Comprehensive pulmonary metabolic responses to silica nanoparticles exposure in Fisher 344 rats.

Silica nanoparticles (SiNPs) could induce adverse pulmonary effects, but the mechanism was not clear enough. Metabolomics is a sensitive and high-throughput approach that could investigate the intrinsic causes of adverse health effects caused by SiNPs. The current investigation represented the first in vivo metabolomics study examining the chronic pulmonary toxicity of SiNPs at a low dosage, mimicking real human exposure situation. The recovery process after the cessation of exposure was also taken into consideration. Fisher 344 rats were treated with either saline or SiNPs for 6 months. Half of the animals in each group received an additional six-month period for recovery. The findings indicated that chronic low-level exposure to SiNPs resulted in notable alterations in pulmonary metabolism of amino acids, lipids, carbohydrates, and nucleotides. SiNPs exerted an impact on various metabolites and metabolic pathways which are linked to oxidative stress, inflammation and tumorigenesis. These included but were not limited to L-carnitine, spermidine, taurine, xanthine, and glutathione metabolism. The metabolic alterations caused by SiNPs exhibited a degree of reversibility. However, the interference of SiNPs on two metabolic pathways related to tumorigenesis was observed to persist after a recovery period. The two metabolic pathways are glycerophospholipid metabolism as well as phenylalanine, tyrosine and tryptophan biosynthesis. This study elucidated the metabolic alterations induced by chronic low-level exposure to SiNPs and presented novel evidence of the chronic pulmonary toxicity and carcinogenicity of SiNPs, from a metabolomic perspective.

Redox-Active Ferrocene Quencher-Based Supramolecular Nanomedicine for NIR-II Fluorescence-Monitored Chemodynamic Therapy.

Real-time monitoring of hydroxyl radical (⋅OH) generation is crucial for both the efficacy and safety of chemodynamic therapy (CDT). Although ⋅OH probe-integrated CDT agents can track ⋅OH production by themselves, they often require complicated synthetic procedures and suffer from self-consumption of ⋅OH. Here, we report the facile fabrication of a self-monitored chemodynamic agent (denoted as Fc-CD-AuNCs) by incorporating ferrocene (Fc) into ß-cyclodextrin (CD)-functionalized gold nanoclusters (AuNCs) via host-guest molecular recognition. The water-soluble CD served not only as a capping agent to protect AuNCs but also as a macrocyclic host to encapsulate and solubilize hydrophobic Fc guest with high Fenton reactivity for in vivo CDT applications. Importantly, the encapsulated Fc inside CD possessed strong electron-donating ability to effectively quench the second near-infrared (NIR-II) fluorescence of AuNCs through photoinduced electron transfer. After internalization of Fc-CD-AuNCs by cancer cells, Fenton reaction between redox-active Fc quencher and endogenous hydrogen peroxide (H2 O2 ) caused Fc oxidation and subsequent NIR-II fluorescence recovery, which was accompanied by the formation of cytotoxic ⋅OH and therefore allowed Fc-CD-AuNCs to in situ self-report ⋅OH generation without undesired ⋅OH consumption. Such a NIR-II fluorescence-monitored CDT enabled the use of renal-clearable Fc-CD-AuNCs for efficient tumor growth inhibition with minimal side effects in vivo.

Real-Time Recognition Method for Key Signals of Rock Fracture Acoustic Emissions Based on Deep Learning.

The characteristics of acoustic emission signals generated in the process of rock deformation and fission contain rich information on internal rock damage. The use of acoustic emissions monitoring technology can analyze and identify the precursor information of rock failure. At present, in the field of acoustic emissions monitoring and the early warning of rock fracture disasters, there is no real-time identification method for a disaster precursor characteristic signal. It is easy to lose information by analyzing the characteristic parameters of traditional acoustic emissions to find signals that serve as precursors to disasters, and analysis has mostly been based on post-analysis, which leads to poor real-time recognition of disaster precursor characteristics and low application levels in the engineering field. Based on this, this paper regards the acoustic emissions signal of rock fracture as a kind of speech signal generated by rock fracture uses this idea of speech recognition for reference alongside spectral analysis (STFT) and Mel frequency analysis to realize the feature extraction of acoustic emissions from rock fracture. In deep learning, based on the VGG16 convolutional neural network and AlexNet convolutional neural network, six intelligent real-time recognition models of rock fracture and key acoustic emission signals were constructed, and the network structure and loss function of traditional VGG16 were optimized. The experimental results show that these six deep-learning models can achieve the real-time intelligent recognition of key signals, and Mel, combined with the improved VGG16, achieved the best performance with 87.68% accuracy and 81.05% recall. Then, by comparing multiple groups of signal recognition models, Mel+VGG-FL proposed in this paper was verified as having a high recognition accuracy and certain recognition efficiency, performing the intelligent real-time recognition of key acoustic emission signals in the process of rock fracture more accurately, which can provide new ideas and methods for related research and the real-time intelligent recognition of rock fracture precursor characteristics.

