Copper Deficiency Induces Oxidative Stress in Liver of Mice by Blocking the Nrf2 Pathway.

Copper (Cu) is an essential metal required for many physiological processes and biological reactions. Liver is the main organ of metabolism of Cu and is also the site where synthesis of some metalloproteins. The purpose of this study is to explore the effects of Cu deficiency on the liver and to evaluate the changes in liver oxidative stress levels to reveal its possible impact mechanisms. Mice were feed to a nutritional Cu-deficiency diet from weaning and injected with copper sulfate (CuSO4) intraperitoneally to correct Cu deficiency. Cu deficiency resulted in reduced liver index, liver histological alteration, and oxidative stress; decreased the contents of Cu and ALB; elevated ALT and AST concentrations in serum together with decreased mRNA and protein expressions of Nrf2 pathway related molecules (Nrf2, HO-1, NQO1); and increased mRNA and protein expressions of Keap1. However, the supplement of copper sulfate (CuSO4) significantly ameliorated the changes mentioned above. Our results indicate that Cu deficiency can cause hepatic damage in mice is associated with the activation of oxidative stress and inhibition of Nrf2 pathway.

Silibinin ameliorates cisplatin-induced acute kidney injury via activating Nfe2l1-mediated antioxidative response to suppress the ROS/MAPK signaling pathway.

Cisplatin, a first-line chemotherapeutic agent commonly used to treat various solid tumors, induce severe adverse effects, especially nephrotoxicity, which largely limits its clinical application. However, the currently used measures to prevent nephrotoxicity are not ideal owing to the mechanisms underlying cisplatin-induced nephrotoxicity are not comprehensively understood. Herein, we examined the effects of silibinin on cisplatin-induced nephrotoxicity and found that silibinin exerted cytoprotection effects during cisplatin treatment in HEK293 cells and in a cisplatin-induced acute kidney injury (AKI) model. Mechanistically, silibinin ameliorated cisplatin-induced AKI via decreasing ROS-mediated MAPK signaling pathway activation, which was confirmed using the inhibitor N-acetylcysteine. Moreover, the protective effect of silibinin against cisplatin-induced ROS generation through the antioxidant transcription factor nuclear factor-erythroid 2-related factor 1 (Nfe2l1), rather than Nfe2l2, mediates HO1 expression. Furthermore, interference with the abundance of Nfe2l1 using siRNA or an overexpression plasmid enhanced or decreased the effect of cisplatin-induced apoptosis, respectively, in HEK293 cells. Interestingly, Nfe2l1 protein stability was more sensitive to cisplatin than that of Nfe2l2. More importantly, the mechanism that silibinin activates Nfe2l1-mediated antioxidant responses was confirmed in a cisplatin-induced AKI model. Silibinin rescued cisplatin-induced Nfe2l1 inhibition by regulating its transcription and post-translational modifications. Taken together, our results reveal a novel mechanism by which silibinin ameliorates cisplatin-induced AKI via activating Nfe2l1-mediated antioxidative response, which provides a new insights to protect patients receiving cisplatin-based cancer treatment against AKI.