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Lanthanide-doped upconversion nanoparticles (Ln-UCNPs) have been considered promising materials for various fields, such as biomedical and industrial applications. However, data and reports regarding its toxicity and environmental risks are scarce. Under these circumstances, data must be obtained to fully understand potential toxicity and adverse outcome pathways. In the present study, the toxicity of uncoated Ln-UCNP cores (NaYF4:Yb, Er) was systematically assessed in zebrafish embryos during early developmental stages. Ln-UCNPs were found to have multiple toxic effects, such as effects on survival rates, delayed hatching times, shorter body lengths, altered heart rates and blood circulation (significantly reduced), and neurobehavioral impairments in response to photoperiod stimulation. Bioimaging showed that Ln-UCNPs were distributed on the chorion, eyes, and skin at 72 hpf. However, it accumulates in the pharynx, esophagus, and intestine after oral administration. Ln-UCNPs disrupt the diversity and abundance of host-associated microorganisms (gut microbiota) leading to an increase in the prevalence of harmful bacteria in zebrafish. Transcriptomic and Ingenuity Pathway Analysis (IPA) predicted Interleukin-8 (IL-8) signaling, neuroinflammation, cardiac hypertrophy signaling pathways, immune and inflammation-related response interferon-gamma (ifnγ), and miR-155 as key mediators in regulatory effects. Based on this, a causal network was built showing the strong links between the induced gene expression of differentially expressed genes (DEGs), such as nitric oxide synthase 2 (nos2) and tumor necrosis factor (tnf) upon Ln-UCNPs treatment, and with the downstream adverse outcomes, in particular, the promotion of apoptosis, liver damage, and inflammatory response. Finally, RT-qPCR analysis confirmed the up-regulated expression of nos2 and tnf in the exposed larvae, consistent with the observation of an increased number of fluorescence-labelled neutrophils and macrophages in lyz: DsRed transgenic zebrafish until 120 hpf exposure, which together demonstrated the proinflammatory effects of Ln-UCNPs on organisms. In conclusion, we illustrated the developmental toxicity, disruption of gut-microbiome, and proinflammatory effects of Ln-UCNP cores on zebrafish, and the causal network from IPA analysis may help further elucidate the adverse outcome pathway of Ln-UCNPs.
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Purpose: Triphenyl phosphate (TPHP) is a widely used organophosphate flame retardant, which can be transformed in vivo into diphenyl phosphate (DPHP) and 4-hydroxyphenyl phosphate (diphenyl) ester (OH-TPHP) through biotransformation process. Accumulation of TPHP and its derivatives in biological tissues makes it necessary to investigate their toxicity and molecular mechanism. Methods: The present study evaluated the cellular effects of TPHP, DPHP, and OH-TPHP on cell survival, cell membrane damage, oxidative damage, and cell apoptosis using HeLa cells as in vitro model. RNA sequencing and bioinformatics analysis were conducted to monitor the differently expressed genes, and then RT-qPCR and Western bolt were used to identify potential molecular mechanisms and key hub genes. Results: Results showed that OH-TPHP had the most significant cytotoxic effect in HeLa cells, followed by TPHP; and no significant cytotoxic effects were observed for DPHP exposure within the experimental concentrations. Biological function enrichment analysis suggested that TPHP and OH-TPHP exposure may induce endoplasmic reticulum stress (ERS) and cell apoptosis. The nodes filtering revealed that ERS and apoptosis related genes were involved in biological effects induced by TPHP and OH-TPHP, which may be mediated through the eukaryotic translation initiation factor 2α/activating transcription factor 4 (ATF4)/ATF3- CCAAT/ enhancer-binding protein homologous protein (CHOP) cascade pathway and death receptor 5 (DR5) /P53 signaling axis. Conclusion: Above all, these findings indicated that ERS-mediated apoptosis might be one of potential mechanisms for cytotoxicity of TPHP and OH-TPHP.
