Hypermethylation and low expression of FANCC involved in multi-walled carbon nanotube-induced toxicity on ARPE-19 cells.

Multi-walled carbon nanotube (MWCNT) exposure was observed to cause damages on the viability of ocular cells, however, the underlying mechanisms remain not well understood. Epigenetic alterations that regulate gene expression have been identified as a major responsiveness to environmental challenge. Thus, the aim of this study was to screen methylation-regulated genes involved in MWCNT exposure. The Illumina Human Methylation 850 K array was employed to determine the genome-wide DNA methylation profile of human retinal pigment epithelial cell line (ARPE-19) exposed to 50% inhibition concentration of MWCNTs (100 µg/ml) for 24 h or without (n = 3 for each group). Then, the transcriptome data obtained by high-throughput RNA sequencing previously were integrated with DNA methylome to identify the overlapped genes. As a result, the integrative bioinformatics analysis identified that compared with controls, FA complementation group C (FANCC) was hypermethylated and downregulated in MWCNT-exposed ARPE-19 cells. Quantitative real-time polymerase chain reaction analysis confirmed the mRNA expression level of FANCC was significantly decreased following MWCNT treatment and the addition of DNA methylation inhibitor 5-Aza-deoxycytidine (10 µM) reversed this decrease. Pyrosequencing analysis further validated the hypermethylation status at the 5'-untranslated promoter region of FANCC (cg14583550) in MWCNT-exposed ARPE-19 cells. Protein-protein interaction network and function analyses predicted that FANCC may contribute to MWCNT-induced cytotoxicity by interacting with heat shock protein 90 beta family member 1 and then upregulating cytokine interleukin-6 and apoptosis biomarker caspase 3. In conclusion, the present study links the epigenetic modification of FANCC with the pathogenesis of MWCNT-induced retinal toxicity.

Evaluating the adverse effects and mechanisms of nanomaterial exposure on longevity of C. elegans: A literature meta-analysis and bioinformatics analysis of multi-transcriptome data.

Exposure to large-size particulate air pollution (PM2.5 or PM10) has been reported to increase risks of aging-related diseases and human death, indicating the potential pro-aging effects of airborne nanomaterials with ultra-fine particle size (which have been widely applied in various fields). However, this hypothesis remains inconclusive. Here, a meta-analysis of 99 published literatures collected from electronic databases (PubMed, EMBASE and Cochrane Library; from inception to June 2023) was performed to confirm the effects of nanomaterial exposure on aging-related indicators and molecular mechanisms in model animal C. elegans. The pooled analysis by Stata software showed that compared with the control, nanomaterial exposure significantly shortened the mean lifespan [standardized mean difference (SMD) = -2.30], reduced the survival rate (SMD = -4.57) and increased the death risk (hazard ratio = 1.36) accompanied by upregulation of ced-3, ced-4 and cep-1, while downregulation of ctl-2, ape-1, aak-2 and pmk-1. Furthermore, multi-transcriptome data associated with nanomaterial exposure were retrieved from Gene Expression Omnibus (GSE32521, GSE41486, GSE24847, GSE59470, GSE70509, GSE14932, GSE93187, GSE114881, and GSE122728) and bioinformatics analyses showed that pseudogene prg-2, mRNAs of abu, car-1, gipc-1, gsp-3, kat-1, pod-2, acdh-8, hsp-60 and egrh-2 were downregulated, while R04A9.7 was upregulated after exposure to at least two types of nanomaterials. Resveratrol (abu, hsp-60, pod-2, egrh-2, acdh-8, gsp-3, car-1, kat-1, gipc-1), naringenin (kat-1, egrh-2), coumestrol (egrh-2) or swainsonine/niacin/ferulic acid (R04A9.7) exerted therapeutic effects by reversing the expression levels of target genes. In conclusion, our study demonstrates the necessity to use phytomedicines that target hub genes to delay aging for populations with nanomaterial exposure.

Melatonin intervention to prevent nanomaterial exposure-induced damages: A systematic review and meta-analysis of in vitro and in vivo studies.

