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1.
J Appl Toxicol ; 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34708887

RESUMO

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.

2.
Nanoscale ; 13(28): 12356-12369, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34254625

RESUMO

Previous studies have revealed that the liver is the main target organ of deposition for engineered nanoparticles. The hepatotoxicity of silver nanoparticles (AgNPs), the widely used antimicrobial nanoparticles, has been of great interest. However, little is known about the regulatory mechanism of the mitochondria in AgNP-induced hepatotoxicity. In the present study, we found that AgNPs, rather than silver ions, induced mitochondrial dynamics disorders, oxidative stress, and mitochondria-dependent hepatocyte apoptosis in mice. Using human hepatocellular carcinoma (HepG2) cells, we confirmed that the interaction between dynamin-related protein 1 (DRP1)-dependent mitochondrial fission and oxidative stress promoted mitochondrial damage and mitochondria-dependent apoptosis induced by AgNPs, as determined by the elimination of DRP1 or addition of N-acetylcysteine (NAC). Interestingly, the crosstalk between DRP1-dependent mitochondrial fission and oxidative stress also activated mitophagy and autophagy flux blocking. Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) gene silencing contributed to the aggravation of mitochondrial damage, oxidative stress, and apoptosis. These results revealed that the interplay between mitochondrial fission and oxidative stress induced mitophagy defects and triggered AgNP-induced mitochondria-dependent apoptosis in liver cells both in vivo and in vitro. Our findings provide a perspective for the mechanism of hepatotoxicity induced by exposure to metal NPs.


Assuntos
Nanopartículas Metálicas , Dinâmica Mitocondrial , Animais , Apoptose , Dinaminas/metabolismo , Hepatócitos/metabolismo , Nanopartículas Metálicas/toxicidade , Camundongos , Estresse Oxidativo , Prata/toxicidade
3.
Environ Toxicol Chem ; 40(9): 2406-2424, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34078000

RESUMO

Along with the rapid development of nanotechnology, the biosafety assessment of nanotechnology products, including nanomaterials (NMs), has become more and more important. The nematode Caenorhabditis elegans is a valuable model organism that has been widely used in the field of biology because of its excellent advantages, including low cost, small size, short life span, and highly conservative genomes with vertebral animals. In recent years, the number of nanotoxicological researchers using C. elegans has been growing. According to these available studies, the present review classified the adverse effects of NMs in C. elegans into systematic, cellular, and molecular toxicity, and focused on summarizing and analyzing the underlying mechanisms of metal, metal oxide, and nonmetallic NMs causing toxic effects in C. elegans. Our findings provide insights into what further studies are needed to assess the biosafety of NMs in the ecosystem using C. elegans. Environ Toxicol Chem 2021;40:2406-2424. © 2021 SETAC.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34072155

RESUMO

Along with the rapid development of nanotechnology, the biosafety of quantum dots (QDs), a widely used kind of nanoparticles, has grabbed the attentions of researchers, because QDs have excellent and unique optical properties that other commonly used nanoparticles, like walled carbon nanotubes, do not have. The understanding of the toxicity of QDs is an important premise for their application in wider fields, including biology and medicine. This study sought to analyze scientific publications on the toxicity of QDs and to construct a bibliometric model for qualitative and quantitative evaluation of these publications over the past decade, which visually presented the status quo and future development trend on the toxicological study of QDs. A search for data using the triple blind method revealed that, as of 31 December 2018, there were 5269 papers published on the toxicity of QDs. RSC ADVANCES (5-year IF, 3.096) ranked first in the number of publications. China had the largest number of publications (2233) and the highest H-index (119), but the United States was still the leading country with regards to the quality of the research. LIU Y (106 publications) published the most papers, while Hardman R (304 co-citations) had the most co-citations. The keyword "walled carbon nanotube" ranked first in the research frontier. The findings not only determine a development trend of the toxicological study of QDs, but also identify further research directions in this field.


