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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.593]   [H-I: 135]   [17 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [3039 journals]
  • Thiamine deficiency induces endoplasmic reticulum stress and oxidative
           stress in human neurons derived from induced pluripotent stem cells
    • Authors: Xin Wang; Mei Xu; Jacqueline A. Frank; Zun-ji Ke; Jia Luo
      Pages: 26 - 31
      Abstract: Publication date: Available online 11 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Xin Wang, Mei Xu, Jacqueline A. Frank, Zun-ji Ke, Jia Luo
      Thiamine (vitamin B1) deficiency (TD) plays a major role in the etiology of Wernicke's encephalopathy (WE) which is a severe neurological disorder. TD induces selective neuronal cell death, neuroinflammation, endoplasmic reticulum (ER) stress and oxidative stress in the brain which are commonly observed in many aging-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and progressive supranuclear palsy (PSP). However, the underlying cellular and molecular mechanisms remain unclear. The progress in this line of research is hindered due to the lack of appropriate in vitro models. The neurons derived for the human induced pluripotent stem cells (hiPSCs) provide a relevant and powerful tool for the research in pharmaceutical and environmental neurotoxicity. In this study, we for the first time used human induced pluripotent stem cells (hiPSCs)-derived neurons (iCell neurons) to investigate the mechanisms of TD-induced neurodegeneration. We showed that TD caused a concentration- and duration-dependent death of iCell neurons. TD induced ER stress which was evident by the increase in ER stress markers, such as GRP78, XBP-1, CHOP, ATF-6, phosphorylated eIF2α, and cleaved caspase-12. TD also triggered oxidative stress which was shown by the increase in the expression 2,4-dinitrophenyl (DNP) and 4-hydroxynonenal (HNE). ER stress inhibitors (STF-083010 and salubrinal) and antioxidant N-acetyl cysteine (NAC) were effective in alleviating TD-induced death of iCell neurons, supporting the involvement of ER stress and oxidative stress. It establishes that the iCell neurons are a novel tool to investigate cellular and molecular mechanisms for TD-induced neurodegeneration.

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.009
      Issue No: Vol. 320 (2017)
  • Improving the International Agency for Research on Cancer's consideration
           of mechanistic evidence
    • Authors: Julie Goodman; Heather Lynch
      Pages: 39 - 46
      Abstract: Publication date: 15 March 2017
      Source:Toxicology and Applied Pharmacology, Volume 319
      Author(s): Julie Goodman, Heather Lynch
      Background The International Agency for Research on Cancer (IARC) recently developed a framework for evaluating mechanistic evidence that includes a list of 10 key characteristics of carcinogens. This framework is useful for identifying and organizing large bodies of literature on carcinogenic mechanisms, but it lacks sufficient guidance for conducting evaluations that fully integrate mechanistic evidence into hazard assessments. Objectives We summarize the framework, and suggest approaches to strengthen the evaluation of mechanistic evidence using this framework. Discussion While the framework is useful for organizing mechanistic evidence, its lack of guidance for implementation limits its utility for understanding human carcinogenic potential. Specifically, it does not include explicit guidance for evaluating the biological significance of mechanistic endpoints, inter- and intra-individual variability, or study quality and relevance. It also does not explicitly address how mechanistic evidence should be integrated with other realms of evidence. Because mechanistic evidence is critical to understanding human cancer hazards, we recommend that IARC develop transparent and systematic guidelines for the use of this framework so that mechanistic evidence will be evaluated and integrated in a robust manner, and concurrently with other realms of evidence, to reach a final human cancer hazard conclusion. Conclusions IARC does not currently provide a standardized approach to evaluating mechanistic evidence. Incorporating the recommendations discussed here will make IARC analyses of mechanistic evidence more transparent, and lead to assessments of cancer hazards that reflect the weight of the scientific evidence and allow for scientifically defensible decision-making.

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.01.020
      Issue No: Vol. 319 (2017)
  • Emodin suppresses TGF-β1-induced epithelial-mesenchymal transition in
           alveolar epithelial cells through Notch signaling pathway
    • Authors: Rundi Gao; Ruilin Chen; Yu Cao; Yuan Wang; Kang Song; Ya Zhang; Junchao Yang
      Pages: 1 - 7
      Abstract: Publication date: 1 March 2017
      Source:Toxicology and Applied Pharmacology, Volume 318
      Author(s): Rundi Gao, Ruilin Chen, Yu Cao, Yuan Wang, Kang Song, Ya Zhang, Junchao Yang
      Pulmonary fibrosis is characterized by the destruction of lung tissue architecture and the formation of fibrous foci, currently has no satisfactory treatment. Emodin is a component of Chinese herb that has been reported to be medicament on pancreatic fibrosis and liver fibrosis. However, its role in pulmonary fibrosis has not been established yet. In the present study, we investigated the hypothesis that Emodin plays an inhibitory role in TGF-β1 induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cell, and Emodin exerts its effect through the Notch signaling pathway. Emodin inhibits the proliferation of Rat alveolar type II epithelial cells RLE-6TN in a concentration-dependent manner; reduces the expression of Collagen I, α-SMA and Vimentin, promotes the expression of E-cadherin. Moreover, Emodin could regulate the expression patterns of the Notch signaling pathway-related factors and reduce the Notch-1 nucleus translocation. Knockdown of Notch-1 enhances the inhibitory effect of Emodin on TGF-β1-induced EMT in RLE-6TN cells. In conclusion, the data of the present study suggests that Emodin suppresses TGF-β1-induced EMT in alveolar epithelial cells through Notch signaling pathway and shows the potential to be effective in the treatment of pulmonary fibrosis.

      PubDate: 2017-01-29T14:45:35Z
      DOI: 10.1016/j.taap.2016.12.009
      Issue No: Vol. 318 (2017)
  • Baicalein attenuates vinorelbine-induced vascular endothelial cell injury
           and chemotherapeutic phlebitis in rabbits
    • Authors: Gang-Feng Ge; Wei-Wen Shi; Chen-Huan Yu; Xiao-Yin Jin; Huan-Huan Zhang; Wen-You Zhang; Lu-Chen Wang; Bing Yu
      Pages: 23 - 32
      Abstract: Publication date: 1 March 2017
      Source:Toxicology and Applied Pharmacology, Volume 318
      Author(s): Gang-Feng Ge, Wei-Wen Shi, Chen-Huan Yu, Xiao-Yin Jin, Huan-Huan Zhang, Wen-You Zhang, Lu-Chen Wang, Bing Yu
      Chemotherapy is one of the major strategies for cancer treatment. Several antineoplastic drugs including vinorelbine (VRB) are commonly intravenously infused and liable to cause serious phlebitis. The therapeutic drugs for preventing this complication are limited. In this study, the mechanism of baicalein (BCN) was investigated on VRB-induced phlebitis in vivo and vascular endothelial cell injury in vitro. Treatment with BCN obviously attenuated vascular endothelial cell loss, edema, inflammatory cell infiltration and blood clots, and reduced the serum levels of TNF-α, IL-1β, IL-6 and ICAM-1 in the rabbit model of phlebitis induced by intravenous injection of VRB compared with vehicle. Further tests in vitro demonstrated that BCN lessened VRB-induced endothelial cell apoptosis, decreased intracellular ROS levels, suppressed phosphorylation of p38 and eventually inhibited activation of NF-κB signaling pathway. And these effects could be reversed by p38 agonist P79350. These results suggested that BCN exerted the protective effects against VRB-induced endothelial disruption in the rabbit model of phlebitis via inhibition of intracellular ROS generation and inactivation of p38/NF-κB pathway, leading to the decreased production of pro-inflammatory cytokines. Thus, BCN could be used as a potential agent for the treatment of phlebitis.

      PubDate: 2017-01-29T14:45:35Z
      DOI: 10.1016/j.taap.2017.01.013
      Issue No: Vol. 318 (2017)
  • Assessing interactions of binary mixtures of Penicillium mycotoxins (PMs)
           by using a bovine macrophage cell line (BoMacs)
    • Authors: Se-Young Oh; Nina Cedergreen; Alexandros Yiannikouris; H.V.L.N. Swamy; Niel A. Karrow
      Pages: 33 - 40
      Abstract: Publication date: 1 March 2017
      Source:Toxicology and Applied Pharmacology, Volume 318
      Author(s): Se-Young Oh, Nina Cedergreen, Alexandros Yiannikouris, H.V.L.N. Swamy, Niel A. Karrow
      Penicillium mycotoxins (PMs) are toxic contaminants commonly found as mixtures in animal feed. Therefore, it is important to investigate potential joint toxicity of PM mixtures. In the present study, we assessed the joint effect of binary combinations of the following PMs: citrinin (CIT), ochratoxin A (OTA), patulin (PAT), mycophenolic acid (MPA) and penicillic acid (PA) using independent action (IA) and concentration addition (CA) concepts. Previously published toxicity data (i.e. IC25; PM concentration that inhibited bovine macrophage (BoMacs) proliferation by 25%) were initially analyzed, and both concepts agreed that OTA+PA demonstrated synergism (p <0.05), while PAT+PA showed antagonism (p <0.05). When a follow-up dilution study was carried out using binary combinations of PMs at three different dilution levels (i.e. IC25, 0.5∗IC25, 0.25∗IC25), only the mixture of CIT+OTA at 0.5∗IC25 was determined to have synergism by both IA and CA concepts with Model Deviation Ratios (MDRs; the ratio of predicted versus observed effect concentrations) of 1.4 and 1.7, respectively. The joint effect of OTA+MPA, OTA+PA and CIT+PAT complied with the IA concept, while CIT+PA, PAT+MPA and PAT+PA were better predicted with the CA over the IA concept. The present study suggests to test both IA and CA concepts using multiple doses when assessing risk of mycotoxin mixtures if the mode of action is unknown. In addition, the study showed that the tested PMs could be predicted by IA or CA within an approximate two-fold certainty, raising the possibility for a joint risk assessment of mycotoxins in food and feed.

