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.

The apoptosis induced by CdTe quantum dots through the mitochondrial pathway in dorsal root ganglion cell line ND7/23.

Recently, the use of CdTe quantum dots in the field of biomedicine, such as biological imaging, biosensors, cell markers, and drug carriers, is increasing due to their special physical and chemical properties. However, their biosafety assessment lags far behind their rapid application. In this study, we observed that CdTe quantum dots with certain exposed doses and time decreased the cell viability and increased the apoptosis rates in ND7/23 cells. In general, CdTe quantum dots exposure could promote the accumulation of reactive oxygen species (ROS) in cells and decrease the mitochondrial membrane potential, which led to pathological changes and subcellular organelle damages. We hypothesized that the mitochondrial pathway could be involved in CdTe quantum dots-induced apoptosis. The results suggested that CdTe quantum dots exposure increased the expression levels of three mitochondrial pathway markers, for example, caspase-3, cytochrome c, and Bax while decreased Bcl-2 protein expression, following with cytochrome c falling out of the inner membrane of mitochondrial and releasing into the cytoplasm. The application of caspase-3 protein inhibitor Ac-DEVD-CHO could decrease apoptosis rates in ND7/23 cells. The results, taken together, demonstrated that CdTe quantum dots could induce apoptosis of ND7/23 cells through the mitochondrial pathway. Our findings provide a novel insight for researchers to explore CdTe quantum dots' toxic mechanisms to reduce their adverse effects.

CdTe quantum dots trigger oxidative stress and endoplasmic reticulum stress-induced apoptosis and autophagy in rat Schwann cell line RSC96.

In the current study, the cytotoxicity and mechanisms of cadmium telluride quantum dots (CdTe QDs) on RSC96 cells were evaluated by exposing different doses of CdTe QDs for 24 h. Two types of cell death, including apoptosis and autophagy, as well as two important organelles, mitochondria and endoplasmic reticulum, were focused after CdTe QDs exposure. The results showed that CdTe QDs induced apoptosis in RSC96 cells in a concentration-dependent manner; promoted the accumulation of intracellular reactive oxygen species; decreased the mitochondrial membrane potential; caused the release of cytochrome c; and also increased the expression of Bcl-2 associated X protein, caspase-3, and cytochrome c proteins and decreased the expression of Bcl-2 protein. Further results also confirmed that CdTe QDs could be internalized by RSC96 cells, and the exposure and internalization of CdTe QDs could induce excessive endoplasmic reticulum stress in the cells, and the expression levels of binding immunoglobulin protein, C/EBP homologous protein, and caspase12 proteins were increased in a concentration-dependent manner. Moreover, autophagy-related proteins LC3II, Beclin1, and P62 all increased after CdTe QDs exposure, suggesting that CdTe QDs exposure both promoted autophagosome formation and inhibited autophagosome degradation, and that CdTe QDs affected the autophagic flow in RSC96 cells. In conclusion, CdTe QDs are able to cause apoptosis and autophagy in RSC96 cells through mitochondrial and endoplasmic reticulum stress pathways, and the possible neurotoxicity of CdTe QDs should be further investigated.

NADPH oxidases regulate endothelial inflammatory injury induced by PM2.5 via AKT/eNOS/NO axis.

Fine particulate matter (PM2.5 )-induced detrimental cardiovascular effects have been widely concerned, especially for endothelial cells, which is the first barrier of the cardiovascular system. Among potential mechanisms involved, reactive oxidative species take up a crucial part. However, source of oxidative stress and its relationship with inflammatory response have been rarely studied in PM2.5 -induced endothelial injury. Here, as a key oxidase that catalyzes redox reactions, NADPH oxidase (NOX) was investigated. Human umbilical vein endothelial cells (EA.hy926) were exposed to Standard Reference Material 1648a of urban PM2.5 for 24 h, which resulted in NOX-sourced oxidative stress, endothelial dysfunction, and inflammation induction. These are manifested by the up-regulation of NOX, increase of superoxide anion and hydrogen peroxide, elevated endothelin-1 (ET-1) and asymmetric dimethylarginine (ADMA) level, reduced nitric oxide (NO) production, and down-regulation of phosphorylation of endothelial NO synthase (eNOS) with increased levels of inducible NO synthase, as well as the imbalance between tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1), and changes in the levels of pro-inflammatory and anti-inflammatory factors. However, administration of NOX1/4 inhibitor GKT137831 alleviated PM2.5 -induced elevated endothelial dysfunction biomarkers (NO, ET-1, ADMA, iNOS, and tPA/PAI-1), inflammatory factors (IL-1ß, IL-10, and IL-18), and adhesion molecules (ICAM-1, VCAM-1, and P-selectin) and also passivated NOX-dependent AKT and eNOS phosphorylation that involved in endothelial activation. In summary, PM2.5 -induced NOX up-regulation is the source of ROS in EA.hy926, which activated AKT/eNOS/NO signal response leading to endothelial dysfunction and inflammatory damage in EA.hy926 cells.