Assuntos
Nanotubos de Carbono , Pontos Quânticos , Bibliometria , China , Publicações , Pontos Quânticos/toxicidade , Estados Unidos
5.
Food Chem Toxicol ; 154: 112324, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34111491

RESUMO

As the release of silver nanoparticles (AgNPs) in the environment continues to increase, great concerns have been raised about their potential toxicity to humans. It is urgent to assess the possible toxicity of AgNPs to the immune cells of the central nervous system due to the continuous accumulation of AgNPs in the brain. This study aimed to evaluate the neurotoxicity of AgNPs and the regulatory mechanism of autophagy in AgNPs-induced inflammation by using mouse microglia BV2 cell lines. AgNPs decreased the microglia cell activity in a concentration and time-dependent manner. The exposure of BV2 cells to AgNPs at a non-cytotoxic level of 5 µg/mL resulted in increase of pro-inflammatory cytokines and decrease of mRNA expression of anti-inflammatory cytokines. AgNPs exposure increased M1 markers of iNOS expression and decreased the expression of M2 markers of CD206 in a time-dependent manner. Meanwhile, the expression of inflammatory proteins IL-1ß and NF-κB increased significantly. Additionally, AgNPs induced an increase in autophagosome and upregulation of LC3II, Beclin1, and p62 expression levels. Pretreatment by an autophagy inhibitor, 3-Methyladenine, caused more AgNPs-treated microglia to polarized into pro-inflammatory phenotypes. Inhibition of autophagy also increased the expression of inflammation-associated mRNA and proteins in BV2 cells. These results indicated that AgNPs could induce pro-inflammatory phenotypic polarization of microglia and the autophagy could play a key regulatory role in the pro-inflammatory phenotypic polarization of microglia induced by AgNPs.


Assuntos
Autofagia/fisiologia , Polaridade Celular/efeitos dos fármacos , Nanopartículas Metálicas/química , Microglia/efeitos dos fármacos , Prata/química , Animais , Linhagem Celular , Inflamação/imunologia , Camundongos
6.
J Appl Toxicol ; 41(12): 2055-2067, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33993517

RESUMO

Silver nanoparticles (AgNPs) have become widespread in the environment with increasing industrial applications. But the studies about their potential health risks are far from enough, especially in neurotoxic effects. This study aimed to investigate the neurotoxic effects of longer-term exposure (prolonged exposure for 48 h and chronic exposure for 6 days) of 20nm AgNPs with/without polyvinylpyrrolidone (PVP) coating at low concentrations (0.01-10 mg·L-1 ) to Caenorhabditis elegans. The results suggested that exposure to AgNPs induced damage to nematode survival, with the longest and relative average life span reduced. Exposure to AgNPs caused neurotoxicity on locomotion behaviors (head thrashes, body bends, pharyngeal pumping frequency, and defecation interval) and sensory perception behaviors (chemotaxis assay and thermotaxis assay), as well as impaired dopaminergic, GABAergic, and cholinergic neurons, except for glutamatergic, based on the alters fluorescence intensity, in a dose- and time-dependent manner. Further investigations suggested that the low-dose AgNPs (0.01-0.1 mg·L-1 ) exposure raises receptors of GABAergic and dopamine in C. elegans at the genetic level, whereas opposite results were observed at higher doses (1-10 mg·L-1 ), which implied that AgNPs could cause neurotoxicity by impairing neurotransmitter delivery. The PVP-AgNPs could cause a higher fatality rate and neurotoxicity at the same dose. Notably, AgNPs did not cause any deleterious effect on nematodes at the lowest dose of 0.01 mg·L-1 . In general, these results suggested that AgNPs possess the neurotoxic potential in C. elegans and provided useful information to understand the neurotoxicity of AgNPs, which would offer an inspiring perspective on the safe application.

7.
Ecotoxicol Environ Saf ; 208: 111672, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396004

RESUMO

Along with the increasing application of graphene quantum dots (GQDs) in the fields of biomedicine and neuroscience, it is important to assess the probably adverse effects of GQDs in the central nervous system (CNS) but their underlying toxic mechanisms is still unclear. In this study, we evaluate the molecular mechanisms associated with circular RNAs (circRNAs) of nitrogen-doped GQDs (N-GQDs) and amino-functionalized GQDs (A-GQDs) damaging the cell viability and cellular structure in microglia by an integrative analysis of RNA microarray. The differentially expressed circRNA (DEcircRNAs)-miRNA- differentially expressed mRNA (DEmRNAs) regulatory networks were conducted in BV2 microglial cells treated with 25 µg/mL N-GQDs, 100 µg/mL N-GQDs and 100 µg/mL A-GQDs. Based on that, the protein-coding genes in each ceRNA network were collected to do bio-functional analysis to evaluate signaling pathways that were indirectly mediated by circRNAs. Some pathways that could play indispensable roles in the neurotoxicity of N-GQDs or both two kinds of GQDs were found. Low-dosed N-GQDs exposure mainly induced inflammatory action in microglia, while high-dosed N-GQDs and A-GQDs exposure both affect olfactory transduction and GABAergic synapse. Meanwhile, several classical signaling pathways, including mTOR, ErbB and MAPK, could make diverse contributions to the neurotoxicity of both two kinds of GQDs. These circRNAs could be toxic biomarkers or protective targets in neurotoxicity of GQDs. More importantly, they emphasized the necessity of comprehensive analysis of latent molecular mechanisms through epigenetics approaches in biosafety assessment of graphene-based nanomaterials.