      PubDate: 2017-01-29T14:45:35Z
      DOI: 10.1016/j.taap.2017.01.015
      Issue No: Vol. 318 (2017)
  • Perfluorooctanoic acid affects endocytosis involving clathrin light chain
           A and microRNA-133b-3p in mouse testes
    • Authors: Yin Lu; Jianshe Wang; Xuejiang Guo; Shengmin Yan; Jiayin Dai
      Pages: 41 - 48
      Abstract: Publication date: 1 March 2017
      Source:Toxicology and Applied Pharmacology, Volume 318
      Author(s): Yin Lu, Jianshe Wang, Xuejiang Guo, Shengmin Yan, Jiayin Dai
      Perfluorooctanoic acid (PFOA) is an abundant perfluoroalkyl substance widely applied in industrial and consumer products. Among its potential health hazards, testicular toxicity is of major concern. To explore the potential effect of miRNA on post-translational regulation after PFOA exposure, changes in miRNAs were detected via miRNA array. Seventeen miRNAs were differentially expressed (eight upregulated, nine downregulated) in male mouse testes after exposure to 5mg/kg/d of PFOA for 28d (>1.5-fold and P <0.05 compared with the control). Eight of these miRNAs were further selected for TaqMan qPCR analysis. Proteomic profile analysis indicated that many changed proteins after PFOA treatment, including intersectin 1 (ITSN1), serine protease inhibitor A3K (Serpina3k), and apolipoprotein a1 (APOA1), were involved in endocytosis and blood-testis barrier (BTB) processes. These changes were further verified by immunohistochemical and Western blot analyses. Endocytosis-related genes were selected for qPCR analysis, with many found to be significantly changed after PFOA treatment, including epidermal growth factor receptor pathway substrate 8 (Eps8), Eps15, cortactin, cofilin, espin, vinculin, and zyxin. We further predicted the potential interaction between changed miRNAs and proteins, which indicated that miRNAs might play a role in the post-translational regulation of gene expression after PFOA treatment in mouse testes. Among them, miR-133b-3p/clathrin light chain A (CLTA) was selected and verified in vitro by transfection and luciferase activity assay. Results showed that PFOA exposure affects endocytosis in mouse testes and that CLTA is a potential target of miR-133b-3p.

      PubDate: 2017-01-29T14:45:35Z
      DOI: 10.1016/j.taap.2017.01.014
      Issue No: Vol. 318 (2017)
  • Prenatal exposure to an environmentally relevant phthalate mixture
           disrupts reproduction in F1 female mice
    • Authors: Changqing Zhou; Liying Gao; Jodi A. Flaws
      Pages: 49 - 57
      Abstract: Publication date: 1 March 2017
      Source:Toxicology and Applied Pharmacology, Volume 318
      Author(s): Changqing Zhou, Liying Gao, Jodi A. Flaws
      Phthalates are used in a large variety of products, such as building materials, medical devices, and personal care products. Most previous studies on the toxicity of phthalates have focused on single phthalates, but it is also important to study the effects of phthalate mixtures because humans are exposed to phthalate mixtures. Thus, we tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture adversely affects female reproduction in mice. To test this hypothesis, pregnant CD-1 dams were orally dosed with vehicle (tocopherol-stripped corn oil) or a phthalate mixture (20 and 200μg/kg/day, 200 and 500mg/kg/day) daily from gestational day 10 to birth. The mixture was based on the composition of phthalates detected in urine samples from pregnant women in Illinois. The mixture included 35% diethyl phthalate, 21% di(2-ethylhexyl) phthalate, 15% dibutyl phthalate, 15% diisononyl phthalate, 8% diisobutyl phthalate, and 5% benzylbutyl phthalate. Female mice born to the exposed dams were subjected to tissue collections and fertility tests at different ages. Our results indicate that prenatal exposure to the phthalate mixture significantly increased uterine weight and decreased anogenital distance on postnatal days 8 and 60, induced cystic ovaries at 13months, disrupted estrous cyclicity, reduced fertility-related indices, and caused some breeding complications at 3, 6, and 9months of age. Collectively, our data suggest that prenatal exposure to an environmentally relevant phthalate mixture disrupts aspects of female reproduction in mice.

      PubDate: 2017-01-29T14:45:35Z
      DOI: 10.1016/j.taap.2017.01.010
      Issue No: Vol. 318 (2017)
  • Phagolysosome acidification is required for silica and engineered
           nanoparticle-induced lysosome membrane permeabilization and resultant
           NLRP3 inflammasome activity
    • Authors: Forrest Jessop; Raymond F. Hamilton; Joseph F. Rhoderick; Paige Fletcher; Andrij Holian
      Pages: 58 - 68
      Abstract: Publication date: 1 March 2017
      Source:Toxicology and Applied Pharmacology, Volume 318
      Author(s): Forrest Jessop, Raymond F. Hamilton, Joseph F. Rhoderick, Paige Fletcher, Andrij Holian
      NLRP3 inflammasome activation occurs in response to hazardous particle exposures and is critical for the development of particle-induced lung disease. Mechanisms of Lysosome Membrane Permeabilization (LMP), a central pathway for activation of the NLRP3 inflammasome by inhaled particles, are not fully understood. We demonstrate that the lysosomal vATPases inhibitor Bafilomycin A1 blocked LMP in vitro and ex vivo in primary murine macrophages following exposure to silica, multi-walled carbon nanotubes, and titanium nanobelts. Bafilomycin A1 treatment of particle-exposed macrophages also resulted in decreased active cathepsin L in the cytosol, a surrogate measure for leaked cathepsin B, which was associated with less NLRP3 inflammasome activity. Silica-induced LMP was partially dependent upon lysosomal cathepsins B and L, whereas nanoparticle-induced LMP occurred independent of cathepsin activity. Furthermore, inhibition of lysosomal cathepsin activity with CA-074-Me decreased the release of High Mobility Group Box 1. Together, these data support the notion that lysosome acidification is a prerequisite for particle-induced LMP, and the resultant leak of lysosome cathepsins is a primary regulator of ongoing NLRP3 inflammasome activity and release of HMGB1.
      Graphical abstract image

      PubDate: 2017-01-29T14:45:35Z
      DOI: 10.1016/j.taap.2017.01.012
      Issue No: Vol. 318 (2017)
  • Myeloid differentiation protein 2-dependent mechanisms in retinal
           ischemia-reperfusion injury
    • Authors: Luqing Ren; Jianjian Tao; Huaicheng Chen; Yang Bian; Xi Yang; Gaozhi Chen; Xin Zhang; Guang Liang; Wencan Wu; Zongming Song; Yi Wang
      Pages: 1 - 11
      Abstract: Publication date: 15 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 317
      Author(s): Luqing Ren, Jianjian Tao, Huaicheng Chen, Yang Bian, Xi Yang, Gaozhi Chen, Xin Zhang, Guang Liang, Wencan Wu, Zongming Song, Yi Wang
      Retinal ischemia-reperfusion (I/R) injury is a common pathological process in many eye disorders. Oxidative stress and inflammation play a role in retinal I/R injury. Recent studies show that toll-like receptor 4 (TLR4) is involved in initiating sterile inflammatory response in retinal I/R. However, the molecular mechanism by which TLR4 is activated is not known. In this study, we show that retinal I/R injury involves a co-receptor of TLR4, myeloid differentiation 2 (MD2). Inhibition of MD2 prevented cell death and preserved retinal function following retinal I/R injury. We confirmed these findings using MD2 knockout mice. Furthermore, we utilized human retinal pigment epithelial cells (ARPE-19 cells) to show that oxidative stress-induced cell death as well as inflammatory response are mediated through MD2. Inhibition of MD2 through a chemical inhibitor or knockdown prevented oxidative stress-induced cell death and expression of inflammatory cytokines. Oxidative stress was found to activate TLR4 in a MD2-dependent manner via increasing the expression of high mobility group box 1. In summary, our study shows that oxidative stress in retinal I/R injury can activate TLR4 signaling via MD2, resulting in induction of inflammatory genes and retinal damage. MD2 may represent an attractive therapeutic target for retinal I/R injury.

      PubDate: 2017-01-08T13:51:22Z
      DOI: 10.1016/j.taap.2017.01.001
      Issue No: Vol. 317 (2017)
  • Cutaneous exposure to vesicant phosgene oxime: Acute effects on the skin
           and systemic toxicity
    • Authors: Neera Tewari-Singh; Dinesh G Goswami; Rama Kant; Claire R Croutch; Robert P Casillas; David J Orlicky; Rajesh Agarwal
      Pages: 25 - 32
      Abstract: Publication date: 15 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 317
      Author(s): Neera Tewari-Singh, Dinesh G Goswami, Rama Kant, Claire R Croutch, Robert P Casillas, David J Orlicky, Rajesh Agarwal
      Phosgene Oxime (CX), an urticant or nettle agent categorized as a vesicant, is a potential chemical warfare and terrorist weapon. Its exposure can result in widespread and devastating effects including high mortality due to its fast penetration and ability to cause immediate severe cutaneous injury. It is one of the least studied chemical warfare agents with no effective therapy available. Thus, our goal was to examine the acute effects of CX following its cutaneous exposure in SKH-1 hairless mice to help establish a relevant injury model. Results from our study show that topical cutaneous exposure to CX vapor causes blanching of exposed skin with an erythematous ring, necrosis, edema, mild urticaria and erythema within minutes after exposure out to 8h post-exposure. These clinical skin manifestations were accompanied with increases in skin thickness, apoptotic cell death, mast cell degranulation, myeloperoxidase activity indicating neutrophil infiltration, p53 phosphorylation and accumulation, and an increase in COX-2 and TNFα levels. Topical CX-exposure also resulted in the dilatation of the peripheral vessels with a robust increase in RBCs in vessels of the liver, spleen, kidney, lungs and heart tissues. These events could cause a drop in blood pressure leading to shock, hypoxia and death. Together, this is the first report on effects of CX cutaneous exposure, which could help design further comprehensive studies evaluating the acute and chronic skin injuries from CX topical exposure and elucidate the related mechanism of action to aid in the identification of therapeutic targets and mitigation of injury.

      PubDate: 2017-01-15T14:10:49Z
      DOI: 10.1016/j.taap.2017.01.003
      Issue No: Vol. 317 (2017)
  • Salecan protected against concanavalin A-induced acute liver injury by
           modulating T cell immune responses and NMR-based metabolic profiles
    • Authors: Qi Sun; Xi Xu; Xiao Yang; Dan Weng; Junsong Wang; Jianfa Zhang
      Pages: 63 - 72
      Abstract: Publication date: 15 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 317
      Author(s): Qi Sun, Xi Xu, Xiao Yang, Dan Weng, Junsong Wang, Jianfa Zhang
      Salecan, a water-soluble extracellular β-glucan produced by Agrobacterium sp. ZX09, has been reported to exhibit a wide range of biological effects. The aims of the present study were to investigate the protective effect of salecan against Concanavalin A (ConA)-induced hepatitis, a well-established animal model of immune-mediated liver injury, and to search for possible mechanisms. C57BL/6 mice were pretreated with salecan followed by ConA injection. Salecan treatment significantly reduced ConA-induced acute liver injury, and suppressed the expression and secretion of inflammatory cytokines including interferon (IFN)-γ, interleukin (IL)-6 and IL-1β in ConA-induced liver injury model. The high expression levels of chemokines and adhesion molecules such as MIP-1α, MIP-1β, ICAM-1, MCP-1 and RANTES in the liver induced by ConA were also down-regulated after salecan treatment. Salecan inhibited the infiltration and activation of inflammatory cells, especially T cells, in the liver induced by ConA. Moreover, salecan reversed the metabolic profiles of ConA-treated mice towards the control group by partly recovering the metabolic perturbations induced by ConA. Our results suggest the preventive and therapeutic potential of salecan in immune-mediated hepatitis.

