查看更多>>摘要：Hazard evaluation of graphene-based materials (GBM) is still in its early stage and it is slowed by their large diversity in the physicochemical properties. This study explores transcriptomic differences in the lung and liver after pulmonary exposure to two GBM with similar physical properties, but different surface chemistry.
查看更多>>摘要：Modern High-Throughput Screening (HTS) techniques allow to determine in vitro bioactivity of tens of thousands of chemicals within a relatively short period of time and tested compounds are usually interpreted as either active or inactive. The interpretation is mostly based on the assumption of monotonic dose-response. This approach ignores potential abnormal dose-response relationships, such as non-monotonic dose-response (NMDR). NMDR presents a serious challenge to toxicologists and pharmacologists, since they undermine the usefulness of such concepts as lowest-observed-adverse-effect level (LOAEL) and no-observed-adverse-effect level (NOAEL). The possible presence of the NMDR in Androgen receptor (AR) agonism was examined for a structurally diverse set of chemicals (similar to 8 300 unique compounds) from Tox21 project library. The source of activity data is Tox21 AR agonism luciferase-based HTS on the MDA-MB-453 cell line. The examination of curve fitting for 35,328 dose-response data entries was based on modified version of existing criteria for determination of NMDR. The bias that arises from compounds' cytotoxicity and interference with firefly luciferase protein was also studied. The examination has shown evidence of NMDR for several compounds, including known AR antagonists (e. g. Cyprotemne acetate) and other known endocrine disruptors (e. g. Tranilast). Compounds were divided into 3 groups based on chemical class, known biological activity profile and the shape of dose-response curve. The challenges of using HTS data to determine NMDR and benefits of this analysis are discussed
查看更多>>摘要：Andrographolide (AND) is the major diterpenoid in A. paniculata with wide clinical application and has been shown to be a potent anti-inflammatory agent. Gout is the leading inflammatory disease of the joints, and the deposition of urate in the articular cavity attracts immune cells that release inflammatory cytokines. Monosodium urate (MSU) is known to be one of the activators of the NLRP3 (NLR family pyrin domain containing 3) inflammasome. After activation, the NLRP3 inflammasome releases interleukin-1 (IL-1 beta), which causes the development of many inflammatory diseases. The aim of the present study was to investigate whether AND attenuates the release of IL-1 beta mediated by the NLRP3 inflammasome. The effects of AND were studied in bone marrow-derived macrophages (BMDMs) treated with lipopolysaccharide (LPS) and MSU and in mice with MSUinduced joint inflammation. AND suppressed MSU phagocytosis dose-dependently and markedly inhibited LPS-and MSU-induced IL-1 beta release in BMDMs. Moreover, AND pretreatment inhibited the LPS-induced NLRP3 inflammasome priming stage by inhibiting the IKK/NF kappa B signaling pathway, which resulted in decreased protein expression of NLRP3 and proIL-1 beta. AND induced HO-1 protein expression in a dose-dependent manner and attenuated MSU-induced ROS generation. Silencing HO-1 mitigated AND inhibition of LPS/MSU-induced IL-1 beta release in J774A.1 cells. In addition, AND decreased MSU-mediated ASC binding to NLRP3. Oral administration of AND attenuated MSU-induced monocyte infiltration in mouse knee joints. These results suggest that the working mechanisms by which AND down-regulates MSU-induced joint inflammation might be via HO-1 induction and attenuation of ROS-mediated NLRP3 inflammasome assembly and subsequent IL-1 beta release.
查看更多>>摘要：Iron overload toxicity has been implicated in retinal pigment epithelial cell injury in age-related macular degeneration. This study investigates the effects of astragaloside IV (AS-IV), a potential retinal protective agent, on the toxicity process of retinal iron overload in vivo and in vitro. AS-IV partially restored the retinal expression of rhodopsin and retinal pigment epithelium-specific 65 kDa protein, suppressed oxidative stress and inflammatory markers, and alleviated iron deposition and retinal pathological changes in vivo. Also, AS-IV inhibited the phosphorylation of p38 and ERK mitogen-activated protein kinases (MAPKs), as well as the nuclear translocation of nuclear factor-kappa B (NF-kappa B). Furthermore, AS-IV prevented cell death by decreasing the ratio of Bax/Bcl-2, caspase-3, and cleaved caspase-3 expression in vitro. Although there are no chelation effects between AS-IV and iron, AS-IV can reduce intracellular iron by regulating iron-handling proteins in ARPE-1 9 cells (Cav1.2, divalent metal transporter-1, transferrin receptor 1, and heavy-chain ferritin). In conclusion, the results show that AS-IV has significant protective effects against retinal iron overload toxicity and suggest that iron regulation and the inhibition of MAPKs and NF-kappa B activation might be mechanisms underlying the effects of AS-IV.