Assuntos
Redes Reguladoras de Genes/efeitos dos fármacos , Grafite/toxicidade , Microglia/efeitos dos fármacos , Pontos Quânticos/toxicidade , RNA Circular/efeitos dos fármacos , Animais , Biomarcadores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Grafite/química , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Microglia/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Ecotoxicol Environ Saf ; 208: 111463, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33130480

RESUMO

With the increasing use of silver nanoparticles (AgNPs) in biological materials, the cytotoxicity caused by these particles has attracted much attention. However, the molecular mechanism underlying AgNP cytotoxicity remains unclear. In this study, we aimed to systematically investigate the toxicity induced by AgNP exposure to the lung adenocarcinoma A549 cell line at the subcellular and signaling pathway levels and elucidate the related molecular mechanism. The survival rate of cells exposed to AgNPs at 0, 20, 40, 80, and 160 µg/mL for 24 or 48 h decreased in a dose- and time-dependent manner. AgNPs induced autophagy and mitophagy, determined by the transmission electron microscopy investigation and upregulation of LC3 II/I, p62, PINK1, and Parkin expression levels. AgNP treatment induced lysosomal injury, including the decline of lysosomal membrane integrity and increase in cathepsin B level. The decreased in mitochondrial membrane potential, along with upregulation of cytochrome c, caspases 9 and 3, and BAX/BCL2, further suggested that mitochondrial injury were involved in AgNP-induced apoptosis. In addition, mitochondrial injury may further lead to excessive production of reactive oxygen species and oxidative/ antioxidant imbalance. The results suggested that AgNPs could regulate autophagy via mitochondrial and lysosome injury in A549 cells. The information of the molecular mechanism will provide an experimental basis for the safe application of nanomaterials.


Assuntos
Nanopartículas Metálicas/toxicidade , Mitofagia/fisiologia , Prata/toxicidade , Células A549 , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Caspase 9 , Morte Celular/efeitos dos fármacos , Humanos , Lisossomos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitofagia/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases
10.
Sci Total Environ ; 749: 141385, 2020 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-32818856

RESUMO

Graphene quantum dots (GQDs) have been broadly applied in biomedicine in recent years. So far, researches have reported that GQDs might contribute to the injury of the central nervous system (CNS), yet the latent toxicological mechanism is not clear. This study aims to investigate the underlying biological mechanism responsible for the neurotoxicity of nitrogen-doped GQDs (N-GQDs) and amino-functionalized GQDs (A-GQDs) by use of genome-wide transcription microarray. The findings showed that 174 and 1341 genes were altered significantly in the BV2 cells treated by 25 µg/mL N-GQDs and 100 µg/mL N-GQDs compared with the control, respectively. As for the BV2 cells exposed to 100 µg/mL A-GQDs, 1396 diversely expressed genes were detected. By comparing the 100 µg/mL N-GQDs exposed group with 100 µg/mL A-GQDs exposed group, the expression of 256 genes was extensively altered, including 58 upregulated genes and 198 downregulated genes. From Gene Ontology (GO) analysis, the altered genes were mainly enriched in functions of ion channel activation and cellular processes. Based on the KEGG pathway and signal-net analysis, the toxicity of GQDs in BV2 cells was closely related to calcium signaling pathway, cell cycle and endocytosis. And the pathways that the shared mRNAs involved all served as the crucial roles in the neurotoxicity of GQDs despite the chemical functionalization (N-GQDs or A-GQDs). In addition, the consequences from qRT-PCR, Western blot, intracellular calcium level measurements and comet assay further confirmed that calcium dyshomeostasis, DNA damage and cell cycle arrest were the key factors responsible for the GQDs-induced neurotoxicity through affecting several classical signaling pathways. In conclusion, our research will supply essential data for further studies on mechanisms of GQDs-induced neurotoxicity by use of genome-wide screening.


