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Protective effects of dioscin against cisplatin-induced nephrotoxicity via the microRNA-34a/sirtuin 1 signalling pathway.
- Source :
-
British Journal of Pharmacology . Aug2017, Vol. 174 Issue 15, p2512-2527. 16p. - Publication Year :
- 2017
-
Abstract
- <bold>Background and Purpose: </bold>Dioscin exhibits a range of pharmacological actions but little is known of its effects on cisplatin (CDDP)-induced nephrotoxicity. Here, we have assessed the effects and the possible mechanisms of dioscin against CDDP-induced nephrotoxicity.<bold>Experimental Approach: </bold>We used an in vivo model of CDDP-induced nephrotoxicity in rats and mice and, in vitro, cultures of NRK-52E and HK-2 cells. The dual luciferase reporter assay was used to demonstrate modulation, by dioscin, of the targeting of sirtuin 1 (Sirt1) by microRNA (miR)-34a. Molecular docking assays were used to analyse the effects of dioscin with Sirt1, Keap1 and NF-κB.<bold>Key Results: </bold>Dioscin attenuated cell damage in vitro and decreased renal injury in rats and mice, treated with CDDP. In terms of mechanisms, dioscin reversed CDDP-induced up-regulation of miR-34a and thus up-regulated Sirt1 levels. In addition, dioscin altered levels of haem oxygenase 1, glutathione-cysteine ligase subunits (GCLC, GCLM) and Keap1, along with increased nuclear translocation of Nrf2, thus decreasing oxidative stress. Also, dioscin affected levels of AP-1, COX-2, HMGB1, IκB-α, IL-1β, IL-6 and TNF-α and decreased the ratio of acetylated NF-κB and normal NF-κB, to suppress inflammation. From molecular docking assays, dioscin directly bound to Sirt1, Keap1 and NF-κBp65 by hydrogen bonding and/or hydrophobic interactions.<bold>Conclusions and Implications: </bold>Our results have linked CDDP-induced nephrotoxicity and the miR-34a/Sirt1 signalling pathway, which was modulated by dioscin. This natural product could be developed as a new candidate to alleviate CDDP-induced renal injury. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CISPLATIN
*NEPHROTOXICOLOGY
*CELLS
*MICRORNA
*SIRTUINS
*RNA metabolism
*ANIMAL experimentation
*ANTINEOPLASTIC agents
*BIOCHEMISTRY
*CELL culture
*CELLULAR signal transduction
*COMPUTER simulation
*DOSE-effect relationship in pharmacology
*KIDNEYS
*PHENOMENOLOGY
*MICE
*MOLECULAR structure
*RATS
*RNA
*STEROIDS
*TRANSFERASES
*OXIDATIVE stress
*CHEMICAL inhibitors
*PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 174
- Issue :
- 15
- Database :
- Academic Search Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 124150526
- Full Text :
- https://doi.org/10.1111/bph.13862