Cadmium (Cd) is a potent neurotoxic metal present in the environment and food. In this study, CdCl2 (2 or 4 μM) induced cytotoxicity and neurotoxicity in PC12 cells, causing decreases in cell viability and NEP protein expression and increase in p‐tau protein expression. For the first time, CdCl2‐initiated injury was found to result from the induction of not only apoptosis but also ferroptosis, as evidenced by the increased iron content, ROS production, and mitochondrial membrane potential along with changes in the expressions of iron death‐related genes (FTH1, GPX4, ASCL4, PTGS2, and NOX1) and levels of caspase9, Bax, and Bcl‐2 proteins. The molecular mechanisms leading to apoptosis and ferroptosis at least included the participation of the miR‐34a‐5p/Sirt1 axis, in which miR‐34a‐5p promoted CdCl2‐induced neurotoxicity through targeting Sirt1. Knocking out miR‐34a‐5p attenuated CdCl2‐induced damage of PC12 cells, cytotoxicity and neurotoxicity. This research provides the underlying molecular mechanisms of CdCl2‐induced damage and asserts the role of miRNAs as critical regulators.
Caffeic acid phenethyl ester (CAPE) is a bioactive component of honeybee propolis, which has protective effect against heavy metal induced toxicology. Cadmium is a kind of heavy metal pollutant that is hazardous to human health especially liver, and apoptosis is an important mechanism related to cadmium injury. Circular RNAs (CircRNAs) are involved in the regulation of apoptosis. However, the protective effects of CAPE on cadmium-induced cell apoptosis through CircRNA related mechanisms remains unclear at the current stage. In the present research, cell-based studies revealed that treating HepG2 cells with CdCl 2 (0-30 μM; 24 h) caused a dose-dependent decrease in cell viability, and CAPE at 10 μM could reverse such a decrease. The circular RNA hsacirc-0010039 may function as a ceRNA for the microRNA miR-661 to enhance caspase 9 expression and regulate apoptosis. The anti-apoptotic effects of CAPE against CdCl 2induced injury may be achieved through inhibiting the expression of hsa-circ-0010039 and caspase 9 while up-regulating miR-661 expression. This is the first report on the involvement of circRNA in CAPE's alleviating effect on CdCl 2 -induced injury and apoptosis. The hsa_circ_0010039/miR-661/caspase9 axis deserves further research efforts especially in search of dietary interventions for cadmium injury.
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