Given its antioxidant, anti-inflammatory, and antiapoptotic properties, melatonin (MEL), a health-caring food to improve sleep disorders, is hypothesized to protect against nanomaterial exposure-induced toxicity. However, the conclusion derived from different studies seemed inconsistent. A meta-analysis of all available preclinical studies was performed to examine the effects of MEL on nanomaterial-induced damages. Eighteen relevant studies were retrieved through searching five electronic databases up to December 2023. The meta-analysis showed that relative to control, MEL treatment significantly increased cell viability (standardized mean difference [SMD = 1.27]) and alleviated liver function (lowered AST [SMD = -3.89] and ALT [SMD = -5.89]), bone formation (enhanced BV/TV [SMD = 4.13] and lessened eroded bone surface [SMD = -5.40]), and brain nerve (inhibition of AChE activity [SMD = -3.60]) damages in animals. The protective mechanisms of MEL against damages caused by nanomaterial exposure were associated with its antiapoptotic (decreased Bax/Bcl-2 ratio [SMD = -4.50] and caspase-3 levels [dose <100 µM: SMD = -3.66]), antioxidant (decreased MDA [in vitro: SMD = -2.84; in vivo: SMD = -4.27]), and anti-inflammatory (downregulated TNF-α [in vitro: SMD = -5.41; in vivo: SMD = -3.21] and IL-6 [in vitro: SMD = -5.90; in vivo: SMD = -2.81]) capabilities. In conclusion, our study suggests that MEL should be supplemented to prevent damages in populations exposed to nanomaterials.

Identification of four methylation-driven genes as candidate biomarkers for monitoring single-walled carbon nanotube-induced malignant transformation of the lung.

Long-term exposure to carbon nanotubes (CNTs) has been reported to induce malignant transformation. This study aimed to screen candidate biomarkers for monitoring occupational workers to prevent the development of lung cancer. mRNA (GSE56104) and methylation (GSE153246) profiles of lung epithelial BEAS-2B cells exposed to malignant transformation dose of single-walled CNTs or control medium were downloaded from Gene Expression Omnibus database. A total of 1513 differentially expressed genes (DEGs) and 912 differentially methylated genes (DMGs) were identified using LIMMA method. The weighted correlation network analysis identified blue and turquoise modules were associated with malignant transformation of BEAS-2B cells, 124 DMGs of which were overlapped with DEGs. The mRNA and methylation levels of four methylation-driven DEGs were validated in both lung adenocarcinoma (LUAD) and squamous cell carcinomas (LUSC) of The Cancer Genome Atlas dataset and they were associated with overall survival of LUAD patients. Downregulation of PXMP4 and MCOLN2, while upregulation of MET was confirmed in both LUSC and LUAD via Human Protein Atlas analysis. PXMP4 and MET protein levels were also supported in the proteomic analysis of LUAD. Receiver operating characteristic (ROC) curve analysis showed the combination of four genes may be the optimal biomarker for predicting lung cancer, with the area under ROC curve >0.9. Function analysis revealed BARX2 may interact with CCND1 to regulate cell cycle; MET and PXMP4/MCOLN2 may positively correlate with CCR5/IL-6 or GATA3/HLA-DPB1/HLA-DPA1 to involve immune regulation. In conclusion, these four methylation-driven genes may be candidate prognostic and diagnostic biomarkers for single-walled CNT-related lung cancer.

Mesoporous Graphitic Carbon-Encapsulated Fe2 O3 Nanocomposite as High-Rate Anode Material for Sodium-Ion Batteries.

A mesoporous graphitic carbon-encapsulated Fe2 O3 nanocomposite is synthesized as a superior anode material for sodium-ion batteries. A threefold strategy is adopted to achieve a high rate performance. First, the mesoporous structure with high specific surface area and large pore volume facilitates the transfer of electrolyte and accommodates the large volume change. Secondly, graphitic carbon encapsulation further improves the electronic conductivity of the nanocomposite. Finally, ultrafine Fe2 O3 nanocrystals effectively shorten the Na+ diffusion length. Consequently, this nanocomposite exhibits stable and fast Na+ storage, thus leading to excellent rate capability and cyclability. Pseudocapacitive behavior is found to dominate in the redox reactions, accounting for the outstanding rate and cycling performance. In addition, full cells, assembled with O3-Na0.9 [Cu0.22 Fe0.30 Mn0.48 ]O2 as cathodes, present good electrochemical performance.

[Effect of ulinastatin on perioperative glycocalyx and lung function in patients undergoing mitral valve replacement surgery].

OBJECTIVE: To explore the effect of ulinastatin on perioperative glycocalyx and lung function in patients undergoing mitral valve replacement surgery.
 Methods: Fourty patients, undergoing mitral valve replacement, were randomly allocated into a control group and an ulinastatin group, which were administrated 50 mL normal saline or 2×104 U/kg ulinastatin at the beginning of cardiopulmonary bypass (CPB), respectively. The radical artery blood was collected at 4 time points: After induction of anesthesia (T0), at 10 min after the start of CPB (T1), 1 h after the end of CPB (T2), and 8 h after operation. The concentration of syndecan-1 and TNF-α in blood was measured. Moreover, the blood gas analysis was preformed and the oxygen index (OI) and difference in alveolar arterial oxygen partial pressure (PA-aO2) were calculated at T0, T2, and T3.
 Results: There were no significant difference between the 2 groups in OI, PA-aO2, and the concentration of syndecan-1 and TNF-α at T0 (P>0.05). The concentration of syndecan-1 and TNF-α was significantly increased at T1 and T2 in the 2 groups, and reached peak at T2. Compared with the control group, the concentration of syndecan-1 and TNF-α was decreased in the ulinastatin group at T1, T2, and T3 (P<0.05). Compared with T0, OI was lower and PA-aO2 was higher at T2 and T3 in both groups, but the 2 indexes were improved in the ulinastatin group compared with those in the control group (P<0.05).
 Conclusion: Ulinastatin can improve the post-operative pulmonary ventilation function in patients with mitral valve replacement. The mechanism may be associated with the inhibition of TNF-α release and the reduction of glycocalyx shedding induced by ulinastatin.