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Triphenyl phosphate (TPHP) has been widely used as flame retardants and been detected with increasing frequency in environment. TPHP can transform into mono-hydroxylated phosphate (OH-TPHP) and diester diphenyl phosphate (DPHP) through biotransformation. So far, information on the cytotoxicity and molecular regulatory mechanisms of TPHP metabolites are still limit. This study investigated the adverse effects of TPHP, OH-TPHP, and DPHP in HepG2 cells in terms of cell proliferation, lactate dehydrogenase release, reactive oxygen species generation, and mitochondrial membrane potential. The transcriptomic changes were measured using RNA sequencing, and bioinformatics characteristics including biological functions, signal pathways and protein-protein interaction were analyzed to explore the potential molecular mechanisms. Results displayed that the order of cytotoxicity was OH-TPHP> TPHP> DPHP. The prioritized biological functions changes induced by TPHP and OH-TPHP were correlated with lipid metabolism. Significant lipid accumulation was observed as confirmed by increased total cholesterol and triglycerides contents, and enhanced oil red O staining. Enrichment of PPARα/γ and down-stream genes suggested the participation of PPARs signal pathway in lipid metabolism disorder. In addition, TPHP and OH-TPHP induced endoplasmic reticulum stress (ERS), which was further confirmed by the ERS inhibitor experiment. In general, TPHP and OH-TPHP had obvious cytotoxic effects in HepG2 cells. PPARs signal pathway and endoplasmic reticulum stress may be involved in the lipid metabolism disorder induced by TPHP and OH-TPHP.
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BACKGROUND: To determine the predictive values of sperm parameters pre- and post-processing by density gradient centrifugation for clinical pregnancy rates (CPRs) following artificial insemination by husband (AIH) in infertile Chinese couples. METHODS: A total of 3,522 AIH cycles from 1,918 couples were retrospectively analyzed. The parameters were compared between the pregnant and non-pregnant groups and further between different etiological groups (Male-factor, Both-male-and-female-factor, and Other-factor). Multivariate logistic regression analysis was performed to create models for predicting the CPRs of each etiological group. RESULTS: The overall CPR was 13.3%. There were significant improvements for most sperm parameters after DGC. Multivariate logistic regression analysis indicated that, in overall AIH cases, the top parameters significantly influencing the CPR of AIH were pre-STR (OR = 1.037; P = 0.048) and post-VSL (OR = 1.036; P = 0.011). In the Male-factor Group, the top influencing parameters were pre-VCL (OR = 2.096; P = 0.008), pre-LIN (OR = 1.930; P = 0.002) and post-VSL (OR = 1.316; P = 0.023). In the Both-factor Group, the top influencing parameters were pre-VCL (OR = 1.451; P = 0.008) and post-motility (OR = 1.218; P = 0.049). In the Other-factor Group, the top influencing parameters were pre-VAP (OR = 1.715; P = 0.024), pre-STR (OR = 1.20; P = 0.011) and post-VSL (OR = 1.04; P = 0.017). Moreover, receiver operating characteristic analysis showed that the logistic regression models of the Male- and Both-factor Groups had greater powers for prognostic classification than those of other groups. CONCLUSIONS: This study demonstrated that some sperm parameters have a collinearity relationship in predicting the CPR following AIH. Moreover, the predictive capacity of a multivariate logistic regression model is better than those of individual parameters, especially for the Male- and Both-factor Groups. In these cases, pre-VCL is the common top influencing factor.