Assuntos
Grafite , Pontos Quânticos , Expressão Gênica , Grafite/toxicidade , Análise em Microsséries , Microglia , Pontos Quânticos/toxicidade
11.
Part Fibre Toxicol ; 17(1): 30, 2020 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-32652997

RESUMO

BACKGROUND: Graphene quantum dots (GQDs) provide a bright prospect in the biomedical application because they contain low-toxic compounds and promise imaging of deep tissues and tiny vascular structures. However, the biosafety of this novel QDs has not been thoroughly evaluated, especially in the central nervous system (CNS). The microarray analysis provides a hint that nitrogen-doped GQDs (N-GQDs) exposure could cause ferroptosis in microglia, which is a novel form of cell death dependent on iron overload and lipid peroxidation. RESULTS: The cytosolic iron overload, glutathione (GSH) depletion, excessive reactive oxygen species (ROS) production and lipid peroxidation (LPO) were observed in microglial BV2 cells treated with N-GQDs, which indicated that N-GQDs could damage the iron metabolism and redox balance in microglia. The pre-treatments of a specific ferroptosis inhibitor Ferrostatin-1 (Fer-1) and an iron chelater Deferoxamine mesylate (DFO) not only inhibited cell death, but also alleviated iron overload, LPO and alternations in ferroptosis biomarkers in microglia, which were caused by N-GQDs. When assessing the potential mechanisms of N-GQDs causing ferroptosis in microglia, we found that the iron content, ROS generation and LPO level in mitochondria of BV2 cells all enhanced after N-GQDs exposure. When the antioxidant ability of mitochondria was increased by the pre-treatment of a mitochondria targeted ROS scavenger MitoTEMPO, the ferroptotic biological changes were effectively reversed in BV2 cells treated with N-GQDs, which indicated that the N-GQDs-induced ferroptosis in microglia could be attributed to the mitochondrial oxidative stress. Additionally, amino functionalized GQDs (A-GQDs) elicited milder redox imbalance in mitochondria and resulted in less ferroptotic effects than N-GQDs in microglia, which suggested a slight protection of amino group functionalization in GQDs causing ferroptosis. CONCLUSION: N-GQDs exposure caused ferroptosis in microglia via inducing mitochondrial oxidative stress, and the ferroptotic effects induced by A-GQDs were milder than N-GQDs when the exposure method is same. This study will not only provide new insights in the GQDs-induced cell damage performed in multiple types of cell death, but also in the influence of chemical modification on the toxicity of GQDs.


Assuntos
Ferroptose/fisiologia , Mitocôndrias/fisiologia , Estresse Oxidativo/fisiologia , Pontos Quânticos/toxicidade , Antioxidantes , Apoptose , Morte Celular , Cicloexilaminas , Glutationa , Grafite , Humanos , Ferro , Peroxidação de Lipídeos , Microglia , Mitocôndrias/efeitos dos fármacos , Oxirredução , Fenilenodiaminas , Espécies Reativas de Oxigênio
12.
Chem Res Toxicol ; 33(7): 1665-1676, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32510209

RESUMO

Available safety evaluations regarding mesoporous silica nanoparticles (mSiNPs) are based on the assumption of a relatively high exposure concentration, which makes the findings less valuable in a realistic environment. In this study, we employed Caenorhabditis elegans (C. elegans) as a model to assess the neuronal damage caused by mSiNPs at the predicted environmentally relevant concentrations. After nematodes were acute and prolonged exposed to mSiNPs at concentrations over 300 µg/L, locomotion degeneration, shrinking behavior, and abnormal foraging behavior were observed, which were associated with the deficits in the development of GABAergic neurons, including D-type and RME motor neurons. Furthermore, the oxidative stress evidenced by excessive ROS generation might contribute to the mechanism of mSiNPs damaging neurons. Although the neurotoxicity of mSiNPs was weaker than (nonmesoporous) SiNPs, it is still necessary for researchers to pay attention to the adverse effects caused by mSiNPs in the environmental animals, especially with the rapid increase in mSiNPs application. Considering the conserved property of GABAergic neurons during evolution, these findings will shed light on our understanding of the potential eco-risks of NPs to the nervous system of other animal models.