Neurotoxicity of tetrabromobisphenol-A-bis(2,3-dibromopropyl ether) through the GABAergic and serotonergic neurotransmission in Caenorhabditis elegans.

Tetrabromobisphenol-A-bis(2,3-dibromopropyl ether) (TBBPA-BDBPE), a novel additive brominated flame retardant, is being developed for use in polyolefin and copolymers. Despite its emerging application, the neurotoxicity and mechanisms of action of TBBPA-BDBPE remain unexplored. Caenorhabditis elegans was utilized as the model organism to study the neurotoxic effects of TBBPA-BDBPE across environmental concentrations ranging from 0 to 100 µg/L. This investigation focused on various toxicological endpoints such as locomotive behavior, neuronal injury, neurotransmitter transmission, and the regulation of nervous system-related gene expression. Acute exposure to TBBPA-BDBPE at concentrations of 10-100 µg/L significantly impaired nematode movement, indicating potential neurotoxicity. In transgenic nematodes, this exposure also caused damage to γ-aminobutyric acid (GABAergic) and serotonergic neurons, along with notable changes in the levels of GABAergic and serotonergic neurotransmitters. Further molecular studies indicated alterations in neurotransmission-related genes (cat-4, mod-1, unc-25, and unc-47). Molecular docking analysis confirmed the binding affinity of TBBPA-BDBPE to key neurotransmission proteins-CAT-4, MOD-1, UNC-25, and UNC-47. These findings demonstrate that TBBPA-BDBPE exerts neurotoxic effects by impacting GABAergic and serotonergic neurotransmission in nematodes. This study provides new insights into the potential environmental risks of TBBPA-BDBPE.

Aged polystyrene microplastics cause reproductive impairment via DNA-damage induced apoptosis in Caenorhabditis elegans.

Although polystyrene microplastics (PS-MPs) could induce toxic effects on environmental organisms, the toxicity of aged PS-MPs with H2O2 on soil organisms remains unclear. Our study utilized Caenorhabditis elegans as model organism to examine the reproductive toxicity of pristine PS-MPs (pPS-MPs) and aged PS-MPs (aPS-MPs) at environmentally relevant concentrations (0.1-100 µg/L). Acute exposure to aPS-MPs could induce greater reproductive impairment compared to pPS-MPs, as evidenced by changes in brood size and egg release. Assessment of gonad development using the number of mitotic cells, length of gonad arm, and relative area of gonad arm as parameters revealed a high reproductive toxicity caused by aPS-MPs exposure. Furthermore, aPS-MPs exposure promoted substantial germline apoptosis. Additionally, exposure to aPS-MPs (100 µg/L) markedly altered the expression of DNA damage-induced apoptosis-related genes (e.g., egl-1, cep-1, clk-2, ced-3, -4, and -9). Alterations in germline apoptosis caused by aPS-MPs were observed in mutants of cep-1, hus-1, egl-1, ced-3, -4, and -9. Consequently, the augmentation of reproductive toxicity resulting from aPS-MPs exposure was attributed to DNA damage-triggered cellular apoptosis. Additionally, the EGL-1-CEP-1-HUS-1-CED-3-CED-4-CED-9 signaling pathway was identified as a key regulator of germline apoptosis in nematodes. Our study provides insights into potential environmental risk of aPS-MPs with H2O2 on environmental organisms.

Chronic neurotoxicity of Tetrabromobisphenol A: Induction of oxidative stress and damage to neurons in Caenorhabditis elegans.