      PubDate: 2017-01-23T14:33:54Z
      DOI: 10.1016/j.taap.2017.01.007
      Issue No: Vol. 317 (2017)
  • In vitro neuroprotective potential of lichen metabolite fumarprotocetraric
           acid via intracellular redox modulation
    • Authors: Carlos Fernández-Moriano; Pradeep Kumar Divakar; Ana Crespo; M. Pilar Gómez-Serranillos
      Pages: 83 - 94
      Abstract: Publication date: 1 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 316
      Author(s): Carlos Fernández-Moriano, Pradeep Kumar Divakar, Ana Crespo, M. Pilar Gómez-Serranillos
      The lichen-forming fungi Cetraria islandica has been largely used in folk medicines, and it has recently showed promising in vitro antioxidant effects in glial-like cells. Current work aimed at investigating the neuroprotective potential of its major isolated secondary metabolite: the depsidone fumarprotocetraric acid (FUM). H2O2 was used herein to induce oxidative stress (OS)-mediated cytotoxicity in two models of neurons and astrocytes cells (SH-SY5Y and U373-MG cell lines). We found that a pre-treatment with FUM significantly enhanced cell viability compared to H2O2-treated cells, and we selected the optimal concentrations in each model (1 and 25μg/ml, respectively) for assessing its cytoprotective mechanisms. FUM, which exerted effective peroxyl radical scavenging effect in the chemical oxygen radical antioxidant capacity (ORAC) assay, alleviated the alterations in OS markers provoked by H2O2. It attenuated intracellular ROS formation, lipid peroxidation and GSH depletion. At mitochondrial level, FUM prevented from the dissipation of mitochondrial membrane potential and the increase in mitochondrial calcium, implying a protective role against oxidative damage in mitochondrial membrane. Similarly, FUM pre-treatment diminished H2O2-induced apoptosis, as evidenced by the reduction in caspase-3 activity and expression; inmunoblot analysis also revealed a decrease in Bax and an increase in Bcl-2 proteins levels. Furthermore, FUM up-regulated the expression of the antioxidant enzymes catalase, superoxide dismutase-1, and hemeoxigenase-1. These findings and the activation of Nrf2 binding activity in nuclear extracts suggest a plausible involvement of Nrf2 signaling pathway in the cytoprotection by FUM. In conclusion, FUM emerges as a potential drug candidate in the therapy of OS-related diseases, such as the neurodegenerative disorders.

      PubDate: 2017-01-08T13:51:22Z
      DOI: 10.1016/j.taap.2016.12.020
      Issue No: Vol. 316 (2017)
  • Comparative analysis of TCDD-induced AhR-mediated gene expression in
           human, mouse and rat primary B cells
    • Authors: Natalia Kovalova; Rance Nault; Robert Crawford; Timothy R. Zacharewski; Norbert E. Kaminski
      Pages: 95 - 106
      Abstract: Publication date: 1 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 316
      Author(s): Natalia Kovalova, Rance Nault, Robert Crawford, Timothy R. Zacharewski, Norbert E. Kaminski
      2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant that activates the aryl hydrocarbon receptor (AhR) resulting in altered gene expression. In vivo, in vitro, and ex vivo studies have demonstrated that B cells are directly impaired by TCDD, and are a sensitive target as evidenced by suppression of antibody responses. The window of sensitivity to TCDD-induced suppression of IgM secretion among mouse, rat and human B cells is similar. Specifically, TCDD must be present within the initial 12h post B cell stimulation, indicating that TCDD disrupts early signaling network(s) necessary for B lymphocyte activation and differentiation. Therefore, we hypothesized that TCDD treatment across three different species (mouse, rat and human) triggers a conserved, B cell-specific mechanism that is involved in TCDD-induced immunosuppression. RNA sequencing (RNA-Seq) was used to identify B cell-specific orthologous genes that are differentially expressed in response to TCDD in primary mouse, rat and human B cells. Time course studies identified TCDD-elicited differential expression of 515 human, 2371 mouse and 712 rat orthologous genes over the 24-h period. 28 orthologs were differentially expressed in response to TCDD in all three species. Overrepresented pathways enriched in all three species included cytokine-cytokine receptor interaction, ECM-receptor interaction, focal adhesion, regulation of actin cytoskeleton and pathways in cancer. Differentially expressed genes functionally associated with cell-cell signaling in humans, immune response in mice, and oxidation reduction in rats. Overall, these results suggest that despite the conservation of the AhR and its signaling mechanism, TCDD elicits species-specific gene expression changes.

      PubDate: 2017-01-08T13:51:22Z
      DOI: 10.1016/j.taap.2016.11.009
      Issue No: Vol. 316 (2017)
  • Prediction of thyroid C-cell carcinogenicity after chronic administration
           of GLP1-R agonists in rodents
    • Authors: Willem van den Brink; Annette Emerenciana; Francesco Bellanti; Oscar Della Pasqua; Jan Willem van der Laan
      Abstract: Publication date: Available online 16 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Willem van den Brink, Annette Emerenciana, Francesco Bellanti, Oscar Della Pasqua, Jan Willem van der Laan
      Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products (exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using nonlinear mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation and C-cell hyperplasia after 2years of treatment. The predictive performance of the model was evaluated using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation for all four products, which is not possible with traditional data analysis methods. It can be concluded that both pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity. The concept is promising for application to other drug classes.

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.010
  • Convergence of hepcidin deficiency, systemic iron overloading, heme
           accumulation, and REV-ERBα/β activation in aryl hydrocarbon
           receptor-elicited hepatotoxicity
    • Authors: Kelly A. Fader; Rance Nault; Mathew P. Kirby; Gena Markous; Jason Matthews; Timothy R. Zacharewski
      Abstract: Publication date: Available online 16 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Kelly A. Fader, Rance Nault, Mathew P. Kirby, Gena Markous, Jason Matthews, Timothy R. Zacharewski
      Persistent aryl hydrocarbon receptor (AhR) agonists elicit dose-dependent hepatic lipid accumulation, oxidative stress, inflammation, and fibrosis in mice. Iron (Fe) promotes AhR-mediated oxidative stress by catalyzing reactive oxygen species (ROS) production. To further characterize the role of Fe in AhR-mediated hepatotoxicity, male C57BL/6 mice were orally gavaged with sesame oil vehicle or 0.01–30μg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4days for 28days. Duodenal epithelial and hepatic RNA-Seq data were integrated with hepatic AhR ChIP-Seq, capillary electrophoresis protein measurements, and clinical chemistry analyses. TCDD dose-dependently repressed hepatic expression of hepcidin (Hamp and Hamp2), the master regulator of systemic Fe homeostasis, resulting in a 2.6-fold increase in serum Fe with accumulating Fe spilling into urine. Total hepatic Fe levels were negligibly increased while transferrin saturation remained unchanged. Furthermore, TCDD elicited dose-dependent gene expression changes in heme biosynthesis including the induction of aminolevulinic acid synthase 1 (Alas1) and repression of uroporphyrinogen decarboxylase (Urod), leading to a 50% increase in hepatic hemin and a 13.2-fold increase in total urinary porphyrins. Consistent with this heme accumulation, differential gene expression suggests that heme activated BACH1 and REV-ERBα/β, causing induction of heme oxygenase 1 (Hmox1) and repression of fatty acid biosynthesis, respectively. Collectively, these results suggest that Hamp repression, Fe accumulation, and increased heme levels converge to promote oxidative stress and the progression of TCDD-elicited hepatotoxicity.
      Graphical abstract image

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.006
  • Enhanced effect of geldanamycin nanocomposite against breast cancer cells
           growing in vitro and as xenograft with vanquished normal cell toxicity
    • Authors: Suma Prabhu; Preeta Ananthanarayanan; Kannangar Aziz Sajida; Sharada Rai; Srinivas Mutalik; Satish Rao Bola Sadashiva
      Abstract: Publication date: Available online 16 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Suma Prabhu, Preeta Ananthanarayanan, Kannangar Aziz Sajida, Sharada Rai, Srinivas Mutalik, Satish Rao Bola Sadashiva
      Despite enormous advances in remedies developed for breast cancer, an effective therapeutic strategy by targeting malignant cells with the least normal tissue toxicity is yet to be developed. Hsp90 is considered to be an important therapeutic target to inhibit cell proliferation. Geldanamycin (GDM), a potent inhibitor of Hsp90 was withdrawn from clinical trials due to its undesirable hepatotoxicity. We report a superparamagnetic iron oxide (SPION) based polymeric nanocomposite of GDM augmenting anticancer competence with decreased hepatic toxicity. The particle size of nanocomposite was ascertained to be 76±10nm with acceptable stability. A comparative dose dependent in vitro validation of cytotoxicity showed an enhanced cellular damage and necrosis in breast cancer (MCF-7) cell line at a low dose of 5.49nM (in GDM nanocomposite) in contrast to 20nM of pure GDM, while normal breast epithelial cells (MCF-10A) were least affected. Besides, in vivo study (in breast cancer xenografts) substantiated 2.7 fold delay in tumor progression mediated by redundancy in the downstream functions of p-Akt and MAPK-Erk leading to apoptosis with negligible hepatotoxicity. Pure GDM disrupted the function and morphology of liver with lesser therapeutic efficacy in than the GDM nanocomposite. These findings deduce that GDM based polymeric magnetite nanocomposite play a vital role in efficacious therapy while vanquishing normal cells and hepatic toxicity and thereby promising it to be reinstated in clinics.