Assuntos
Neurônios GABAérgicos/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Nanopartículas/química , Dióxido de Silício/toxicidade , Animais , Caenorhabditis elegans , Relação Dose-Resposta a Droga , Neurônios GABAérgicos/metabolismo , Neurônios Motores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Porosidade , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/química , Propriedades de Superfície
13.
Int J Nanomedicine ; 15: 3217-3233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32440120

RESUMO

Introduction: Since CdTe quantum dots (QDs) are still widely considered as advanced fluorescent probes because of their far superior optical performance and fluorescence efficiency over non-cadmium QDs, it is important to find ways to control their toxicity. Methods: In this study, the adverse effects of two cadmium-containing QDs, ie, CdTe QDs and CdTe@ZnS QDs, on the nervous system of nematode C. elegans, the hippocampus of mice, and cultured microglia were measured in order to evaluate the neuroinflammation caused by cadmium-containing QDs and the potential mechanisms. Results: Firstly, we observed that cadmium-containing QD exposure-induced immune responses and neurobehavioral deficit in nematode C. elegans. In the mice treated with QDs, neuroinflammatory responses to QDs in the hippocampus, including microglial activation and IL-1ß release, occurred as well. When investigating the mechanisms of cadmium-containing QDs causing IL-1ß-mediated inflammation, the findings suggested that cadmium-containing QDs activated the NLRP3 inflammasome by causing excessive ROS generation, and resulted in IL-1ß release. Discussion: Even though the milder immune responses and neurotoxicity of CdTe@ZnS QDs compared with CdTe QDs indicated the protective role of ZnS coating, the inhibitions of NLRP3 expression and ROS production completely reduced the IL-1ß-mediated inflammation. This provided valuable information that inhibiting target molecules is an effective and efficient way to alleviate  the toxicity of cadmium-containing QDs, so it is important to evaluate QDs through a mechanism-based risk assessment.


Assuntos
Encéfalo/patologia , Compostos de Cádmio/farmacologia , Inflamação/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pontos Quânticos/química , Sulfetos/farmacologia , Telúrio/farmacologia , Compostos de Zinco/farmacologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/imunologia , Linhagem Celular , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos ICR , Microglia/efeitos dos fármacos , Microglia/patologia , Espécies Reativas de Oxigênio/metabolismo
14.
Environ Pollut ; 264: 114639, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32388296

RESUMO

Since ambient particulate matter (APM) is closely related to cardiovascular damage with mitochondria being its potential targets, this study was designed to explore the impact of APM on mitochondrial homeostasis, especially on mitochondrial dynamics and biogenesis in human vascular endothelial cells, using a kind of standard material, PM SRM1648a. As a result, internalized particles lead to mitochondrial dysfunction in EA.hy926 human endothelial cells, including mitochondrial reactive oxygen species (mtROS) overproduction, mitochondrial membrane potential (MMP) reduction and adenosine triphosphate (ATP) inhibition, coupled with additional release of mitochondrial DNA (mtDNA) into the cytosol. Moreover, morphological and structural changes in mitochondria are observed in response to PM SRM1648a. In that aspect, according to the evidence of shorter fragmented mitochondria dispersed throughout the cytoplasm, along with aberrant upregulation of fission-related mRNAs/proteins, the mitochondria exhibit a fission phenotype shifting from intact reticular network to fragmentized punctate shapes. Mechanistically, PM SRM1648a facilitates phosphorylation of DRP1 at Ser616 in HUVECs, and triggers its dephosphorylation at Ser637 residue in both EA.hy926 and HUVECs, which are supportive events for mitochondrial fission during particle exposure. Additionally, suppression of a master energy modulator, PGC-1α, reveals that PM SRM1648a has the ability to impair mitochondrial biogenesis. Collectively, it could be well concluded that PM SRM1648a interferes with the equilibrium of mitochondrial dynamics and biogenesis, which is likely to play a pivotal role in mitochondrial dysfunction driven by particles, eventually contributing to endothelial cell damage. Of note, it is more reasonable to conduct risk assessment from both cellular level and subcellular structures, among which mitochondria-targeted toxicity supplements more comprehensive understanding of APM inducible vascular toxicity.


