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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  [3038 journals]
  • A silk peptide fraction restores cognitive function in AF64A-induced
           Alzheimer disease model rats by increasing expression of choline
           acetyltransferase gene
    • Authors: Yeseul Cha; Sang Hoon Lee; Su Kil Jang; Haiyu Guo; Young-Hwan Ban; Dongsun Park; Gwi Yeong Jang; Sungho Yeon; Jeong-Yong Lee; Ehn-Kyoung Choi; Seong Soo Joo; Heon-Sang Jeong; Yun-Bae Kim
      Pages: 48 - 54
      Abstract: Publication date: 1 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 314
      Author(s): Yeseul Cha, Sang Hoon Lee, Su Kil Jang, Haiyu Guo, Young-Hwan Ban, Dongsun Park, Gwi Yeong Jang, Sungho Yeon, Jeong-Yong Lee, Ehn-Kyoung Choi, Seong Soo Joo, Heon-Sang Jeong, Yun-Bae Kim
      This study investigated the effects of a silk peptide fraction obtained by incubating silk proteins with Protease N and Neutrase (SP-NN) on cognitive dysfunction of Alzheimer disease model rats. In order to elucidate underlying mechanisms, the effect of SP-NN on the expression of choline acetyltransferase (ChAT) mRNA was assessed in F3.ChAT neural stem cells and Neuro2a neuroblastoma cells; active amino acid sequence was identified using HPLC-MS. The expression of ChAT mRNA in F3.ChAT cells increased by 3.79-fold of the control level by treatment with SP-NN fraction. The active peptide in SP-NN was identified as tyrosine-glycine with 238.1 of molecular weight. Male rats were orally administered with SP-NN (50 or 300mg/kg) and challenged with a cholinotoxin AF64A. As a result of brain injury and decreased brain acetylcholine level, AF64A induced astrocytic activation, resulting in impairment of learning and memory function. Treatment with SP-NN exerted recovering activities on acetylcholine depletion and brain injury, as well as cognitive deficit induced by AF64A. The results indicate that, in addition to a neuroprotective activity, the SP-NN preparation restores cognitive function of Alzheimer disease model rats by increasing the release of acetylcholine.
      Graphical abstract image

      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.11.008
      Issue No: Vol. 314 (2016)
       
  • Multidrug and toxin extrusion proteins mediate cellular transport of
           cadmium
    • Authors: Hong Yang; Dong Guo; Obinna N. Obianom; Tong Su; James E. Polli; Yan Shu
      Pages: 55 - 62
      Abstract: Publication date: 1 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 314
      Author(s): Hong Yang, Dong Guo, Obinna N. Obianom, Tong Su, James E. Polli, Yan Shu
      Cadmium (Cd) is an environmentally prevalent toxicant posing increasing risk to human health worldwide. As compared to the extensive research in Cd tissue accumulation, little was known about the elimination of Cd, particularly its toxic form, Cd ion (Cd2+). In this study, we aimed to examine whether Cd2+ is a substrate of multidrug and toxin extrusion proteins (MATEs) that are important in renal xenobiotic elimination. HEK-293 cells overexpressing the human MATE1 (HEK-hMATE1), human MATE2-K (HEK-hMATE2-K) and mouse Mate1 (HEK-mMate1) were used to study the cellular transport and toxicity of Cd2+. The cells overexpressing MATEs showed a 2–4 fold increase of Cd2+ uptake that could be blocked by the MATE inhibitor cimetidine. A saturable transport profile was observed with the Michaelis-Menten constant (K m ) of 130±15.8μM for HEK-hMATE1; 139±21.3μM for HEK-hMATE2-K; and 88.7±13.5μM for HEK-mMate1, respectively. Cd2+ could inhibit the uptake of metformin, a substrate of MATE transporters, with the half maximal inhibitory concentration (IC50) of 97.5±6.0μM, 20.2±2.6μM, and 49.9±6.9μM in HEK-hMATE1, HEK-hMATE2-K, and HEK-mMate1 cells, respectively. In addition, hMATE1 could transport preloaded Cd2+ out of the HEK-hMATE1 cells, thus resulting in a significant decrease of Cd2+-induced cytotoxicity. The present study has provided the first evidence supporting that MATEs transport Cd2+ and may function as cellular elimination machinery in Cd intoxication.

      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.11.007
      Issue No: Vol. 314 (2016)
       
  • The unexpected teratogenicity of RXR antagonist UVI3003 via activation of
           PPARγ in Xenopus tropicalis
    • Authors: Jingmin Zhu; Amanda Janesick; Lijiao Wu; Lingling Hu; Weiyi Tang; Bruce Blumberg; Huahong Shi
      Pages: 91 - 97
      Abstract: Publication date: 1 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 314
      Author(s): Jingmin Zhu, Amanda Janesick, Lijiao Wu, Lingling Hu, Weiyi Tang, Bruce Blumberg, Huahong Shi
      The RXR agonist (triphenyltin, TPT) and the RXR antagonist (UVI3003) both show teratogenicity and, unexpectedly, induce similar malformations in Xenopus tropicalis embryos. In the present study, we exposed X. tropicalis embryos to UVI3003 in seven specific developmental windows and identified changes in gene expression. We further measured the ability of UVI3003 to activate Xenopus RXRα (xRXRα) and PPARγ (xPPARγ) in vitro and in vivo. We found that UVI3003 activated xPPARγ either in Cos7 cells (in vitro) or Xenopus embryos (in vivo). UVI3003 did not significantly activate human or mouse PPARγ in vitro; therefore, the activation of Xenopus PPARγ by UVI3003 is novel. The ability of UVI3003 to activate xPPARγ explains why UVI3003 and TPT yield similar phenotypes in Xenopus embryos. Our results indicate that activating PPARγ leads to teratogenic effects in Xenopus embryos. More generally, we infer that chemicals known to specifically modulate mammalian nuclear hormone receptors cannot be assumed to have the same activity in non-mammalian species, such as Xenopus. Rather they must be tested for activity and specificity on receptors of the species in question to avoid making inappropriate conclusions.

      PubDate: 2016-12-01T08:25:54Z
      DOI: 10.1016/j.taap.2016.11.014
      Issue No: Vol. 314 (2016)
       
  • Up-regulation of granzyme B and perforin by staphylococcal enterotoxin C2
           mutant induces enhanced cytotoxicity in Hepa1–6 cells
    • Authors: Guojun Zhang; Mingkai Xu; Huiwen Zhang; Yubo Song; Jian Wang; Chenggang Zhang
      Pages: 1 - 9
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Guojun Zhang, Mingkai Xu, Huiwen Zhang, Yubo Song, Jian Wang, Chenggang Zhang
      Staphylococcal enterotoxin C2 (SEC2), a member of bacterial superantigen, is one of the most potent known activators of T lymphocytes. With this property, SEC2 has already been used in clinic as a tumor immunotherapy agent in China. To increase the antitumor activity, a SEC2 mutant named ST-4 (GKVTG102-106WWH) with amino acid substitutions in T cell receptor (TCR)-binding domain was generated by site-directed mutagenesis, and the molecular mechanism of the enhanced antitumor activity was investigated. Results showed that ST-4 could activate much more Vβ 8.2 and 8.3 T cells and NK cells compared with SEC2, and exhibited significantly enhanced immunocyte stimulation and antitumor activity in vitro. The synthetic peptide sequencing the residues of mutant TCR-binding domain could competitively inhibit the immunocyte stimulation activity of ST-4. Most importantly, ST-4 up-regulated granzyme B and perforin at both mRNA and protein levels. We also found that expression of proapoptotic proteins cytochrome c, BAX and activation of caspase-3, 9 was up-regulated, and antiapoptotic protein Bcl-xL was down-regulated in the treatment with either ST-4 or SEC2. When granzyme B inhibitor or perforin inhibitor is presented, tumor cell viability was significantly rescued. Taken together, we demonstrate that increased ST-4-TCR recognition contributed to massive T cells and NK cells activation. These activated cells released up-regulated granzyme B and perforin, which induced the enhanced tumor cells apoptosis by mitochondrial apoptotic pathway, and ultimately led to enhanced tumor cell growth inhibition. ST-4 may be a promising candidate for antitumor clinic usage in future.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.009
      Issue No: Vol. 313 (2016)
       
