A human cell panel for evaluating safe application of nano-ZrO2/polymer composite in water remediation.

Nanomaterials, such as ZrO2 nanoparticles (ZrO2 NPs), are very effective in water remediation. However, the safety issues related to nanoparticle release and toxicity to humans remain to be resolved. Here we evaluated the cytotoxicity of ZrO2 NPs and their adducts with pollutants using a human cell panel containing stomach, intestine, liver and kidney cells. We found that different pollutants or ZrO2NP/pollutant adducts targeted cells from different organs, suggesting the necessity of a cell panel to model oral exposures. The cooperation of ZrO2 NPs and pollutants was quite complex, consisting of synergistic, antagonistic, or additive effects. For example, ZrO2 NPs enhanced the cytotoxicity of Pb2+ in GES-1 cells and of Pb2+, Cd2+ in FHC cells, while alleviating the toxicity of Pb2+ and As (III) in HepG2 and Hek293 cells. Our results also indicated that even concentrations of pollutants that meet the national standard, the ZrO2 NPs concentration should be kept below 17 µg/mL to avoid ZrO2 NP/pollutant adduct synergistic toxicity.

Gold Nanoparticle-Induced Cell Death and Potential Applications in Nanomedicine.

Cell death is crucial to human health and is related to various serious diseases. Therefore, generation of new cell death regulators is urgently needed for disease treatment. Nanoparticles (NPs) are now routinely used in a variety of fields, including consumer products and medicine. Exhibiting stability and ease of decoration, gold nanoparticles (GNPs) could be used in diagnosis and disease treatment. Upon entering the human body, GNPs contact human cells in the blood, targeting organs and the immune system. This property results in the disturbance of cell function and even cell death. Therefore, GNPs may act as powerful cell death regulators. However, at present, we are far from establishing a structure-activity relationship between the physicochemical properties of GNPs and cell death, and predicting GNP-induced cell death. In this review, GNPs' size, shape, and surface properties are observed to play key roles in regulating various cell death modalities and related signaling pathways. These results could guide the design of GNPs for nanomedicine.

Reprogramming cellular signaling machinery using surface-modified carbon nanotubes.

Nanoparticles, such as carbon nanotubes (CNTs), interact with cells and are easily internalized, causing various perturbations to cell functions. The mechanisms involved in such perturbations are investigated by a systematic approach that utilizes modified CNTs and various chemical-biological assays. Three modes of actions are (1) CNTs bind to different cell surface receptors and perturb different cell signaling pathways; (2) CNTs bind to a receptor with different affinity and, therefore, strengthen or weaken signals; (3) CNTs enter cells and bind to soluble signaling proteins involved in a signaling pathway. Understanding of such mechanisms not only clarifies how CNTs cause cytotoxicity but also demonstrates a useful method to modulate biological/toxicological activities of CNTs for their various industrial, biomedical, and consumer applications.

P-glycoprotein-evading anti-tumor activity of a novel tubulin and HSP90 dual inhibitor in a non-small-cell lung cancer model.

P-glycoprotein (P-gp)-induced drug resistance is a major road block for successful cancer chemotherapy. Through phenotypic screening, the compound 2-(2-chlorophenylimino)-5-(4-dimethylaminobenzylidene) thiazolidin-4-one (CDBT) was discovered to have potent anti-tumor activity in P-gp over-expressing drug-resistant non-small-cell lung cancer (NSCLC) H460TaxR cells. Here, we report mechanistic investigations of the P-gp-evading anti-tumor activity of CDBT. CDBT is evidently not a P-gp substrate and escapes the P-gp efflux pump. As a novel microtubule and heat shock protein 90 (HSP90) dual targeting inhibitor, CDBT causes the destabilization of microtubules and degradation of HSP90 client proteins CRAF-1 and ERBB2, resulting in cell cycle arrest at the G2/M phase and apoptosis. Furthermore, CDBT effectively inhibits tumor growth by 60.4% relative to the vehicle control after intraperitoneal administration at 30 mg/kg for 11 days and shows no toxicity in normal tissues in the NSCLC H460TaxR xenograft mouse model. Our data suggest a novel drug discovery strategy to combat P-gp over-expressing drug-resistant NSCLC cancer cells with a single therapeutic agent.

Mechanistic understanding of toxicity from nanocatalysts.

Nanoparticle-based catalysts, or nanocatalysts, have been applied in various industrial sectors, including refineries, petrochemical plants, the pharmaceutical industry, the chemical industry, food processing, and environmental remediation. As a result, there is an increasing risk of human exposure to nanocatalysts. This review evaluates the toxicity of popular nanocatalysts applied in industrial processes in cell and animal models. The molecular mechanisms associated with such nanotoxicity are emphasized to reveal common toxicity-inducing pathways from various nanocatalysts and the uniqueness of each specific nanocatalyst.

Adsorption of bisphenol A to a carbon nanotube reduced its endocrine disrupting effect in mice male offspring.