Tetrachlorobisphenol A (TCBPA) has been used as an alternative flame retardant in various fields. However, the long-term effects of TCBPA on the nervous system remain unclear. Thus, Caenorhabditis elegans (L4 larvae) were selected as a model animal to investigate the neurotoxic effects and underlying mechanisms after 10 d of TCBPA exposure. Exposure to TCBPA (0.01-100 µg/L) decreased locomotive behavior in a concentration-dependent manner. In addition, reactive oxygen species (ROS) formation and lipofuscin accumulation were significantly increased, and the expression of sod-3 was upregulated in the exposed nematodes, indicating that TCBPA exposure induced oxidative damage. Furthermore, 100 µg/L TCBPA exposure caused a reduction in dopamine and serotonin levels, and damage in dopaminergic and serotoninergic neurons, which was further confirmed by the downregulated expression of related genes (e.g., dop-1, dop-3, cat-1, and mod-1). Molecular docking analysis demonstrated the potential of TCBPA to bind to the neurotransmitter receptor proteins DOP-1, DOP-3, and MOD-1. These results indicate that chronic exposure to TCBPA induces neurotoxic effects on locomotive behavior, which is associated with oxidative stress and damage to dopaminergic and serotoninergic neurons.

Inflammatory Genes Associated with Pristine Multi-Walled Carbon Nanotubes-Induced Toxicity in Ocular Cells.

Background: The wide application of multi-walled carbon nanotubes (MWCNTs) in various fields has raised enormous concerns regarding their safety for humans. However, studies on the toxicity of MWCNTs to the eye are rare and potential molecular mechanisms are completely lacking. This study was to evaluate the adverse effects and toxic mechanisms of MWCNTs on human ocular cells. Methods: Human retinal pigment epithelial cells (ARPE-19) were treated with pristine MWCNTs (7-11 nm) (0, 25, 50, 100 or 200 µg/mL) for 24 hours. MWCNTs uptake into ARPE-19 cells was examined using transmission electron microscopy (TEM). The cytotoxicity was evaluated by CCK-8 assay. The death cells were detected by Annexin V-FITC/PI assay. RNA profiles in MWCNT-exposed and non-exposed cells (n = 3) were analyzed using RNA-sequencing. The differentially expressed genes (DEGs) were identified through the DESeq2 method and hub of which were filtered by weighted gene co-expression, protein-protein interaction (PPI) and lncRNA-mRNA co-expression network analyses. The mRNA and protein expression levels of crucial genes were verified using quantitative polymerase chain reaction (qPCR), colorimetric analysis, ELISA and Western blotting. The toxicity and mechanisms of MWCNTs were also validated in human corneal epithelial cells (HCE-T). Results: TEM analysis indicated the internalization of MWCNTs into ARPE-19 cells to cause cell damage. Compared with untreated ARPE-19 cells, those exposed to MWCNTs exhibited significantly decreased cell viabilities in a dose-dependent manner. The percentages of apoptotic (early, Annexin V positive; late, Annexin V and PI positive) and necrotic (PI positive) cells were significantly increased after exposure to IC50 concentration (100 µg/mL). A total of 703 genes were identified as DEGs; 254 and 56 of them were, respectively, included in darkorange2 and brown1 modules that were significantly associated with MWCNT exposure. Inflammation-related genes (including CXCL8, MMP1, CASP3, FOS, CXCL2 and IL11) were screened as hub genes by calculating the topological characteristics of genes in the PPI network. Two dysregulated long non-coding RNAs (LUCAT1 and SCAT8) were shown to regulate these inflammation-related genes in the co-expression network. The mRNA levels of all eight genes were confirmed to be upregulated, while caspase-3 activity and the release of CXCL8, MMP1, CXCL2, IL11 and FOS proteins were demonstrated to be increased in MWCNT-treated ARPE-19 cells. MWCNTs exposure also can induce cytotoxicity and increase the caspase-3 activity and the expression of LUCAT1, MMP1, CXCL2, and IL11 mRNA and protein in HCE-T cells. Conclusion: Our study provides promising biomarkers for monitoring MWCNT-induced eye disorders and targets for developing preventive and therapeutic strategies.

Effects of nanomaterial exposure on telomere dysfunction, hallmarks of mammalian and zebrafish cell senescence, and zebrafish mortality.

Environmental and occupational exposure to hazardous substances accelerates biological aging. However, the toxic effects of nanomaterials on telomere and cellular senescence (major hallmarks of the biological aging) remained controversial. This study was to synthesize all published evidence to explore the effects of nanomaterial exposure on the telomere change, cellular senescence and mortality of model animals. Thirty-five studies were included by searching electronic databases (PubMed, Embase and Web of Science). The pooled analysis by Stata 15.0 software showed that compared with the control, nanomaterial exposure could significantly shorten the telomere length [measured as kbp: standardized mean difference (SMD) = -1.88; 95% confidence interval (CI) = -3.13 - - 0.64; % of control: SMD = -1.26; 95%CI = -2.11- - 0.42; < 3 kbp %: SMD = 5.76; 95%CI = 2.92 - 8.60), increase the telomerase activity (SMD = -1.00; 95%CI = -1.74 to -0.26), senescence-associated ß-galactosidase levels in cells (SMD = 8.20; 95%CI = 6.05 - 10.34) and zebrafish embryos (SMD = 7.32; 95%CI = 4.70 - 9.94) as well as the mortality of zebrafish (SMD = 3.83; 95%CI = 2.94 - 4.72)]. The expression levels of telomerase TERT, shelterin components (TRF1, TRF2 and POT1) and senescence biomarkers (p21, p16) were respectively identified to be decreased or increased in subgroup analyses. In conclusion, this meta-analysis demonstrates that nanomaterial exposure is associated with telomere attrition, cell senescence and organismal death.