  • High risks of lung disease associated with early-life and moderate
           lifetime arsenic exposure in northern Chile
    • Authors: Craig Steinmaus; Catterina Ferreccio; Johanna Acevedo; John R Balmes; Jane Liaw; Patricia Troncoso; David C Dauphiné; Anthony Nardone; Allan H Smith
      Pages: 10 - 15
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Craig Steinmaus, Catterina Ferreccio, Johanna Acevedo, John R Balmes, Jane Liaw, Patricia Troncoso, David C Dauphiné, Anthony Nardone, Allan H Smith
      Background Arsenic in drinking water has been associated with increases in lung disease, but information on the long-term impacts of early-life exposure or moderate exposure levels are limited. Methods We investigated pulmonary disease and lung function in 795 subjects from three socio-demographically similar areas in northern Chile: Antofagasta, which had a well-described period of high arsenic water concentrations (860μg/L) from 1958 to 1970; Iquique, which had long-term arsenic water concentrations near 60μg/L; and Arica, with long-term water concentrations ≤10μg/L. Results Compared to adults never exposed >10μg/L, adults born in Antofagasta during the high exposure period had elevated odds ratios (OR) of respiratory symptoms (e.g., OR for shortness of breath=5.56, 90% confidence interval (CI): 2.68–11.5), and decreases in pulmonary function (e.g., 224mL decrease in forced vital capacity in nonsmokers, 90% CI: 97–351mL). Subjects with long-term exposure to arsenic water concentrations near 60μg/L also had increases in some pulmonary symptoms and reduced lung function. Conclusions Overall, these findings provide new evidence that in utero or childhood arsenic exposure is associated with non-malignant pulmonary disease in adults. They also provide preliminary new evidence that long-term exposures to moderate levels of arsenic may be associated with lung toxicity, although the magnitude of these latter findings were greater than expected and should be confirmed.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.006
      Issue No: Vol. 313 (2016)
       
  • Nerve cell-mimicking liposomes as biosensor for botulinum neurotoxin
           complete physiological activity
    • Authors: Oliver G. Weingart; Martin J. Loessner
      Pages: 16 - 23
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Oliver G. Weingart, Martin J. Loessner
      Botulinum neurotoxins (BoNT) are the most toxic substances known, and their neurotoxic properties and paralysing effects are exploited for medical treatment of a wide spectrum of disorders. To accurately quantify the potency of a pharmaceutical BoNT preparation, its physiological key activities (binding to membrane receptor, translocation, and proteolytic degradation of SNARE proteins) need to be determined. To date, this was only possible using animal models, or, to a limited extent, cell-based assays. We here report a novel in vitro system for BoNT/B analysis, based on nerve-cell mimicking liposomes presenting motoneuronal membrane receptors required for BoNT binding. Following triggered membrane translocation of the toxin's Light Chain, the endopeptidase activity can be quantitatively monitored employing a FRET-based reporter assay within the functionalized liposomes. We were able to detect BoNT/B physiological activity at picomolar concentrations in short time, opening the possibility for future replacement of animal experimentation in pharmaceutical BoNT testing.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.010
      Issue No: Vol. 313 (2016)
       
  • Cadmium modulates hematopoietic stem and progenitor cells and skews toward
           myelopoiesis in mice
    • Authors: Yandong Zhang; Xinchun Yu; Shuhui Sun; Qian Li; Yunli Xie; Qiang Li; Yifan Zhao; Jianfeng Pei; Wenmin Zhang; Peng Xue; Zhijun Zhou; Yubin Zhang
      Pages: 24 - 34
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Yandong Zhang, Xinchun Yu, Shuhui Sun, Qian Li, Yunli Xie, Qiang Li, Yifan Zhao, Jianfeng Pei, Wenmin Zhang, Peng Xue, Zhijun Zhou, Yubin Zhang
      The heavy metal cadmium (Cd) is known to modulate immunity and cause osteoporosis. However, how Cd influences on hematopoiesis remain largely unknown. Herein, we show that wild-type C57BL/6 (B6) mice exposed to Cd for 3months had expanded bone marrow (BM) populations of long-term hematopoietic stem cells (LT-HSCs), common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs), while having reduced populations of multipotent progenitors (MPPs) and common lymphoid progenitors (CLPs). A competitive mixed BM transplantation assay indicates that BM from Cd-treated mice had impaired LT-HSC ability to differentiate into mature cells. In accordance with increased myeloid progenitors and decreased lymphoid progenitors, the BM and spleens of Cd-treated mice had more monocytes and/or neutrophils and fewer B cells and T cells. Cd impaired the ability of the non-hematopoietic system to support LT-HSCs, in that lethally irradiated Cd-treated recipients transplanted with normal BM cells had reduced LT-HSCs after the hematopoietic system was fully reconstituted. This is consistent with reduced osteoblasts, a known critical component for HSC niche, observed in Cd-treated mice. Conversely, lethally irradiated control recipients transplanted with BM cells from Cd-treated mice had normal LT-HSC reconstitution. Furthermore, both control mice and Cd-treated mice that received Alendronate, a clinical drug used for treating osteoporosis, had BM increases of LT-HSCs. Thus, the results suggest Cd increase of LT-HSCs is due to effects on HSCs and not on osteoblasts, although, Cd causes osteoblast reduction and impaired niche function for maintaining HSCs. Furthermore, Cd skews HSCs toward myelopoiesis.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.016
      Issue No: Vol. 313 (2016)
       
  • Progressive effects of silver nanoparticles on hormonal regulation of
           reproduction in male rats
    • Authors: K. Dziendzikowska; A. Krawczyńska; M. Oczkowski; T. Królikowski; K. Brzóska; A. Lankoff; M. Dziendzikowski; T. Stępkowski; M. Kruszewski; J. Gromadzka-Ostrowska
      Pages: 35 - 46
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): K. Dziendzikowska, A. Krawczyńska, M. Oczkowski, T. Królikowski, K. Brzóska, A. Lankoff, M. Dziendzikowski, T. Stępkowski, M. Kruszewski, J. Gromadzka-Ostrowska
      The growing use of silver nanoparticles (AgNPs) in various applications, including consumer, agriculture and medicine products, has raised many concerns about the potential risks of nanoparticles (NPs) to human health and the environment. An increasing body of evidence suggests that AgNPs may have adverse effects of humans, thus the aim of this study was to investigate the effects of AgNPs on the male reproductive system. Silver particles (20nm AgNPs (groups Ag I and Ag II) and 200nm Ag sub-micron particles (SPs) (group Ag III)) were administered intravenously to male Wistar rats at a dose of 5 (groups Ag I and Ag III) or 10 (group Ag II) mg/kg of body weight. The biological material was sampled 24h, 7days and 28days after injection. The obtained results revealed that the AgNPs had altered the luteinising hormone concentration in the plasma and the sex hormone concentration in the plasma and testes. Plasma and intratesticular levels of testosterone and dihydrotestosterone were significantly decreased both 7 and 28days after treatment. No change in the prolactin and sex hormone-binding globulin concentration was observed. Exposure of the animals to AgNPs resulted in a considerable decrease in 5α-reductase type 1 and the aromatase protein level in the testis. Additionally, expression analysis of genes involved in steroidogenesis and the steroids metabolism revealed significant down-regulation of Star, Cyp11a1, Hsd3b1, Hsd17b3 and Srd5a1 mRNAs in AgNPs/AgSPs-exposed animals. The present study demonstrates the potential adverse effect on the hormonal regulation of the male reproductive function following AgNP/AgSP administration, in particular alterations of the sex steroid balance and expression of genes involved in steroidogenesis and the steroids metabolism.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.013
      Issue No: Vol. 313 (2016)
       
  • Occupational exposures at a polyvinyl chloride production facility are
           associated with significant changes to the plasma metabolome
    • Authors: John J. Guardiola; Juliane I. Beier; K. Cameron Falkner; Benjamin Wheeler; Craig James McClain; Matt Cave
      Pages: 47 - 56
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): John J. Guardiola, Juliane I. Beier, K. Cameron Falkner, Benjamin Wheeler, Craig James McClain, Matt Cave
      Background Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. Methods Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS2 analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed. Results 613 unique named metabolites were identified. Of these, 189 metabolites were increased in the VC exposure group while 94 metabolites were decreased. Random Forest analysis indicated that the metabolite signature could separate the groups with 94% accuracy. VC exposures were associated with increased long chain (including arachidonic acid) and essential (including linoleic acid) fatty acids. Occupational exposure increased lipid peroxidation products including monohydroxy fatty acids (including 13-HODE); fatty acid dicarboxylates; and oxidized arachidonic acid products (including 5,9, and 15-HETE). Carnitine and carnitine esters were decreased, suggesting peroxisomal/mitochondrial dysfunction and alternate modes of lipid oxidation. Differentially regulated metabolites were shown to interact with extracellular-signal-regulated kinase 1/2 (ERK1/2), Akt, AMP-activated protein kinase (AMPK), and the N-Methyl-d-aspartate (NMDA) receptor. The top canonical pathways affected by occupational exposure included tRNA charging, nucleotide degradation, amino acid synthesis/degradation and urea cycle. Methionine and homocysteine was increased with decreased cysteine, suggesting altered 1-carbon metabolism. Conclusions Occupational exposure generated a distinct plasma metabolome with markedly altered lipid and amino acid metabolites. ERK1/2, Akt, AMPK, and NMDA were identified as protein targets for vinyl chloride toxicity.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.001
      Issue No: Vol. 313 (2016)
       
