Diabetic Male Wistar Rats" @default.
- W2770552203 doi "https://doi.org/10.1016/j.freeradbiomed.2017.10.236" @default.
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