Carboxyl-modified polystyrene microplastics induces neurotoxicity by affecting dopamine, glutamate, serotonin, and GABA neurotransmission in Caenorhabditis elegans.

Microplastics (MPs) are ubiquitous in various environmental media and have potential toxicity. However, the neurotoxicity of carboxyl-modified polystyrene microplastics (PS-COOH) and their mechanisms remain unclear. In this study, Caenorhabditis elegans was used as a model to examine the neurotoxicity of polystyrene microplastic (PS) and PS-COOH concentrations ranging from 0.1 to 100 µg/L. Locomotion behavior, neuron development, neurotransmitter level, and neurotransmitter-related gene expression were selected as assessment endpoints. Exposure to low concentrations (1 µg/L) of PS-COOH caused more severe neurotoxicity than exposure to pristine PS. In transgenic nematodes, exposure to PS-COOH at 10-100 µg/L significantly increased the fluorescence intensity of dopaminergic, glutamatergic, serotonergic, and aminobutyric acid (GABA)ergic neurons compared to that of the control. Further studies showed that exposure to 100 µg/L PS-COOH can significantly affect the levels of glutamate, serotonin, dopamine, and GABA in nematodes. Likewise, in the present study, the expression of genes involved in neurotransmission was altered in worms. These results suggest that PS-COOH exerts neurotoxicity by affecting neurotransmission of dopamine, glutamate, serotonin, and GABA. This study provides new insights into the underlying mechanisms and potential risks associated with PS-COOH.

Photoaged microplastics induce neurotoxicity associated with damage to serotonergic, glutamatergic, dopaminergic, and GABAergic neuronal systems in Caenorhabditis elegans.

Microplastics (MPs) are ubiquitous environmental contaminants that cause neurotoxicity in various organisms. MPs are typically affected by light irradiation and undergo photoaging. However, the neurotoxic effects of photoaged polystyrene (P-PS) and its underlying mechanisms remain unclear. In this study, locomotion behaviors, neuronal development, neurotransmitter levels, and the expression of neurotransmission-related genes were investigated in Caenorhabditis elegans exposed to P-PS at environment-relevant concentrations (0.1-100 µg/L). The characterization results showed that photoaging accelerated the aging process and changed the physicochemical properties of the MPs. The toxicity results suggested that exposure to 1-100 µg/L P-PS caused more severe neurotoxicity than virgin polystyrene (V-PS) with endpoints of head thrashes, body bends, wavelength, and mean amplitude. Exposure to P-PS also altered the fluorescence intensity and neurodegeneration percentage of serotonergic, glutamatergic, dopaminergic, and aminobutyric acid (GABA) in transgenic nematodes. Similarly, significant reductions in the levels of these neurotransmitters were also observed. Based on Pearson's correlation, locomotion behaviors were negatively correlated with the neurotransmission of serotonin, glutamate, dopamine, and GABA. Further investigation suggested that the expression of neurotransmitter-related genes (e.g., tph-1, eat-4, and unc-46) was significantly altered in the nematodes. Collectively, the neurotoxic effects of P-PS were attributed to abnormal neurotransmission. This study highlights the potential toxicity of MPs photoaged under environmentally relevant conditions.

Potential Biomarkers and Drugs for Nanoparticle-Induced Cytotoxicity in the Retina: Based on Regulation of Inflammatory and Apoptotic Genes.