Ferritinophagy was involved in long-term SiNPs exposure induced ferroptosis and liver fibrosis.

SiNPs could induce liver fibrosisinvivo, but the mechanism was not completely clear. This study focused on exploring whether long-term SiNPs exposure at human-related exposure dosage could lead to ferritinophagy-mediated ferroptosis and liver fibrosis. In vivo, long-term SiNPs exposure induced liver fibrosis inrats accompanied by ferritinophagy and ferroptosis in hepatocytes. Interestingly, the progression of liver fibrosis was alleviated after exposure cessation and recovery, meanwhile ferritinophagy and ferroptosis were not further activated. In vitro, after long-term SiNPs exposure, the mitochondrial membrane ruptured, lipid peroxidation intensified, the level of redox active iron increased and the repair protein of lipid peroxidation were consumed in L-02 cells, demonstrating ferroptosis occurrence. Notably, NCOA4 knockdown inhibited ferritin degradation, alleviated the increase of intracellular ferrous iron level, reduced lipid peroxidation and the depletion of glutathione peroxidase 4 (GPX4). In conclusion, ferritinophagy mediated by NCOA4 was responsible for long-term SiNPs exposure induced hepatocytes ferroptosis and liver fibrosis, which provided a scientific basis for toxicological assessment of SiNPs and would be benefited for the safety design of SiNPs-based products.

Engineering Single-Atom Nanozymes for Catalytic Biomedical Applications.

Nanomaterials with enzyme-mimicking properties, coined as nanozymes, are a promising alternative to natural enzymes owing to their remarkable advantages, such as high stability, easy preparation, and favorable catalytic performance. Recently, with the rapid development of nanotechnology and characterization techniques, single atom nanozymes (SAzymes) with atomically dispersed active sites, well-defined electronic and geometric structures, tunable coordination environment, and maximum metal atom utilization are developed and exploited. With superior catalytic performance and selectivity, SAzymes have made impressive progress in biomedical applications and are expected to bridge the gap between artificial nanozymes and natural enzymes. Herein, the recent advances in SAzyme preparation methods, catalytic mechanisms, and biomedical applications are systematically summarized. Their biomedical applications in cancer therapy, oxidative stress cytoprotection, antibacterial therapy, and biosensing are discussed in depth. Furthermore, to appreciate these advances, the main challenges, and prospects for the future development of SAzymes are also outlined and highlighted in this review.

Iron-siRNA Nanohybrids for Enhanced Chemodynamic Therapy via Ferritin Heavy Chain Downregulation.

Ferrous iron (Fe2+ ) has more potent hydroxyl radical (⋅OH)-generating ability than other Fenton-type metal ions, making Fe-based nanomaterials attractive for chemodynamic therapy (CDT). However, because Fe2+ can be converted by ferritin heavy chain (FHC) to nontoxic ferric form and then sequestered in ferritin, therapeutic outcomes of Fe-mediated CDT agents are still far from satisfactory. Here we report the synthesis of siRNA-embedded Fe0 nanoparticles (Fe0 -siRNA NPs) for self-reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH-responsive Fe0 -siRNA NPs are degraded to release Fe2+ and FHC siRNA in acidic endo/lysosomes with the aid of oxygen (O2 ). The accompanied O2 depletion causes an intracellular pH decrease, which further promotes the degradation of Fe0 -siRNA NPs. In addition to initiating chemodynamic process, Fe2+ -catalyzed ⋅OH generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulation-enhanced CDT.

Enhancing Catalytic Activity of a Nickel Single Atom Enzyme by Polynary Heteroatom Doping for Ferroptosis-Based Tumor Therapy.

