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Abstract 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. Graphical abstract Image 1 Highlights • Ultrafine black carbon (uBC) caused early Alzheimer-like pathogenic changes. • Autophagy related to these Alzheimer-like pathogenic changes induced by uBC. • Autophagy inhibition at initial membrane expansion stage aggravated p-Tau accumulation. • Autophagy dysfunction at final stage alleviate p-Tau accumulation. Autophagy regulated Alzheimer-like pathogenic changes promoted by uBC. [ABSTRACT FROM AUTHOR]

Highlights: [•] Fengdingshan granites and Taoyuan Complex were formed in Silurian period. [•] Fengdingshan granites were formed by reworking of Neoproterozoic basaltic crust. [•] Taoyuan mafic rocks originated from a previously metasomatized lithospheric mantle. [•] The Fengdingshan and Taoyuan Plutons were formed in a post-orogenic collapse stage. [•] Nd–Hf decoupling may be a fingerprint of an ancient oceanic subduction. [ABSTRACT FROM AUTHOR]

Ambient fine particulate matter (PM 2.5) 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 PM 2.5 remain to be clarified. This study investigated the whole transcriptomic changes in THP-1 derived macrophages treated with different types of PM 2.5 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 PM 2.5 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 PM 2.5 , and cell cycle dysregulation may play an important role in biological effects induced by organic components. The different transcriptomic changes induced by seasonal PM 2.5 extracts may partially depend on the contents of PAHs and metal ions, respectively. [Display omitted] • The oxidative stress and inflammation response are closely correlated with water soluble components-induced cytotoxicity. • Cell cycle dysregulation may play an important role in biological effects induced by organic components of PM 2.5. • The transcriptomic changes induced by seasonal PM 2.5 extracts partially depend on the contents of PAHs and metal ions. [ABSTRACT FROM AUTHOR]

• Causal interactions between the CEN and DMN in depressed patients were investigated by spectral dynamic causal modeling. • Inhibitory influences from the CEN to the DMN were detected with node-level PEB analyses. • Patients with MDD showed increased effective connectivity within the CEN. • Decreased connectivity from regions of the CEN to DMN was found in the patients. 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. [ABSTRACT FROM AUTHOR]

Abstract: Polychlorinated biphenyls (PCBs) are still prevalent in the environment despite the fact that they have been banned in many countries for several decades. Recent epidemiologic studies have demonstrated a link between PCBs exposure and pathological alterations of bone tissues. The aim of this study was to investigate the toxic effects of the PCBs mixture Aroclor 1254 on MC3T3-E1 preosteoblasts and explore the underlying molecular mechanism. Different doses of Aroclor 1254 were used to treat MC3T3-E1 and the cell viability, apoptosis, ALP activity, intracellular calcium (Ca2+) level and oxidative stress response were measured. The expression level of related proteins TRPV6, Apaf-1 and Bax was evaluated with Western blot assay. The subcellular distribution of TRPV6 protein was detected with immunofluorescence assay. The results indicated that the higher dose of Aroclor 1254 (>10mg/L) could inhibit the cell proliferation and induce apoptosis in MC3T3-E1. The ROS level following Aroclor 1254 exposure was elevated with the concentration, while the ALP activity and intracellular calcium (Ca2+) level decreased. After Aroclor 1254 exposure, the expression level of calcium transport related protein TRPV6 was down-regulated, while the expression level of apoptosis related proteins Apaf-1 and Bax up-regulated in a dose dependant manner. The immunofluorescence assay results showed that the expression of TRPV6 in the cytoplasm was greatly suppressed after Aroclor 1254 exposure. In conclusion, Aroclor 1254 exposure could induce toxic effects in MC3T3-E1 as evidenced by inhibition of proliferation, induction of apoptosis and suppression of ALP activity. The ROS production and alteration of intracellular Ca2+ level induced by down-regulation of TRPV6 might involve the toxic effects, and cell apoptosis induced by Aroclor 1254 exposure is associated with the pro-apoptotic Apaf-1 pathway as well as alteration of Bcl-2/Bax ratio. [Copyright &y& Elsevier]