The eye is a superficial organ directly exposed to the surrounding environment. Thus, the toxicity of nanoparticle (NP) pollutants to the eye may be potentially severer relative to inner organs and needs to be monitored. However, the cytotoxic mechanisms of NPs on the eyes remain rarely reported. This study was to screen crucial genes associated with NPs-induced retinal injuries. The gene expression profiles in the retina induced by NPs [GSE49371: Au20, Au100, Si20, Si100; GSE49048: presumptive therapeutic concentration (PTC) TiO2, 10PTC TiO2] and commonly used retinal cell injury models (optic nerve injury procedure: GSE55228, GSE120257 and GSE131486; hypoxia exposure: GSE173233, GSE151610, GSE135844; H2O2 exposure: GSE122270) were obtained from the Gene Expression Omnibus database. A total of 381 differentially expressed genes (including 372 mRNAs and 9 lncRNAs) were shared between NP exposure and the optic nerve injury model when they were compared with their corresponding controls. Function enrichment analysis of these overlapped genes showed that Tlr2, Crhbp, Ccl2, Cxcl10, Fas, Irf8, Socs3, Stat3, Gbp6, Casp1 and Syk were involved in inflammatory- and apoptotic-related processes. Protein-protein interaction network analysis revealed eight of them (Tlr2, Ccl2, Cxcl10, Irf8, Socs3, Stat3, Casp1 and Syk) were hub genes. Moreover, Socs3 could interact with upstream Stat3 and downstream Fas/Casp1/Ccl2/Cxcl10; Irf8 could interact with upstream Tlr2, Syk and downstream Cxcl10. Competing endogenous RNAs network analysis identified Socs3, Irf8, Gdf6 and Crhbp could be regulated by lncRNAs and miRNAs (9330175E14Rik-mmu-miR-762-Socs3, 6430562O15Rik-mmu-miR-207-Irf8, Gm9866-mmu-miR-669b-5p-Gdf6, 4933406C10Rik-mmu-miR-9-5p-Crhbp). CMap-CTD database analyses indicated the expression levels of Tlr2, Ccl2, Cxcl10, Fas, Irf8, Socs3, Stat3, Gbp6, Casp1 and Syk could be reversed by folic acid. Crhbp and Gdf6 were also verified to be downregulated, while Tlr2, Ccl2, Irf8, Socs3 and Stat3 were upregulated in hypoxia/H2O2-induced retinal injury models. Hereby, our findings suggest that Crhbp, Irf8, Socs3 and Gdf6 as well as their upstream mRNAs, lncRNAs and miRNAs may be potential monitoring biomarkers and therapeutic targets for NP-induced retinal injuries. Folic acid supplementation may be a preventive and therapeutic approach.

Oxidative Stress and Inflammatory Biomarkers for Populations with Occupational Exposure to Nanomaterials: A Systematic Review and Meta-Analysis.

Exposure to nanomaterials (NMs) is suggested to have the potential to cause harmful health effects. Activations of oxidative stress and inflammation are assumed as main contributors to NM-induced toxicity. Thus, oxidative stress- and inflammation-related indicators may serve as biomarkers for occupational risk assessment. However, the correlation between NM exposure and these biomarkers remains controversial. This study aimed to perform a meta-analysis to systematically investigate the alterations of various biomarkers after NM exposure. Twenty-eight studies were found eligible by searching PubMed, EMBASE and Cochrane Library databases. The pooled results showed NM exposure was significantly associated with increases in the levels of malonaldehyde (MDA) [standardized mean difference (SMD) = 2.18; 95% confidence interval (CI), 1.50-2.87], 4-hydroxy-2-nonhenal (HNE) (SMD = 2.05; 95% CI, 1.13-2.96), aldehydes C6-12 (SMD = 3.45; 95% CI, 2.80-4.10), 8-hydroxyguanine (8-OHG) (SMD = 2.98; 95% CI, 2.22-3.74), 5-hydroxymethyl uracil (5-OHMeU) (SMD = 1.90; 95% CI, 1.23-2.58), o-tyrosine (o-Tyr) (SMD = 1.81; 95% CI, 1.22-2.41), 3-nitrotyrosine (3-NOTyr) (SMD = 2.63; 95% CI, 1.74-3.52), interleukin (IL)-1ß (SMD = 1.76; 95% CI, 0.87-2.66), tumor necrosis factor (TNF)-α (SMD = 1.52; 95% CI, 1.03-2.01), myeloperoxidase (MPO) (SMD = 0.25; 95% CI, 0.16-0.34) and fibrinogen (SMD = 0.11; 95% CI, 0.02-0.21), and decreases in the levels of glutathione peroxidase (GPx) (SMD = -0.31; 95% CI, -0.52--0.11) and IL-6 soluble receptor (IL-6sR) (SMD = -0.18; 95% CI, -0.28--0.09). Subgroup analysis indicated oxidative stress biomarkers (MDA, HNE, aldehydes C6-12, 8-OHG, 5-OHMeU, o-Tyr, 3-NOTyr and GPx) in exhaled breath condensate (EBC) and blood samples were strongly changed by NM exposure; inflammatory biomarkers (IL-1ß, TNF-α, MPO, fibrinogen and IL-6sR) were all significant in EBC, blood, sputum and nasal lavage samples. In conclusion, our findings suggest that these oxidative stress and inflammatory indicators may be promising biomarkers for the biological monitoring of occupationally NM-exposed workers.

Vitamin Supplementation Protects against Nanomaterial-Induced Oxidative Stress and Inflammation Damages: A Meta-Analysis of In Vitro and In Vivo Studies.