As a rising generation of nanozymes, single atom enzymes show significant promise for cancer therapy, due to their maximum atom utilization efficiency and well-defined electronic structures. However, it remains a tremendous challenge to precisely produce a heteroatom-doped single atom enzyme with an expected coordination environment. Herein, we develop an anion exchange strategy for precisely controlled production of an edge-rich sulfur (S)- and nitrogen (N)-decorated nickel single atom enzyme (S-N/Ni PSAE). In particular, sulfurized S-N/Ni PSAE exhibits stronger peroxidase-like and glutathione oxidase-like activities than the nitrogen-monodoped nickel single atom enzyme, which is attributed to the vacancies and defective sites of sulfurized nitrogen atoms. Moreover, both in vitro and in vivo results demonstrate that, compared with nitrogen-monodoped N/Ni PSAE, sulfurized S-N/Ni PSAE more effectively triggers ferroptosis of tumor cells via inactivating glutathione peroxidase 4 and inducing lipid peroxidation. This study highlights the enhanced catalytic efficacy of a polynary heteroatom-doped single atom enzyme for ferroptosis-based cancer therapy.

Amplification of Lipid Peroxidation by Regulating Cell Membrane Unsaturation To Enhance Chemodynamic Therapy.

Lipid peroxidation (LPO) is one of the most damaging processes in chemodynamic therapy (CDT). Although it is well known that polyunsaturated fatty acids (PUFAs) are much more susceptible than saturated or monounsaturated ones to LPO, there is no study exploring the effect of cell membrane unsaturation degree on CDT. Here, we report a self-reinforcing CDT agent (denoted as OA@Fe-SAC@EM NPs), consisting of oleanolic acid (OA)-loaded iron single-atom catalyst (Fe-SAC)-embedded hollow carbon nanospheres encapsulated by an erythrocyte membrane (EM), which promotes LPO to improve chemodynamic efficacy via modulating the degree of membrane unsaturation. Upon uptake of OA@Fe-SAC@EM NPs by cancer cells, Fe-SAC-catalyzed conversion of endogenous hydrogen peroxide into hydroxyl radicals, in addition to initiating the chemodynamic therapeutic process, causes the dissociation of the EM shell and the ensuing release of OA that can enrich cellular membranes with PUFAs, enabling LPO amplification-enhanced CDT.

Co-exposure of PM2.5 and high-fat diet induce lipid metabolism reprogramming and vascular remodeling.

Fine particulate matter (PM2.5) exposure has been proved to increase the cardiovascular disease risk. However, there is a lack of comprehensive knowledge on whether a high-fat diet (HFD) affects PM2.5-induced cardiovascular disease. The purpose of this study was to investigate the impairment of lipid metabolism and vascular function by PM2.5 and HFD exposure in ApoE-/- mice. Oil red O staining indicated that co-treatment of PM2.5 and HFD resulted in markedly lipid deposition in the mice aorta. Blood biochemical analysis demonstrated that co-exposure of PM2.5 and HFD could cause dyslipidemia in vivo. Vascular Doppler ultrasound and histopathological analysis found that the functional and structural alterations with fibrosis and calcified remodeling of the vessels were detected after PM2.5 and HFD exposure. For in-depth study, the genome-wide transcriptional analysis performed in macrophages was further revealed that the endoplasmic reticulum stress, immune system process, regulation of cell proliferation etc. were response to PM2.5 exposure; while Lipid and atherosclerosis signaling pathways had a critical role in PM2.5-induced vascular injury. Results from validation experiments manifested that the release of supernatant in PM2.5- or ox-LDL-treated macrophages could decrease the cell viability and increase the lipid ROS in vascular smooth muscle cells (VSMCs). Moreover, the up-regulations of CCL2, IL-6 and IL-1ß in aortic arch of mice were observed after co-exposure with PM2.5 and HFD. Our data hinted that PM2.5 could affect the lipid metabolism reprogramming and induce vascular remodeling, accompanied with synergistic effects of HFD.

Melatonin alleviates PM2.5 -induced glucose metabolism disorder and lipidome alteration by regulating endoplasmic reticulum stress.