Integrated Analysis of Transcriptome and microRNA Profile Reveals the Toxicity of Euphorbia Factors toward Human Colon Adenocarcinoma Cell Line Caco-2.

Euphorbia factors, lathyrane-type diterpenoids isolated from the medical herb Euphorbia lathyris L. (Euphorbiaceae), have been associated with intestinal irritation toxicity, but the mechanisms underlying this phenomenon are still unknown. The objective of this study was to evaluate the transcriptome and miRNA profiles of human colon adenocarcinoma Caco-2 cells in response to Euphorbia factors L1 (EFL1) and EFL2. Whole transcriptomes of mRNA and microRNA (miRNA) were obtained using second generation high-throughput sequencing technology in response to 200 µM EFL treatment for 72 h, and the differentially expressed genes and metabolism pathway were enriched. Gene structure changes were analyzed by comparing them with reference genome sequences. After 72 h of treatment, 16 miRNAs and 154 mRNAs were differently expressed between the EFL1 group and the control group, and 47 miRNAs and 1101 mRNAs were differentially expressed between the EFL2 group and the control. Using clusters of orthologous protein enrichment, the sequenced mRNAs were shown to be mainly involved in transcription, post-translational modification, protein turnover, chaperones, signal transduction mechanisms, intracellular trafficking, secretion, vesicular transport, and the cytoskeleton. The differentially expressed mRNA functions and pathways were enriched in transmembrane transport, T cell extravasation, the IL-17 signaling pathway, apoptosis, and the cell cycle. The differentially expressed miRNA EFLs caused changes in the structure of the gene, including alternative splicing, insertion and deletion, and single nucleotide polymorphisms. This study reveals the underlying mechanism responsible for the toxicity of EFLs in intestinal cells based on transcriptome and miRNA profiles of gene expression and structure.

Potential health impact of environmental micro- and nanoplastics pollution.

Micro- and nanoplastics are generated from plastics and have negative impacts on the environment due to their high level of fragmentation. They can originate from various sources such as fragments, fibers and foams. The large proportion of the waste and resistance to degradation means micro- and nanoplastics have become a serious global environmental problem, but there are few studies on their potential toxicity for human health. In this review, we discussed routes of exposure and the potential effects of micro- and nanoplastics to human health. Human beings could mainly be exposed to micro- and nanoplastics orally and by inhalation. The possible toxic effects of plastic particles are due to the potential toxicity of plastics themselves, and their combined toxicity with leachable additives and adsorbed contaminants. The potential risks for human health focused on their gastrointestinal toxicity and liver toxicity. The toxic mechanisms could involve oxidative stress, inflammatory reactions and metabolism disorders. More studies are needed to carry out and explore the potential toxicological mechanisms of micro- and nanoplastics and evaluate the combined toxicity of their adsorbed contaminants.

The glycolytic shift was involved in CdTe/ZnS quantum dots inducing microglial activation mediated through the mTOR signaling pathway.