Assuntos
Dinâmica Mitocondrial , Material Particulado , Células Endoteliais , Humanos , Mitocôndrias , Biogênese de Organelas , Espécies Reativas de Oxigênio
15.
Toxicol In Vitro ; 65: 104827, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32179110

RESUMO

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.


Assuntos
Compostos de Cádmio/toxicidade , Interleucina-1beta/metabolismo , Microglia/efeitos dos fármacos , Pontos Quânticos/toxicidade , Sulfetos/toxicidade , Telúrio/toxicidade , Compostos de Zinco/toxicidade , Animais , Linhagem Celular , Inflamação/induzido quimicamente , Inflamação/metabolismo , Camundongos , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo
16.
J Hazard Mater ; 394: 122439, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32200236

RESUMO

Ambient particulate matter (APM) is becoming a global environmental problem that seriously jeopardizes public health. Previous evidence hinted that APM correlates to cardiovascular diseases. As a potential target, equilibrium of endothelial cell is a prerequisite for vascular health which could be vulnerably attacked by particles, but the specific mechanisms whereby APM damages endothelial cells have not been fully elucidated. In the current study, based on two classical mechanisms of oxidative stress and intracellular calcium overload, we aimed to explore their roles in APM-induced endothelial cell apoptosis from the perspective of subcellular levels, including endoplasmic reticulum (ER) stress and mitochondrial dysfunction. As a result, PM SRM1648a results in oxidative stress and calcium overload in EA.hy926 cells. Additionally, ERs and mitochondria could be severely disturbed by particles in morphology and function, characterized by swelling ERs, mitochondrial fission and disappearance of cristae, coupled with ER damage, mtROS overproduction and significant reduction in mitochondrial membrane potential (MMP). Adverse effects on these organelles are the prime culprits of following apoptosis in endothelial cells. Fortunately, additional antioxidants and calcium inhibitors could mitigate cellular lesion through improvement of subcellular function. Intriguingly, antioxidants relieve cell stress via both mitochondrial and ER stress-mediated pathways, whereas the role of calcium modulators in cell apoptosis is independent of the mitochondrial pathway but could be explained by amelioration of ER stress. In conclusion, our data basically revealed that internalized PM SRM1648a triggers oxidative stress and calcium influx in EA.hy926 endothelial cells, followed by multiple subcellular damage and eventually contributes to cell death, during which antioxidants and calcium inhibitors confer protective effects.


Assuntos
Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Células Endoteliais/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Material Particulado/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
17.
Chemosphere ; 246: 125629, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31927360

RESUMO

In this study, a metabolomic analysis was used to reveal the neurotoxicity of the CdTe/ZnS QDs via microglia polarization. A gas chromatography-mass spectrometer (GC-MS) was applied to uncover the metabonomic changes in microglia (BV-2 cell line) after exposure to 1.25 µM CdTe/ZnS QDs. 11 annotated metabolic pathways (KEGG database) were significantly changed in all exposed groups (3 h, 6 h, 12 h), 3 of them were related to glucose metabolism. The results of the Seahorse XFe96 Analyzer indicated that the CdTe/ZnS QDs increased the glycolysis level of microglia by 86% and inhibited the aerobic respiration level by 54% in a non-hypoxic environment. In vivo study, 3 h after the injection of CdTe/ZnS QDs (2.5 mM) through the tail vein in mice, the concentration of the CdTe/ZnS QDs in hippocampus reached the peak (1.25 µM). The polarization level of microglia (Iba-1 immunofluorescence) increased 2.7 times. In vitro study, the levels of the extracellular TNF-α, IL-1ß and NO of BV-2 cells were all increased significantly after a 6 h or 12 h exposure. According to the results of the Cell Counting Kit-8, after a 6 h or 12 h exposure to the CdTe/ZnS QDs, the exposed microglia could significantly decrease the number of neurons (HT-22 cell line). This study proved that CdTe/ZnS QDs could polarize microglia in the brain and cause secondary inflammatory damage to neurons. There are potential risks in the application of the CdTe/ZnS QDs in brain tissue imaging.