查看更多>>摘要：Semaphorin (Sema) 3A and Sema 4A are immunomodulatory molecules with a common receptor, neuropilin-1 (NRP-1), on the immune cells. Sema 3A binds to NRP-1 and inhibits T cell activation and inflammation, while Sema 4A binds to NRP-1 and promotes T cell activation and inflammation. These molecules are associated closely with the regulation of protein kinase B (AKT)/nuclear factor-kappaB (NF-kappa B) signaling, which are poorly understood in arsenic toxicity. The present study explored the role of Sema 3A or Sema 4A in arsenic-induced hepatotoxicity in mice. Arsenic exposure induced hepatic injury and resulted in the activations of p-AKT2, NF-kappa B p65, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, downregulation of Sema 3A, and upregulation of Sema 4A or NRP-1. Interestingly, intervention with anti-Sema 4A antibody showed the mitigation of arsenic-induced hepatotoxicity, accompanied by the downregulation of Sema 4A, rebound of Sema 3A, and upregulation of NRP-1. And, the inflammatory signaling p-AKT2 or NF-kappa B p65, and NLRP3 inflammasome showed a downregulation compared with arsenic treatment group. In contrast, anti-Sema 3A antibody intervention did not show the significant effect in the histopathological features compared with arsenic treatment group. In conclusion, the anti-Sema 4A antibody antagonizes arsenic-induced hepatotoxicity in mice and may be involved in the inhibitions of AKT2/NF-kappa B and NLRP3 inflammatory signaling mediated synergistically by Sema 4A or Sema 3A and their receptor NRP-1.
查看更多>>摘要：A critical part of community based human health risk assessment following chemical exposure is identifying sources of susceptibility. Life stage is one such susceptibility. A prototypic air pollutant, ozone (O-3) induces dysfunction of the pulmonary, cardiac, and nervous systems. Long-term exposure may cause oxidative stress (OS). The current study explored age-related and subchronic O-3-induced changes in OS in brain regions of rats. To build a comprehensive assessment of OS-related effects of O-3, a tripartite approach was implemented focusing on 1) the production of reactive oxygen species (ROS) [NADPH Quinone oxidoreductase 1, NADH Ubiquinone reductase] 2) antioxidant homeostasis [total antioxidant substances, superoxide dismutase, gamma-glutamylcysteine synthetase] and 3) an assessment of oxidative damage [total aconitase and protein carbonyls]. Additionally, a neurobehavioral evaluation of motor activity was compared to these OS measures. Male Brown Norway rats (4, 12, and 24 months of age) were exposed to air or O-3 (0.25 or 1 ppm) via inhalation for 6 h/day, 2 days per week for 13 weeks. A significant decrease in horizontal motor activity was noted only in 4-month old rats. Results on OS measures in frontal cortex (FC), cerebellum (CB), striatum (STR), and hippocampus (HIP) indicated life stage related increases in ROS production, small decreases in antioxidant homeostatic mechanisms, a decrease in aconitase activity, and an increase in protein carbonyls. The effects of O-3 exposure were brain area-specific, with the STR being more sensitive. Regarding life stage, the effects of O-3 were greater in 4-month-old rats, which correlated with horizontal motor activity. These results indicate that OS may be increased in specific brain regions after subchronic O-3 exposure, but the interactions between age and exposure along with their consequences on the brain require further investigation.
Zhou, XixiXue, BingyeMedina, SebastianBurchiel, Scott W....