The excellent optical property and relatively low toxicity of CdTe/ZnS core/shell quantum dots (QDs) make them an advanced fluorescent probe in the application of biomedicines, particularly in neuroscience. Thus, it is important to evaluate the biosafety of CdTe/ZnS QDs on the central nervous system (CNS). Our previous studies have suggested that the high possibility of CdTe/ZnS QDs being transported into the brain across the blood-brain barrier resulted in microglial activation and a shift of glycometabolism, but their underlying mechanism remains unclear. In this study, when mice were injected intravenously with CdTe/ZnS QDs through tail veins, the microglial activation, polarized into both M1 phenotype and M2 phenotype, and the neuronal impairment were observed in the hippocampus. Meanwhile, the increased pro- and anti-inflammatory cytokines released from BV2 microglial cells treated with CdTe/ZnS QDs also indicated that QD exposure was capable of inducing microglial activation in vitro. We further demonstrated that the glycolytic shift from oxidative phosphorylation switching into aerobic glycolysis was required in the microglial activation into M1 phenotype induced by CdTe/ZnS QD treatment, which was mediated through the mTOR signaling pathway. The findings, taken together, provide a mechanistic insight regarding the CdTe/ZnS QDs inducing microglial activation and the role of the glycolytic shift in it.

Identification of mRNA-miRNA crosstalk in human endothelial cells after exposure of PM2.5 through integrative transcriptome analysis.

PM2.5 has implications in cardiovascular adverse events, but the underlying mechanisms are still obscure. The aim of this study is to evaluate miRNA expression in endothelial cells in response to two realistic doses of PM2.5 and to identify the possible gene targets of deregulated miRNAs through microarray profiling and computational technology. As a result, there are 18 differentially expressed miRNAs between 2.5 µg/cm2 group and the control, of which 11 miRNAs are up-regulated and 7 miRNAs are down-regulated. Relative to the control group, 40 miRNAs are significantly changed in 10 µg/cm2 group with 21 miRNAs being upregulated and 19 miRNAs being downregulated. Interestingly, when two PM2.5-treated groups respectively compared with the control, the expressed trends of 12 miRNAs in 2.5 µg/cm2 group are the same as those in 10 µg/cm2 group, with 8 being upregulated and 4 miRNAs being simultaneously downregulated. Gene ontology (GO) analysis shows that the crucial functional categories of miRNA-targeted genes incorporate transcription-related process and intracellular signal transduction. Pathway analysis reveals that endocytosis, FoxO signaling pathway and PI3K-Akt signaling pathway are involved in the PM2.5-caused cardiotoxicity. Further confirmation by RT-qPCR indicates that PM2.5 could induce the down-regulation of hsa-miR-128-3p, hsa-miR-96-5p, hsa-miR-28-5p, hsa-miR-4478 and hsa-miR-6808-5p, which are in accordance with the results of array data. With the comprehensive analysis of mRNAs and miRNAs, a great number of pairs have been identified, suggesting abnormally expressed miRNAs have functions in the cardiotoxicity of PM2.5, and the function may be achieved through the post-transcriptional regulation of certain genes on the related pathways.

Transcriptome analysis of different sizes of 3-mercaptopropionic acid-modified cadmium telluride quantum dot-induced toxic effects reveals immune response in rat hippocampus.

Recently, the increasing number of bio-safety assessments on cadmium-containing quantum dots (QDs) suggested that they could lead to detrimental effects on the central nervous system (CNS) of living organisms, but the underlying action mechanisms are still rarely reported. In this study, whole-transcriptome sequencing was performed to analyze the changes in genome-wide gene expression pattern of rat hippocampus after treatments of cadmium telluride (CdTe) QDs with two sizes to understand better the mechanisms of CdTe QDs causing toxic effects in the CNS. We identified 2095 differentially expressed genes (DEGs). Fifty-five DEGs were between the control and 2.2 nm CdTe QDs, 1180 were between the control and 3.5 nm CdTe QDs and 860 were between the two kinds of CdTe QDs. It seemed that the 3.5 nm CdTe QD exposure might elicit severe effects in the rat hippocampus than 2.2 nm CdTe QDs at the transcriptome level. After bioinformatics analysis, we found that most DEG-enriched Gene Ontology subcategories and Kyoto Encyclopedia of Genes and Genomes pathways were related with the immune system process. For example, the Gene Ontology subcategories included immune response, inflammatory response and T-cell proliferation; Kyoto Encyclopedia of Genes and Genomes pathways included NOD/Toll-like receptor signaling pathway, nuclear factor-κB signaling pathway, tumor necrosis factor signaling pathway, natural killer cell-mediated cytotoxicity and T/B-cell receptor signaling pathway. The traditional toxicological examinations confirmed the systemic immune response and CNS inflammation in rats exposed to CdTe QDs. This transcriptome analysis not only revealed the probably molecular mechanisms of CdTe QDs causing neurotoxicity, but also provided references for the further related studies.