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.012
  • Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant
           hepatic failure in d-galactosamine-sensitized mice by up-regulating
           expression of interleukin-1 receptor-associated kinase-M
    • Authors: Xinru Yin; Gong Xia; Li Zhang; Rong Jiang; Ge Kuang; Bin Wang; Xinyu Chen; Jingyuan Wan
      Abstract: Publication date: Available online 14 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Xinru Yin, Gong Xia, Li Zhang, Rong Jiang, Ge Kuang, Bin Wang, Xinyu Chen, Jingyuan Wan
      Glycyrrhetinic acid (GA), the main active ingredient of licorice, reportedly has anti-inflammatory and hepatoprotective properties, but its molecular mechanisms remain be elusive. In the present study, Balb/c mice were pretreated with GA (10, 30, or 100mg/kg) 1h before lipopolysaccharide (LPS)/d-galactosamine (D-GalN) administration. In other in vitro experiment, RAW264.7 macrophages were pretreated with GA before LPS exposure. The mortality, hepatic tissue histology, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed. Toll like receptor 4 (TLR4), interleukin-1 receptor-associated kinases (IRAKs), activation of mitogen-activated protein kinases (MAPKs) and NF-κB, and production of TNF-α were assessed by flow cytometry, western blotting, and enzyme-linked immunosorbent assay (ELISA), respectively. Our results showed that pretreatment with GA protected mice against LPS/D-GalN-induced fulminant hepatic failure (FHF), including a dose-dependent alleviation of mortality and ALT/AST elevation, ameliorating hepatic pathological damage, and decreasing TNF-α release. Moreover, GA inhibited LPS-induced activation of MAPKs and NF-κB in response to LPS, but the expression of TLR4 was not affected in vivo and in vitro. Notably, GA pretreatment in vivo suppressed IRAK-1 activity while inducing IRAK-M expression. Silencing of IRAK-M expression with siRNA blocked these beneficial effects of GA on the activation of MAPKs and NF-κB as well as TNF-α production in LPS-primed macrophages. Taken together, we conclude that GA could prevent LPS/D-GalN-induced FHF. The underlying mechanisms may be related to up-regulation of IRAK-M, which in turn caused deactivation of IRAK-1 and subsequent MAPKs and NF-κB, resulting in inhibiting TNF-α production.
      Graphical abstract image

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.011
  • Mdr1a plays a crucial role in regulating the analgesic effect and toxicity
           of aconitine by altering its pharmacokinetic characteristics
    • Authors: Lijun Zhu; Jinjun Wu; Min Zhao; Wenjie Song; Xiaoxiao Qi; Ying Wang; Linlin Lu; Zhongqiu Liu
      Abstract: Publication date: Available online 11 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Lijun Zhu, Jinjun Wu, Min Zhao, Wenjie Song, Xiaoxiao Qi, Ying Wang, Linlin Lu, Zhongqiu Liu
      Aconitine (AC) is the primary bioactive/toxic alkaloid in plants of the Aconitum species. Our previous study demonstrated that Mdr1 was involved in efflux of AC. However, the mechanism by which Mdr1 regulates the efficacy/toxicity of AC in vivo remains unclear. The present study aimed to determine the effects of Mdr1a on the efficacy/toxicity and pharmacokinetics of AC in wild-type and Mdr1a −/− FVB mice. After oral administration of AC, significantly higher analgesic effect was observed in Mdr1a −/− mice (49% to 105%) compared to wild-type mice (P <0.05). The levels of s100-β protein and creatine kinase, which indicate cerebral and myocardial damage, respectively, were also significantly increased (P <0.05) in Mdr1a −/− mice. Histopathological examination revealed that the Mdr1a −/− mice suffered from evident cerebral and myocardial damages, but the wild-type mice did not. These findings suggested that Mdr1a deficiency significantly promoted the analgesic effect of AC and exacerbated its toxicity. Pharmacokinetic experiments showed that T1/2 of AC in the Mdr1a −/− mice was significantly higher (from 87% to 300%) than that in wild-type mice (P <0.05). The distribution of AC in the brain of Mdr1a −/− mice was 2- to 32-fold higher than that in the brains of wild-type mice (P <0.05). Toxic reactions were more severe in Mdr1a −/− mice compared to wild-type mice. In conclusion, Mdr1a deficiency significantly enhanced the analgesic effect of AC and exacerbated its toxicity by upregulating its distribution to the brain and decreasing its plasma elimination rate. Thus, Mdr1a dysfunction may cause severe AC poisoning.

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.008
  • Relationship between mercury in kidney, blood, and urine in
           environmentally exposed individuals, and implications for biomonitoring
    • Authors: Magnus Akerstrom; Lars Barregard; Thomas Lundh; Gerd Sallsten
      Abstract: Publication date: Available online 9 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Magnus Akerstrom, Lars Barregard, Thomas Lundh, Gerd Sallsten
      Background Individuals without occupational exposure are exposed to mercury (Hg) from diet and dental amalgam. The kidney is a critical organ, but there is limited information regarding the relationship between Hg in kidney (K-Hg), urine (U-Hg), blood (B-Hg), and plasma (P-Hg). Objectives The aim was to determine the relationship between K-Hg, U-Hg, B-Hg, and P-Hg among environmentally exposed individuals, estimate the biological half-time of K-Hg, and provide information useful for biomonitoring of Hg. Methods Kidney cortex biopsies and urine and blood samples were collected from 109 living kidney donors. Total Hg concentrations were determined and the relationships between K-Hg, U-Hg, P-Hg, and B-Hg were investigated in regression models. The half-time of K-Hg was estimated from the elimination constant. Results There were strong associations between K-Hg and all measures of U-Hg and P-Hg (rp =0.65–0.84, p<0.001), while the association with B-Hg was weaker (rp =0.29, p=0.002). Mean ratios between K-Hg (in μg/g) and U-Hg/24h (in μg) and B-Hg (in μg/L) were 0.22 and 0.19 respectively. Estimates of the biological half-time varied between 30 and 92days, with significantly slower elimination in women. Adjusting overnight urine samples for dilution using urinary creatinine resulted in less bias in relation to K-Hg or U-Hg/24h, compared with other adjustment techniques. Conclusions The relationship between K-Hg and U-Hg is approximately linear. K-Hg can be estimated using U-Hg and gender. Women have longer half-time of Hg in kidney compared to men. Adjusting overnight urine samples for creatinine concentration resulted in less bias.

      PubDate: 2017-02-11T01:53:41Z
      DOI: 10.1016/j.taap.2017.02.007
  • Corrigendum to “Activation of AMPK by berberine induces hepatic lipid
           accumulation by upregulation of fatty acid translocase CD36 in mice”
           [Toxicol. Appl. Pharmacol. 316 (2017) 74–82]
    • Authors: You-Jin Choi; Kang-Yo Lee; Seung-Hwan Jung; Hyung Sik Kim; Gayong Shim; Mi-Gyeong Kim; Yu-Kyoung Oh; Seon-Hee Oh; Dae Won Jun; Byung-Hoon Lee
      Abstract: Publication date: Available online 8 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): You-Jin Choi, Kang-Yo Lee, Seung-Hwan Jung, Hyung Sik Kim, Gayong Shim, Mi-Gyeong Kim, Yu-Kyoung Oh, Seon-Hee Oh, Dae Won Jun, Byung-Hoon Lee

      PubDate: 2017-02-11T01:53:41Z
      DOI: 10.1016/j.taap.2017.02.005
  • Amentoflavone protects dopaminergic neurons in MPTP-induced Parkinson's
           disease model mice through PI3K/Akt and ERK signaling pathways
    • Authors: Qin Cao; Liyue Qin; Fei Huang; Xiaoshuang Wang; Liu Yang; Hailian Shi; Hui Wu; Beibei Zhang; Ziyu Chen; Xiaojun Wu
      Abstract: Publication date: Available online 7 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Qin Cao, Liyue Qin, Fei Huang, Xiaoshuang Wang, Liu Yang, Hailian Shi, Hui Wu, Beibei Zhang, Ziyu Chen, Xiaojun Wu
      Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Mitochondrial dysfunction and cell apoptosis are suggested to be actively involved in the pathogenesis of PD. In the present study, the neuroprotective effect of amentoflavone (AF), a naturally occurring biflavonoid from Selaginella tamariscina, was examined in PD models both in vitro and in vivo. On SH-SY5Y cells, AF treatment dose-dependently reduced 1-methyl-4-phenylpyridinium (MPP+)-induced nuclear condensation and loss of cell viability without obvious cytotoxicity. It inhibited the activation of caspase-3 and p21 but increased the Bcl-2/Bax ratio. Further study disclosed that AF enhanced phosphorylation of PI3K, Akt and ERK1/2 down-regulated by MPP+ in SH-SY5Y cells, the effect of which could be blocked by LY294002, the inhibitor of PI3K. Consistently, AF alleviated the behavioral deterioration in pole and traction tests and rescued the loss of dopaminergic neurons in SNpc and fibers in striatum in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mice. It also could enhance the activation of PI3K and Akt as well as Bcl-2/Bax ratio in SN. Moreover, AF alleviated gliosis as well as the gene expression levels of IL-1β and iNOS in SN. Collectively, these results suggested that AF protected dopaminergic neurons against MPTP/MPP+-induced neurotoxicity, which might be mediated through activation of PI3K/Akt and ERK signaling pathways in dopaminergic neurons and attenuation of neuroinflammation.

      PubDate: 2017-02-11T01:53:41Z
      DOI: 10.1016/j.taap.2017.01.019
  • Potential transfer of neurotoxic amino acid β-N-methylamino-alanine
           (BMAA) from mother to infant during breast-feeding: Predictions from human
           cell lines
    • Authors: Marie Andersson; Lisa Ersson; Ingvar Brandt; Ulrika Bergström
      Abstract: Publication date: Available online 4 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Marie Andersson, Lisa Ersson, Ingvar Brandt, Ulrika Bergström
      β-N-methylamino-alanine (BMAA) is a non-protein amino acid produced by cyanobacteria, diatoms and dinoflagellates. BMAA has potential to biomagnify in a terrestrial food chain, and to bioaccumulate in fish and shellfish. We have reported that administration of [14C]l-BMAA to lactating mice and rats results in a mother to off-spring transfer via the milk. A preferential enantiomer-specific uptake of [14C]l-BMAA has also been demonstrated in differentiated murine mammary epithelium HC11 cells. These findings, together with neurotoxic effects of BMAA demonstrated both in vitro and in vivo, highlight the need to determine whether such transfer could also occur in humans. Here, we used four cell lines of human origin to examine and compare the transport of the two BMAA enantiomers in vitro. The uptake patterns of [14C]l- and [14C]d-BMAA in the human mammary MCF7 cell line were in agreement with the results in murine HC11 cells, suggesting a potential secretion of BMAA into human breast milk. The permeability coefficients for both [14C]l- and [14C]d-BMAA over monolayers of human intestinal Caco2 cells supported an efficient absorption from the human intestine. As a final step, transport experiments confirmed that [14C]l-and [14C]d-BMAA can be taken up by human SHSY5Y neuroblastoma cells and even more efficiently by human U343 glioblastoma cells. In competition experiments with various amino acids, the ASCT2 specific inhibitor benzylserine was the most effective inhibitor of [14C]l-BMAA uptake tested here. Altogether, our results suggest that BMAA can be transferred from an exposed mother, via the milk, to the brain of the nursed infant.

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.02.004
  • Xenobiotics and the Glucocorticoid Receptor
    • Authors: Linda S M Gulliver
      Abstract: Publication date: Available online 4 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Linda S M Gulliver
      Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate.