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Motilidad Espermática , Esposos , Femenino , Humanos , Inseminación Artificial Homóloga , Masculino , Embarazo , Índice de Embarazo , Estudios Retrospectivos , Semen , EspermatozoidesRESUMEN
The sperm chromatin structure assay (SCSA) is crucial for assessing male fertility. However, the predictive value of the SCSA parameters, including the DNA fragment indices (DFI) and the percentages of high DNA stainability (HDS), for outcomes of artificial insemination by husband (AIH) remains controversial. This study aims to evaluate the correlations between SCSA parameters and male aging as well as other routine semen parameters, and explore their prognostic powers on AIH outcomes of the Chinese infertile couples. A total of 809 AIH cycles were retrospectively analyzed. The results showed that DFI in the age groups < 35 years were significantly lower than that in the age groups ≥ 35 years (P < 0.001). Meanwhile, there was no statistical difference in HDS between the age groups (P = 0.063). DFI and HDS are negatively correlated with most routine semen parameters (all P < 0.05). The chi-square and generalized linear model tests indicated that neither DFI nor HDS influenced the clinical pregnancy rate of AIH. In summary, this study found that aging is a critical factor leading to increased sperm DFI but not HDS. DFI and HDS are negatively correlated with most semen parameters but do not significantly influence AIH outcomes.
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Infertilidad , Esposos , China , Cromatina , ADN , Fragmentación del ADN , Femenino , Humanos , Inseminación Artificial , Masculino , Embarazo , Estudios Retrospectivos , EspermatozoidesRESUMEN
Previous study suggests that gratitude intervention evokes indebtedness among people from an interdependent society. This study furtherly hypothesized that perceived social distance moderates the effect of gratitude intervention on felt indebtedness. A total of 275 adolescents were randomly assigned to three gratitude intervention conditions, namely, writing gratitude to significant others, the health of one's own, or nothing. After completing the writing task, they rated their experienced emotions on ten dimensions, including gratitude and indebtedness. They also reported perceived social distance from surrounding people and other demographical information. Results indicated that participants in the condition of writing about gratitude to significant others felt indebted regardless of perceived social distance, while those in the condition of writing about gratitude to his/her own health and those in the control condition experienced lesser indebtedness as the perceived social distance with others becomes closer. Gratitude increases as perceived social connectedness increases across all conditions. Theoretical and practical implications were discussed.
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Two different but interacting neural systems exist in the human brain: the task positive networks and task negative networks. One of the most important task positive networks is the central executive network (CEN), while the task negative network generally refers to the default mode network (DMN), which usually demonstrates task-induced deactivation. Although previous studies have clearly shown the association of both the CEN and DMN with major depressive disorder (MDD), how the causal interactions between these two networks change in depressed patients remains unclear. In the current study, 99 subjects (43 patients with MDD and 56 healthy controls) were recruited with their resting-state fMRI data collected. After data preprocessing, spectral dynamic causal modeling (spDCM) was used to investigate the causal interactions within and between the DMN and CEN. Group commonalities and differences in causal interaction patterns within and between the CEN and DMN in patients and controls were assessed by a parametric empirical Bayes (PEB) model. Both subject groups demonstrated significant effective connectivity between regions of the CEN and DMN. In particular, we detected inhibitory influences from the CEN to the DMN with node-level PEB analyses, which may help to explain the anticorrelations between these two networks consistently reported in previous studies. Compared with healthy controls, patients with MDD showed increased effective connectivity within the CEN and decreased connectivity from regions of the CEN to DMN, suggesting impaired control of the DMN by the CEN in these patients. These findings might provide new insights into the neural substrates of MDD.