  • Friedelane-type triterpenoids as selective anti-inflammatory agents by
           regulation of differential signaling pathways in LPS-stimulated
           macrophages
    • Authors: Andrea Villar-Lorenzo; Alejandro E. Ardiles; Ana I. Arroba; Enrique Hernández-Jiménez; Virginia Pardo; Eduardo López-Collazo; Ignacio A. Jiménez; Isabel L. Bazzocchi; Águeda González-Rodríguez; Ángela M. Valverde
      Pages: 57 - 67
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Andrea Villar-Lorenzo, Alejandro E. Ardiles, Ana I. Arroba, Enrique Hernández-Jiménez, Virginia Pardo, Eduardo López-Collazo, Ignacio A. Jiménez, Isabel L. Bazzocchi, Águeda González-Rodríguez, Ángela M. Valverde
      A series of 31 pentacyclic triterpenoids isolated from the root barks of Celastrus vulcanicola and Maytenus jelskii were tested for cytotoxicity and inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 18 (C18) and 25 (C25) exhibited significant inhibition of LPS-induced NO release at 50 and 25μM concentrations, respectively, and decreased mRNAs of pro-inflammatory cytokines. At the molecular level, C18 neither inhibited LPS-mediated phosphorylation of mitogen activated protein kinases (MAPKs) nor nuclear translocation of nuclear factor kappa beta (NFκB). Instead, C18 enhanced and prolonged nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and increased the expression of its target genes including hemeoxigenase 1 (HO1). C25 efficiently inhibited LPS-mediated phosphorylation of JNK, p38 and ERK, without affecting NFκB or Nrf2 signaling pathways. Both compounds reduced LPS-mediated processing of caspase-1 and the cleavage of interleukin 1β (IL1β) proform, reflecting their ability to target the inflammasome. C25 also counteracted LPS effects on iNOS expression and pro-inflammatory cytokines mRNA levels in Bv-2 microglial cells. The anti-inflammatory effect of both compounds was also assessed in human macrophages. Our results suggest that triterpenoids C18 and C25 possess anti-inflammatory effects, which may be therapeutically relevant for diseases linked to inflammation.
      Graphical abstract image

      PubDate: 2016-11-10T14:09:26Z
      DOI: 10.1016/j.taap.2016.10.004
      Issue No: Vol. 313 (2016)
       
  • Intraperitoneal exposure of whitefish to microcystin-LR induces rapid
           liver injury followed by regeneration and resilience to subsequent
           exposures
    • Authors: Maciej Woźny; Bogdan Lewczuk; Natalia Ziółkowska; Piotr Gomułka; Stefan Dobosz; Alicja Łakomiak; Maciej Florczyk; Paweł Brzuzan
      Pages: 68 - 87
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Maciej Woźny, Bogdan Lewczuk, Natalia Ziółkowska, Piotr Gomułka, Stefan Dobosz, Alicja Łakomiak, Maciej Florczyk, Paweł Brzuzan
      To date, there has been no systematic approach comprehensively describing the sequence of pathological changes in fish during prolonged exposure to microcystin-LR (MC-LR). Towards this aim, juvenile whitefish individuals received an intraperitoneal injection with pure MC-LR, and the injection was repeated every week to maintain continuous exposure for 28days. During the exposure period, growth and condition of the fish were assessed based on biometric measurements. Additionally, selected biochemical markers were analysed in the fishes' blood, and their livers were carefully examined for morphological, ultrastructural, and molecular changes. The higher dose of MC-LR (100μg·kg−1) caused severe liver injury at the beginning of the exposure period, whereas the lower dose (10μg·kg−1) caused less, probably reversible injury, and its effects began to be observed later in the exposure period. These marked changes were accompanied by substantial MC-LR uptake by the liver. However, starting on the 7th day of exposure, cell debris began to be removed by phagocytes, then by 14th day, proliferation of liver cells had markedly increased, which led to reconstruction of the liver parenchyma at the end of the treatment. Surprisingly, despite weekly-repeated intraperitoneal injections, MC-LR did not accumulate over time of exposure which suggests its limited uptake in the later phase of exposure. In support, mRNA expression of the membrane transport protein oatp1d was decreased at the same time as the regenerative processes were observed. Our study shows that closing of active membrane transport may serve as one defence mechanism against further MC-LR intoxication.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.014
      Issue No: Vol. 313 (2016)
       
  • Effects of a human recombinant alkaline phosphatase on renal hemodynamics,
           oxygenation and inflammation in two models of acute kidney injury
    • Authors: Esther Peters; Bülent Ergin; Asli Kandil; Ebru Gurel-Gurevin; Andrea van Elsas; Rosalinde Masereeuw; Peter Pickkers; Can Ince
      Pages: 88 - 96
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Esther Peters, Bülent Ergin, Asli Kandil, Ebru Gurel-Gurevin, Andrea van Elsas, Rosalinde Masereeuw, Peter Pickkers, Can Ince
      Two small clinical trials indicated that administration of bovine intestinal alkaline phosphatase (AP) improves renal function in critically ill patients with sepsis-associated acute kidney injury (AKI), for which the mechanism of action is not completely understood. Here, we investigated the effects of a newly developed human recombinant AP (recAP) on renal oxygenation and hemodynamics and prevention of kidney damage and inflammation in two in vivo AKI models. To induce AKI, male Wistar rats (n=18) were subjected to renal ischemia (30min) and reperfusion (I/R), or sham-operated. In a second model, rats (n=18) received a 30min infusion of lipopolysaccharide (LPS; 2.5mg/kg), or saline, and fluid resuscitation. In both models, recAP (1000U/kg) was administered intravenously (15min before reperfusion, or 90min after LPS). Following recAP treatment, I/R-induced changes in renal blood flow, renal vascular resistance and oxygen delivery at early, and cortical microvascular oxygen tension at late reperfusion were no longer significantly affected. RecAP did not influence I/R-induced effects on mean arterial pressure. During endotoxemia, recAP treatment did not modulate the LPS-induced changes in systemic hemodynamics and renal oxygenation. In both models, recAP did exert a clear renal protective anti-inflammatory effect, demonstrated by attenuated immunostaining of inflammatory, tubular injury and pro-apoptosis markers. Whether this renal protective effect is sufficient to improve outcome of patients suffering from sepsis-associated AKI is being investigated in a large clinical trial.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.015
      Issue No: Vol. 313 (2016)
       
  • Locomotor activity and tissue levels following acute administration of
           lambda- and gamma-cyhalothrin in rats
    • Authors: Virginia C. Moser; Zhiwei Liu; Christopher Schlosser; Terri L. Spanogle; Appavu Chandrasekaran; Katherine L. McDaniel
      Pages: 97 - 103
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Virginia C. Moser, Zhiwei Liu, Christopher Schlosser, Terri L. Spanogle, Appavu Chandrasekaran, Katherine L. McDaniel
      Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavioral effects include locomotor activity changes and specific toxic syndromes (types I and II). In general these neurobehavioral effects correlate well with peak internal dose metrics. Products of cyhalothrin, a type II pyrethroid, include mixtures of isomers (e.g., λ-cyhalothrin) as well as enriched active isomers (e.g., γ-cyhalothrin). We measured acute changes in locomotor activity in adult male rats and directly correlated these changes to peak brain and plasma concentrations of λ- and γ-cyhalothrin using a within-subject design. One-hour locomotor activity studies were conducted 1.5h after oral gavage dosing, and immediately thereafter plasma and brains were collected for analyzing tissue levels using LC/MS/MS methods. Both isomers produced dose-related decreases in activity counts, and the effective dose range for γ-cyhalothrin was lower than for λ-cyhalothrin. Doses calculated to decrease activity by 50% were 2-fold lower for the γ-isomer (1.29mg/kg) compared to λ-cyhalothrin (2.65mg/kg). Salivation, typical of type II pyrethroids, was also observed at lower doses of γ-cyhalothrin. Administered dose correlated well with brain and plasma concentrations, which furthermore showed good correlations with activity changes. Brain and plasma levels were tightly correlated across doses. While γ-cyhalothrin was 2-fold more potent based on administered dose, the differences based on internal concentrations were less, with γ-cyhalothrin being 1.3- to 1.6-fold more potent than λ-cyhalothrin. These potency differences are consistent with the purity of the λ-isomer (approximately 43%) compared to the enriched isomer γ-cyhalothrin (approximately 98%). Thus, administered dose as well as differences in cyhalothrin isomers is a good predictor of behavioral effects.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.020
      Issue No: Vol. 313 (2016)
       
  • DNA damage response in nephrotoxic and ischemic kidney injury
    • Authors: Mingjuan Yan; Chengyuan Tang; Zhengwei Ma; Shuang Huang; Zheng Dong
      Pages: 104 - 108
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Mingjuan Yan, Chengyuan Tang, Zhengwei Ma, Shuang Huang, Zheng Dong
      DNA damage activates specific cell signaling cascades for DNA repair, cell cycle arrest, senescence, and/or cell death. Recent studies have demonstrated DNA damage response (DDR) in experimental models of acute kidney injury (AKI). In cisplatin-induced AKI or nephrotoxicity, the DDR pathway of ATR/Chk2/p53 is activated and contributes to renal tubular cell apoptosis. In ischemic AKI, DDR seems more complex and involves at least the ataxia telangiectasia mutated (ATM), a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, and p53; however, while ATM may promote DNA repair, p53 may trigger cell death. Targeting DDR for kidney protection in AKI therefore relies on a thorough elucidation of the DDR pathways in various forms of AKI.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.022
      Issue No: Vol. 313 (2016)
       