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.02.003
  • Toxicological evaluation of 5-methoxy-2-aminoindane (MEAI): Binge
           mitigating agent in development
    • Authors: Jakob A. Shimshoni; Ilan Winkler; Nir Edery; Ezekiel Golan; René van Wettum; David Nutt
      Abstract: Publication date: Available online 4 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Jakob A. Shimshoni, Ilan Winkler, Nir Edery, Ezekiel Golan, René van Wettum, David Nutt
      5-Methoxy-2-aminoindane (MEAI) is a psychoactive compound of the aminoindane class, which in recent years has been recreationally used by many people, who reported of a mild euphoric, alcohol-like tipsy experience and reduced desire to consume alcoholic beverages. In the light of these observations it was decided to progress MEAI through a preliminary drug development route and evaluate the acute and subacute toxicity of MEAI administrated orally to Sprague Dawley rats, as well as to determine potential in-vitro cytotoxic and mutagenic effects using state-of-the-art protocols. Furthermore, the interaction of MEAI at the highest non-toxic concentration (100mg/L) with ethanol at cytotoxic levels of 6% and 7.5% was explored, in order to identify possible additive or synergistic effects. MEAI showed a good safety profile in rats at 10 and 30mg/kg body weight, corresponding to the human doses of 1.6mg/kg and 4.8mg/kg body weight, respectively. Cytotoxic effect was demonstrated using concentrations of 500 and 1000mg/L with calculated IC50 value of 368.2mg/L for rat brain striatum primary neurons and 403.1mg/L for human primary healthy hepatocytes. The combination of 6% or 7.5% ethanol with 100mg/L MEAI revealed no statistically significant increase of cytotoxic effect. Further studies, especially long term chronic and addictive behavior studies, are required in-order to assess MEAI safety profile.

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.01.018
  • Identification of sperm mRNA biomarkers associated with testis injury
           during preclinical testing of pharmaceutical compounds
    • Authors: Edward Dere; Daniel J. Spade; Susan J. Hall; Aimee Altemus; James D. Smith; Jonathan A. Phillips; Jeffrey S. Moffit; Kerry T. Blanchard; Kim Boekelheide
      Abstract: Publication date: Available online 4 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Edward Dere, Daniel J. Spade, Susan J. Hall, Aimee Altemus, James D. Smith, Jonathan A. Phillips, Jeffrey S. Moffit, Kerry T. Blanchard, Kim Boekelheide
      The human testis is sensitive to toxicant-induced injury but current methods for detecting adverse effects are limited, insensitive and unreliable. Animal studies use sensitive histopathological endpoints to assess toxicity, but require testicular tissue that is not available during human clinical trials. More sensitive and reliable molecular biomarkers of testicular injury are needed to better monitor testicular toxicity in both clinical and preclinical. Adult male Wistar Han rats were exposed for 4weeks to compounds previously associated with testicular injury, including cisplatin (0, 0.2, 0.3, or 0.4mg/kg/day), BI665915 (0, 20, 70, 100mg/kg/d), BI665636 (0, 20, 100mg/kg/d) or BI163538 (0, 70, 150, 300mg/kg/d) to evaluate reproductive toxicity and assess changes in sperm mRNA levels. None of the compounds resulted in any significant changes in body, testis or epididymis weights, nor were there decreases in testicular homogenization resistant spermatid head counts. Histopathological evaluation found that only BI665915 treatment caused any testicular effects, including minor germ cell loss and disorganization of the seminiferous tubule epithelium, and an increase in the number of retained spermatid heads. A custom PCR-array panel was used to assess induced changes in sperm mRNA. BI665915 treatment resulted in a significant increase in clusterin (Clu) levels and decreases in GTPase, IMAP family member 4 (Gimap4), prostaglandin D2 synthase (Ptgds) and transmembrane protein with EGF like and two follistatin like domains 1 (Tmeff1) levels. Correlation analysis between transcript levels and quantitative histopathological endpoints found a modest association between Clu with retained spermatid heads. These results demonstrate that sperm mRNA levels are sensitive molecular indicators of testicular injury that can potentially be translated into a clinical setting.

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.02.001
  • Anti-allergic activity of 2,4,6-trihydroxy-3-geranylacetophenone (tHGA)
           via attenuation of IgE-mediated mast cell activation and inhibition of
           passive systemic anaphylaxis
    • Authors: Ji Wei Tan; Daud Ahmad Israf Ali; Hanis Hazeera Harith; Nur Fariesha Md Hashim; Chean Hui Ng; Khozirah Shaari; Chau Ling Tham
      Abstract: Publication date: Available online 4 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Ji Wei Tan, Daud Ahmad Israf Ali, Hanis Hazeera Harith, Nur Fariesha Md Hashim, Chean Hui Ng, Khozirah Shaari, Chau Ling Tham
      tHGA, a geranyl acetophenone compound originally isolated from a local shrub called Melicope ptelefolia, has been previously reported to prevent ovalbumin-induced allergic airway inflammation in a murine model of allergic asthma by targeting cysteinyl leukotriene synthesis. Mast cells are immune effector cells involved in the pathogenesis of allergic diseases including asthma by releasing cysteinyl leukotrienes. The anti-asthmatic properties of tHGA could be attributed to its inhibitory effect on mast cell degranulation. As mast cell degranulation is an important event in allergic responses, this study aimed to investigate the anti-allergic effects of tHGA in cellular and animal models of IgE-mediated mast cell degranulation. For in vitro model of IgE-mediated mast cell degranulation, DNP-IgE-sensitized RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA to induce degranulation. For IgE-mediated passive systemic anaphylaxis, Sprague Dawley rats were sensitized by intraperitoneal injection of DNP-IgE before challenged with DNP-BSA. Both in vitro and in vivo models showed that tHGA significantly inhibited the release of preformed mediators (β-hexosaminidase and histamine) as well as de novo mediators (interleukin-4, tumour necrosis factor-α, prostaglandin D2 and leukotriene C 4). Pre-treatment of tHGA also prevented IgE-challenged RBL-2H3 cells and peritoneal mast cells from undergoing morphological changes associated with mast cell degranulation. These findings indicate that tHGA possesses potent anti-allergic activity via attenuation of IgE-mediated mast cell degranulation and inhibition of IgE-mediated passive systemic anaphylaxis. Thus, tHGA may have the potential to be developed as a mast cell stabilizer for the treatment of allergic diseases in the future.
      Graphical abstract image

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.02.002
  • Environmental obesogen tributyltin chloride leads to abnormal
           hypothalamic-pituitary-gonadal axis function by disruption in
           kisspeptin/leptin signaling in female rats
    • Authors: Gabriela C. Sena; Leandro C. Freitas-Lima; Eduardo Merlo; Priscila L. Podratz; Julia F.P. de Araújo; Poliane A.A. Brandão; Maria T.W.D. Carneiro; Marina C. Zicker; Adaliene V.M. Ferreira; Christina M. Takiya; Carolina M. de Lemos Barbosa; Marcelo M. Morales; Ana Paula Santos-Silva; Leandro Miranda-Alves; Ian V. Silva; Jones B. Graceli
      Abstract: Publication date: Available online 2 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Gabriela C. Sena, Leandro C. Freitas-Lima, Eduardo Merlo, Priscila L. Podratz, Julia F.P. de Araújo, Poliane A.A. Brandão, Maria T.W.D. Carneiro, Marina C. Zicker, Adaliene V.M. Ferreira, Christina M. Takiya, Carolina M. de Lemos Barbosa, Marcelo M. Morales, Ana Paula Santos-Silva, Leandro Miranda-Alves, Ian V. Silva, Jones B. Graceli
      Tributyltin chloride (TBT) is a xenobiotic used as a biocide in antifouling paints that has been demonstrated to induce endocrine-disrupting effects, such as obesity and reproductive abnormalities. An integrative metabolic control in the hypothalamus-pituitary-gonadal (HPG) axis was exerted by leptin. However, studies that have investigated the obesogenic TBT effects on the HPG axis are especially rare. We investigated whether metabolic disorders as a result of TBT are correlated with abnormal hypothalamus-pituitary-gonadal (HPG) axis function, as well as kisspeptin (Kiss) action. Female Wistar rats were administered vehicle and TBT (100ng/kg/day) for 15days via gavage. We analyzed their effects on the tin serum and ovary accumulation (as biomarker of TBT exposure), estrous cyclicity, surge LH levels, GnRH expression, Kiss action, fertility, testosterone levels, ovarian apoptosis, uterine inflammation, fibrosis, estrogen negative feedback, body weight gain, insulin, leptin, adiponectin levels, as well as the glucose tolerance (GTT) and insulin sensitivity tests (IST). TBT led to increased serum and ovary tin levels, irregular estrous cyclicity, and decreased surge LH levels, GnRH expression and Kiss responsiveness. A strong negative correlation between the serum and ovary tin levels with lower Kiss responsiveness and GnRH mRNA expression was observed in TBT rats. An increase in the testosterone levels, ovarian and uterine fibrosis, ovarian apoptosis, and uterine inflammation and a decrease in fertility and estrogen negative feedback were demonstrated in the TBT rats. We also identified an increase in the body weight gain and abnormal GTT and IST tests, which were associated with hyperinsulinemia, hyperleptinemia and hypoadiponectinemia, in the TBT rats. TBT disrupted proper functioning of the HPG axis as a result of abnormal Kiss action. The metabolic dysfunctions co-occur with the HPG axis abnormalities. Hyperleptinemia as a result of obesity induced by TBT may be associated with abnormal HPG function. A strong negative correlation between the hyperleptinemia and lower Kiss responsiveness was observed in the TBT rats. These findings provide evidence that TBT leads to toxic effects direct on the HPG axis and/or indirectly by abnormal metabolic regulation of the HPG axis.

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.01.021
  • Ciproxifan, a histamine H3 receptor antagonist and inverse agonist,
           presynaptically inhibits glutamate release in rat hippocampus
    • Authors: Cheng-Wei Lu; Tzu-Yu Lin; Chia-Ying Chang; Shu-Kuei Huang; Su-Jane Wang
      Abstract: Publication date: Available online 27 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Cheng-Wei Lu, Tzu-Yu Lin, Chia-Ying Chang, Shu-Kuei Huang, Su-Jane Wang
      Ciproxifan is an H3 receptor antagonist and inverse agonist with antipsychotic effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus. In a synaptosomal preparation, ciproxifan reduced 4-aminopyridine (4-AP)-evoked Ca2+-dependent glutamate release and cytosolic Ca2+ concentration elevation but did not affect the membrane potential. The inhibitory effect of ciproxifan on 4-AP-evoked glutamate release was prevented by the Gi/Go-protein inhibitor pertussis toxin and Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was not affected by the intracellular Ca2+-release inhibitors dantrolene and CGP37157. Furthermore, the phospholipase A2 (PLA2) inhibitor OBAA, prostaglandin E2 (PGE2), PGE2 subtype 2 (EP2) receptor antagonist PF04418948, and extracellular signal-regulated kinase (ERK) inhibitor FR180204 eliminated the inhibitory effect of ciproxifan on glutamate release. Ciproxifan reduced the 4-AP-evoked phosphorylation of ERK and synapsin I, a presynaptic target of ERK. The ciproxifan-mediated inhibition of glutamate release was prevented in synaptosomes from synapsin I-deficient mice. Moreover, ciproxifan reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. Our data suggest that ciproxifan, acting through the blockade of Gi/Go protein-coupled H3 receptors present on hippocampal nerve terminals, reduces voltage-dependent Ca2+ entry by diminishing PLA2/PGE2/EP2 receptor pathway, which subsequently suppresses the ERK/synapsin I cascade to decrease the evoked glutamate release.