Assuntos
Metabolômica/métodos , Microglia/efeitos dos fármacos , Pontos Quânticos/toxicidade , Animais , Compostos de Cádmio , Polaridade Celular/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Glicólise/efeitos dos fármacos , Hipocampo/patologia , Camundongos , Síndromes Neurotóxicas/etiologia , Pontos Quânticos/química , Sulfetos , Telúrio , Compostos de Zinco
18.
J Appl Toxicol ; 40(6): 815-831, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31984544

RESUMO

This study evaluated the biodistribution and organ oxidative effects of silver nanoparticles (AgNPs) coated with/without polyvinylpyrrolidone (PVP) (AgNP-20 and AgNP-PVP) in mice; these were administered by gavage at a dose of 10-250 mg/kg body weight per day for 28 days. The results showed that both the AgNPs could induce subacute toxicity and oxidative damage to mice and were mainly accumulated in the liver and spleen and excreted by feces. AgNPs could be absorbed into blood and might cross the blood-brain barrier, and be distributed extensively in mice. The malondialdehyde content in the liver, lungs and kidneys increased in both AgNP groups, while the content of glutathione decreased, and the activity of superoxide dismutase increased at first and then decreased along with the increased doses. Inflammatory pathological changes in the lung and liver at high dose of both AgNPs were consistent with increases in glutamate pyruvic transaminase, glutamate oxaloacetic transaminase and the total protein in serum detection. The Ag content was detected in organs, with the highest content in the liver, followed by spleen, while the Ag content in feces was about 500 times higher than that in urine. AgNP-PVP could induce higher oxidative stress and subacute toxicity than AgNP-20 at the same dose, which might be related to the higher concentrations and more Ag+ ions released in mice after AgNP-PVP exposure. The data from this research provided information on toxicity and biodistribution of AgNPs following gavage administration in mice, and might shed light for future application of AgNPs in daily life.


Assuntos
Nanopartículas Metálicas/toxicidade , Povidona/toxicidade , Compostos de Prata/toxicidade , Administração Oral , Animais , Feminino , Masculino , Nanopartículas Metálicas/administração & dosagem , Camundongos Endogâmicos ICR , Povidona/metabolismo , Compostos de Prata/administração & dosagem , Compostos de Prata/metabolismo , Distribuição Tecidual
19.
Environ Pollut ; 256: 113430, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31685329

RESUMO

Silver nanoparticles (AgNPs) are inevitably released into the environment owing to their widespread applications in industry and medicine. The potential of their toxicity has aroused a great concern. Previous studies have shown that AgNPs exposure in HepG2 cells is primarily related to the damage of mitochondria, which includes induction of mitochondrial swelling and increase of intracellular levels of reactive oxygen species (ROS), the collapse of mitochondrial membrane potential and induction of apoptosis through a mitochondrial pathway. In this study, the effects of AgNPs exposure in HepG2 cells on mitochondrial dynamics and biogenesis were investigated. AgNPs were found to induce mitochondrial morphological and structural alterations. The expressions of key proteins (Drp1, Fis1, OPA1, Mff, Mfn1, and Mfn2) related to mitochondrial fission/fusion event were changed. Especially the expression of fission-related protein 1 (p-Drp1) (Ser616) was significantly up-regulated, whereas the expression of mitochondrial biogenesis protein (PGC-1α) was reduced in AgNP-treated cells. Concomitantly, the expression of autophagy marker proteins (LC3B and p62) was increased. The results suggested that AgNPs could trigger cytotoxicity by targeting the mitochondria, resulting in the disruption of mitochondrial function, damage to the mitochondrial structure and morphology, interfering in mitochondrial dynamics and biogenesis. The mitochondria could be a critical target of AgNPs in cells. The functions of mitochondria could be used for assessing the cytotoxic effects associated with AgNPs in cells.


Assuntos
Nanopartículas Metálicas/toxicidade , Mitocôndrias/efeitos dos fármacos , Prata/toxicidade , Animais , Apoptose , Substâncias Perigosas , Células Hep G2 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Espécies Reativas de Oxigênio/metabolismo , Testes de Toxicidade
20.
J Appl Toxicol ; 40(3): 388-402, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31802521

RESUMO

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.


Assuntos
Compostos de Cádmio/toxicidade , Glicólise/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Microglia/efeitos dos fármacos , Pontos Quânticos/toxicidade , Sulfetos/toxicidade , Serina-Treonina Quinases TOR/metabolismo , Telúrio/toxicidade , Compostos de Zinco/toxicidade , Animais , Linhagem Celular , Hipocampo/enzimologia , Hipocampo/ultraestrutura , Masculino , Camundongos Endogâmicos ICR , Microglia/enzimologia , Microglia/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Transdução de Sinais
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