The rational for the study was to review the literature on the toxicity and corresponding mechanisms associated with lead (Pb), mercury (Hg), cadmium (Cd), and arsenic (As), individually and as mixtures, in the environment. Heavy metals are ubiquitous and generally persist in the environment, enabling them to biomagnify in the food chain. Living systems most often interact with a cocktail of heavy metals in the environment. Heavy metal exposure to biological systems may lead to oxidation stress which may induce DNA damage, protein modification, lipid peroxidation, and others. In this review, the major mechanism associated with toxicities of individual metals was the generation of reactive oxygen species (ROS). Additionally, toxicities were expressed through depletion of glutathione and bonding to sulfhydryl groups of proteins. Interestingly, a metal like Pb becomes toxic to organisms through the depletion of antioxidants while Cd indirectly generates ROS by its ability to replace iron and copper. ROS generated through exposure to arsenic were associated with many modes of action, and heavy metal mixtures were found to have varied effects on organisms. Many models based on concentration addition (CA) and independent action (IA) have been introduced to help predict toxicities and mechanisms associated with metal mixtures. An integrated model which combines CA and IA was further proposed for evaluating toxicities of non-interactive mixtures. In cases where there are molecular interactions, the toxicogenomic approach was used to predict toxicities. The high-throughput toxicogenomics combines studies in genetics, genome-scale expression, cell and tissue expression, metabolite profiling, and bioinformatics.

This study investigates the role of circular RNA (circRNA) hsa_circ_0000515 in cervical cancer and the underlying mechanism associated with microRNA-326 (miR-326). hsa_circ_0000515 and ETS transcription factor ELK1 (ELK1) were initially over-expressed and miR-326 was down-regulated in cervical cancer tissues and cells. Low hsa_circ_0000515 expression was found to be associated with favorable prognosis of patients with cervical cancer. A series of mimics, inhibitors, over-expression plasmids or siRNAs were introduced into cervical cancer cells to alter the expression of hsa_circ_0000515, miR-326 and ELK1. In vitro experiments exhibited that silencing of hsa_circ_0000515 or upregulation of miR-326 resulted in suppressed proliferation and invasion, along with induced apoptosis and autophagy of cervical cancer cells. Dual-luciferase reporter assay, RNA pulldown and RIP assays highlighted that hsa_circ_0000515 was able to act as a ceRNA of miR-326 to increase ELK1. Furthermore, enhancement of ELK1 expression resulted in enhanced proliferation and invasion but repressed apoptosis and autophagy of cervical cancer cells. In vivo experiments further confirmed the suppressed tumor growth by hsa_circ_0000515 silencing. Our findings demonstrated that hsa_circ_0000515 acts as a tumor promoter in cervical cancer. The study provides evidence for targeting hsa_circ_0000515 for therapeutic purposes in treating cervical cancer.

Bisphenol A (BPA) and nonylphenol (NP) are well-known endocrine-disrupting chemicals (EDCs) present in the aquatic environment, but little is known about their oxidative stress effects on fish embryos. In the present study, we examined the oxidative stress indices and antioxidant parameters of zebrafish embryos after a short-term exposure to various concentrations of BPA, NP, and their mixture (BPA-NP) for 4 h postfertilization (hpf) to 168 hpf. Exposure to the chemicals was found to enhance the production of hydroxyl radicals and lipid peroxidation in a concentration-dependent manner. The content of total glutathione (TG), reduced glutathione (GSH), and oxidized glutathione (GSSH), as well as the activity of antioxidant enzymes including catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase were all significantly inhibited after exposure to BPA, NP, and BPA-NP, indicating the occurrence of oxidative stress. Coexposure to BPA-NP resulted in an additive effect on some antioxidant parameters. In addition, the alkaline phosphatase activity was also significantly inhibited after exposure to BPA, NP, and their mixtures. Our results demonstrated that BPA, NP, and BPA-NP in aquatic systems can affect antioxidant responses in zebrafish embryos.

Mesothelin (MSLN) is an attractive antigen for chimeric antigen receptor (CAR) T therapy and the epitope selection within MSLN is essential. In this study, we constructed two types of CARs targeting either region I of MSLN (meso1 CAR, also known as a membrane-distal region) or region III of MSLN (meso3 CAR, also known as a membrane-proximal region) using a modified piggyBac transposon system. We reported that, compared with meso1 CAR T cells, meso3 CAR T cells express higher levels of CD107α upon activation and produce increased levels of interleukin-2, TNF-α, and IFN-γ against multiple MSLN-expressing cancer cells in vitro. In a real-time cell analyzer system and a three-dimensional spheroid cancer cell model, we also demonstrated that meso3 CAR T cells display an enhanced killing effect compared with that of meso1 CAR T cells. More importantly, in a gastric cancer NSG mice model, meso3 CAR T cells mediated stronger antitumor responses than meso1 CAR T cells did. We further identified that meso3 CAR T cells can effectively inhibit the growth of large ovarian tumors in vivo. Collectively, our study provides evidences that meso3 CAR T-cell therapy performs as a better immunotherapy than meso1 CAR T-cell therapy in treating MSLN-positive solid tumors.

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