Exposure to fine particulate matter (PM2.5 ) was associated with an increased incidence of liver metabolic disease. Melatonin has been shown to prevent liver glucolipid metabolism disorders. However, whether melatonin could rescue PM2.5 -induced liver metabolic abnormalities remains uncertain. This study was to evaluate the mitigating effect of melatonin on PM2.5 -accelerated hepatic glucose metabolism imbalance in vivo and in vitro. Schiff periodic acid shiff staining and other results showed that PM2.5 led to a decrease in hepatic glycogen reserve and an increase in glucose content, which was effectively alleviated by melatonin. Targeted lipidomics is used to identify lipid biomarkers associated with this process, including glycerolipids, glycerophospholipids, and sphingolipids. In addition, gene microarray and quantitative polymerase chain reaction analysis of ApoE-/- mice liver suggested that PM2.5 activated the miR-200a-3p and inhibited DNAJB9, and the targeting relationship was verified by luciferase reports for the first time. Further investigation demonstrated that DNAJB9 might motivate endoplasmic reticulum (ER) stress by regulating Ca2+ homeostasis, thus altering the protein expression of GSK3B, FOXO1, and PCK2. Meanwhile, melatonin effectively inhibited miR-200a-3p and glucose metabolism disorder. Knockout of miR-200a-3p in L02 cells revealed that miR-200a-3p is indispensable in the damage of PM2.5 and the therapeutic effect of melatonin. In summary, melatonin alleviated PM2.5 -induced liver metabolic dysregulation by regulating ER stress via miR-200a-3p/DNAJB9 signaling pathway. Our data provide a prospective targeted therapy for air pollution-related liver metabolism disorders.

Combined exposure to PM2.5 and high-fat diet facilitates the hepatic lipid metabolism disorders via ROS/miR-155/PPARγ pathway.

Environmental fine particulate matter (PM2.5), which has attracted worldwide attention, is associated with the progression of metabolic-associated fatty liver disease (MAFLD). However, it is unclear whether dietary habit exacerbate liver damage caused by PM2.5. The current study aimed to investigate the combined negative effects of PM2.5 and high-fat diet (HFD) on liver lipid metabolism in C57BL/6J mice. Histopathological and Oil-Red O staining analysis illustrated that PM2.5 exposure resulted in increased liver fat content in HFD-fed C57BL/6J mice, but not in standard chow diet (STD)-fed mice. And there was a synergistic effect between PM2.5 and HFD on hepatic lipotoxicity. The increased ROS levels and augmented oxidative damage were evaluated in liver tissue of mice treated with PM2.5 and HFD together. In addition, excessive ROS production could activate the miR-155/peroxisome proliferator-activated receptor gamma (PPARγ) pathway, including up-regulation of lipid accumulation-related protein expressions of recombinant liver X receptor alpha (LXRα), sterol regulatory element binding protein-1 (SREBP-1), stearoyl-CoA desaturase-1 (SCD1), fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1).The use of miR-155 inhibitors demonstrated the indispensable role of miR-155 in the activation of lipid-regulated proteins by PM2.5 and palmitic acid (PA). Collectively, altering high-fat dietary habits could protect against MAFLD motivated by air pollution, and miR-155 might be an effective preventive and therapeutic target for this process.

Microarray analysis of mRNA expression profiles in liver of ob/ob mice with real-time atmospheric PM2.5 exposure.

Epidemiological studies have demonstrated the association between exposure to fine particulate matter (PM2.5) and the onset of non-alcoholic fatty liver disease (NAFLD). However, the potential biological mechanism is largely unknown. Our study was aimed to explore the impact of PM2.5 on the transcriptome level in the liver of ob/ob mice by atmosphere PM2.5 whole-body dynamic exposure system, and meanwhile preliminarily investigated the effects of metformin intervention in this process. More than three thousand differentially expressed genes (DEGs) was screened out by microarray analysis (p < 0.05, |FC|> 1.5). KEGG pathway enrichment analysis showed that these DEGs were mainly enriched in cancers, infectious diseases, and signal transduction, and the most significant pathways were thyroid hormone signaling pathway, chronic myeloid leukemia and metabolic pathways. Then, 12 hub genes were gained through weighted gene correlation network analysis (WGCNA) and verified by qRT-PCR. The expression of 5 genes in darkslateblue module (cd53, fcer1g, cd68, ctss, laptm5) increased after PM2.5 exposure and decreased after metformin intervention. They were related to insulin resistance, glucose and lipid metabolism and other liver metabolism, and also neurodegenerative diseases. This study provided valuable clues and possible protective measures to the liver damage in ob/ob mice caused by PM2.5 exposure, and further research is needed to explore the related mechanism in detail.