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Trastorno Depresivo Mayor , Teorema de Bayes , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Red en Modo Predeterminado , Depresión , Trastorno Depresivo Mayor/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Red Nerviosa/diagnóstico por imagenRESUMEN
Ambient fine particulate matter (PM2.5) is a worldwide environmental problem and is posing a serious threat to human health. Until now, the molecular toxicological mechanisms and the crucial toxic components of PM2.5 remain to be clarified. This study investigated the whole transcriptomic changes in THP-1 derived macrophages treated with different types of PM2.5 extracts using RNA sequencing technique. Bioinformatics analyses covering biological functions, signal pathways, protein networks and node genes were performed to explore the candidate pathways and critical genes, and to find the potential molecular mechanisms. Results of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes pathway (KEGG), and protein-protein interaction (PPI) networks revealed that water extracts (WEs) of PM2.5 obviously influenced genes and molecular pathways responded to oxidative stress and inflammation. Dichloromethane extracts (DEs) specifically affected genes and signal cascades related to cell cycle progress process. Furthermore, compared with WEs collected in heating season, non-heating season WEs induced much higher expression levels of Ca-associated genes (including phosphodiesterase 4B and cyclooxygenase-2), which may consequently result in more severe inflammatory responses. While, for DEs exposure, the heating season (DH) group showed extensive induction of deferentially expressed genes (DEGs) related to cell cycle pathway, which may be caused by the higher polycyclic aromatic hydrocarbons (PAHs) contents in DH samples than those from non-heating season. In conclusion, the oxidative stress and inflammation response are closely correlated with cellular responses in THP-1 derived macrophages induced by water soluble components of PM2.5, and cell cycle dysregulation may play an important role in biological effects induced by organic components. The different transcriptomic changes induced by seasonal PM2.5 extracts may partially depend on the contents of PAHs and metal ions, respectively.
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Contaminantes Atmosféricos , Hidrocarburos Policíclicos Aromáticos , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Humanos , Macrófagos , Material Particulado/análisis , Material Particulado/toxicidad , Hidrocarburos Policíclicos Aromáticos/toxicidad , TranscriptomaRESUMEN
Micro- and nano- polystyrene particles have been widely detected in environment, posing potential threats to human health. This study was designed to evaluate the neurodevelopmental toxicity of polystyrene nanoparticles (NPs) in Caenorhabditis elegans (C. elegans), to screen crucial genes and investigate the underlying mechanism. In wild-type C. elegans, polystyrene NPs (diameter 50 nm) could concentration-dependently induce significant inhibition in body length, survival rate, head thrashes, and body bending, accompanying with increase of reactive oxygen species (ROS) production, lipofuscin accumulation, and apoptosis and decrease of dopamine (DA) contents. Moreover, pink-1 mutant was demonstrated to alleviate the locomotion disorders and oxidative damage induced by polystyrene NPs, indicating involvement of pink-1 in the polystyrene NPs-induced neurotoxicity. RNA sequencing results revealed 89 up-regulated and 56 down-regulated differently expressed genes (DEGs) response to polystyrene NPs (100 µg/L) exposure. Gene Ontology (GO) enrichment analysis revealed that predominant enriched DEGs were correlated with biological function of cuticle development and molting cycle. Furthermore, mutant strains test showed that the neurodevelopmental toxicity and oxidative stress responses induced by 50 nm polystyrene NPs were regulated by dpy-5 and rol-6. In general, polystyrene NPs induced obvious neurodevelopmental toxicity in C. elegans through oxidative damage and dopamine reduction. Crucial genes dpy-5 and rol-6 might participate in polystyrene NPs-induced neurodevelopmental toxicity through regulation on synthesis and deposition of cuticle collagen.
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Proteínas de Caenorhabditis elegans , Nanopartículas , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Colágeno , Humanos , Nanopartículas/toxicidad , Estrés Oxidativo , Poliestirenos , Especies Reactivas de OxígenoRESUMEN
Background: To determine the independent prognostic factors and develop a multivariate logistic regression model for predicting successful pregnancy following artificial insemination by husband (AIH) in infertile Chinese couples. Methods: A total of 3,015 AIH cycles with superovulation from 1,853 infertile Chinese couples were retrospectively analyzed. The clinical characteristics and sperm parameters were compared between the pregnant and non-pregnant groups. Multivariate logistic regression analysis was performed to remove the confounding factors and create an equation to predict the successful pregnancy. Receiver operating characteristic (ROC) curves were constructed for evaluating the abilities for prognostic classification of the independent predictors and the equation. Results: The overall pregnancy rate was 13.0%. The pregnancy rate of double intrauterine insemination (IUI) (18.9%) was significantly higher than that of single IUI (11.4%). The pregnancy rate of the stimulated cycle (14.4%) was significantly higher than that of the natural cycle (9.0%). The pregnancy rates of the age groups <40 years are ~3 times higher than that of the ≥40 years age group. Among sperm parameters, the influencing factors included straight-line velocity (VSL), sperm deformity index (SDI), and normal form rate (all P < 0.05). A multivariate logistic regression equation was created based on the above influencing factors. ROC analysis showed that the prognostic power of the equation is better than those of individual predictors. Conclusion: Cycle treatment options, single/double IUI, female age, sperm VSL, SDI, and normal form rate could predict successful pregnancy following AIH in China. The multivariate logistic regression equation exhibited a greater value for prognostic classification than single predictors.
