Influence of silver doping on pro-inflammatory and pro-fibrogenic effects of nano-titanium dioxide in murine lung.

Silver is usually loaded on nano-titanium dioxide (TiO2 ) through photodeposition method to enhance visible-light catalytic functions for environment purification. However, little is known about how the toxicity changes after silver doping and how the physicochemical properties of loaded components affect nanocomposite toxicity. In this study, Ag-TiO2 with different sizes and contents of silver particles were obtained by controlling photodeposition time (PDT) and silver addition amount. Pro-inflammatory and pro-fibrogenic responses of these photocatalysts were evaluated in male C57BL/6J murine lung. As a result, silver was well assembled on TiO2 , promoting visible-light catalytic activity. Notably, the size of silver particles increased with PDT. Meanwhile, toxicity results showed that pure TiO2 (P25) mainly caused neutrophil infiltration, while 2 wt/wt% silver-loaded TiO2 recruited more types of inflammatory cells in the lung. Both of them caused the increase of proinflammatory cytokines while decreasing the anti-inflammatory cytokine in bronchoalveolar lavage fluid. However, 2 wt/wt% silver doping also accelerated the lung pro-fibrogenic response of photocatalysts in the subacute phase from evidence of collagen deposition and hydroxyproline concentrations. Mechanistically, the overactivation of TGFBR2 receptors in TGF-ß/smads pathways by silver-loaded TiO2 rather than pure TiO2 may be the reason why silver-loaded TiO2 can promote pro-fibrogenic effect response. Intriguingly, the increased toxicity caused by silver doping can be rescued by increasing the size of the loaded silver or decreasing the silver amount. These results may be important for the new understanding of the toxicity of TiO2 -based photocatalysts.

Toxicity mechanism of nanomaterials: Focus on endoplasmic reticulum stress.

Over the years, although the broad application of nanomaterials has not brought convenience to people's life, growing concern surrounds their safety. Recently, much emphasis has been placed on exploring the toxicity mechanism of nanoparticles. Currently established toxic mechanisms include oxidative stress, inflammatory response, autophagy, and DNA damage. In recent years, endoplasmic reticulum stress (ERS) has gained widespread attention as another toxic mechanism of nanomaterials. It is widely acknowledged that the endoplasmic reticulum (ER) is an important site for protein synthesis, and lipids and Ca+ storage, playing an esseential role in the normal operation of the body functions. When the body's internal environment is damaged, the structure and function of the endoplasmic reticulum are destroyed, leading to a series of biological reactions called endoplasmic reticulum stress (ERS.) This paper reviews the mechanism of ERS in nanomaterial-associated toxicity. The process of ERS and its related unfolded protein response were briefly introduced, summarizing the factors affecting the nanoparticle ability to induce ERS and expounding on the changes of ER morphology after exposure to nanoparticles. Finally, the specific role and molecular mechanism of ERS under the action of different nanoparticles were comprehensively analyzed, including the relationship between ERS and inflammation, oxidative stress, lipid metabolism and apoptosis. This review provides a foothold for future studies on the toxic mechanism of nanoparticles, and provides novel insights into the safe application of nanoparticles and the treatment of diseases.

Urban fine particulate matter causes cardiac hypertrophy through calcium-mediated mitochondrial bioenergetics dysfunction in mice hearts and human cardiomyocytes.

In recent years, the cardiovascular toxicity of urban fine particulate matter (PM2.5) has sparked significant alarm. Mitochondria produce 90% of ATP and make up 30% of the volume of cardiomyocytes. Thus knowledge of myocardial mitochondrial dysfunction due to PM2.5 exposure is essential for further cardiotoxic effects. Here, the mechanism of PM2.5-induced cardiac hypertrophy through calcium overload and mitochondrial dysfunction was investigated in vivo and in vitro. Male and female BALB/c mice were given 1.28, 5.5, and 11 mg PM2.5/kg bodyweight weekly through oropharyngeal inhalation for four weeks and were assigned to low, medium, and high dose groups, respectively. PM2.5-induced myocardial edema and cardiac hypertrophy were detected in the high-dose group. Mitochondria were scattered and ruptured with abnormal ultrastructural morphology. In vitro experiments on human cardiomyocyte AC16 showed that exposure to PM2.5 for 24 h caused opened mitochondrial permeability transition pore --leading to excessive calcium production, decreased mitochondrial membrane potential, weakened mitochondrial respiratory metabolism capacity, and decreased ATP production. Nevertheless, the administration of calcium chelator ameliorated the mitochondrial damage in the PM2.5-treated group. Our in vivo and in vitro results confirmed that calcium overload under PM2.5 exposure triggered mTOR/AKT/GSK-3ß activation, leading to mitochondrial bioenergetics dysfunction and cardiac hypertrophy.

Research progress of nanoparticle toxicity signaling pathway.

Fast development of nanoscience has drawn increasing attentions and expanded its usage in industry. The research on the toxicity mechanism of nanoparticles is limited comparing to other aspects of study. Oxidative stress and inflammation are publicly known to explain the mechanism of nanoparticles toxicity. Recent years the cell signaling pathways are also being considered as a new explanation. Cell signaling pathways are various and many of them are related to inflammation effects and oxidative stress, while JAK-STAT, NF-κB, Nrf2/ARE and PI3K/Akt are mostly researched. This review concludes the characterizations and properties of nanoparticles and summarizes the pathways related to inflammation and oxidative stress, while reference to the possible mechanisms of nanoparticle toxicity is provided.