  • Aluminum exposure for one hour decreases vascular reactivity in
           conductance and resistance arteries in rats
    • Authors: Patrícia Medeiros Schmidt; Alyne Goulart Escobar; João Guilherme Dini Torres; Caroline Silveira Martinez; Danize Aparecida Rizzetti; Simone Noremberg Kunz; Dalton Valentim Vassallo; María Jesús Alonso; Franck Maciel Peçanha; Giulia Alessandra Wiggers
      Pages: 109 - 118
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Patrícia Medeiros Schmidt, Alyne Goulart Escobar, João Guilherme Dini Torres, Caroline Silveira Martinez, Danize Aparecida Rizzetti, Simone Noremberg Kunz, Dalton Valentim Vassallo, María Jesús Alonso, Franck Maciel Peçanha, Giulia Alessandra Wiggers
      Aims Aluminum (Al) is an important environmental contaminant; however, there are not enough evidences of Al-induced cardiovascular dysfunction. We investigated the effects of acute exposure to aluminum chloride (AlCl3) on blood pressure, vascular reactivity and oxidative stress. Methods and results Male Wistar rats were divided into two groups: Untreated: vehicle (ultrapure water, ip) and AlCl 3 : single dose of AlCl3 (100mg/kg,ip). Concentration-response curves to phenylephrine in the absence and presence of endothelium, the nitric oxide synthase inhibitor l-NAME, the potassium channel blocker tetraethylammonium, and the NADPH oxidase inhibitor apocynin were performed in segments from aortic and mesenteric resistance arteries. NO released was assessed in aorta and reactive oxygen species (ROS), malondialdehyde, non-protein thiol levels, antioxidant capacity and enzymatic antioxidant activities were investigated in plasma, aorta and/or mesenteric arteries. After one hour of AlCl3 exposure serum Al levels attained 147.7±25.0μg/L. Al treatment: 1) did not affect blood pressure, heart rate and vasodilator responses induced by acetylcholine or sodium nitroprusside; 2) decreased phenylephrine-induced vasoconstrictor responses; 3) increased endothelial modulation of contractile responses, NO release and vascular ROS production from NADPH oxidase; 4) increased plasmatic, aortic and mesenteric malondialdehyde and ROS production, and 5) decreased antioxidant capacity and affected the antioxidant biomarkers non-protein thiol levels, glutathione peroxidase, glutathione-S-transferase, superoxide dismutase and catalase enzymatic activities. Conclusion AlCl3-acute exposure reduces vascular reactivity. This effect is associated with increased NO production, probably acting on K+ channels, which seems to occur as a compensatory mechanism against Al-induced oxidative stress. Our results suggest that Al exerts toxic effects to the vascular system.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.023
      Issue No: Vol. 313 (2016)
       
  • Dual effect of insulin resistance and cadmium on human granulosa cells -
           In vitro study
    • Authors: Muskaan Belani; Preeti Shah; Manish Banker; Sarita Gupta
      Pages: 119 - 130
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Muskaan Belani, Preeti Shah, Manish Banker, Sarita Gupta
      Combined exposure of cadmium (Cd) and insulin resistance (IR) might be responsible for subfertility. In the present study, we investigated the effects of Cd in vitro in IR human granulosa cells. Isolated human granulosa cells from control and polycystic ovary syndrome (PCOS) follicular fluid samples were confirmed for IR by decrease in protein expression of insulin receptor-β. Control and IR human granulosa cells were then incubated with or without 32μM Cd. The combined effect of IR with 32μM Cd in granulosa cells demonstrated significant decrease in expression of StAR, CYP11A1, CYP19A1, 17β-HSD, 3β-HSD, FSH-R and LH-R. Decrease was also observed in progesterone and estradiol concentrations as compared to control. Additionally, increase in protein expression of cleaved PARP-F2, active caspase-3 and a positive staining for Annexin V and PI indicated apoptosis as the mode of increased cell death ultimately leading to decreased steroidogenesis, as observed through the combined exposure. Taken together the results suggest decrease in steroidogenesis ultimately leading to abnormal development of the follicle thus compromising fertility at the level of preconception.
      Graphical abstract image

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.019
      Issue No: Vol. 313 (2016)
       
  • Enhanced photo(geno)toxicity of demethylated chlorpromazine metabolites
    • Authors: Fabrizio Palumbo; Guillermo Garcia-Lainez; Daniel Limones-Herrero; M. Dolores Coloma; Javier Escobar; M. Consuelo Jiménez; Miguel A. Miranda; Inmaculada Andreu
      Pages: 131 - 137
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Fabrizio Palumbo, Guillermo Garcia-Lainez, Daniel Limones-Herrero, M. Dolores Coloma, Javier Escobar, M. Consuelo Jiménez, Miguel A. Miranda, Inmaculada Andreu
      Chlorpromazine (CPZ) is an anti-psychotic drug widely used to treat disorders such as schizophrenia or manic-depression. Unfortunately, CPZ exhibits undesirable side effects such as phototoxic and photoallergic reactions in humans. In general, the influence of drug metabolism on this type of reactions has not been previously considered in photosafety testing. Thus, the present work aims to investigate the possible photo(geno)toxic potential of drug metabolites, using CPZ as an established reference compound. In this case, the metabolites selected for the study are demethylchlorpromazine (DMCPZ), didemethylchlorpromazine (DDMCPZ) and chlorpromazine sulfoxide (CPZSO). The demethylated CPZ metabolites DMCPZ and DDMCPZ maintain identical chromophore to the parent drug. In this work, it has been found that the nature of the aminoalkyl side chain modulates the hydrophobicity and the photochemical properties (for instance, the excited state lifetimes), but it does not change the photoreactivity pattern, which is characterized by reductive photodehalogenation, triggered by homolytic carbon-chlorine bond cleavage with formation of highly reactive aryl radical intermediates. Accordingly, these metabolites are phototoxic to cells, as revealed by the 3T3 NRU assay; their photo-irritation factors are even higher than that of CPZ. The same trend is observed in photogenotoxicity studies, both with isolated and with cellular DNA, where DMCPZ and DDMCPZ are more active than CPZ itself. In summary, side-chain demethylation of CPZ, as a consequence of Phase I biotransformation, does not result a photodetoxification. Instead, it leads to metabolites that exhibit in an even enhanced photo(geno)toxicity.
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      PubDate: 2016-11-10T14:09:26Z
      DOI: 10.1016/j.taap.2016.10.024
      Issue No: Vol. 313 (2016)
       
  • Differential modulation of FXR activity by chlorophacinone and ivermectin
           analogs
    • Authors: Chia-Wen Hsu; Jui-Hua Hsieh; Ruili Huang; Dirk Pijnenburg; Thai Khuc; Jon Hamm; Jinghua Zhao; Caitlin Lynch; Rinie van Beuningen; Xiaoqing Chang; René Houtman; Menghang Xia
      Pages: 138 - 148
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Chia-Wen Hsu, Jui-Hua Hsieh, Ruili Huang, Dirk Pijnenburg, Thai Khuc, Jon Hamm, Jinghua Zhao, Caitlin Lynch, Rinie van Beuningen, Xiaoqing Chang, René Houtman, Menghang Xia
      Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches. (Z)-Guggulsterone, chlorophacinone, ivermectin, and their analogs were profiled for their ability to alter CDCA-mediated FXR binding using a panel of 154 coregulator motifs and to induce or inhibit transactivation and coactivator recruitment activities of constitutive androstane receptor (CAR), liver X receptor alpha (LXRα), or pregnane X receptor (PXR). Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors. These findings collectively provide mechanistic insights regarding compound activities against FXR and possible explanations for in vivo toxicological observations of chlorophacinone, ivermectin, and their analogs.