6页
查看更多>>摘要：People living in southwest part of United States are exposed to uranium (U) through drinking water, air, and soil. U is radioactive, but independent of this radioactivity also has important toxicological considerations as an environmental metal. At environmentally relevant concentrations, U is both mutagenic and carcinogenic. Emerging evidence shows that U inhibits DNA repair activity, but how U interacts with DNA repair proteins is still largely unknown. Herein, we report that U directly interacts with the DNA repair protein, Protein Poly (ADP ribose) Polymerase 1 (PARP-1) through direct binding with the zinc finger motif, resulting in zinc release from zinc finger and DNA binding activity loss of the protein. At the peptide level, instead of direct competition with zinc ion in the zinc finger motif, U does not show thermodynamic advantages over zinc. Furthermore, zinc preoccupied PARP-1 zinc finger is insensitive to U treatment, but U bound to PARP-1 zinc finger can be partially replaced by zinc. These results provide mechanistic basis on molecular level to U inhibition of DNA repair.
查看更多>>摘要：Famciclovir (FCV) is an antiviral drug that is often utilized after bone marrow transplantation to prevent viral infection. Yet, its role in hematopoiesis is poorly understood. Here, by utilizing a zebrafish model, we found that FCV exposure led to hematopoietic failure by impairing the proliferation of hematopoietic stem and progenitor cell (HSPC) and inducing HSPC apoptosis. On the other hand, FCV treatment could effectively relieve myeloid malignancies in the c-myb(hyper) MDS-like fish model, and played a role not only in the embryonic stage but also in adult zebrafish. This study reveals that FCV functions as a double-edged sword, with hematotoxicity at a high level, but that appropriate FCV treatment may be beneficial for the treatment of MDS.
查看更多>>摘要：Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide. The abnormal activation of glycolytic metabolism and PTEN/AKT signaling in NSCLC cells are highly correlated with their proliferation abilities and viability. Ligustilide is one of the major bioactive components of multiple Chinese traditional medicine including Angelica sinensis and Ligusticum. Ligustilide exposure inhibits the proliferation and viability of multiple cancer cell lines in vitro. However, the impact of ligustilide to the progression of NSCLC and its detailed pharmacological mechanisms remain unclear. In this research, CCK-8 and colony formation assay were performed to demonstrate ligustilide treatment inhibited the viability and proliferation ability of NSCLC cells in vitro. Caspase-3/-7 activity assay and nucleosome ELISA assay were utilized to show ligustilide promoted the apoptosis of NSCLC cells. Metabolic analysis and qRT-PCR assay were used to demonstrated that ligustilide dampened aerobic glycolysis of NSCLC cells. Nude mice were exposed to 5 mg/kg ligustilide and ligustilide inhibited orthotopic NSCLC growth in vivo. qRT-PCR and Western blot analysis were performed to substantiate the regulatory function of ligustilide to PTEN/AKT signaling in NSCLC cells. Overall, this study revealed that ligustilide regulated the proliferation, apoptosis and aerobic glycolysis of NSCLC cells through PTEN/AKT signaling pathway.
Durrani, KulsoomEl Din, Sarah-Marie AlamSun, YuchenRule, Ana M....
7页
查看更多>>摘要：Ethyl maltol (EM) is a flavoring agent commonly used in foods that falls under the generally recognized as safe category. It is added to many commercial e-cigarette vaping fluids and has been detected in the aerosols. Considering that EM facilitates heavy metal transport across plasma membranes, and that heavy metals have been detected in aerosols generated from e-cigarettes, this study examines whether EM enhances heavy metal mediated toxicity. A decrease in viability was observed in the Calu-6 and A549 lung epithelial cell lines co-exposed to EM and copper (Cu) but no decrease was observed after co-exposure to EM with iron (Fe). Interestingly, co exposure to EM and Fe decreased viability of the HEK293 and IMR-90 fibroblast cell lines but co-exposure to EM and Cu did not. Increases in the apoptotic markers Annexin V staining and fragmented nuclei were observed in Calu-6 cells co-exposed to EM and Cu. Co-exposure to EM and Cu in Calu-6 cells resulted in DNA damage as indicated by activation of ATM and expression of gamma H2A.x foci. Finally, co-exposure to EM and Cu caused oxidative stress as indicated by increases in the generation of reactive oxygen species and the expression of ferritin light chain mRNA and hemeoxygenase-1 mRNA and protein. These data show that co-exposure to EM and Cu, at concentrations that are not toxic for either chemical individually, induce apoptosis and evoke oxidative stress and DNA damage in lung epithelial cells. We suggest that there is a greater risk of lung damage in users of c-cigarette who vape with vaping fluid containing EM.Y
NSTL
Elsevier