      PubDate: 2017-01-29T14:45:35Z
      DOI: 10.1016/j.taap.2017.01.017
  • Autophagy contributes to 4-Amino-2-Trifluoromethyl-Phenyl Retinate-induced
           differentiation in human acute promyelocytic leukemia NB4 cells
    • Authors: Yue Li; Ge Li; Ke Wang; Ya-Ya Xie; Ren-Peng Zhou; Yao Meng; Ran Ding; Jin-Fang Ge; Fei-Hu Chen
      Abstract: Publication date: Available online 25 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Yue Li, Ge Li, Ke Wang, Ya-Ya Xie, Ren-Peng Zhou, Yao Meng, Ran Ding, Jin-Fang Ge, Fei-Hu Chen
      As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in treatment of acute promyelocytic leukemia (APL). However, clinical application of ATRA has limitations. Our previous studies suggested that 4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, could induce differentiation of APL cells in vivo and in vitro. To explore the underlying mechanism of ATPR, the effect of ATPR on autophagy of APL cells was observed in the present study. The results showed that the differentiation effect of ATPR on APL cells was accompanied with autophagy induction and PML-RARα degradation via activating Notch1 signaling pathway. Moreover, inhibition of autophagy using 3-methyladenine (3-MA) or small interfering RNA (siRNA) that targets essential autophagy gene ATG5 abrogated the ATPR-induced cell differentiation. Furthermore, when pretreated with DAPT, a γ-secretase inhibitor, the Notch1 signaling pathway was blocked in APL cells, followed by the reduction of ATPR-induced autophagy and differentiation. Taken together, these results suggested that autophagy play an important role in ATPR-induced cell differentiation, which may provide a novel approach to cure APL patients.

      PubDate: 2017-01-29T14:45:35Z
      DOI: 10.1016/j.taap.2017.01.016
  • IN0523 (Urs-12-ene-3α,24β-diol) a plant based derivative of boswellic
           acid protect Cisplatin induced urogenital toxicity
    • Authors: Amarinder Singh; S Arvinda; Surjeet Singh; Jyotsna Suri; Surinder Koul; Dilip M. Mondhe; Gurdarshan Singh; Ram Vishwakarma
      Abstract: Publication date: Available online 22 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Amarinder Singh, S Arvinda, Surjeet Singh, Jyotsna Suri, Surinder Koul, Dilip M. Mondhe, Gurdarshan Singh, Ram Vishwakarma
      The limiting factor for the use of Cisplatin in the treatment of different type of cancers is its toxicity and more specifically urogenital toxicity. Oxidative stress is a well-known phenomenon associated with Cisplatin toxicity. However, in Cisplatin treated group, abnormal animal behavior, decreased body weight, cellular and sub-cellular changes in the kidney and sperm abnormality were observed. Our investigation revealed that Cisplatin when administered in combination with a natural product derivative (Urs-12-ene-3α,24β-diol, labeled as IN0523) resulted in significant restoration of body weight and protection against the pathological alteration caused by Cisplatin to kidney and testis. Sperm count and motility were significantly restored near to normal. Cisplatin caused depletion of defense system i.e. glutathione peroxidase, catalase and superoxide dismutase, which were restored close to normal by treatment of IN0523. Reduction in excessive lipid peroxidation induced by Cisplatin was also found by treatment with IN0523. The result suggests that IN0523 is a potential candidate for ameliorating Cisplatin induced toxicity in the kidney and testes at a dose of 100mg/kg p.o. via inhibiting the oxidative stress/redox status imbalance and may be improving the efflux mechanism.
      Graphical abstract image

      PubDate: 2017-01-23T14:33:54Z
      DOI: 10.1016/j.taap.2017.01.011
  • Rosmarinic acid counteracts activation of hepatic stellate cells via
           inhibiting the ROS-dependent MMP-2 activity: Involvement of Nrf2
           antioxidant system
    • Authors: Changfang Lu; Yu Zou; Yuzhang Liu; Yingcai Niu
      Abstract: Publication date: Available online 20 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Changfang Lu, Yu Zou, Yuzhang Liu, Yingcai Niu
      Recently, oxidative stress is involved in hepatofibrogenesis. Matrix metalloproteinase-2 (MMP-2) is required for activation of hepatic stellate cells (HSCs) in response to reactive oxygen species (ROS). This study was designed to explore the hypothesis that the inhibitory effect of rosmarinic acid (RA) on HSCs activation might mainly result from its antioxidant capability by increasing the synthesis of glutathione (GSH) involved in nuclear factor kappa B (NF-κB)-dependent inhibition of MMP-2 activity. Here, we demonstrate that RA reverses activated HSCs to quiescent cells. Concomitantly, RA inhibits MMP-2 activity. RNA interference-imposed knockdown of NF-κB abolished down-regulation of MMP-2 by RA. RA-mediated inactivation of NF-κB could be blocked by the diphenyleneiodonium chloride (DPI; a ROS inhibitor). Conversely, transfection of dominant-negative (DN) mutant of extracellular signal-regulated kinases 2 (ERK2), c-Jun N-terminal kinase 1 (JNK1), or p38α kinase had no such effect. Simultaneously, RA suppresses ROS generation and lipid peroxidation (LPO) whereas increases cellular GSH in HSC-T6 cells. Furthermore, RA significantly increased antioxidant response element (ARE)-mediated luciferase activity, nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and catalytic subunits from glutamate cysteine ligase (GCLc) expression, but not modulatory subunits from GCL (GCLm). RA-mediated up-regulation of GClc is inhibited by the shRNA-induced Nrf2 knockdown. The knocking down of Nrf2 or buthionine sulfoximine (a GCL inhibitor) abolished RA-mediated inhibition of ROS. Collectively, these results provide novel insights into the mechanisms of RA as an antifibrogenic candidate in the prevention and treatment of liver fibrosis.
      Graphical abstract image

      PubDate: 2017-01-23T14:33:54Z
      DOI: 10.1016/j.taap.2017.01.008
  • Identification of a compound isolated from German chamomile (Matricaria
           chamomilla) with dermal sensitization potential
    • Authors: Cristina Avonto; Diego Rua; Pradeep B. Lasonkar; Amar G. Chittiboyina; Ikhlas A. Khan
      Abstract: Publication date: Available online 19 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Cristina Avonto, Diego Rua, Pradeep B. Lasonkar, Amar G. Chittiboyina, Ikhlas A. Khan
      German chamomile is one of the most popular herbal ingredients used in cosmetics and personal care products. Allergic skin reactions following topical application of German chamomile have been occasionally reported, although it is not fully understood which of the chemical constituents is responsible for this adverse effect. In the present work, three candidate sensitizers were isolated from German chamomile based on activity-guided fractionation of chamomile extracts tested using the in vitro KeratinoSens™ assay. The compounds were identified as the polyacetylene tonghaosu (1), and both trans- and cis-glucomethoxycinnamic acids (2 and 3). These three compounds were classified as non- to weakly reactive using in chemico methods; however, aged tonghaosu was found to be more reactive when compared to freshly isolated tonghaosu. The polyacetylene (1) constituent was determined to be chemically unstable, generating a small electrophilic spirolactone, 1,6-dioxaspiro[4.4]non-3-en-2-one (4), upon aging. This small lactone (4) was strongly reactive in both in chemico HTS- and NMR-DCYA methods and further confirmed as a potential skin sensitizer by Local Lymph Node Assay (LLNA).

      PubDate: 2017-01-23T14:33:54Z
      DOI: 10.1016/j.taap.2017.01.009
  • Discriminating between adaptive and carcinogenic liver hypertrophy in rat
           studies using logistic ridge regression analysis of toxicogenomic data:
           The mode of action and predictive models
    • Authors: Shujie Liu; Taisuke Kawamoto; Osamu Morita; Kouichi Yoshinari; Hiroshi Honda
      Abstract: Publication date: Available online 18 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Shujie Liu, Taisuke Kawamoto, Osamu Morita, Kouichi Yoshinari, Hiroshi Honda
      Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic ridge regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism–related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment.
      Graphical abstract image

      PubDate: 2017-01-23T14:33:54Z
      DOI: 10.1016/j.taap.2017.01.006
  • The role of PTEN in regulation of hepatic macrophages activation and
           function in progression and reversal of liver fibrosis
    • Authors: Yahui Cheng; Yuanyao Tian; Jialu Xia; Xiaoqin Wu; Yang Yang; Xiaofeng Li; Cheng Huang; Xiaoming Meng; Taotao Ma; Jun Li
      Abstract: Publication date: Available online 14 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Yahui Cheng, Yuanyao Tian, Jialu Xia, Xiaoqin Wu, Yang Yang, Xiaofeng Li, Cheng Huang, Xiaoming Meng, Taotao Ma, Jun Li
      Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl4-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl4-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantly decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis.
      Graphical abstract image

      PubDate: 2017-01-15T14:10:49Z
      DOI: 10.1016/j.taap.2017.01.005
  • Zearalenone exposure impairs ovarian primordial follicle formation via
           down-regulation of Lhx8 expression in vitro
    • Authors: Guo-Liang Zhang; Xiao-Feng Sun; Yan-Zhong Feng; Bo Li; Ya-Peng Li; Fan Yang; Charles Martin Nyachoti; Wei Shen; Shi-Duo Sun; Lan Li
      Abstract: Publication date: Available online 12 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Guo-Liang Zhang, Xiao-Feng Sun, Yan-Zhong Feng, Bo Li, Ya-Peng Li, Fan Yang, Charles Martin Nyachoti, Wei Shen, Shi-Duo Sun, Lan Li
      Zearalenone (ZEA) is an estrogenic mycotoxin mainly produced as a secondary metabolite by numerous species of Fusarium. Previous work showed that ZEA had a negative impact on domestic animals with regard to reproduction. The adverse effects and the mechanisms of ZEA on mammalian ovarian folliculogenesis remain largely unknown, particularly its effect on primordial follicle formation. Thus, we investigated the biological effects of ZEA exposure on murine ovarian germ cell cyst breakdown and primordial follicle assembly. Our results demonstrated that newborn mouse ovaries exposed to 10 or 30μM ZEA in vitro had significantly less germ cell numbers compared to the control group. Moreover, the presence of ZEA in vitro increased the numbers of TUNEL and γH2AX positive cells within mouse ovaries and the ratio of mRNA levels of the apoptotic genes Bax/Bcl-2. Furthermore, ZEA exposure reduced the mRNA of oocyte specific genes such as LIM homeobox 8 (Lhx8), newborn ovary homeobox (Nobox), spermatogenesis and oogenesis helix-loop-helix (Sohlh2), and factor in the germline alpha (Figlα) in a dose dependent manner. Exposure to ZEA led to remarkable changes in the Lhx8 3′-UTR DNA methylation dynamics in oocytes and severely impaired folliculogenesis in ovaries after transplantation under the kidney capsules of immunodeficient mice. In conclusion, ZEA exposure impairs mouse primordial follicle formation in vitro.