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Nano-sized ambient black carbon (BC) is hypothesized to pose a serious threat to human health. After emission into the air, the atmospheric oxidation process can modify its physiochemical properties and change its biological responses. In this study, we aimed to compare different DNA damage and repair responses promoted by fresh BC (FBC) and ozone oxidized-BC (OBC). The cell apoptosis, cell arrest, DNA damage and repair were investigated in A549 cells after treatment with FBC and OBC. Associated gene expressions were measured with the reverse transcription quantitative polymerase chain reaction (RT-qPCR) method. Both FBC and OBC could induce cell apoptosis in A549 cells with up-regulated gene of promyelocytic leukemia protein (pml) and down-regulated gene of anti-apoptotic B-cell lymphoma-2 (bcl-2). FBC caused cell cycle arrest at S and G2/M phases, which was associated with up-regulated ataxia telangiectasia mutated (atm), checkpoint kinase 2 (chk2), structural maintenance of chromosomes 1 (smc1) and cell division cycle 25 homolog A (cdc25a) genes. OBC promoted cell cycle arrest at the S phase with up-regulated genes of atm, chk2 and smc1. Both FBC and OBC induced oxidative DNA damage and time-dependent DNA repair responses with increased gene expressions of breast cancer susceptibility protein 1 (brca1), recombination protein A paralog B (rad51b), methyl methanesulfonate-sensitivity protein 22-like and tonsoku-like (mms22l). Compared to FBC, OBC could cause more sufficient DNA damage repair responses through cell cycle arrest at the S phase, resulting in relatively weaker DNA damages.
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Triclosan (TCS) is used as an antimicrobial agent and has been widely dispersed and detected in the environment and organisms including human samples. Methyl-triclosan (MTCS) is the predominant bacterial TCS metabolite. At present, the toxicological effects and mechanism of TCS and MTCS are still not fully understood. In this study, the cytotoxic effects of TCS and MTCS in HepG2 cells were investigated in terms of cell proliferation, comet assay, cell cycle, and apoptosis. In addition, the expressions of related proteins were detected with western blotting analysis. The results showed that TCS could significantly inhibit cell proliferation, while MTCS had no obvious effect on cell growth. Both TCS and MTCS caused oxidative injury associated with HO-1 induction and increased DNA strand breaks, which consequently initiated the damage repair process via up-regulation of DNA-PKcs. In addition, TCS blocked the HepG2 cells in S and G2/M phases of cell cycle through down-regulation of cyclin A2 and CDK; while MTCS induced cell cycle arrest at the S phase through up-regulation of cyclin A2 and CDK. Furthermore, TCS activated p53 mediated apoptosis in HepG2 cells in a caspase-independent manner, while MTCS induced apoptosis was dependent on caspase. Moreover, TCS exposure exhibited more severe toxicity in HepG2 cells as compared with MTCS exposure, indicating that the replacement of the ionizable proton in TCS by the methyl group in MTCS is correlated with the cellular toxicity and the molecular mechanism.