Metabolomics-based safety evaluation of acute exposure to electronic cigarettes in mice.

INTRODUCTION: A growing number of epidemiological evidence reveals that electronic cigarettes (E-cigs) were associated with pneumonia, hypertension and atherosclerosis, but the toxicological evaluation and mechanism of E-cigs were largely unknown. OBJECTIVE: Our study was aimed to explore the adverse effects on organs and metabolomics changes in C57BL/6J mice after acute exposure to E-cigs. METHODS AND RESULTS: Hematoxylin and eosin (H&E) staining found pathological changes in tissues after acute exposure to E-cigs, such as inflammatory cell infiltration, nuclear pyknosis, and intercellular interstitial enlargement. E-cigs could increase apoptosis-positive cells in a time-dependent way using Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Oxidative damage indicators of reactive oxygen species (ROS), malondialdehyde (MDA) and 4-hydroxynonena (4-HNE) were also elevated after E-cigs exposure. There was an increasing trend of total glycerol and cholesterol in serum, while the glucose and liver enzymes including alanine aminotransferase (ALT), aspartate transaminase (AST), gamma-glutamyltranspeptidase (γ-GT) had no significant change compared to that of control. Further, Q Exactive high field (HF) mass spectrometer was used to conduct metabolomics, which revealed that differential metabolites including l-carnitine, Capryloyl glycine, etc. Trend analysis showed the type of compounds that change over time. Pathway enrichment analysis indicated that E-cigs affected 24 metabolic pathways, which were mainly regulated amino acid metabolism, further affected the tricarboxylic acid (TCA) cycle. Additionally, metabolites-diseases network analysis found that the type 2 diabetes mellitus, propionic acidemia, defect in long-chain fatty acids transport and lung cancer may be related to E-cigs exposure. CONCLUSIONS: Our findings provided important clues for metabolites biomarkers of E-cigs acute exposure and are beneficial for disease prevention.

Impact of PM2.5 exposure on plasma metabolome in healthy adults during air pollution waves: A randomized, crossover trial.

Air pollution, especially PM2.5 (particulate matter with an aerodynamic diameter ≤2.5 µm) in China, is severe and related to a variety of diseases while the potential mechanisms have not been clearly clarified yet. This study was conducted using a randomized crossover trial protocol among young and healthy college students. Plasma samples were collected before, during, and post two typical air pollution waves with a washout interval of at least 2 weeks under true and sham air purification treatments, respectively. A total of 144 blood samples from 24 participants were included in the final analysis. Metabolomics analysis for the plasma samples was completed by Ultrahigh Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). Orthogonal Partial Least Squares Discrimination Analysis (OPLS-DA) and linear mixed-effect models were used to identify the differentially expressed metabolites and their associations with PM2.5 exposure. MetaboAnalyst 5.0 was further used to conduct pathway enrichment analysis and correlation analysis of differentially expressed metabolites. A total of 40 metabolites were identified to be differentially expressed between the true and sham air purification treatments, and eleven metabolites showed consistent significant changes upon outdoor, indoor, and time-weighted personal PM2.5 exposures. Short-term exposure to PM2.5 may cause disturbances in metabolic pathways such as linoleic acid metabolism, arachidonic acid metabolism, and tryptophan metabolism.

Enhanced Cancer Starvation Therapy Enabled by an Autophagy Inhibitors-Encapsulated Biomimetic ZIF-8 Nanodrug: Disrupting and Harnessing Dual Pro-Survival Autophagic Responses.

Autophagy is an important protective mechanism in maintaining or restoring cell homeostasis under physiological and pathological conditions. Nanoparticles (NPs) with certain components and morphologies can induce autophagic responses in cancer cells, providing a new perspective for establishing cancer therapy strategies. Herein, a novel nanodrug system, cell membranes-coated zeolitic imidazolate framework-8 (ZIF-8) NPs encapsulating chloroquine (CQ) and glucose oxidase (GOx) (defined as mCG@ZIF), is designed to achieve an enhanced anticancer effect with the combination of starvation therapy and an autophagy regulation strategy. It is found that ZIF-8 as a nanocarrier can induce autophagy to promote survival of cancer cells via the upstream Zn2+-stimulated mitochondrial reactive oxygen species (ROS) so that the anticancer effect is directly achieved by inhibiting this pro-survival autophagy using CQ released from mCG@ZIF under a tumor acidic microenvironment. Moreover, a cancer cell under starvation caused by GOx harnesses autophagy to maintain intracellular ATP levels and resist starvation therapy. The released CQ further inhibits the starvation-induced pro-survival autophagy and cuts off the protective pathway of cancer cells, enhancing the anticancer efficiency of GOx-based starvation therapy. Significantly, the cell membrane coating endows mCG@ZIF with excellent in vivo homotypic targeting ability. Both in vitro and in vivo results have confirmed the enhanced anticancer effect achieved by mCG@ZIF with a negligible side effect.