      PubDate: 2016-11-10T14:09:26Z
      DOI: 10.1016/j.taap.2016.10.017
      Issue No: Vol. 313 (2016)
       
  • Regulation of steroid hormones and energy status with cysteamine and its
           effect on spermatogenesis
    • Authors: Yandi Wang; Yong Zhao; Shuai Yu; Yanni Feng; Hongfu Zhang; Xin Kou; Meiqiang Chu; Liantao Cui; Lan Li; Pengfei Zhang; Wei Shen; Lingjiang Min
      Pages: 149 - 158
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Yandi Wang, Yong Zhao, Shuai Yu, Yanni Feng, Hongfu Zhang, Xin Kou, Meiqiang Chu, Liantao Cui, Lan Li, Pengfei Zhang, Wei Shen, Lingjiang Min
      Although it is well known that cysteamine is a potent chemical for treating many diseases including cystinosis and it has many adverse effects, the effect of cysteamine on spermatogenesis is as yet unknown. Therefore the objective of this investigation was to explore the effects of cysteamine on spermatogenesis and the underlying mechanisms. Sheep were treated with vehicle control, 10mg/kg or 20mg/kg cysteamine for six months. After that, the semen samples were collected to determine the spermatozoa motility by computer-assisted sperm assay method. Blood samples were collected to detect the levels of hormones and the activity of enzymes. Spermatozoa and testis samples were collected to study the mechanism of cysteamine's actions. It was found that the effects of cysteamine on spermatogenesis were dose dependent. A low dose (10mg/kg) cysteamine treatment increased ovine spermatozoa motility; however, a higher dose (20mg/kg) decreased both spermatozoa concentration and motility. This decrease might be due to a reduction in steroid hormone production by the testis, a reduction in energy in the testis and spermatozoa, a disruption in the blood-testis barrier, or a breakdown in the vital signaling pathways involved in spermatogenesis. The inhibitory effects of cysteamine on sheep spermatogenesis may be used to model its effects on young male patients with cystinosis or other diseases that are treated with this drug. Further studies on spermatogenesis that focus on patients treated with cysteamine during the peripubertal stage are warranted.
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      PubDate: 2016-11-10T14:09:26Z
      DOI: 10.1016/j.taap.2016.10.025
      Issue No: Vol. 313 (2016)
       
  • Identification of the key pathway of oxazolinoanthracyclines mechanism of
           action in cells derived from human solid tumors
    • Authors: Marta Denel-Bobrowska; Małgorzata Łukawska; Aneta Rogalska; Ewa Forma; Magdalena Bryś; Irena Oszczapowicz; Agnieszka Marczak
      Pages: 159 - 169
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Marta Denel-Bobrowska, Małgorzata Łukawska, Aneta Rogalska, Ewa Forma, Magdalena Bryś, Irena Oszczapowicz, Agnieszka Marczak
      Oxazolinodoxorubicin (O-DOX) and oxazolinodaunorubicin (O-DAU) are novel anthracycline derivatives with a modified daunosamine moiety. In the present study, we evaluated the cytotoxicities, genotoxicities and abilities of O-DOX and O-DAU to induce apoptosis in cancer cell lines (SKOV-3; A549; HepG2), and compared the results with their parent drugs. We assessed antiproliferative activity by MTT assay. We evaluated apoptosis-inducing ability by double-staining with fluorescent probes (Hoechst 33258/propidium iodide), and by determining expression levels of genes involved in programmed cell death by reverse transcription-polymerase chain reaction. Genotoxicities of the compounds were tested by comet assays. Oxazolinoanthracyclines demonstrated high anti-tumor activity. O-DOX had significantly higher cytotoxicity, apoptosis-inducing ability, and genotoxicity compared with parental doxorubicin (DOX) in all tested conditions, while O-DAU activity differed among cell lines. The mechanism of oxazoline analog action appeared to involve the mitochondrial pathway of programmed cell death. These results provide further information about oxazoline derivatives of commonly used anthracycline chemotherapy agents. O-DOX and O-DAU have the ability to induce apoptosis in tumor cells.
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      PubDate: 2016-11-10T14:09:26Z
      DOI: 10.1016/j.taap.2016.10.018
      Issue No: Vol. 313 (2016)
       
  • Enterolactone: A novel radiosensitizer for human breast cancer cell lines
           through impaired DNA repair and increased apoptosis
    • Authors: Bahareh Bigdeli; Bahram Goliaei; Nastaran Masoudi-Khoram; Najmeh Jooyan; Alireza Nikoofar; Maryam Rouhani; Abbas Haghparast; Fatemeh Mamashli
      Pages: 180 - 194
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Bahareh Bigdeli, Bahram Goliaei, Nastaran Masoudi-Khoram, Najmeh Jooyan, Alireza Nikoofar, Maryam Rouhani, Abbas Haghparast, Fatemeh Mamashli
      Introduction Radiotherapy is a potent treatment against breast cancer, which is the most commonly diagnosed cancer among women. However, the emergence of radioresistance due to increased DNA repair leads to radiotherapeutic failure. Applying polyphenols combined with radiation is a more promising method leading to better survival. Enterolactone, a phytoestrogenic polyphenol, has been reported to inhibit an important radioresistance signaling pathway, therefore we conjectured that enterolactone could enhance radiosensitivity in breast cancer. To assess this hypothesis, radiation response of enterolactone treated MDA-MB-231 and T47D cell lines and corresponding cellular mechanisms were investigated. Methods Cytotoxicity of enterolactone was measured via MTT assay. Cells were treated with enterolactone before X-irradiation, and clonogenic assay was used to evaluate radiosensitivity. Cell cycle distribution and apoptosis were measured by flow cytometric analysis. In addition, DNA damages and corresponding repair, chromosomal damages, and aberrations were assessed by comet, micronucleus, and cytogenetic assays, respectively. Results Enterolactone decreased the viability of cells in a concentration- and time dependent manner. Enterolactone significantly enhanced radiosensitivity of cells by abrogating G2/M arrest, impairing DNA repair, and increasing radiation-induced apoptosis. Furthermore, increased chromosomal damages and aberrations were detected in cells treated with enterolactone combined with X-rays than X-ray alone. These effects were more prominent in T47D than MDA-MB-231 cells. Discussion To our knowledge, this is the first report that enterolactone is a novel radiosensitizer for breast cancer irrespective of estrogen receptor status.
      Authors propose enterolactone as a candidate for combined therapy to decrease the radiation dose delivered to patients and subsequent side effects.
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      PubDate: 2016-11-17T04:55:33Z
      DOI: 10.1016/j.taap.2016.10.021
      Issue No: Vol. 313 (2016)
       
  • Inhibition of glycogen synthase kinase 3beta ameliorates
           triptolide-induced acute cardiac injury by desensitizing mitochondrial
           permeability transition
    • Authors: Wenwen Wang; Yanqin Yang; Zhewen Xiong; Jiamin Kong; Xinlu Fu; Feihai Shen; Zhiying Huang
      Pages: 195 - 203
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Wenwen Wang, Yanqin Yang, Zhewen Xiong, Jiamin Kong, Xinlu Fu, Feihai Shen, Zhiying Huang
      Triptolide (TP), a diterpene triepoxide, is a major active component of Tripterygium wilfordii extracts, which are prepared as tablets and has been used clinically for the treatment of inflammation and autoimmune disorders. However, TP's therapeutic potential is limited by severe adverse effects. In a previous study, we reported that TP induced mitochondria dependent apoptosis in cardiomyocytes. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase that plays important roles in the necrosis and apoptosis of cardiomyocytes. Our study aimed to investigate the role of GSK-3β in TP-induced cardiotoxicity. Inhibition of GSK-3β activity by SB 216763, a potent and selective GSK-3 inhibitor, prominently ameliorated the detrimental effects in C57BL/6J mice with TP administration, which was associated with a correction of GSK-3β overactivity. Consistently, in TP-treated H9c2 cells, SB 216763 treatment counteracted GSK-3β overactivity, improved cell viability, and prevented apoptosis by modulating the expression of Bcl-2 family proteins. Mechanistically, GSK-3β interacted with and phosphorylated cyclophilin F (Cyp-F), a key regulator of mitochondrial permeability transition pore (mPTP). GSK-3β inhibition prevented the phosphorylation and activation of Cyp-F, and desensitized mPTP. Our findings suggest that pharmacological targeting of GSK-3β could represent a promising therapeutic strategy for protecting against cardiotoxicity induced by TP.
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      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.10.007
      Issue No: Vol. 313 (2016)
       
  • Isoliquiritigenin exhibits anti-proliferative properties in the pituitary
           independent of estrogen receptor function
    • Authors: Karen E. Weis; Lori T. Raetzman
      Pages: 204 - 214
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Karen E. Weis, Lori T. Raetzman
      The plant flavonoid isoliquiritigenin (ISL) is a botanical estrogen widely taken as an herbal supplement to ease the symptoms of menopause. ISL has been also shown to have anti-tumor properties in a number of cancer cell backgrounds. However, the effects of ISL on normal cells are less well known and virtually unstudied in the context of the pituitary gland. We have established a pituitary explant culture model to screen chemical agents for gene expression changes within the pituitary gland during a period of active proliferation and differentiation. Using this whole-organ culture system we found ISL to be weakly estrogenic based on its ability to induce Cckar mRNA expression, an estrogen receptor (ER) mediated gene. Using a range of ISL from 200nM to 200μM, we discovered that ISL promoted cell proliferation at a low concentration, yet potently inhibited proliferation at the highest concentration. ICI 182,780 failed to antagonize ISL's repression of pituitary cell proliferation, indicating the effect is independent of ER signaling. Coincident with a decrease in proliferating cells, we observed down-regulation of transcript for cyclin D2 and E2 and a strong induction of mRNA and protein for the cyclin dependent kinase inhibitor Cdkn1a (p21). Importantly, high dose ISL did not alter the balance of progenitor vs. differentiated cell types within the pituitary explants and they seemed otherwise healthy; however, TUNEL staining revealed an increase in apoptotic cell death in ISL treated cultures. Our results merit further examination of ISL as an anti-tumor agent in the pituitary gland.