Role of NF-κB activation and Th1/Th2 imbalance in pulmonary toxicity induced by nano NiO.

With the progress of nanotechnology, nano nickel oxide (NiO) has been extensively used as sensors, battery electrodes, catalysts, and cosmetics. Previous researches verified that nano NiO could exert pulmonary toxicity, but its mechanism was unclear. To shed light upon this, the role of nuclear factor-κB (NF-κB) activation and Th1/Th2 imbalance were to explore in pulmonary damage induced by nano NiO. Male Wistar rats were randomized into control group, nano NiO groups (0.015, 0.06, and 0.24 mg kg-1 ) and micro NiO group (0.024 mg kg-1 ) and treated by intratracheal instillation twice a week for 6 weeks. The results showed that the abnormal changes induced by nano NiO were found on indicators of nitrative stress (NO, TNOS, and iNOS), inflammatory cytokines (TNF-α, IL-2, and IL-10) and cytokine-induced neutrophil chemoattractants (CINC-1, CINC-2αß, and CINC-3) in lung tissue. In addition, nano NiO instillation induced the upregulated mRNA and protein expression of NF-κB, inhibitor of κB kinase-α (IKK-α) and nuclear factor-inducing kinase (NIK). The protein content of GATA-3 increased as well as T-bet decreased in nano NiO groups, and the ratio of T-bet/GATA-3, as a key evaluation indicator of Th1/Th2 balance, was lower than the control group. The findings indicated that nano NiO could enhance the nitrative stress and inflammatory response in lung tissue, and its mechanism was related to the NF-κB activation and Th1/Th2 imbalance. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1354-1362, 2017.

Nickel sulfate induced apoptosis via activating ROS-dependent mitochondria and endoplasmic reticulum stress pathways in rat Leydig cells.

Nickel can induce apoptosis of testicular Leydig cells in mice, whereas the mechanisms remain unclear. In this study, we investigated the role of nickel-induced reactive oxygen species (ROS) generation in mitochondria and endoplasmic reticulum stress (ERS) mediated apoptosis pathways in rat Leydig cells. Fluorescent DCF and Annexin-V FITC/PI staining were performed to measure the production of ROS and apoptosis in Leydig cells. RT-qPCR and Western blot were conducted to analyze the key genes and proteins involved in mitochondria and ERS apoptotic pathways. The results showed that nickel sulfate induced ROS generation, consequently resulted in nucleolus deformation and apoptosis in testicular Leydig cells, which were then attenuated by ROS inhibitors of N-acetylcysteine (NAC) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). Nickel sulfate-triggered Leydig cells apoptosis via mitochondria and ERS pathways was characterized by the upregulated mRNA and proteins expression of Bak, cytochrome c, caspase 9, caspase 3, GRP78, GADD153, and caspase 12, which were inhibited by NAC and TEMPO respectively. The findings indicated that nickel-induced ROS generation was involved in apoptosis via mitochondria and ERS pathways in rat Leydig cells.

[Role of nitrative stress in nano nickel oxide-induced lung injury in rats].

