Background: Zinc oxide nanoparticles (ZnO NPs) are one of the most widely used nanomaterials in a variety of fields such as industrial, pharmaceutical, and household applications. Increasing evidence suggests that ZnO NPs could elicit unignorable harmful effect to the cardiovascular system, but the potential deleterious effects to human cardiomyocytes remain to be elucidated. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been increasingly used as a promising in vitro model of cardiomyocyte in various fields such as drug cardiac safety evaluation. Herein, the present study was designed to elucidate the cardiac adverse effects of ZnO NPs and explore the possible underlying mechanism using hiPSC-CMs. Methods: ZnO NPs were characterized by transmission electron microscopy and dynamic light scattering. The cytotoxicity induced by ZnO NPs in hiPSC-CMs was evaluated by determination of cell viability and lactate dehydrogenase release. Cellular reactive oxygen species (ROS) and mitochondrial membrane potential were measured by high-content analysis (HCA). Mitochondrial biogenesis was assayed by detection of mtDNA copy number and PGC-1α pathway. Moreover, microelectrode array techniques were used to investigate cardiac electrophysiological alterations. Results: We demonstrated that ZnO NPs concentration- and time-dependently elicited cytotoxicity in hiPSC-CMs. The results from HCA revealed that ZnO NPs exposure at low-cytotoxic concentrations significantly promoted ROS generation and induced mitochondrial dysfunction. We further demonstrated that ZnO NPs could impair mitochondrial biogenesis and inhibit PGC-1α pathway. In addition, ZnO NPs at insignificantly cytotoxic concentrations were found to trigger cardiac electrophysiological alterations as evidenced by decreases of beat rate and spike amplitude. Conclusion: Our findings unveiled the potential harmful effects of ZnO NPs to human cardiomyocytes that involve mitochondrial biogenesis and the PGC-1α pathway that could affect cardiac electrophysiological function.

Oxidative stress has been identified as a key mechanism in liver damage caused by various chemicals. The transcription factor FOXO3a has emerged as a critical regulator of redox imbalance. Multiple post-translational changes and epigenetic processes closely regulate the activity of FOXO3a, resulting in synergistic or competing impacts on its subcellular localization, stability, protein–protein interactions, DNA binding affinity, and transcriptional programs. Depending on the chemical nature and subcellular context, the oxidative-stress-mediated activation of FOXO3a can induce multiple transcriptional programs that play crucial roles in oxidative injury to the liver by chemicals. Here, we mainly review the role of FOXO3a in coordinating programs of genes that are essential for cellular homeostasis, with an emphasis on exploring the regulatory mechanisms and potential application of FOXO3a as a therapeutic target to prevent and treat liver oxidative injury.

Flutamide is a widely used nonsteroidal antiandrogen for prostate cancer therapy, but its clinical application is restricted by the concurrent liver injury. Increasing evidence suggests that flutamide‐induced liver injury is associated with oxidative stress, though the precise mechanism is poorly understood. Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a master transcription factor regulating endogenous antioxidants including heme oxygenase‐1 (HO‐1). This study was designed to delineate the role of Nrf2/HO‐1 in flutamide‐induced hepatic cell injury. Our results showed that flutamide concentration dependently induced cytotoxicity, hydrogen peroxide accumulation, and mitochondrial dysfunction as indicated by mitochondrial membrane potential loss and ATP depletion. The protein expression of Nrf2 and HO‐1 was induced by flutamide at 12.5 μM but was downregulated by higher concentrations of flutamide. Silencing either Nrf2 or HO‐1 was found to aggravate flutamide‐induced hydrogen peroxide accumulation and mitochondrial dysfunction as well as inhibition of the Nrf2 pathway. Moreover, preinduction of HO‐1 by Copp significantly attenuated flutamide‐induced oxidative stress and mitochondrial dysfunction, while inhibition of HO‐1 by Snpp aggravated these deleterious effects. These findings suggest that flutamide‐induced hepatic cell death and mitochondrial dysfunction is assoicated with inhibition of Nrf2‐mediated HO‐1. Pharmacologic intervention of Nrf2/HO‐1 may provide a promising therapeutic approach in flutamide‐induced liver injury.