Living organisms are surrounded with heavy metals such as methylmercury, manganese, cobalt, cadmium, arsenic, as well as pesticides such as deltamethrin and paraquat, or atmospheric pollutants such as quinone. Extensive studies have demonstrated a strong link between environmental pollutants and human health. Redox toxicity is proposed as one of the main mechanisms of chemical-induced pathology in humans. Acting as both a sensor of oxidative stress and a positive regulator of antioxidants, the nuclear factor erythroid 2-related factor 2 (NRF2) has attracted recent attention. However, the role NRF2 plays in environmental pollutant-induced toxicity has not been systematically addressed. Here, we characterize NRF2 function in response to various pollutants, such as metals, pesticides and atmospheric quinones. NRF2 related signaling pathways and epigenetic regulations are also reviewed.

Background: As the demand and application of engineered nanomaterials have increased, their potential toxicity to the central nervous system has drawn increasing attention. Tunneling nanotubes (TNTs) are novel cell–cell communication that plays a crucial role in pathology and physiology. However, the relationship between TNTs and nanomaterials neurotoxicity remains unclear. Here, three types of commonly used engineered nanomaterials, namely cobalt nanoparticles (CoNPs), titanium dioxide nanoparticles (TiO₂NPs), and multi-walled carbon nanotubes (MWCNTs), were selected to address this limitation. Results: After the complete characterization of the nanomaterials, the induction of TNTs formation with all of the nanomaterials was observed using high-content screening system and confocal microscopy in both primary astrocytes and U251 cells. It was further revealed that TNT formation protected against nanomaterial-induced neurotoxicity due to cell apoptosis and disrupted ATP production. We then determined the mechanism underlying the protective role of TNTs. Since oxidative stress is a common mechanism in nanotoxicity, we first observed a significant increase in total and mitochondrial reactive oxygen species (namely ROS, mtROS), causing mitochondrial damage. Moreover, pretreatment of U251 cells with either the ROS scavenger N-acetylcysteine or the mtROS scavenger mitoquinone attenuated nanomaterial-induced neurotoxicity and TNTs generation, suggesting a central role of ROS in nanomaterials-induced TNTs formation. Furthermore, a vigorous downstream pathway of ROS, the PI3K/AKT/mTOR pathway, was found to be actively involved in nanomaterials-promoted TNTs development, which was abolished by LY294002, Perifosine and Rapamycin, inhibitors of PI3K, AKT, and mTOR, respectively. Finally, western blot analysis demonstrated that ROS and mtROS scavengers suppressed the PI3K/AKT/mTOR pathway, which abrogated TNTs formation. Conclusion: Despite their biophysical properties, various types of nanomaterials promote TNTs formation and mitochondrial transfer, preventing cell apoptosis and disrupting ATP production induced by nanomaterials. ROS/mtROS and the activation of the downstream PI3K/AKT/mTOR pathway are common mechanisms to regulate TNTs formation and mitochondrial transfer. Our study reveals that engineered nanomaterials share the same molecular mechanism of TNTs formation and intercellular mitochondrial transfer, and the proposed adverse outcome pathway contributes to a better understanding of the intercellular protection mechanism against nanomaterials-induced neurotoxicity. Graphical

Natural products are small molecules naturally produced by multiple sources such as plants, animals, fungi, bacteria and archaea. They exert both beneficial and detrimental effects by modulating biological targets and pathways involved in oxidative stress and antioxidant response. Natural products’ oxidative or antioxidative properties are usually investigated in preclinical experimental models, including virtual computing simulations, cell and tissue cultures, rodent and nonhuman primate animal models, and human studies. Due to the renewal of the concept of experimental animals, especially the popularization of alternative 3R methods for reduction, replacement and refinement, many assessment experiments have been carried out in new alternative models. The model organism Caenorhabditis elegans has been used for medical research since Sydney Brenner revealed its genetics in 1974 and has been introduced into pharmacology and toxicology in the past two decades. The data from C. elegans have been satisfactorily correlated with traditional experimental models. In this review, we summarize the advantages of C. elegans in assessing oxidative and antioxidative properties of natural products and introduce methods to construct an oxidative damage model in C. elegans. The biomarkers and signaling pathways involved in the oxidative stress of C. elegans are summarized, as well as the oxidation and antioxidation in target organs of the muscle, nervous, digestive and reproductive systems. This review provides an overview of the oxidative and antioxidative properties of natural products based on the model organism C. elegans.

Broad applications of cobalt nanoparticles (CoNPs) have raised increased concerns regarding their potential toxicity. However, the underlining mechanisms of their toxicity have yet to be characterized. Here, we demonstrated that CoNPs reduced cell viability and induced membrane leakage. CoNPs induced oxidative stress, as indicated by the generation of reactive oxygen species (ROS) secondary to the increased expression of hypoxia-induced factor 1 alpha. Moreover, CoNPs led to mitochondrial damage, including generation of mitochondrial ROS, reduction in ATP content, morphological damage and autophagy. Interestingly, exogenous mitochondria were observed between neurons and astrocytes upon CoNPs exposure. Concomitantly, tunneling nanotubes (TNTs)-like structures were observed between neurons and astrocytes upon CoNPs exposure. These structures were further verified to be TNTs as they were found to be F-actin rich and lacking tubulin. We then demonstrated that TNTs were utilized for mitochondrial transfer between neurons and astrocytes, suggesting a novel crosstalk phenomenon between these cells. Moreover, we found that the inhibition of TNTs (using actin-depolymerizing drug latrunculin B) intensified apoptosis triggered by CoNPs. Therefore, we demonstrate, for the first time, that the inhibition of intercellular mitochondrial transfer via TNTs aggravates CoNPs-induced cellular and mitochondrial toxicity in neuronal cells, implying a novel intercellular protection mechanism in response to nanoparticle exposure.