OBJECTIVE: To investigate the subchronic lung injury induced by nano nickel oxide( nano NiO) and its mechanism from the view of nitrative stress in rats. METHODS: A total of 40 adult male Wistar rats were randomly divided into 5 groups, control group( normal saline), 0. 015, 0. 06 and 0. 24 mg / kg nano NiO groups and 0. 24 mg / kg micro NiO group. Rats received intratracheally instilled nano NiO, micro NiO and normal saline twice a week for 6 weeks, respectively. All rats were sacrificed after the exposure to obtain lung tissues. HE staining was used to observe the lung pathological changes. The content of nitric oxide, and the activities of total nitric oxide synthase( TNOS) and inducible nitric oxide synthase( iNOS) in pulmonary tissue homogenate were measured by microplate reader. The levels of interleukin-2( IL-2), transforminggrowth factor-beta( TGF-ß), interferon-gamma( IFN-γ) and 8-hydroxy-2'-deoxyguanosine( 8-OHd G) in serum were detected by enzyme-linked immunosorbent assay( ELISA). RESULTS: The results of lung histopathology showed that the widened alveolar speta, inflammatory infiltration and nanoparticles deposition increased with the increasing dosage of nano NiO. Compared to control group, the content of NO and the activities of TNOS and iNOS in 0. 24 mg / kg nano NiO group increased in lung homogenate( P < 0. 05). The levels of IL-2, TGF-ß and IFN-γ in nano NiO 0. 06 and 0. 24 mg /kg group were higher than that of control group, and the level of 8-OHd G increased in nano NiO 0. 24 mg / kg group when compared to control group in serum( P < 0. 05). Compared to micro NiO group, the levels of NO and iNOS in lung homogenate, and the serum levels of IL-2 and 8-OHd G increased after exposed to 0. 24 mg / kg nano NiO in rats( P < 0. 05). CONCLUSION: Nano NiO can lead to lung injury in rats which may be related with nitrative stress reaction based on pulmonary inflammation.

Ag/TiO2 nanohybrids induce fibrosis-related epithelial-mesenchymal transition in lung epithelial cells and the influences of silver content and silver particle size.

The controlled synthesis of silver nanoparticles (AgNPs) decorated TiO2 nanohybrids (Ag/TiO2) for photocatalysis has received considerable attention. These photocatalysts are widely used in environment and energy, resulting in human exposure through inhalation. Pure TiO2 is generally considered a low-toxic nanomaterial. However, little is known about the toxicity after AgNPs loading. In this study, silver-decorated TiO2 nanohybrids were controllably synthesized by the photodeposition method, and their toxic effects on murine lung and human lung epithelial cells were explored. As a result, silver loading significantly enhanced the effect of TiO2 photocatalyst on EMT in lung epithelial cells, potentially acting as a pro-fibrogenic effect in murine lung. Meanwhile, the increase in autophagy vacuoles, LC3-II marker, stub-RFP-sens-GFP-LC3 fluorescence assay, and LC3 turnover assay showed that silver loading also significantly increased autophagy flux. Furthermore, analysis of autophagy inhibition by 3-Methyladenine indicated that the promotion of EMT by silver loading was related to the increased autophagy flux. Intriguingly, the autophagy and EMT biological effects could be alleviated when the silver loading amount was reduced or silver particle size was increased, and the enhanced pro-fibrogenic effect was mitigated at the same time. This study supplemented safety information of Ag-decorated TiO2 nanohybrids and provided methods of controlled synthesis for reducing toxicity.

The role of ferroptosis mediated by NRF2/ERK-regulated ferritinophagy in CdTe QDs-induced inflammation in macrophage.

Cadmium telluride quantum dots (CdTe QDs) exist in the environment due to the abandonment of products. There is a potential risk to organisms and toxic mechanism is worth exploring. In this study, 12.5 µmol/Kg body weight CdTe QDs triggered systemic and local inflammatory response in mice and activated macrophages, then the mechanism of activating macrophages to overexpress IL-1ß and IL-6 was explored. RAW264.7 macrophages were used, and after macrophages exposing to 1 µM CdTe QDs for 24 h, oxidative stress occurred. Further investigation found that CdTe QDs triggered ferroptosis in RAW264.7 cells. And deferoxamine mesylate alleviated the excessive lipid hydroperoxide caused by QDs. Mechanistically, CdTe QDs-provoked decrease of nuclear factor erythroid 2-related factor 2 (NRF2) elicited phosphorylation of extracellular regulated protein kinases1/2 (ERK1/2) and then activated ferritinophagy, which made ferritin heavy chain 1 (FTH1) degraded in lysosome and proteasome to release free iron ions to initiate ferroptosis in macrophages. This paper updates the mechanism of macrophage activation by CdTe QDs with regard to ferritinophagy, and more importantly, identifies the key role of NRF2 and ERK1/2. Our research extends the role of ferroptosis in inflammatory responses triggered by nanoparticles (NPs) in macrophages and provides insightful reference for toxicity assessment of NPs.