The extensive applications of nanomaterials have increased their toxicities to human health. As a commonly recommended health care product, vitamins have been reported to exert protective roles against nanomaterial-induced oxidative stress and inflammatory responses. However, there have been some controversial conclusions in regards to this field of research. This meta-analysis aimed to comprehensively evaluate the roles and mechanisms of vitamins for cells and animals exposed to nanomaterials. Nineteen studies (seven in vitro, eleven in vivo and one in both) were enrolled by searching PubMed, EMBASE, and Cochrane Library databases. STATA 15.0 software analysis showed vitamin E treatment could significantly decrease the levels of oxidants [reactive oxygen species (ROS), total oxidant status (TOS), malondialdehyde (MDA)], increase anti-oxidant glutathione peroxidase (GPx), suppress inflammatory mediators (tumor necrosis factor-α, interleukin-6, C-reactive protein, IgE), improve cytotoxicity (manifested by an increase in cell viability and a decrease in pro-apoptotic caspase-3 activity), and genotoxicity (represented by a reduction in the tail length). These results were less changed after subgroup analyses. Pooled analysis of in vitro studies indicated vitamin C increased cell viability and decreased ROS levels, but its anti-oxidant potential was not observed in the meta-analysis of in vivo studies. Vitamin A could decrease MDA, TOS and increase GPx, but its effects on these indicators were weaker than vitamin E. Also, the combination of vitamin A with vitamin E did not provide greater anti-oxidant effects than vitamin E alone. In summary, we suggest vitamin E alone supplementation may be a cost-effective option to prevent nanomaterial-induced injuries.

Effects of Flavonoid Supplementation on Nanomaterial-Induced Toxicity: A Meta-Analysis of Preclinical Animal Studies.

Background: Nanomaterials, widely applied in various fields, are reported to have toxic effects on human beings; thus, preventive or therapeutic measures are urgently needed. Given the anti-inflammatory and antioxidant activities, supplementation with flavonoids that are abundant in the human diet has been suggested as a potential strategy to protect against nanomaterial-induced toxicities. However, the beneficial effects of flavonoids remain inconclusive. In the present study, we performed a meta-analysis to comprehensively explore the roles and mechanisms of flavonoids for animals intoxicated with nanomaterials. Methods: A systematic literature search in PubMed, EMBASE, and Cochrane Library databases was performed up to April 2022. STATA 15.0 software was used for meta-analyses. Results: A total of 26 studies were identified. The results showed that flavonoid supplementation could significantly increase the levels of antioxidative enzymes (superoxide dismutase, catalase, glutathione, glutathione peroxidase, and glutathione-S-transferase), reduce the production of oxidative agents (malonaldehyde) and pro-inflammatory mediators (tumor necrosis factor-α, interleukin-6, IL-1ß, C-reactive protein, immunoglobulin G, nitric oxide, vascular endothelial growth factor, and myeloperoxidase), and alleviate cell apoptosis (manifested by decreases in the mRNA expression levels of pro-apoptotic factors, such as caspase-3, Fas cell surface death receptor, and Bax, and increases in the mRNA expression levels of Bcl2), DNA damage (reductions in tail length and tail DNA%), and nanomaterial-induced injuries of the liver (reduced alanine aminotransferase and aspartate aminotransferase activities), kidney (reduced urea, blood urea nitrogen, creatinine, and uric acid concentration), testis (increased testosterone, sperm motility, 17ß-hydroxysteroid dehydrogenase type, and reduced sperm abnormalities), and brain (enhanced acetylcholinesterase activities). Most of the results were not changed by subgroup analyses. Conclusion: Our findings suggest that appropriate supplementation of flavonoids may be effective to prevent the occupational detriments resulting from nanomaterial exposure.

Identification of Candidate lncRNA and Pseudogene Biomarkers Associated with Carbon-Nanotube-Induced Malignant Transformation of Lung Cells and Prediction of Potential Preventive Drugs.