      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.09.027
      Issue No: Vol. 313 (2016)
       
  • Carvedilol suppresses circulating and hepatic IL-6 responsible for
           hepatocarcinogenesis of chronically damaged liver in rats
    • Authors: Mohamed Balaha; Samah Kandeel; Waleed Barakat
      Pages: 1 - 11
      Abstract: Publication date: 15 November 2016
      Source:Toxicology and Applied Pharmacology, Volume 311
      Author(s): Mohamed Balaha, Samah Kandeel, Waleed Barakat
      Carvedilol is an anti-oxidant non-selective β-blocker used for reduction of portal blood pressure, prophylaxis of esophageal varices development and bleeding in chronic liver diseases. Recently, it exhibited potent anti-inflammatory, anti-fibrotic, anti-proliferative and anti-carcinogenic effects. In the present study, we evaluated the possible suppressive effect of carvedilol on circulating and hepatic IL-6 levels responsible for hepatocarcinogenesis in a rat model of hepatic cirrhosis. Besides, its effect on hepatic STAT-3 levels, function tests, oxidative stress markers, and hydroxyproline content, hepatic tissue histopathological changes and immunohistochemical expression of E & N-cadherin. Nine-week-old male Wistar rats injected intraperitoneal by 1ml/kg 10% CCL4 in olive oil three times/week (every other day) for 12weeks to induce hepatic cirrhosis. Carvedilol (10mg/kg/day suspended in 0.5% CMC orally), silymarin (50mg/kg/day suspended in 0.5% CMC orally) or combination of both used to treat hepatic cirrhosis from 15th to 84th day. Our data showed that carvedilol and silymarin co-treatment each alone or in combination efficiently reduced the elevated serum IL-6, ALT, AST, ALP and BIL, hepatic IL-6, STAT-3, MDA levels and hydroxyproline content. In addition, it elevated the reduced serum ALB level, hepatic CAT activity and GSH level. Meanwhile, it apparently restored the normal hepatic architecture, collagen distribution and immunohistochemical E & N-cadherin expression. Furthermore, carvedilol was superior to silymarin in improving MDA level. Moreover, the combination of carvedilol and silymarin showed an upper hand in amelioration of the CCL4 induced hepatotoxicity than each alone. Therefore, carvedilol could be promising in prevention of hepatocarcinogenesis in chronic hepatic injuries.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.012
      Issue No: Vol. 311 (2016)
       
  • UDCA and CDCA alleviate 17α-ethinylestradiol-induced cholestasis through
           PKA-AMPK pathways in rats
    • Authors: Xiaojiaoyang Li; Zihang Yuan; Runping Liu; Hozeifa M. Hassan; Hang Yang; Rong Sun; Luyong Zhang; Zhenzhou Jiang
      Pages: 12 - 25
      Abstract: Publication date: 15 November 2016
      Source:Toxicology and Applied Pharmacology, Volume 311
      Author(s): Xiaojiaoyang Li, Zihang Yuan, Runping Liu, Hozeifa M. Hassan, Hang Yang, Rong Sun, Luyong Zhang, Zhenzhou Jiang
      Estrogen-induced cholestasis, known as intrahepatic cholestasis of pregnancy (ICP), is an estrogen-related liver disease that is widely recognized as female or pregnancy-specific. Our previous findings showed that the synthetic estrogen, 17α-ethinylestradiol (EE), induced cholestatic injury through ERK1/2-LKB1-AMP-activated protein kinase (AMPK) signaling pathway and its mediated suppression of farnesoid X receptor (FXR). To investigate the role played by bile acids in EE-induced cholestasis, we evaluated the effects of chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) on sandwich cultured rat primary hepatocytes (SCRHs) and an in vivo rat model. Our results showed that, both CDCA and UDCA significantly induced time- and concentration-dependent reduction in AMPK phosphorylation in SCRHs. Despite having different effects on FXR activation, CDCA and UDCA both inhibited EE-induced AMPK activation, accompanied with the up-regulation of FXR and its downstream bile acid transporters. However, although DCA activates FXR and induces SHP, it was unable to alleviate EE-induced FXR suppression and further aggravated EE-induced cholestasis. We further demonstrated that both CDCA and UDCA, but not DCA, activated cyclic AMP dependent protein kinase (PKA) in SCRHs and the livers of male rats (8weeks old) liver. Furthermore, PKA antagonist, H89, blocked the AMPK inhibition by CDCA and UDCA, and pharmacological and genetic activation of PKA suppressed EE-induced AMPK activation and its downstream effects. Collectively, these results suggest that CDCA and UDCA protect against estrogen-induced cholestatic injury via PKA signaling pathway and up-regulation of EE-suppressed FXR, which suggests a potential therapeutic target for ICP.
      Graphical abstract image

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.011
      Issue No: Vol. 311 (2016)
       
  • Omeprazole induces heme oxygenase-1 in fetal human pulmonary microvascular
           endothelial cells via hydrogen peroxide-independent Nrf2 signaling pathway
           
    • Authors: Ananddeep Patel; Shaojie Zhang; Amrit Kumar Shrestha; Paramahamsa Maturu; Bhagavatula Moorthy; Binoy Shivanna
      Pages: 26 - 33
      Abstract: Publication date: 15 November 2016
      Source:Toxicology and Applied Pharmacology, Volume 311
      Author(s): Ananddeep Patel, Shaojie Zhang, Amrit Kumar Shrestha, Paramahamsa Maturu, Bhagavatula Moorthy, Binoy Shivanna
      Omeprazole (OM) is an aryl hydrocarbon receptor (AhR) agonist and a proton pump inhibitor that is used to treat humans with gastric acid related disorders. Recently, we showed that OM induces NAD (P) H quinone oxidoreductase-1 (NQO1) via nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent mechanism. Heme oxygenase-1 (HO-1) is another cytoprotective and antioxidant enzyme that is regulated by Nrf2. Whether OM induces HO-1 in fetal human pulmonary microvascular endothelial cells (HPMEC) is unknown. Therefore, we tested the hypothesis that OM will induce HO-1 expression via Nrf2 in HPMEC. OM induced HO-1 mRNA and protein expression in a dose-dependent manner. siRNA-mediated knockdown of AhR failed to abrogate, whereas knockdown of Nrf2 abrogated HO-1 induction by OM. To identify the underlying molecular mechanisms, we determined the effects of OM on cellular hydrogen peroxide (H2O2) levels since oxidative stress mediated by the latter is known to activate Nrf2. Interestingly, the concentration at which OM induced HO-1 also increased H2O2 levels. Furthermore, H2O2 independently augmented HO-1 expression. Although N-acetyl cysteine (NAC) significantly decreased H2O2 levels in OM-treated cells, we observed that OM further increased HO-1 mRNA and protein expression in NAC-pretreated compared to vehicle-pretreated cells, suggesting that OM induces HO-1 via H2O2-independent mechanisms. In conclusion, we provide evidence that OM transcriptionally induces HO-1 via AhR - and H2O2 - independent, but Nrf2 - dependent mechanisms. These results have important implications for human disorders where Nrf2 and HO-1 play a beneficial role.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.002
      Issue No: Vol. 311 (2016)
       
  • 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases necroinflammation and
           hepatic stellate cell activation but does not exacerbate experimental
           liver fibrosis in mice
    • Authors: Cheri L. Lamb; Giovan N. Cholico; Xinzhu Pu; Gerald D. Hagler; Kenneth A. Cornell; Kristen A. Mitchell
      Pages: 42 - 51
      Abstract: Publication date: 15 November 2016
      Source:Toxicology and Applied Pharmacology, Volume 311
      Author(s): Cheri L. Lamb, Giovan N. Cholico, Xinzhu Pu, Gerald D. Hagler, Kenneth A. Cornell, Kristen A. Mitchell
      2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant and high-affinity ligand for the aryl hydrocarbon receptor (AhR). Increasing evidence indicates that AhR signaling contributes to wound healing, which involves the coordinated deposition and remodeling of the extracellular matrix. In the liver, wound healing is attributed to the activation of hepatic stellate cells (HSCs), which mediate fibrogenesis through the production of soluble mediators and collagen type I. We recently reported that TCDD treatment increases the activation of human HSCs in vitro. The goal of this study was to determine how TCDD impacts HSC activation in vivo using a mouse model of experimental liver fibrosis. To elicit fibrosis, C57BL6/male mice were treated twice weekly for 8weeks with 0.5ml/kg carbon tetrachloride (CCl4). TCDD (20μg/kg) or peanut oil (vehicle) was administered once a week during the last 2weeks. Results indicate that TCDD increased liver-body-weight ratios, serum alanine aminotransferase activity, and hepatic necroinflammation in CCl4-treated mice. Likewise, TCDD treatment increased mRNA expression of HSC activation and fibrogenesis genes, namely α-smooth muscle actin, desmin, delta-like homolog-1, TGF-β1, and collagen type I. However, TCDD treatment did not exacerbate fibrosis, nor did it increase the collagen content of the liver. Instead, TCDD increased hepatic collagenase activity and increased expression of matrix metalloproteinase (MMP)-13 and the matrix regulatory proteins, TIMP-1 and PAI-1. These results support the conclusion that TCDD increases CCl4-induced liver damage and exacerbates HSC activation, yet collagen deposition and the development of fibrosis may be limited by TCDD-mediated changes in extracellular matrix remodeling.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.09.025
      Issue No: Vol. 311 (2016)
       