Soluble carbon nanotubes (CNTs) have shown promise as materials for adsorption of environmental contaminants such as Bisphenol A (BPA), due to the high adsorption capacity and strong desorption hysteresis of BPA on CNTs. The adsorption of BPA to CNTs may change the properties of both BPA and CNTs, and induce different toxicity to human and living systems from that of BPA and CNTs alone. Herein, we report that oral exposure of BPA/MWCNT-COOH (carboxylated multi-walled carbon nantubes) adduct to mice during gestation and lactation period decreased the male offspring reproductive toxicity compared with those induced by BPA alone. The adduct decreased malondialdehyde (MDA) level in testis and follicle-stimulating hormone (FSH) in serum, but increased the level of serum testosterone in male offspring in comparison to BPA alone. Our investigations broadened the knowledge of nanotoxicity and provided important information on the safe application of CNTs.

Synergistic effects of carbon nanoparticle-Cr-Pb in PM2.5 cause cell cycle arrest via upregulating a novel lncRNA NONHSAT074301.2 in human bronchial epithelial cells.

Inhalation of carcinogenic PM2.5 particles is a severe threat to all the people in both developing and developed nations. However, which components of PM2.5 and how they perturb human cells to cause various diseases are still not understood. Here, employing a reductionism approach, we revealed that one of the crucial toxic and pathogenic mechanisms of PM2.5 was the blocking of human bronchial cell cycle through upregulation of a novel long non-coding RNA NONHSAT074301.2 by carbon particles with payloads of Cr(VI) and Pb2+. We also discovered that NONHSAT074301.2 is a key regulatory molecule controlling cell cycle arrest at G2/M phase. This work highlights cellular function and molecular signaling events investigations using a 16-membered combinational model PM2.5 library which contain carbon particles carrying four toxic pollutants in all possible combinations at environmental relevant concentrations. This work demonstrates a very powerful methodology to elucidate mechanisms at molecular level and help unlock the "black box" of PM2.5-induced toxicities.

Fetotoxicity of Nanoparticles: Causes and Mechanisms.

The application of nanoparticles in consumer products and nanomedicines has increased dramatically in the last decade. Concerns for the nano-safety of susceptible populations are growing. Due to the small size, nanoparticles have the potential to cross the placental barrier and cause toxicity in the fetus. This review aims to identify factors associated with nanoparticle-induced fetotoxicity and the mechanisms involved, providing a better understanding of nanotoxicity at the maternal-fetal interface. The contribution of the physicochemical properties of nanoparticles (NPs), maternal physiological, and pathological conditions to the fetotoxicity is highlighted. The underlying molecular mechanisms, including oxidative stress, DNA damage, apoptosis, and autophagy are summarized. Finally, perspectives and challenges related to nanoparticle-induced fetotoxicity are also discussed.

The leading role of adsorbed lead in PM2.5-induced hippocampal neuronal apoptosis and synaptic damage.

Neurodegenerative diseases may be caused by air pollution, such as PM2.5. However, particles still need to be elucidated the mechanism of synergistic neurotoxicity induced by pollutant-loading PM2.5. In this study, we used a reductionist approach to study leading role of lead (Pb) in PM2.5-induced hippocampal neuronal apoptosis and synaptic damage both in vivo and in vitro. Pb in PM2.5 caused neurotoxicity: 1) by increasing ROS levels and thus causing apoptosis in neuronal cells and 2) by decreasing the expression of PSD95 via interfering with the calcium signaling pathway through cAMP/CREB/pCREB/BDNF/PSD95 pathway and reducing the synapse length by 50%. This study clarifies a key factor in PM2.5-induced neurotoxicity and provides the experimental basis for reducing PM2.5-induced neurotoxicity.

Cytotoxicity-Related Bioeffects Induced by Nanoparticles: The Role of Surface Chemistry.

Nanoparticles (NPs) are widely used in a variety of fields, including those related to consumer products, architecture, energy, and biomedicine. Once they enter the human body, NPs contact proteins in the blood and interact with cells in organs, which may induce cytotoxicity. Among the various factors of NP surface chemistry, surface charges, hydrophobicity levels and combinatorial decorations are found to play key roles inregulating typical cytotoxicity-related bioeffects, including protein binding, cellular uptake, oxidative stress, autophagy, inflammation, and apoptosis. In this review, we summarize the recent progress made in directing the levels and molecular pathways of these cytotoxicity-related effects by the purposeful design of NP surface charge, hydrophobicity, and combinatorial decorations.

Interactions Between Nanoparticles and Dendritic Cells: From the Perspective of Cancer Immunotherapy.

Dendritic cells (DCs) are the primary antigen-presenting cells and play key roles in the orchestration of the innate and adaptive immune system. Targeting DCs by nanotechnology stands as a promising strategy for cancer immunotherapy. The physicochemical properties of nanoparticles (NPs) influence their interactions with DCs, thus altering the immune outcome of DCs by changing their functions in the processes of maturation, homing, antigen processing and antigen presentation. In this review, we summarize the recent progress in targeting DCs using NPs as a drug delivery carrier in cancer immunotherapy, the recognition of NPs by DCs, and the ways the physicochemical properties of NPs affect DCs' functions. Finally, the molecular pathways in DCs that are affected by NPs are also discussed.