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Fine particles (PM2.5) emitted from municipal solid waste incineration (MSWI) contain high amounts of toxic compounds and pose a serious threat to environment and human health. In this study, entire particles as well as extracted water-soluble and -insoluble fractions of PM2.5 collected from MSWI and biomass incineration (BMI) were subjected to physiochemical characterization and cytotoxic tests in A549 and BEAS-2B cells. MSWI PM2.5 had higher contents of heavy metals (including Pb, Zn, and Cu) and dioxins (PCDD/Fs) than did BMI PM2.5. The metals were enriched in the water-insoluble fraction, as measured by inductively coupled plasma-atomic emission spectrometry. BMI PM2.5 had a higher content of endotoxin, which was also enriched in the water-insoluble fraction. MSWI PM2.5 caused more serious cell injuries, as indicated by the lower viability, higher ROS generation, and DNA damage, whereas BMI PM2.5 presented higher pro-inflammatory potential, as indicated by increased mRNA levels of interleukin 6. Normal human BEAS-2B cells were more sensitive than A549 cells in all these tests. Toxic effects caused by MSWI and BMI PM2.5 were mostly attributable to their water-insoluble fractions. Our results indicate different chemical and biological compositions in MSWI and BMI PM2.5 probably dominate in different toxic endpoints in vitro.
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Contaminantes Atmosféricos/toxicidad , Dioxinas/toxicidad , Incineración , Metales Pesados/toxicidad , Material Particulado/toxicidad , Contaminantes Atmosféricos/química , Biomasa , Línea Celular , Supervivencia Celular/efectos de los fármacos , Daño del ADN , Dioxinas/química , Humanos , Interleucina-6/genética , Metales Pesados/química , Material Particulado/química , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Residuos Sólidos , Solubilidad , Agua/químicaRESUMEN
Ambient ultrafine black carbon (uBC) can potentially cross blood-brain barrier, however, very little is currently known about the effects they may have on central nervous system. This study aimed to explore the roles of autophagy in Alzheimer-like pathogenic changes promoted by uBC in SH-SY5Y cells. We firstly found uBC could cause cytotoxicity and oxidative stress in SH-SY5Y cells. Additionally we found uBC initiated progressive development of Alzheimer's disease (AD) associated features, mainly including neuro-inflammation and phosphorylation of tau protein (p-Tau) accumulation. Meanwhile, autophagy process was activated by uBC probably through phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. RNA interference and autophagosome-lysosome fusion inhibitor were applied to block autophagy process at different stages. Autophagy dysfunction at the initial membrane expansion stage could aggravate p-Tau accumulation and other Alzheimer-like changes in SH-SY5Y cells promoted by uBC. However, autophagy inhibition at the final stage could alleviate p-Tau accumulation caused by uBC. This suggested that inhibition of the infusion of autophagosome and lysosome could possibly activate ubiquitination degradation pathway to regulate p-Tau equilibrium in SH-SY5Y cells. Our findings further raise the concerns about the effects of uBC on the risk of AD and indicate potential roles of autophagy in early Alzheimer-like pathogenic changes caused by ambient uBC.
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Enfermedad de Alzheimer/metabolismo , Autofagia/efectos de los fármacos , Carbono/metabolismo , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/metabolismo , Neuroblastoma/metabolismo , HumanosRESUMEN
After emitted from incomplete combustion of fossil fuels and biomass, ambient black carbon (BC) was then undergone photochemical oxidization processes in the air to form aged BC particles, also called oxidized BC (OBC). This study aimed to investigate the interactions between oxidative stress, autophagy and apoptosis induced by OBC in A549 cells and to explore associated molecular mechanisms. First, OBC could stimulate oxidative stress, autophagy and apoptosis dose-dependently, as evidenced by increased intercellular reactive oxygen species (ROS) levels, up-regulated autophagosome markers (light chain 3, LC3), and elevated apoptosis rate. Inhibitors of oxidative stress (N-acetylcysteine, NAC), autophagy (bafilomycin A1, Baf) and apoptosis (Z-DEVD-FMK) were used to investigate their interactions. NAC pretreatment could significantly reduce autophagy and apoptosis. Additionally, pretreatment with Baf or Z-DEVD-FMK could also significantly suppress the other two biological effects. Furthermore, OBC up regulated the expressions of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), phosphorylated protein kinase B (Akt) and mammalian target of rapamycin (mTOR). The Akt inhibitor (MK-2206) significantly reduced both autophagy and apoptosis. Taken together, dual-direction regulation existed between each two of oxidative stress, autophagy, and apoptosis in A549 cells exposed to OBC. In addition, the autophagy process is modulated by the PI3K/Akt pathway regardless of mTOR activity.
