Morin hydrate ameliorates cisplatin-induced ER stress, inflammation and autophagy in HEK-293 cells and mice kidney via PARP-1 regulation

Morin hydrate ameliorates cisplatin-induced ER stress, inflammation and autophagy in HEK-293... The present study assessed the possible therapeutic potential of a natural flavonoid morin hydrate (MH), against cisplatin (CP) induced toxicity in HEK-293 cells and mice kidney. Herein, we observed that exposure of HEK-293 cells to CP (20 μM, 24 h) reduced the cell viability, and increased the intracellular ROS generation, nuclear DNA damage, Ca++ release, and accumulation of acidic vacuoles. Concomitantly, acute exposure of CP (30 mg/kg, 72 h) to male ICR mice induced histopathological changes in kidney tissue, and alterations in serum creatinine and blood urea nitrogen (BUN) levels. Oxidative stress mediated ER-stress was evidenced by the reduced expression of antioxidant enzymes such as SOD-1, SOD-2, GR, and Trx, and increased expression levels of CytP450, IRE1-α, PERK, and CHOP. The expression levels of major inflammatory response markers such as NF-κB, TNF-α, IL-1β, COX-2 and iNOS were significantly increased in the HEK-293 cells and mice kidney. Temporal up-regulation of p-AMPK and LC3I/II, and down regulation of mTOR was also noticed after CP treatment. CP-induced DNA damage led to activation of PARP-1, which plays a crucial role in inflammation, apoptosis and autophagy activation. Concurrently, co-treatment of CP-MH and CP-ANI (PARP-1 inhibitor) significantly attenuated the expression level of PARP-1, reduced cellular death, alleviated inflammatory responses, and inhibited autophagy stimulation in HEK-293 cells and mice kidney. On the basis of above findings, we suggest MH as a potential therapeutic agent against CP-induced nephrotoxicity. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Immunopharmacology Elsevier

Morin hydrate ameliorates cisplatin-induced ER stress, inflammation and autophagy in HEK-293 cells and mice kidney via PARP-1 regulation

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Publisher
Elsevier
Copyright
Copyright © 2018 Elsevier B.V.
ISSN
1567-5769
eISSN
1878-1705
D.O.I.
10.1016/j.intimp.2018.01.031
Publisher site
See Article on Publisher Site

Abstract

The present study assessed the possible therapeutic potential of a natural flavonoid morin hydrate (MH), against cisplatin (CP) induced toxicity in HEK-293 cells and mice kidney. Herein, we observed that exposure of HEK-293 cells to CP (20 μM, 24 h) reduced the cell viability, and increased the intracellular ROS generation, nuclear DNA damage, Ca++ release, and accumulation of acidic vacuoles. Concomitantly, acute exposure of CP (30 mg/kg, 72 h) to male ICR mice induced histopathological changes in kidney tissue, and alterations in serum creatinine and blood urea nitrogen (BUN) levels. Oxidative stress mediated ER-stress was evidenced by the reduced expression of antioxidant enzymes such as SOD-1, SOD-2, GR, and Trx, and increased expression levels of CytP450, IRE1-α, PERK, and CHOP. The expression levels of major inflammatory response markers such as NF-κB, TNF-α, IL-1β, COX-2 and iNOS were significantly increased in the HEK-293 cells and mice kidney. Temporal up-regulation of p-AMPK and LC3I/II, and down regulation of mTOR was also noticed after CP treatment. CP-induced DNA damage led to activation of PARP-1, which plays a crucial role in inflammation, apoptosis and autophagy activation. Concurrently, co-treatment of CP-MH and CP-ANI (PARP-1 inhibitor) significantly attenuated the expression level of PARP-1, reduced cellular death, alleviated inflammatory responses, and inhibited autophagy stimulation in HEK-293 cells and mice kidney. On the basis of above findings, we suggest MH as a potential therapeutic agent against CP-induced nephrotoxicity.

Journal

International ImmunopharmacologyElsevier

Published: Mar 1, 2018

References

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