Effects of ambient air pollution on glycosylated hemoglobin: a systematic review and meta-analysis.

Air pollution is one of the biggest environmental health problems in the world; accumulative studies have shown that air pollution was closely related to metabolism disorders. HbA1c is a stable indicator for blood glucose level monitoring. However, studies on the impact of ambient air pollution on HbA1c have inconsistent conclusions. The objective of the study is to explore the influence of ambient air pollution on HbA1c. By searching keywords, a systematic literature retrieval was carried out on PubMed, Cochrane Library, Web of Science, and Embase databases up to April 2022. Pooled percentage change (%-change) and 95% confidence intervals (95% CI) were estimated using random effect models for particulate matter (PM) and nitrogen dioxide (NO2). A subgroup analysis of body mass index (BMI), study region, exposure period, sample size, sensitivity analysis, and publication bias detection was also performed. There were 8, 12, and 6 studies included in this meta-analysis to explore the association between PM10, PM2.5, NO2, and HbA1c, respectively. The results showed that for every increase of 10 µg/m3 in PM10, PM2.5, and NO2, the %-changes in HbA1c were 0.13%, 0.814%, and 0.02%, respectively. The subgroup analysis showed that exposure period, sample size, and BMI were associated with HbA1c in response to air pollution. PM10, PM2.5, and NO2 exposure were significantly associated with increased HbA1c levels.

Melatonin alleviates PM2.5-triggered macrophage M1 polarization and atherosclerosis via regulating NOX2-mediated oxidative stress homeostasis.

It is reported that oxidative stress homeostasis was involved in PM2.5-induced foam cell formation and progression of atherosclerosis, but the exact molecular mechanism is still unclear. Melatonin is an effective antioxidant that could reverse the cardiopulmonary injury. The main purpose of this study is to investigate the latent mechanism of PM2.5-triggered atherosclerosis development and the protective role of melatonin administration. Vascular Doppler ultrasound showed that PM2.5 exposure reduced aortic elasticity in ApoE-/- mice. Meanwhile, blood biochemical and pathological analysis demonstrated that PM2.5 exposure caused dyslipidemia, elicited oxidative damage of aorta and was accompanied by an increase in atherosclerotic plaque area; while the melatonin administration could effectively alleviate PM2.5-induced macrophage M1 polarization and atherosclerosis in mice. Further investigation verified that NADPH oxidase 2 (NOX2) and mitochondria are two prominent sources of PM2.5-induced ROS production in vascular macrophages. Whereas, the combined use of two ROS-specific inhibitors and adopted with melatonin markedly rescued PM2.5-triggered macrophage M1 polarization and foam cell formation by inhibiting NOX2-mediated crosstalk of Keap1/Nrf2/NF-κB and TLR4/TRAF6/NF-κB signaling pathways. Our results demonstrated that NOX2-mediated oxidative stress homeostasis is critical for PM2.5-induced atherosclerosis and melatonin might be a potential treatment for air pollution-related cardiovascular diseases.

Adverse outcome pathway of fine particulate matter leading to increased cardiovascular morbidity and mortality: An integrated perspective from toxicology and epidemiology.