  • Dapoxetine attenuates testosterone-induced prostatic hyperplasia in rats
           by the regulation of inflammatory and apoptotic proteins
    • Authors: Rabab H. Sayed; Muhammed A. Saad; Ayman E. El-Sahar
      Pages: 52 - 60
      Abstract: Publication date: 15 November 2016
      Source:Toxicology and Applied Pharmacology, Volume 311
      Author(s): Rabab H. Sayed, Muhammed A. Saad, Ayman E. El-Sahar
      Serotonin level plays a role in suppressing the pathological findings of benign prostatic hyperplasia (BPH). Thus a new selective serotonin reuptake inhibitor, dapoxetine was used to test its ability to ameliorate the pathological changes in the rat prostate. A dose response curve was constructed between the dose of dapoxetine and prostate weight as well as relative prostate weight, then a 5mg/kg dose was used as a representative dose for dapoxetine administration. Rats were divided into four groups; the control group that received the vehicle; the BPH-induced group received daily s.c injection of 3mg/kg testosterone propionate dissolved in olive oil for four weeks; BPH-induced group treated with finasteride 5mg/kg/day p.o and BPH-induced group treated with dapoxetine 5mg/kg/day p.o. Injection of testosterone increased prostate weight and relative prostate weight which were both returned back to the normal value after treatment with dapoxetine as well as finasteride. Testosterone also upregulated androgen receptor (AR) and proliferating cell nuclear antigen gene expression. Furthermore, testosterone injection elevated cyclooxygenase-II (COX II), inducible nitric oxide synthase (iNOS), B-cell lymphoma-2 (Bcl2) expression and tumor necrosis factor alpha content and reduced caspase-3 activity, Bcl-2-associated X protein (Bax) expression and Bax/Bcl2 ratio. Dapoxetine and finasteride administration reverted most of the changes made by testosterone injection. In conclusion, the current study provides an evidence for the protective effects of dapoxetine against testosterone-induced BPH in rats. This can be attributed, at least in part, to decreasing AR expression, and the anti-proliferative, anti-inflammatory and pro-apoptotic activities of dapoxetine in BPH.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.09.024
      Issue No: Vol. 311 (2016)
       
  • Effects of Trans-Resveratrol on hyperglycemia-induced abnormal
           spermatogenesis, DNA damage and alterations in poly (ADP-ribose)
           polymerase signaling in rat testis
    • Authors: Ala` Abdelali; Maie Al-Bader; Narayana Kilarkaje
      Pages: 61 - 73
      Abstract: Publication date: 15 November 2016
      Source:Toxicology and Applied Pharmacology, Volume 311
      Author(s): Ala` Abdelali, Maie Al-Bader, Narayana Kilarkaje
      Diabetes induces oxidative stress, DNA damage and alters several intracellular signaling pathways in organ systems. This study investigated modulatory effects of Trans-Resveratrol on type 1 diabetes mellitus (T1DM)-induced abnormal spermatogenesis, DNA damage and alterations in poly (ADP-ribose) polymerase (PARP) signaling in rat testis. Trans-Resveratrol administration (5mg/kg/day, ip) to Streptozotocin-induced T1DM adult male Wistar rats from day 22–42 resulted in recovery of induced oxidative stress, abnormal spermatogenesis and inhibited DNA synthesis, and led to mitigation of 8-hydroxy-2'-deoxyguanosine formation in the testis and spermatozoa, and DNA double-strand breaks in the testis. Trans-Resveratrol aggravated T1DM-induced up-regulation of aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 expression; however, it did not modify the up-regulated total PARP and down-regulated PARP1 expressions, but recovered the decreased SirT1 (Sirtuin 1) levels in T1DM rat testis. Trans-Resveratrol, when given alone, reduced the poly (ADP-ribosyl)ation (pADPr) process in the testis due to an increase in PAR glycohydrolase activity, but when given to T1DM rats it did not affect the pADPr levels. T1DM with or without Trans-Resveratrol did not induce nuclear translocation of apoptosis-inducing factor and the formation of 50 kb DNA breaks, suggesting to the lack of caspase-3-independent cell death called parthanatos. T1DM with or without Trans-Resveratrol did not increase necrotic cell death in the testis. Primary spermatocytes, Sertoli cells, Leydig cells and intra-testicular vessels showed the expression of PARP pathway related proteins. In conclusion, Trans-Resveratrol mitigates T1DM-induced sperm abnormality and DNA damage, but does not significantly modulate PARP signaling pathway, except the SirT1 expression, in the rat testis.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.09.023
      Issue No: Vol. 311 (2016)
       
  • Characterization of heme oxygenase and biliverdin reductase gene
           expression in zebrafish (Danio rerio): Basal expression and response to
           pro-oxidant exposures
    • Authors: Andrew Holowiecki; Britton O'Shields; Matthew J. Jenny
      Pages: 74 - 87
      Abstract: Publication date: 15 November 2016
      Source:Toxicology and Applied Pharmacology, Volume 311
      Author(s): Andrew Holowiecki, Britton O'Shields, Matthew J. Jenny
      While heme is an important cofactor for numerous proteins, it is highly toxic in its unbound form and can perpetuate the formation of reactive oxygen species. Heme oxygenase enzymes (HMOX1 and HMOX2) degrade heme into biliverdin and carbon monoxide, with biliverdin subsequently being converted to bilirubin by biliverdin reductase (BVRa or BVRb). As a result of the teleost-specific genome duplication event, zebrafish have paralogs of hmox1 (hmox1a and hmox1b) and hmox2 (hmox2a and hmox2b). Expression of all four hmox paralogs and two bvr isoforms were measured in adult tissues (gill, brain and liver) and sexually dimorphic differences were observed, most notably in the basal expression of hmox1a, hmox2a, hmox2b and bvrb in liver samples. hmox1a, hmox2a and hmox2b were significantly induced in male liver tissues in response to 96h cadmium exposure (20μM). hmox2a and hmox2b were significantly induced in male brain samples, but only hmox2a was significantly reduced in male gill samples in response to the 96h cadmium exposure. hmox paralogs displayed significantly different levels of basal expression in most adult tissues, as well as during zebrafish development (24 to 120hpf). Furthermore, hmox1a, hmox1b and bvrb were significantly induced in zebrafish eleutheroembryos in response to multiple pro-oxidants (cadmium, hemin and tert-butylhydroquinone). Knockdown of Nrf2a, a transcriptional regulator of hmox1a, was demonstrated to inhibit the Cd-mediated induction of hmox1b and bvrb. These results demonstrate distinct mechanisms of hmox and bvr transcriptional regulation in zebrafish, providing initial evidence of the partitioning of function of the hmox paralogs.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.09.022
      Issue No: Vol. 311 (2016)
       
  • A microtubule inhibitor, ABT-751, induces autophagy and delays apoptosis
           in Huh-7 cells
    • Authors: Ren-Jie Wei; Su-Shuan Lin; Wen-Ren Wu; Lih-Ren Chen; Chien-Feng Li; Han-De Chen; Chien-Ting Chou; Ya-Chun Chen; Shih-Shin Liang; Shang-Tao Chien; Yow-Ling Shiue
      Pages: 88 - 98
      Abstract: Publication date: 15 November 2016
      Source:Toxicology and Applied Pharmacology, Volume 311
      Author(s): Ren-Jie Wei, Su-Shuan Lin, Wen-Ren Wu, Lih-Ren Chen, Chien-Feng Li, Han-De Chen, Chien-Ting Chou, Ya-Chun Chen, Shih-Shin Liang, Shang-Tao Chien, Yow-Ling Shiue
      The objective was to investigate the upstream mechanisms of apoptosis which were triggered by a novel anti-microtubule drug, ABT-751, in hepatocellular carcinoma-derived Huh-7 cells. Effects of ABT-751 were evaluated by immunocytochemistry, flow cytometric, alkaline comet, soft agar, immunoblotting, CytoID, green fluorescent protein-microtubule associated protein 1 light chain 3 beta detection, plasmid transfection, nuclear/cytosol fractionation, coimmunoprecipitation, quantitative reverse transcription-polymerase chain reaction, small-hairpin RNA interference and mitochondria/cytosol fractionation assays. Results showed that ABT-751 caused dysregulation of microtubule, collapse of mitochondrial membrane potential, generation of reactive oxygen species (ROS), DNA damage, G2/M cell cycle arrest, inhibition of anchorage-independent cell growth and apoptosis in Huh-7 cells. ABT-751 also induced early autophagy via upregulation of nuclear TP53 and downregulation of the AKT serine/threonine kinase (AKT)/mechanistic target of rapamycin (MTOR) pathway. Through modulation of the expression levels of DNA damage checkpoint proteins and G2/M cell cycle regulators, ABT-751 induced G2/M cell cycle arrest. Subsequently, ABT-751 triggered apoptosis with marked downregulation of B-cell CLL/lymphoma 2, upregulation of mitochondrial BCL2 antagonist/killer 1 and BCL2 like 11 protein levels, and cleavages of caspase 8 (CASP8), CASP9, CASP3 and DNA fragmentation factor subunit alpha proteins. Suppression of ROS significantly decreased ABT-751-induced autophagic and apoptotic cells. Pharmacological inhibition of autophagy significantly increased the percentages of ABT-751-induced apoptotic cells. The autophagy induced by ABT-751 plays a protective role to postpone apoptosis by exerting adaptive responses following microtubule damage, ROS and/or impaired mitochondria.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.09.021
      Issue No: Vol. 311 (2016)
       