Protein corona mitigated the cytotoxicity of CdTe QDs to macrophages by targeting mitochondria.

Despite the potential of cadmium telluride quantum dots (CdTe QDs) in bioimaging and drug delivery, their toxic effects have been documented. It is known that the immunotoxicity of CdTe QDs targeting macrophages is one of their adverse effects, and the protein corona (PC) will affect the biological effects of QDs. In order to prove whether the PC-CdTe QDs complexes could alleviate the toxicity of CdTe QDs without weakening their luminescence, we investigated the impact of protein corona formed in fetal bovine serum (FBS) on the cytotoxicity of CdTe QDs to mitochondria. RAW264.7 cells were used as the model to compare the effects of CdTe QDs and PC-CdTe QDs complexes on the structure, function, quantity, morphology, and mitochondrial quality control of mitochondria. As result, the protein corona form in FBS alleviated the inhibition of CdTe QDs on mitochondrial activity, the damage to mitochondrial membrane, the increase of ROS, and the reduction of ATP content. Also, CdTe QDs increased the number of mitochondria in macrophages, while the complexes did not. In line with this, the morphology of mitochondrial network in macrophages which were exposed to CdTe QDs and PC-CdTe QDs complexes was different. CdTe QDs transformed the network into fragments, punctuations, and short rods, while PC-CdTe QDs complexes made the mitochondrial network highly branched, which was related to the imbalance of mitochondrial fission and fusion. Mechanically, CdTe QDs facilitated mitochondrial fission and inhibited mitochondrial fusion, while protein corona reversed the phenomenon caused by QDs. Besides mitochondrial dynamics, mitochondrial biogenesis and mitophagy were also affected. CdTe QDs increased the expression of mitochondrial biogenesis signaling molecules including PGC-1α, NRF-1 and TFAM, while PC-CdTe QDs complexes played the opposite role. With regard to mitophagy, they both showed promoting effect. In conclusion, the formation of protein corona alleviated the toxic effects of CdTe QDs on the mitochondria in macrophages and affected mitochondrial quality control. Under the premise of ensuring the fluorescence properties of CdTe QDs, these findings provided useful insight into reducing the toxicity of CdTe QDs from two perspectives: protein corona and mitochondria, and shared valuable information for the safe use of QDs.

Intermittent exposure to airborne particulate matter induces subcellular dysfunction and aortic cell damage in BALB/c mice through multi-endpoint assessment at environmentally relevant concentrations.

Airborne particulate matter (PM) has been linked to cardiovascular diseases, but the underlying mechanisms remain unclear, especially at realistic exposure levels. In this study, both male and female BALB/c mice were employed to assess vascular homeostasis following a standard urban particulate matter, PM SRM1648a, via oropharyngeal aspiration at three environmentally relevant concentrations. The tested indicators included histopathological observation and lipid deposition, as well as redox biology and inflammatory responses. Furthermore, endothelial monolayer, vascular cell apoptosis and subcellular function were assessed to decipher whether episodic PM SRM1648a exposure leads to vascular damage after multiple periods of treatment, including subacute (4 weeks) and subchronic (8 weeks) durations. As a result, PM aspiration caused thickening of airways, leukocytes infiltration and adhesion to alveoli, with the spot of particles engulfed by pulmonary macrophages. Meanwhile, it induced local and systemic oxidative stress and inflammation, but limited pathological changes were captured throughout aortic tissues after either subacute or subchronic treatment. Furthermore, even in the absence of aortic impairment, vascular cell equilibrium has been disturbed by the characteristics of endothelial monolayer disintegration and cell apoptosis. Mechanistically, PM SRM1648a activated molecular markers of ER stress (BIP) and mitochondrial dynamics (DRP1) at both transcriptional and translational levels, which were strongly correlated to ox-inflammation and could serve as early checkpoints of hazardous events. In summary, our data basically indicate that episodic exposure of BALB/c mice to PM SRM1648a exerts limited effects on vascular histopathological alterations, but induces vascular cell apoptosis and subcellular dysfunction, to which local and systemic redox biology and inflammation are probably correlated.

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.

CdTe and CdTe@ZnS quantum dots induce IL-1ß-mediated inflammation and pyroptosis in microglia.