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Carbono/toxicidad , Células A549 , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Humanos , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Ambient particulate matter (PM) is a worldwide health issue of concern. However, limited information is available regarding the toxic contributions of the nitro-derivatives of polycyclic aromatic hydrocarbons (nitro-PAHs). This study intend to examine whether 1-nitropyrene (1-NP) and 3-nitrofluoranthene (3-NF) could activate the nuclear factor-erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) antioxidant defense system, and whether the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway participates in regulating pro-inflammatory responses in A549 cells. Firstly, 1-NP and 3-NF concentration-dependently induced cellular apoptosis, reactive oxygen species (ROS) generation, DNA damage, S phase cell cycle arrest and differential expression of related cytokine genes. Secondly, 1-NP and 3-NF activated the Nrf2/ARE defense system, as evidenced by increased protein expression levels and nuclear translocation of transcription factor Nrf2, elevated Nrf2/ARE binding activity, up-regulated expression of the target gene heme oxygenase-1 (HO-1). Significantly increased protein expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and phosphorylation level of Akt indicated that the PI3K/Akt pathway was activated during pro-inflammatory process. Further, both PI3K inhibitor (LY294002) and Akt inhibitor (MK-2206) reversed the elevated TNF-α expression to control level. Our results suggested that Nrf2/ARE pathway activation might cause an initiation step in cellular protection against oxidative stress caused by nitro-PAHs, and the PI3K/Akt pathway participated in regulating inflammatory responses.
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Contaminantes Atmosféricos/toxicidad , Fluorenos/toxicidad , Pirenos/toxicidad , Células A549 , Elementos de Respuesta Antioxidante , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Ensayo Cometa , Daño del ADN , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Oral ingestion plays an important role in human exposure to polybrominated diphenyl ethers (PBDEs). The uptake of PBDEs primarily occurs in the small intestine. The aim of the present study is to investigate the transepithelial transport characteristics and mechanisms of PBDEs in the small intestine using a Caco-2 cell monolayer model. The apparent permeability coefficients of PBDEs indicated that tri- to hepta-BDEs were poorly absorbed compounds. A linear increase in transepithelial transport was observed with various concentrations of PBDEs, which suggested that passive diffusion dominated their transport at the concentration range tested. In addition, the pseudo-first-order kinetics equation can be applied to the transepithelial transport of PBDEs. The rate-determining step in transepithelial transport of PBDEs was trans-cell transport including the trans-pore process. The significantly lower transepithelial transport rates at low temperature for bidirectional transepithelial transport suggested that an energy-dependent transport mechanism was involved. The efflux transporters (P-glycoprotein, multidrug resistance-associated protein, and breast cancer resistance protein) and influx transporters (organic cation transporters) participated in the transepithelial transport of PBDEs. In addition, the transepithelial transport of PBDEs was pH sensitive; however, more information is required to understand the influence of pH.