      PubDate: 2017-01-15T14:10:49Z
      DOI: 10.1016/j.taap.2017.01.004
  • Iron oxide nanoparticles modulate heat shock proteins and organ specific
           markers expression in mice male accessory organs
    • Authors: Kiruthika Sundarraj; Azhwar Raghunath; Lakshmikanthan Panneerselvam; Ekambaram Perumal
      Abstract: Publication date: Available online 7 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Kiruthika Sundarraj, Azhwar Raghunath, Lakshmikanthan Panneerselvam, Ekambaram Perumal
      With increased industrial utilization of iron oxide nanoparticles (Fe2O3-NPs), concerns on adverse reproductive health effects following exposure have been immensely raised. In the present study, the effects of Fe2O3-NPs exposure in the seminal vesicle and prostate gland were studied in mice. Mice were exposed to two different doses (25 and 50 mg/kg) of Fe2O3-NPs along with the control and analyzed the expressions of heat shock proteins (HSP60, HSP70 and HSP90) and organ specific markers (Caltrin, PSP94, and SSLP1). Fe2O3-NPs decreased food consumption, water intake, and organo-somatic index in mice with elevated iron levels in serum, urine, fecal matter, seminal vesicle and prostate gland. FTIR spectra revealed alterations in the functional groups of biomolecules on Fe2O3-NPs treatment. These changes are accompanied by increased lactate dehydrogenase levels with decreased total protein and fructose levels. The investigation of oxidative stress biomarkers demonstrated a significant increase in reactive oxygen species, nitric oxide, lipid peroxidation, protein carbonyl content and glutathione peroxidase with a concomitant decrement in the glutathione and ascorbic acid in the male accessory organs which confirmed the induction of oxidative stress. An increase in NADPH-oxidase-4 with a decrease in glutathione-S-transferase was observed in the seminal vesicle and prostate gland of the treated groups. An alteration in HSP60, HSP70, HSP90, Caltrin, PSP94, and SSLP1 expression was also observed. Moreover, accumulation of Fe2O3-NPs brought pathological changes in the seminal vesicle and prostate gland of treated mice. These findings provide evidence that Fe2O3-NPs could be an environmental risk factor for reproductive disease.

      PubDate: 2017-01-08T13:51:22Z
      DOI: 10.1016/j.taap.2017.01.002
  • Gemcitabine: Selective cytotoxicity, induction of inflammation and effects
           on urothelial function
    • Authors: Stefanie E Farr; Russ Chess-Williams; Catherine M McDermott
      Pages: 1 - 9
      Abstract: Publication date: 1 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 316
      Author(s): Stefanie E Farr, Russ Chess-Williams, Catherine M McDermott
      Intravesical gemcitabine has recently been introduced for the treatment of superficial bladder cancer and has a favourable efficacy and toxicity profile in comparison to mitomycin c (MMC), the most commonly used chemotherapeutic agent. The aim of this study was to assess the cytotoxic potency of gemcitabine in comparison to MMC in urothelial cell lines derived from non-malignant (UROtsa) and malignant (RT4 and T24) tissues to assess selectivity. Cells were treated with gemcitabine or mitomycin C at concentrations up to the clinical doses for 1 or 2h respectively (clinical duration). Treatment combined with hyperthermia was also examined. Cell viability, ROS formation, urothelial function (ATP, acetylcholine and PGE2 release) and secretion of inflammatory cytokines were assessed. Gemcitabine displayed a high cytotoxic selectivity for the two malignant cell lines (RT4, T24) compared to the non-malignant urothelial cells (UROtsa, proliferative and non-proliferative). In contrast, the cytotoxic effects of MMC were non-selective with equivalent potency in each of the cell lines. The cytotoxic effect of gemcitabine in the malignant cell lines was associated with an elevation in free radical formation and was significantly decreased in the presence of an equilibrative nucleoside transporter inhibitor. Transient changes in urothelial ATP and PGE2 release were observed, with significant increase in release of interleukin-6, interleukin-8 and interleukin-1β from urothelial cells treated with gemcitabine. The selectivity of gemcitabine for malignant urothelial cells may account for the less frequent adverse urological effects with comparison to other commonly used chemotherapeutic agents.

      PubDate: 2016-12-23T08:56:00Z
      DOI: 10.1016/j.taap.2016.12.011
      Issue No: Vol. 316 (2016)
  • Di-(2-ethylhexyl) phthalate could disrupt the insulin signaling pathway in
           liver of SD rats and L02 cells via PPARγ
    • Authors: Wang Zhang; Xin -yue Shen; Wen-wen Zhang; Hao Chen; Wei-ping Xu; Wei Wei
      Pages: 17 - 26
      Abstract: Publication date: 1 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 316
      Author(s): Wang Zhang, Xin -yue Shen, Wen-wen Zhang, Hao Chen, Wei-ping Xu, Wei Wei
      Di-(2-ethylhexyl)-phthalate (DEHP), a ubiquitous industrial pollutant in our daily life, has been reported to cause adverse effects on glucose homeostasis and insulin sensitivity in epidemiological studies previously. Recently, it has been reported to be an endocrine disrupter and ligand to peroxisome proliferator activated receptor, which could influence the homeostasis of liver metabolic systems and contribute to the development of type-2 diabetes. However, the potential mechanisms are not known yet. This study was designed to solve these problems with male SD rats and normal human hepatocyte line, L02 cells, exposed to DEHP for toxicological experiments. Adult male SD rats were divided into four groups, normal group fed with regular diets and three DEHP-treated groups (dissolved in olive oil at doses of 0.05, 5 and 500mg/kg body weight, respectively, once daily through gastric intubations for 15weeks). L02 cells were divided into 6 groups, normal group with 5, 10, 25, 50, and 100μmol/l DEHP groups. DEHP-exposed rats exhibited significant liver damage, glucose tolerance, and insulin tolerance along with reduced expression of insulin receptor and GLUT4 proteins in the liver tissues. The results of in vitro experiments could determine that the DEHP-induced activation of peroxisome proliferator activated receptor γ (PPARγ) played a key role in the production of oxidative stress and down-regulated expression of insulin receptor and GLUT4 proteins in L02 cells. This conclusion could be supported by the results of in vitro experiments, in which the cells were exposed to DEHP with GW9662 (PPARγ inhibitor). In general, these results highlight the key role of PPARγ in the process of insulin resistance induced by DEHP.

      PubDate: 2016-12-29T13:33:08Z
      DOI: 10.1016/j.taap.2016.12.010
      Issue No: Vol. 316 (2016)
  • A semi-quantitative translational pharmacology analysis to understand the
           relationship between in vitro ENT1 inhibition and the clinical incidence
           of dyspnoea and bronchospasm
    • Authors: Lyn Rosenbrier Ribeiro; R. Ian Storer
      Abstract: Publication date: Available online 29 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lyn Rosenbrier Ribeiro, R. Ian Storer
      Adenosine contributes to the pathophysiology of respiratory disease, and adenosine challenge leads to bronchospasm and dyspnoea in patients. The equilibrative nucleoside transporter 1 (ENT1) terminates the action of adenosine by removal from the extracellular environment. Therefore, it is proposed that inhibition of ENT1 in respiratory disease patients leads to increased adenosine concentrations, triggering bronchospasm and dyspnoea. This study aims to assess the translation of in vitro ENT1 inhibition to the clinical incidence of bronchospasm and dyspnoea in respiratory disease, cardiovascular disease and healthy volunteer populations. Four marketed drugs with ENT1 activity were assessed; dipyridamole, ticagrelor, draflazine, cilostazol. For each patient population, the relationship between in vitro ENT1 [3H]-NBTI binding affinity (Ki) and [3H]-adenosine uptake (IC50) to the incidence of: (1) bronchospasm/severe dyspnoea; (2) tolerated dyspnoea and; (3) no adverse effects, was evaluated. A high degree of ENT1 inhibition (≥13.3x Ki, ≥4x IC50) associated with increased incidence of bronchospasm/severe dyspnoea for patients with respiratory disease only, whereas a lower degree of ENT1 inhibition (≥0.1x Ki, ≥0.05x IC50) associated with a tolerable level of dyspnoea in both respiratory and cardiovascular disease patients. ENT1 inhibition had no effect in healthy volunteers. Furthermore, physicochemical properties correlative with ENT1 binding were assessed using a set of 1625 diverse molecules. Binding to ENT1 was relatively promiscuous (22% compounds Ki <1 μM) especially for neutral or basic molecules, and greater incidence tracked with higher lipophilicity (clogP >5). This study rationalises inclusion of an assessment of ENT1 activity during early safety profiling for programs targeting respiratory disorders.

      PubDate: 2016-12-29T13:33:08Z
      DOI: 10.1016/j.taap.2016.12.021
  • Activation of AMPK by berberine induces hepatic lipid accumulation by
           upregulation of fatty acid translocase CD36 in mice
    • Authors: You-Jin Choi; Kang-Yo Lee; Seung-Hwan Jung; Hyung Sik Kim; Gayong Shim; Mi-Gyeong Kim; Yu-Kyoung Oh; Seon-Hee Oh; Dae Won Jun; Byung-Hoon Lee
      Abstract: Publication date: Available online 28 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): You-Jin Choi, Kang-Yo Lee, Seung-Hwan Jung, Hyung Sik Kim, Gayong Shim, Mi-Gyeong Kim, Yu-Kyoung Oh, Seon-Hee Oh, Dae Won Jun, Byung-Hoon Lee
      Emerging evidence has shown that berberine has a protective effect against metabolic syndrome such as obesity and type II diabetes mellitus by activating AMP-activated protein kinase (AMPK). AMPK induces CD36 trafficking to the sarcolemma for fatty acid uptake and oxidation in contracting muscle. However, little is known about the effects of AMPK on CD36 regulation in the liver. We investigated whether AMPK activation by berberine affects CD36 expression and fatty acid uptake in hepatocytes and whether it is linked to hepatic lipid accumulation. Activation of AMPK by berberine or transduction with adenoviral vectors encoding constitutively active AMPK in HepG2 and mouse primary hepatocytes increased the expression and membrane translocation of CD36, resulting in enhanced fatty acid uptake and lipid accumulation as determined by BODIPY-C16 and Nile red fluorescence, respectively. Activation of AMPK by berberine induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and subsequently induced CCAAT/enhancer-binding protein β (C/EBPβ) binding to the C/EBP-response element in the CD36 promoter in hepatocytes. In addition, hepatic CD36 expression and triglyceride levels were increased in normal diet-fed mice treated with berberine, but completely prevented when hepatic CD36 was silenced with adenovirus containing CD36-specific shRNA. Taken together, prolonged activation of AMPK by berberine increased CD36 expression in hepatocytes, resulting in fatty acid uptake via processes linked to hepatocellular lipid accumulation and fatty liver.