Mounting evidence has linked carbon nanotube (CNT) exposure with malignant transformation of lungs. Long non-coding RNAs (lncRNAs) and pseudogenes are important regulators to mediate the pathogenesis of diseases, representing potential biomarkers for surveillance of lung carcinogenesis in workers exposed to CNTs and possible targets to develop preventive strategies. The aim of this study was to screen crucial lncRNAs and pseudogenes and predict preventive drugs. GSE41178 (small airway epithelial cells exposed to single- or multi-walled CNTs or dispersant control) and GSE56104 (lung epithelial cells exposed to single-walled CNTs or dispersant control) datasets were downloaded from the Gene Expression Omnibus database. Weighted correlation network analysis was performed for these two datasets, and the turquoise module was preserved and associated with CNT-induced malignant phenotypes. In total, 24 lncRNAs and 112 pseudogenes in this module were identified as differentially expressed in CNT-exposed cells compared with controls. Four lncRNAs (MEG3, ARHGAP5-AS1, LINC00174 and PVT1) and five pseudogenes (MT1JP, MT1L, RPL23AP64, ZNF826P and TMEM198B) were predicted to function by competing endogenous RNA (MEG3/RPL23AP64-hsa-miR-942-5p-CPEB2/PHF21A/BAMBI; ZNF826P-hsa-miR-23a-3p-SYNGAP1, TMEM198B-hsa-miR-15b-5p-SYNGAP1/CLU; PVT1-hsa-miR-423-5p-PSME3) or co-expression (MEG3/MT1L/ZNF826P/MT1JP-ATM; ARHGAP5-AS1-TMED10, LINC00174-NEDD4L, ARHGAP5-AS1/PVT1-NIP7; MT1L/MT1JP-SYNGAP1; MT1L/MT1JP-CLU) mechanisms. The expression levels and prognosis of all genes in the above interaction pairs were validated using lung cancer patient samples. The receiver operating characteristic curve analysis showed the combination of four lncRNAs, five pseudogenes or lncRNAs + pseudogenes were all effective for predicting lung cancer (accuracy >0.8). The comparative toxicogenomics database suggested schizandrin A, folic acid, zinc or gamma-linolenic acid may be preventive drugs by reversing the expression levels of lncRNAs or pseudogenes. In conclusion, this study highlights lncRNAs and pseudogenes as candidate diagnostic biomarkers and drug targets for CNT-induced lung cancer.

Evaluation of the protective roles of alpha-lipoic acid supplementation on nanomaterial-induced toxicity: A meta-analysis of in vitro and in vivo studies.

Extensive exposure to nanomaterials causes oxidative stress and inflammation in various organs and leads to an increased risk of adverse health outcomes; therefore, how to prevent the toxic effects are of great concern to human. Alpha-lipoic acid (ALA) has anti-oxidant and anti-inflammatory activities, suggesting it may be effective to prevent nanomaterial-induced toxicity. However, the results obtained in individual studies remained controversial. We aimed to comprehensively evaluate the effects of ALA supplementation on nanomaterial-induced toxicity by performing a meta-analysis. Databases of PubMed, EMBASE, and Cochrane Library were searched up to May 2022. STATA 15.0 software was used for statistical analysis. Twelve studies were included. Meta-analysis of eight in vivo studies showed ALA supplementation could exert significant effects on nanomaterial-induced oxidative stress (by reducing MDA, ROS and increasing GSH, CAT, GPx, and SOD), inflammation (by downregulating NO, IgG, TNF-α, IL-6, and CRP), apoptosis (by activation of pro-apoptotic caspase-3), DNA damage (by a reduction in the tail length) and organ damage (by a decrease in the liver biomarker ALT and increases in brain neuron biomarker AChE and heart biomarker CPK). Pooled analysis of four in vitro studies indicated ALA intervention increased cell viability, decreased ROS levels, inhibited cell apoptosis and chelated metal ions. Subgroup analyses revealed changing the levels of GSH, IL-6, and metal ions were the main protective mechanisms of ALA supplementation because they were not changed by any subgroup factors. In conclusion, ALA supplementation may represent a potential strategy for the prevention of the toxicity induced by nanomaterials.

Reproductive toxicity of UV-photodegraded polystyrene microplastics induced by DNA damage-dependent cell apoptosis in Caenorhabditis elegans.

Although many studies have investigated the toxic effects of polystyrene microplastics (PS-MPs), toxicity of natural aged of PS-MPs to soil organisms remains unclear. The photodegradation of virgin PS-MPs under UV irradiation was investigated, and reproductive toxicity of pristine and UV-photodegraded PS-MPs at environmental concentrations (0.1-100 µg/L) was examined to Caenorhabditis elegans. Using brood size and egg ejection rate as endpoints, acute exposure to aged PS-MPs resulted in more severe reproductive toxicity than pristine PS-MPs. Exposure to 100 µg/L aged PS-MPs significantly increased the number of HUS-1::GFP foci and the expression of genes required for DNA damage, such as clk-2, cep-1, and egl-1, suggesting induction of DNA damage. Additionally, the number of cell corpses and apoptosis-related gene expression (e.g., ced-3, ced-4, and ced-9) were significantly altered, indicating induction of apoptosis. Germline apoptosis induced by aged PS-MPs was altered in egl-1, hus-1, cep-1, ced-3, ced-4, and ced-9 mutants. Thus, the reproductive toxicity of aged PS-MPs may be due to DNA damage-induced cell apoptosis, and the HUS-1-CEP-1-EGL-1-CED-9-CED-4-CED-3 signalling pathway is involved in regulating cell apoptosis in nematodes.