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Contaminantes Ambientales/farmacocinética , Éteres Difenilos Halogenados/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transporte Biológico , Células CACO-2/efectos de los fármacos , Supervivencia Celular , Cimetidina/farmacología , Humanos , Concentración de Iones de Hidrógeno , Intestinos/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Temperatura , Factores de TiempoRESUMEN
In this work, sediments were treated with calcium nitrate, aluminum sulfate, ferric sulfate, and Phoslock®, respectively. The impact of treatments on internal phosphorus release, the abundance of nitrogen cycle-related functional genes, and the growth of submerged macrophytes were investigated. All treatments reduced total phosphorus (TP) and soluble reactive phosphorus (SRP) in interstitial water, and aluminum sulfate was most efficient. Aluminum sulfate also decreased TP and SRP in overlying water. Treatments significantly changed P speciations in the sediment. Phoslock® transformed other P species into calcium-bound P. Calcium nitrate, ferric sulfate, and Phoslock® had negative influence on ammonia oxidizers, while four chemicals had positive influence on denitrifies, indicating that chemical treatment could inhibit nitrification but enhance denitrification. Aluminum sulfate had decreased chlorophyll content of the leaves of submerged macrophytes, while ferric sulfate and Phoslock® treatment would inhibit the growth of the root. Based on the results that we obtained, we emphasized that before application of chemical treatment, the effects on submerged macrophyte revegetation should be taken into consideration.
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Amoníaco/análisis , Conservación de los Recursos Naturales/métodos , Sedimentos Geológicos/química , Hydrocharitaceae/crecimiento & desarrollo , Consorcios Microbianos , Fósforo/análisis , Contaminantes Químicos del Agua/análisis , Amoníaco/química , Desnitrificación , Ecosistema , Agua Dulce/química , Agua Dulce/microbiología , Sedimentos Geológicos/microbiología , Nitrificación , Oxidación-Reducción , Fósforo/químicaRESUMEN
The purpose of this study was to investigate the cytotoxic effects of tributylphosphate (TBP) and tris (2-butoxyethyl) phosphate (TBEP) and to explore the underlying molecular mechanism focusing on oxidative stress, apoptosis, and cell cycle arrest. The results showed that TBP and TBEP could inhibit cell proliferation, induce cellular reactive oxidative stress, and suppress the mitochondrial membrane potential in HepG2 cells. TBP and TBEP could induce both mitochondrial and p53 mediated apoptosis through different mitogen-activated protein kinase (MAPK) signal pathways. TBP activated the c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinase (ERK1/2) pathways, while TBEP activated the JNK pathway. Furthermore, TBP and TBEP caused a concentration-dependent decrease of cyclin D1 expression and an increase of cyclin-dependent kinase (CDK) inhibitor proteins such as p21 and p27, resulting in significant cell cycle arrest in the G0/G1 phase. Taken together, the toxicity of TBP and TBEP on the HepG2 cells was associated with apoptosis and cell cycle arrest induced by oxidative stress.
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In order to clarify the cytotoxicity of hexabromocyclododecane (HBCD) diastereoisomers, and to investigate the correlation of cytotoxicity and biotransformation of HBCDs, the immortalized human liver cells L02 and human hepatoma cells HepG2 were exposed to individual HBCD diastereoisomer (α-, ß- and γ-HBCD). Cytotoxicity was assayed in terms of cell viability, reactive oxygen species (ROS) level and DNA damage. Metabolic rate, bioisomerization and enantiomer fractions were analyzed using the liquid chromatograph coupled to triple quadrupole mass spectrometer (LC-MS/MS). The α-, ß- and γ-HBCD all had cytotoxicity in L02 and HepG2 cells with the toxicity order ß-HBCD ≥ γ-HBCD > α-HBCD according to the results of proliferation assay. The cytotoxicity mechanism between the two cells seemed different: a) the stability of intracellular redox state plays an important role in inducing cell toxicity in HepG2 cells. b) DNA damage status is central to inhibit proliferation in L02 cells. The metabolic capability of HepG2 was superior to L02 for HBCD diastereoisomers, which may explain the greater toxicity of HBCDs in HepG2 cells. The bioisomerization and enantiomer enrichment were also detected in this study, although the results were inconsistent with other reports, which might result from species-specific differences in HBCDs metabolism or experimental conditions. The cytotoxicity and metabolic mechanism of individual enantiomers must be further investigated to evaluate the health risks of HBCDs.