Dunnione protects against experimental cisplatin-induced nephrotoxicity by modulating NQO1 and NAD⁺ levels

Abstract

Despite being an efficacious anticancer agent, the clinical utility of cisplatin is hindered by its cardinal side effects. This investigation aimed to appraise potential protective impact of dunnione, a natural naphthoquinone pigment with established NQO1 stimulatory effects, on cisplatin nephrotoxicity of rats. Dunnione was administered orally at 10 and 20 mg/kg doses for 4 d and a single injection of cisplatin was delivered at the second day. Renal histopathology, inflammatory/oxidative stress/apoptotic markers, kidney function, and urinary markers of renal injury were assessed. Dunnione repressed cisplatin-induced inflammation in the kidneys as indicated by decreased TNF-α/IL-1β levels, and reduced nuclear phosphorylated NF-κB p65. This agent also obviated cisplatin-invoked oxidative stress as elucidated by decreased MDA/GSH levels and increased SOD/CAT activities. Dunnione, furthermore, improved renal histological deteriorations as well as caspase-3 activities and terminal deoxynucleotidyl transferase (TUNEL) positive cells, the indicators of apoptosis. Moreover, it up-regulated nuclear Nrf2 and cytosolic haeme-oxygenase-1 (HO-1) and NQO1 levels; meanwhile, promoted NAD/NADH ratios followed by enhancing the activities of Sirt1 and PARP1; and further attenuated nuclear acetylated NF-κB p65. Dunnione additionally declined cisplatin-evoked retrogression in renal function and upraise in urinary markers of glomerular and tubular injury as demonstrated by decreased serum urea and creatinine with simultaneous reductions in urinary excretions of collagen type IV, podocin, cystatin C, and retinol-binding protein (RBP). Altogether, these findings offer dunnione as a potential protective agent against cisplatin-induced nephrotoxicity in rats.

Nephroprotective effect of umbelliferone against cisplatin‐induced kidney damage is mediated by regulation of NRF2, cytoglobin, SIRT1/FOXO‐3, and NF‐kB‐p65 signaling pathways

“…Interestingly, Cis decreased the molecular antioxidant defense system, as evidenced by the significant downregulation of renal NRF2, cytoglobin, CREB, SIRT1, and PPAR‐γ expressions along with FOXO‐3 upregulation. These results are in agreement with previous studies done by Cao et al [ 58 ] and Nassari Soltan Ahmad et al [ 59 ] On the contrary, UMB treatment resulted in a significant upregulation of NRF2 and cytoglobin proteins as well as an effective increase in the expression of NRF2, CREB, SIRT1, and PPAR‐γ genes along with FOXO‐3 downregulation. Our previous work showed that UMB attenuated oxidative injury and enhanced oxidant/antioxidant status in the methotrexate‐induced nephrotoxicity model, [ 29 ] supporting the role of UMB in attenuation of ROS injury.…”

β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

“…In favour of these findings, it has been demonstrated that dunnione, a natural quinone with extensive structural analogies to B-LAP, elevates nuclear presence of Nrf2 and simultaneously up-regulates the expressions of HO-1 and NQO1 in the kidneys of cisplatin nephrotoxic rats. 28 Additionally, Wang et al 29 showed that the activation of SIRT/LKB1/AMPK signalling pathway protects H9c2 cells, adult mice cardiomyocytes and 129S1/ SyImJ mice against DOX-induced cardiotoxicity through anti-oxidative, anti-apoptotic and anti-inflammatory actions. Moreover, it was reported that DOX-induced cardiotoxicity can be reversed by activation of Sirt1/AMPK/Nrf2 pathway by suppression of intracellular oxidative stress.…”

“…In the present study, B‐LAP, apart from modulating the inflammatory markers IL‐1β and TNF‐α, elevated nuclear accumulation of Nrf2 in cardiac tissues of DOX‐treated mice and enhanced both the gene expression and protein levels of HO‐1, as well as GST; it, additionally, up‐regulated the gene expression of NQO‐1 and cardiac activities of GPX, SOD and CAT, leading to diminished levels of MDA. In favour of these findings, it has been demonstrated that dunnione, a natural quinone with extensive structural analogies to B‐LAP, elevates nuclear presence of Nrf2 and simultaneously up‐regulates the expressions of HO‐1 and NQO1 in the kidneys of cisplatin nephrotoxic rats . Additionally, Wang et al .…”

Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD+-Dependent Enzymes and Plant-Derived Natural Products

“…Targeting NAD + redox balance has been suggested as a strategy for fighting cisplatin-induced kidney injury [ 18 , 60 ]. Therefore, there has been an increasing interest in studying redox biochemistry and NAD + redox signaling in the pathogenesis of cisplatin renal toxicity [ 32 , 61 , 62 , 63 , 64 ]. The major NAD + -dependent redox enzymes that may be involved in cisplatin-induced kidney injury are shown in Figure 4 .…”