      PubDate: 2016-12-29T13:33:08Z
      DOI: 10.1016/j.taap.2016.12.019
  • Apigenin potentiates the antitumor activity of 5-FU on solid Ehrlich
           Carcinoma: Crosstalk between apoptotic and JNK-mediated autophagic cell
           death platforms
    • Authors: Hanaa Gaballah; Rasha Gaber Darin Mohamed
      Abstract: Publication date: Available online 23 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Hanaa H. Gaballah, Rasha A. Gaber, Darin A. Mohamed
      Background Although 5- Fluorouracil (5-FU) has exhibited effectiveness against cancer, novel therapeutic strategies are needed to enhance its antitumor efficiency and modulate its cytotoxity. Apigenin, a flavonoid present in fruits and vegetables, is a potent dietary phytochemical effective in cancer chemoprevention. Aim This study was undertaken to investigate the potential synergistic antitumor activity of apigenin and 5-FU on Solid Ehrlich carcinoma (SEC). Methods Eighty Swiss albino male mice were divided into four equal groups: vehicle treated control SEC, SEC+5-FU, SEC+apigenin, SEC+ 5-FU+apigenin. Beclin-1 and caspases 3, 9 and JNK activities were estimated by ELISA; mRNA expression levels of the antiapoptotic gene Mcl-1 were estimated using quantitative real-time RT-PCR, while tissue malondialdehyde (MDA), glutathione peroxidase and total antioxidant capacity were evaluated spectrophotometrically. A part of the tumor was examined for histopathological and Ki-67 immunohistochemistry analysis. Results 5-FU and/or apigenin caused significant increase in tissue levels of Beclin-1, caspases 3, 9 and JNK activities, MDA with significant decrease in tumor volume, Mcl-1expression, tissue glutathione peroxidase and total antioxidant capacity and alleviated the histopathological changes with significant decrease of Ki-67 proliferation index compared to vehicle treated SEC control group. In conclusion The combination of 5-FU and apigenin had a greater effect than each of 5-FU or apigenin alone against solid Ehrlich carcinoma in mice.

      PubDate: 2016-12-29T13:33:08Z
  • Hypomethylation of inflammatory genes (COX2, EGR1, and SOCS3) and
    • Authors: Preeyaphan Phookphan; Panida Navasumrit Somchamai Waraprasit Jeerawan Promvijit Krittinee Chaisatra
      Abstract: Publication date: Available online 23 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Preeyaphan Phookphan, Panida Navasumrit, Somchamai Waraprasit, Jeerawan Promvijit, Krittinee Chaisatra, Thitirat Ngaotepprutaram, Mathuros Ruchirawat
      Early-life exposure to arsenic increases risk of developing a variety of non-malignant and malignant diseases. Arsenic-induced carcinogenesis may be mediated through epigenetic mechanisms and pathways leading to inflammation. Our previous study reported that prenatal arsenic exposure leads to increased mRNA expression of several genes related to inflammation, including COX2, EGR1, and SOCS3. This study aimed to investigate the effects of arsenic exposure on promoter DNA methylation and mRNA expression of these inflammatory genes (COX2, EGR1, and SOCS3), as well as the generation of 8-nitroguanine, which is a mutagenic DNA lesion involved in inflammation-related carcinogenesis. Prenatally arsenic-exposed newborns had promoter hypomethylation of COX2, EGR1, and SOCS3 in cord blood lymphocytes (p<0.01). A follow-up study in these prenatally arsenic-exposed children showed a significant hypomethylation of these genes in salivary DNA (p<0.01). In vitro experiments confirmed that arsenite treatment at short-term high doses (10–100μM) and long-term low doses (0.5–1μM) in human lymphoblasts (RPMI 1788) caused promoter hypomethylation of these genes, which was in concordance with an increase in their mRNA expression. Additionally, the level of urinary 8-nitroguanine was significantly higher (p<0.01) in exposed newborns and children, by 1.4- and 1.8-fold, respectively. Arsenic accumulation in toenails was negatively correlated with hypomethylation of these genes and positively correlated with levels of 8-nitroguanine. These results indicated that early-life exposure to arsenic causes hypomethylation of COX2, EGR1, and SOCS3, increases mRNA expression of these genes, and increases 8-nitroguanine formation. These effects may be linked to mechanisms of arsenic-induced inflammation and cancer development later in life.

      PubDate: 2016-12-29T13:33:08Z
  • DEET Potentiates the Development and Persistence of Anticholinesterase
           Dependent Chronic Pain Signs in a Rat Model of Gulf War Illness Pain
    • Authors: L.K. Flunker; T.J. Nutter R.D. Johnson B.Y. Cooper
      Abstract: Publication date: Available online 23 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): L.K. Flunker, T.J. Nutter, R.D. Johnson, B.Y. Cooper
      Exposure to DEET (N,N-diethyl-meta-toluamide) may have influenced the pattern of symptoms observed in soldiers with GWI (Gulf War Illness; Haley and Kurt, 1997). We examined how the addition of DEET (400mg/kg; 50% topical) to an exposure protocol of permethrin (2.6mg/kg; topical), chlorpyrifos (CP; 120mg/kg), and pyridostigmine bromide (PB;13mg/kg) altered the emergence and pattern of pain signs in an animal model of GWI pain (Nutter et al., 2015). Rats underwent behavioral testing before, during and after a 4week exposure: 1) hindlimb pressure withdrawal threshold; 2) ambulation (movement distance and rate); and 3) resting duration. Additional studies were conducted to assess the influence of acute DEET (10–100μM) on muscle and vascular nociceptor Kv7, KDR, Nav1.8 and Nav1.9. We report that a 50% concentration of DEET enhanced the development and persistence of pain-signs. Rats exposed to all 4 compounds exhibited ambulation deficits that appeared 5–12weeks post-exposure and persisted through weeks 21–24. Rats exposed to only three agents (CP or PB excluded), did not fully develop ambulation deficits. When PB was excluded, rats also developed rest duration pain signs, in addition to ambulation deficits. There was no evidence that physiological doses of DEET acutely modified nociceptor Kv7, KDR, Nav1.8 or Nav1.9 activities. Nevertheless, DEET augmented protocols decreased the conductance of Kv7 expressed in vascular nociceptors harvested from chronically exposed rats. We concluded that DEET enhanced the development and persistence of pain behaviors, but the anticholinesterases CP and PB played a determinant role.

      PubDate: 2016-12-29T13:33:08Z
  • Pharmacological activation of aldehyde dehydrogenase 2 promotes osteoblast
           differentiation via bone morphogenetic protein-2 and induces bone anabolic
    • Authors: Monika Mittal; Subhashis Pal Shyamsundar Pal China Konica Porwal Kapil
      Abstract: Publication date: Available online 23 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Monika Mittal, Subhashis Pal, Shyamsundar Pal China, Konica Porwal, Kapil Dev, Richa Shrivastava, Kanumuri Siva Rama Raju, Mamunur Rashid, Arun Kumar Trivedi, Sabyasachi Sanyal, Muhammad Wahajuddin, Smrati Bhaduria, Rakesh Maurya, Naibedya Chattopadhyay
      Aldehyde dehydrogenases (ALDHs) are a family of enzymes involved in detoxifying aldehydes. Previously, we reported that an ALDH inhibitor, disulfiram caused bone loss in rats and among ALDHs osteoblast expressed only ALDH2. Loss-of-function mutation in ALDH2 gene is reported to cause bone loss in humans which suggested its importance in skeletal homeostasis. We thus studied whether activating ALDH2 by N-(1, 3-benzodioxol-5-ylmethyl)-2, 6-dichlorobenzamide (alda-1) had osteogenic effect. We found that alda-1 increased and acetaldehyde decreased the differentiation of rat primary osteoblasts and expressions of ALDH2 and bone morphogenetic protein-2 (BMP-2). Silencing ALDH2 in osteoblasts abolished the alda-1 effects. Further, alda-1 attenuated the acetaldehyde-induced lipid-peroxidation and oxidative stress. BMP-2 is essential for bone regeneration and alda-1 increased its expression in osteoblasts. We then showed that alda-1 (40mg/kg dose) augmented bone regeneration at the fracture site with concomitant increase in BMP-2 protein compared with control. The osteogenic dose (40mg/kg) of alda-1 attained a bone marrow concentration that was stimulatory for osteoblast differentiation, suggesting that the tissue concentration of alda-1 matched its pharmacological effect. In addition, alda-1 promoted modelling-directed bone growth and peak bone mass achievement, and increased bone mass in adult rats which reiterated its osteogenic effect. In osteopenic ovariectomized (OVX) rats, alda-1 reversed trabecular osteopenia with attendant increase in serum osteogenic marker (procollagen type I N-terminal peptide) and decrease in oxidative stress. Alda-1 has no effect on liver and kidney function. We conclude that activating ALDH2 by alda-1 had an osteoanabolic effect involving increased osteoblastic BMP-2 production and decreased OVX-induced oxidative stress.

      PubDate: 2016-12-23T08:56:00Z
  • Clozapine-induced agranulocytosis: Evidence for an immune-mediated
           mechanism from a patient-specific in-vitro approach
    • Authors: Francesca Regen; Irmelin Herzog; Eric Hahn; Claudia Ruehl; Nathalie Le Bret; Michael Dettling; Isabella Heuser; Julian Hellmann-Regen
      Abstract: Publication date: Available online 6 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Francesca Regen, Irmelin Herzog, Eric Hahn, Claudia Ruehl, Nathalie Le Bret, Michael Dettling, Isabella Heuser, Julian Hellmann-Regen
      Use of the atypical antipsychotic clozapine (CZP) is compromised by the risk of potentially fatal agranulocytosis/granulocytopenia (CIAG). To address this, we have established a simple, personalized cell culture-based strategy to identify CIAG-susceptible patients, hypothesizing that an immunogenic and possibly haptene-based mechanism underlies CIAG pathophysiology. To detect a putative haptene-induced response to CZP in vitro exposure, a traditional lymphocyte stimulation assay was adapted and applied to patient-specific peripheral blood-derived mononuclear cells (PBMC). 6 patients with a history of CIAG, 6 patients under CZP treatment (without CIAG) and 12 matched healthy controls were studied. In vitro CZP exposure, even at strikingly low levels, resulted in significantly increased proliferation rates only in CIAG patients' PBMC. Other parameters including cell viability and mitogen-induced proliferation were also affected by in vitro CZP exposure, yet there was no significant difference between the groups. This personalized approach is a starting point for further investigations into a putative haptene-based mechanism underlying CIAG development, and may facilitate the future development of predictive testing.

      PubDate: 2016-12-08T08:42:16Z
      DOI: 10.1016/j.taap.2016.12.003
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