Fine particulate matter (PM2.5) exposure is a major threat to public health, and is listed as one of the leading factors associated with global premature mortality. Among the adverse health effects on multiple organs or tissues, the influence of PM2.5 exposure on cardiovascular system has drawn more and more attention. Although numerous studies have investigated the mechanisms responsible for the cardiovascular toxicity of PM2.5, the various mechanisms have not been integrated due to the variety of the study models, different levels of toxicity assessment endpoints, etc. Adverse Outcome Pathway (AOP) framework is a useful tool to achieve this goal so as to facilitate comprehensive understanding of toxicity assessment of PM2.5 on cardiovascular system. This review aims to illustrate the causal mechanistic relationships of PM2.5-triggered cardiovascular toxicity from different levels (from molecular/cellular/organ to individual/population) by using AOP framework. Based on the AOP Wiki and published literature, we propose an AOP framework focusing on the cardiovascular toxicity induced by PM2.5 exposure. The molecular initiating event (MIE) is identified as reactive oxygen species generation, followed by the key events (KEs) of oxidative damage and mitochondria dysfunction, which induces vascular endothelial dysfunction via vascular endothelial cell autophagy dysfunction, vascular fibrosis via vascular smooth muscle cell activation, cardiac dysregulation via myocardial apoptosis, and cardiac fibrosis via fibroblast proliferation and myofibroblast differentiation, respectively; all of the above cardiovascular injuries ultimately elevate cardiovascular morbidity and mortality in the general population. As far as we know, this is the first work on PM2.5-related cardiovascular AOP construction. In the future, more work needs to be done to explore new markers in the safety assessment of cardiovascular toxicity induced by PM2.5.

Silica nanoparticles induce pyroptosis and cardiac hypertrophy via ROS/NLRP3/Caspase-1 pathway.

Growing literatures suggest that silica nanoparticles (SiNPs) exposure is correlated with adverse cardiovascular effects. Cardiac hypertrophy is one of the most common risk factors for heart failure. However, whether SiNPs involved in cardiac hypertrophy and the underlying mechanisms was remained unexploited. Our study aimed to investigate the molecular mechanisms of SiNPs on pyroptosis and cardiac hypertrophy. The in vivo results found that SiNPs induced ultrastructural change and histopathological damage, accompanied by oxidative damage occurred and increased levels of inflammatory factors (IL-18 and IL-1ß) in heart tissue. In addition, SiNPs could upregulate the expressions of cardiac hypertrophy-related special marker including ANP, BNP, ß-MHC, it also elevated the pyroptosis-related protein, such as NLRP3, Cleaved-Caspase-1, GSDMD, IL-18 and Cleaved-IL-1ß in vivo. For in vitro study, SiNPs increased the intracellular ROS generation and activated the NLRP3/Caspase-1/GSDMD signaling pathway in cardiomyocytes. Whereas, the NADPH oxidase (NOX) inhibitor VAS2870 had effectively inhibited the ROS level and suppressed the expression of NLRP3, ASC, Pro-Caspase-1, Cleaved-Caspase-1, N-GSDMD, IL-18, Cleaved-IL-1ß, ANP, BNP and ß-MHC. Moreover, transfected with si-NLRP3 or adopted with Caspase-1 inhibitor VX-765 in cardiomyocytes showed an inhibitory effect on SiNPs-induced pyroptosis and cardiac hypertrophy. In summary, our results demonstrated that SiNPs could trigger pyroptosis and cardiac hypertrophy via ROS/NLRP3/Caspase-1 signaling pathway.

Silica nanoparticles induce pulmonary autophagy dysfunction and epithelial-to-mesenchymal transition via p62/NF-κB signaling pathway.

It has been reported that silica nanoparticles (SiNPs) could cause epithelial-to-mesenchymal transition (EMT), but the specific mechanism is still unclear. Thus, the purpose of this study was to investigate the underlying mechanisms of pulmonary EMT after subacute exposure to SiNPs. The results showed intratracheal instillation of SiNPs increased the pulmonary MDA content, while decreased the activity of SOD and GSH-Px in rats. Western blot analysis demonstrated that SiNPs induced autophagy dysfunction via the upregulation of p62. Meanwhile, the inflammation cytokines (TNF-α, IL-18, IL-1ß) were released in rat lung. Immunohistochemistry and western blot assays both showed that SiNPs could regulate the related protein biomarkers of EMT through decreasing E-cadherin and increasing vimentin in a dose-dependent manner. Besides, SiNPs activated the proteins expression involved in p62/NF-κB signaling pathway, whereas the pulmonary EMT induced by SiNPs was significantly dampened after the knock down of p62. In this study, we illustrated that subacute exposure to SiNPs could trigger the autophagy dysfunction and pulmonary inflammation, further lead to EMT via activating the p62/NF-κB signaling pathway. Our findings provide new molecular evidence for SiNPs-induced pulmonary toxicity.