CdTe quantum dots (QDs) are still widely considered as excellent fluorescent probes because of their far more superior optical performance and fluorescence efficiency than non­cadmium QDs. Thus, it is important to find ways to control their toxicity. In this study, CdTe QDs and CdTe@ZnS QDs both could cause IL-1ß-mediated inflammation following with pyroptosis in BV2 cells, but the toxic effects caused by CdTe@ZnS QDs was weaker than CdTe QDs, which demonstrated the partial protection of ZnS shell. When investigating the molecular mechanisms of QDs causing the inflammatory injury, the findings suggested that cadmium-containing QDs exposure activated NF-κB that participated in the NLRP3 inflammasome priming and pro-IL-1ß expression. After that, QDs-induced excessive ROS generation triggered the NLRP3 inflammasome activation and resulted in active caspase-1 to process pro-IL-1ß into mature IL-1ß release and inflammatory cell death, i.e. pyroptosis. Fortunately, the inhibitions of caspase-1, NF-κB and ROS or knocking down of NLRP3 all effectively attenuated the increases in the IL-1ß secretion and cell death caused by QDs in BV2 cells. This study provided two methods to alleviate the toxicity of cadmium-containing QDs, in which one is to encapsulate bare-core QDs with a shell and the other is to inhibit their toxic pathways. Since the latter way is more effective than the former one, it is significant to evaluate QDs through a mechanism-based risk assessment to identify controllable toxic targets.

The apoptosis induced by silica nanoparticle through endoplasmic reticulum stress response in human pulmonary alveolar epithelial cells.

Recently, the use of silica nanoparticles (SiO2-NPs) and mesoporous silica nanoparticles (mSiO2-NPs) in the biomedical field, such as biosensors, drug deliveries and bioactivator carriers, is increasing due to their special physiochemical properties. However, the biosafety assessment of them is far lagging behind their rapid application. In this study, we observed that both SiO2-NPs and mSiO2-NPs with certain exposed doses decreased the cell viability while increased the apoptosis rates in the human pulmonary alveolar epithelial cells (HPAEpiC). Generally, mSiO2-NPs presented less toxic effects than SiO2-NPs with same treated dose, which assures the positive application prospect of mSiO2-NPs in the area of biomedicine. Since both SiO2-NPs could be taken into cells and accumulated in the endoplasmic reticulum (ER), which resulted in pathologically morphological changes and subcellular organelle damages, we hypothesized that the ER stress response could be involved in the NPs-induced apoptosis. The findings suggested that SiO2-NPs and mSiO2-NPs exposure increased the expression levels of two ER stress markers, e.g. BiP and CHOP, which could be inhibited by the ER stress inhibitor 4-PBA, following with decreased apoptosis rates in HPAEpiC. Even though it is still unclear of the direct target of NPs causing ER stress response following with cell apoptosis, our findings provide a novel insight for researchers to explore the toxic mechanisms of SiO2-NPs and mSiO2-NPs in order to reduce the adverse effects of them.

Genome-wide identification and functional analysis of long non-coding RNAs in human endothelial cell line after incubation with PM2.5.

Epidemiological studies and experimental research have illustrated that PM2.5 has an association with cardiovascular adverse events. However, the underlying mechanisms are still unknown. Long non-coding RNAs (lncRNAs) have been proposed to take part in diverse diseases. To comprehensively gain insight into the molecular toxicity of PM2.5, expression patterns are analyzed in EA.hy926 cell line through RNAs microarray. A total of 356 lncRNA transcripts are dysregulated in 2.5 µg/cm2 group, and there are 1283 lncRNAs differentially expressed in 10 µg/cm2 group. From functional analysis, several lncRNAs may be implicated in the bio-pathways of phagosome, TNF signaling pathway, chemokine signaling pathway and gap junction. Moreover, certain lncRNAs participate in the toxicity of PM2.5 through cis- and/or trans-regulation of their co-expressed genes. Therefore, lncRNAs may be used as new candidate biomarkers and potentially preventive targets in cardiotoxicity of PM2.5. Our study indicates that not limited to transcriptional regulation, post-transcriptional regulation plays a pivotal role in PM2.5-caused toxicity.