Abstract: Polybrominated diphenyl ethers (PBDEs) had been used extensively in electrical and electronic products as brominated flame retardants. PBDEs are widely distributed in environment media and wildlife since they are lipophilic and persistent, resulting in bioaccumulation and bioamplification through food chains. Accumulation of PBDEs in the environment and human tissues will consequently cause potential negative effects on the ecological environment and human health. To date, some in vitro and in vivo studies have reported that PBDEs possess neurotoxicity, hepatotoxicity, immunotoxicity, reproduction toxicity, endocrine disrupting activity and carcinogenicity. BDE-47 is one of the most predominant PBDE congeners detected in human tissues. The objective of this study is to investigate whether low concentration of BDE-47 could cause hormesis effect in the human hepatoma HepG2 cells, and to explore the possible molecular mechanism. The results showed that low concentration of BDE-47 (10−10, 10−9 and 10−8 M) could promote cell proliferation and cause no obvious change in DNA damage or cell apoptosis, while the high concentration significantly inhibit cell proliferation. Meanwhile, the reactive oxygen species (ROS) in low concentration BDE-47 (10−10, 10−9 and 10−8 M) treated groups significantly elevated compared with the control group. After low concentration BDE-47 treatment, the expression of proliferating cell nuclear antigen (PCNA), Cyclin D1, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and phosphorylated protein kinase B (p-Akt) in the HepG2 cells was markedly up-regulated. However, in DNA-PKcs inhibited cells, the promotion effect on cell proliferation was significantly suppressed. Cell cycle analysis showed a significant decrease in G1 phase after exposure to low concentration of BDE-47. Moreover, pre-exposure to low concentration BDE-47 seemed alleviate the negative effects of high concentration (50μM) exposure to cause DNA damage and apoptosis. These results suggested that BDE-47 has a hormesis effect in HepG2 cells and DNA-PKcs/Akt pathway may be involved in regulation of cell proliferation and apoptosis. [Copyright &y& Elsevier]

Abstract 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. Graphical abstract Unlabelled Image Highlights • Oxidized BC containing PAHs activated autophagy, apoptosis and oxidative stress in A549 cells. • Dual-direction regulations existed between autophagy and apoptosis. • Autophagy and apoptosis were regulated by PI3K/Akt pathway. • Autophagy and apoptosis were independent of mTOR pathway [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-, β- 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-, β- and γ-HBCD all had cytotoxicity in L02 and HepG2 cells with the toxicity order β-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. [ABSTRACT FROM AUTHOR]

A facile vesicle-templating approach has been developed for synthesis of multi-shelled mesoporous silica nanoparticles (MMSNs) through a self-assembly of cetyltrimethylammonium bromide (CTAB) and sodium dodecyl benzene sulfonate (SDBS). The obtained MMSNs displayed a spherical morphology, relatively uniform size distribution with an average diameter of 185 nm and a good biocompatibility. Controlled experiments demonstrated that the morphology and structure of MMSNs were mainly determined by the mass ratio of CTAB/SDBS in the reagents. A possible growth mechanism of MMSNs was proposed based on TEM, SEM, and N 2 sorption analysis, etc. Moreover, the Au-decorated MMSNs (Au@MMSNs) were constructed as the catalyst, which exhibited superior catalytic activity and good cycle stability for the reduction of 4-nitrophenol (4-NP). Additionally, the MMSNs also showed high drug loading efficiency and the controlled pH-responsive release behavior for doxorubicin hydrochloride (DOX). More importantly, the anticancer effect of DOX@MMSNs towards A549 cell further confirmed MMSNs could be employed as an ideal drug carrier. As a consequence, the MMSNs prepared are potential excellent candidates for various applications including nanoreactors, drug delivery, and cancer therapy. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the “adaptive responses” of hexabromocyclododecanes (HBCD) at environmentally relevant concentrations in human hepatocytes L02. L02 cells were pre-treated with low concentrations of HBCD (10 −13 –10 −11 M), followed by treatment with high concentrations of HBCD, α-hexachlorocyclohexane (α-HCH), polychlorinated biphenyls (PCBs), or polybrominated diphenyl ether-47 (BDE47). The results showed that the pre-treatment with low concentrations of HBCD induced “adaptive responses” to high concentrations of HBCD/α-HCH exposure (but not to PCBs and BDE47), as evidenced by attenuation of survival inhibition, reactive oxygen species (ROS) over-production, and deoxyribonucleic acid (DNA) damage induction. The “adaptive responses” induced by low concentrations of HBCD, which depended on the activation of the phosphatidylinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, reduced the phosphorylation of adenosine monophosphate-activated kinase (AMPK) and enhanced the phosphorylation of p38 mitogen-activated protein kinases (p38 MAPK). The observations were further confirmed by the experiments with inhibitors. Moreover, the evaluation on the changes of metabolic enzymes revealed that HBCD and α-HCH shared a similar pattern of cytochrome P450 induction (CYP2B6), which was different from those of PCBs and BDE47 (CYP1A1 and CYP2B6). These results indicated that low concentrations of HBCD could induce “adaptive responses” to the subsequent treatment with high concentrations of HBCD/α-HCH in L02 cells, which was associated with the PI3K/Akt pathway, and AMPK and p38 MAPK signaling. The “adaptive responses” seemed to be dependent on the types of chemicals in terms of the metabolic patterns and chemical structures. [ABSTRACT FROM AUTHOR]

Highlights: [•] HBCD induced obvious oxidative damage in HepG2 cells. [•] OPCs could effectively protect cells against HBCD-induced cytotoxicity. [•] ROS formation, mitochondrial pathway, and Ca2+ level are involved in OPCs effect regulation. [ABSTRACT FROM AUTHOR]