  • Dietary flavonoid derivatives enhance chemotherapeutic effect by
           inhibiting the DNA damage response pathway
    • Authors: Ching-Ying Kuo; István Zupkó; Fang-Rong Chang; Attila Hunyadi; Chin-Chung Wu; Teng-Song Weng; Hui-Chun Wang
      Pages: 99 - 105
      Abstract: Publication date: 15 November 2016
      Source:Toxicology and Applied Pharmacology, Volume 311
      Author(s): Ching-Ying Kuo, István Zupkó, Fang-Rong Chang, Attila Hunyadi, Chin-Chung Wu, Teng-Song Weng, Hui-Chun Wang
      Flavonoids are the most common group of polyphenolic compounds and abundant in dietary fruits and vegetables. Diet high in vegetables or dietary flavonoid supplements is associated with reduced mortality rate for patients with breast cancer. Many studies have been proposed for mechanisms linking flavonoids to improving chemotherapy efficacy in many types of cancers, but data on this issue is still limited. Herein, we report on a new mechanism through which dietary flavonoids inhibit DNA damage checkpoints and repair pathways. We found that dietary flavonoids could inhibit Chk1 phosphorylation and decrease clonogenic cell growth once breast cancer cells receive ultraviolet irradiation, cisplatin, or etoposide treatment. Since the ATR-Chk1 pathway mainly involves response to DNA replication stress, we propose that flavonoid derivatives reduce the side effect of chemotherapy by improving the sensitivity of cycling cells. Therefore, we propose that increasing intake of common dietary flavonoids is beneficial to breast cancer patients who are receiving DNA-damaging chemotherapy, such as cisplatin or etoposide-based therapy.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.09.019
      Issue No: Vol. 311 (2016)
       
  • Downregulation of NEDD9 by apigenin suppresses migration, invasion, and
           metastasis of colorectal cancer cells
    • Authors: Jin Dai; Peter G. Van Wie; Leonard Yenwong Fai; Donghern Kim; Lei Wang; Pratheeshkumar Poyil; Jia Luo; Zhuo Zhang
      Pages: 106 - 112
      Abstract: Publication date: 15 November 2016
      Source:Toxicology and Applied Pharmacology, Volume 311
      Author(s): Jin Dai, Peter G. Van Wie, Leonard Yenwong Fai, Donghern Kim, Lei Wang, Pratheeshkumar Poyil, Jia Luo, Zhuo Zhang
      Apigenin is a natural flavonoid which possesses multiple anti-cancer properties such as anti-proliferation, anti-inflammation, and anti-metastasis in many types of cancers including colorectal cancer. Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is a multi-domain scaffolding protein of the Cas family which has been shown to correlate with cancer metastasis and progression. The present study investigates the role of NEDD9 in apigenin-inhibited cell migration, invasion, and metastasis of colorectal adenocarcinoma DLD1 and SW480 cells. The results show that knockdown of NEDD9 inhibited cell migration, invasion, and metastasis and that overexpression of NEDD9 promoted cell migration and invasion of DLD1 cells and SW4890 cells. Apigenin treatment attenuated NEDD9 expression at protein level, resulting in reduced phosphorylations of FAK, Src, and Akt, leading to inhibition on cell migration, invasion, and metastasis of both DLD1 and SW480 cells. The present study has demonstrated that apigenin inhibits cell migration, invasion, and metastasis through NEDD9/Src/Akt cascade in colorectal cancer cells. NEDD9 may function as a biomarker for evaluation of cancer aggressiveness and for selection of therapeutic drugs against cancer progression.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.09.016
      Issue No: Vol. 311 (2016)
       
  • Acute lung injury and persistent small airway disease in a rabbit model of
           chlorine inhalation
    • Authors: Sadiatu Musah; Connie F. Schlueter; David M. Humphrey; Karen S. Powell; Andrew M. Roberts; Gary W. Hoyle
      Abstract: Publication date: Available online 30 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Sadiatu Musah, Connie F. Schlueter, David M. Humphrey, Karen S. Powell, Andrew M. Roberts, Gary W. Hoyle
      Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24h after exposure to 800ppm chlorine for 4min to study acute effects or up to 7days after exposure to 400ppm for 8min to study longer term effects. Acute effects observed 6 or 24h after inhalation of 800ppm chlorine for 4min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400ppm chlorine for 8min, rabbits exhibited mild hypoxemia, increased area of pressure–volume loops, and airway hyperreactivity. Lung histology 7days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury.

      PubDate: 2016-12-01T08:25:54Z
      DOI: 10.1016/j.taap.2016.11.017
       
  • Benznidazole, the trypanocidal drug used for Chagas disease, induces
           hepatic NRF2 activation and attenuates the inflammatory response in a
           murine model of sepsis
    • Authors: Flavia Lambertucci; Omar Motiño; Silvina Villar; Juan Pablo Rigalli; María de Luján Alvarez; Viviana Catania; Paloma Martín-Sanz; Cristina Ester Carnovale; Ariel Darío Quiroga; Daniel Eleazar Francés; María Teresa Ronco
      Abstract: Publication date: Available online 27 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Flavia Lambertucci, Omar Motiño, Silvina Villar, Juan Pablo Rigalli, María de Luján Alvarez, Viviana Catania, Paloma Martín-Sanz, Cristina Ester Carnovale, Ariel Darío Quiroga, Daniel Eleazar Francés, María Teresa Ronco
      Molecular mechanisms on sepsis progression are linked to the imbalance between reactive oxygen species (ROS) production and cellular antioxidant capacity. Previous studies demonstrated that benznidazole (BZL), known for its antiparasitic action on Trypanosoma cruzi, has immunomodulatory effects, increasing survival in C57BL/6 mice in a model of polymicrobial sepsis induced by cecal ligation puncture (CLP). The mechanism by which BZL inhibits inflammatory response in sepsis is poorly understood. Also, our group recently reported that BZL is able to activate the nuclear erythroid 2-related factor 2 (NRF2) in vitro. The aim of the present work was to delineate the beneficial role of BZL during sepsis, analyzing its effects on the cellular redox status and the possible link to the innate immunity receptor TLR4. Specifically, we analyzed the effect of BZL on Nrf2 regulation and TLR4 expression in liver of mice 24hours post-CLP. BZL was able to induce NRF2 nuclear protein localization in CLP mice. Also, we found that protein kinase C (PKC) is involved in the NRF2 nuclear accumulation and induction of its target genes. In addition, BZL prompted a reduction in hepatic CLP-induced TLR4 protein membrane localization, evidencing its immunomodulatory effects. Together, our results demonstrate that BZL induces hepatic NRF2 activation with the concomitant increase in the antioxidant defenses, and the attenuation of inflammatory response, in part, by inhibiting TLR4 expression in a murine model of sepsis.
      Graphical abstract image

      PubDate: 2016-12-01T08:25:54Z
      DOI: 10.1016/j.taap.2016.11.015
       
  • 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
      Abstract: Publication date: Available online 30 November 2016
      Source:Toxicology and Applied Pharmacology
      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: 2016-12-01T08:25:54Z
      DOI: 10.1016/j.taap.2016.11.009
       
  • Protective role of hypoxia-inducible factor-1α-dependent CD39 and CD73 in
           fulminant acute liver failure
    • Authors: Eunyoung Tak; Dong-Hwan Jung; Seok-Hwan Kim; Gil-Chun Park; Dae Young Jun; Jooyoung Lee; Bo-hyun Jung; Varvara A. Kirchner; Shin Hwang; Gi-Won Song; Sung-Gyu Lee
      Abstract: Publication date: Available online 27 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Eunyoung Tak, Dong-Hwan Jung, Seok-Hwan Kim, Gil-Chun Park, Dae Young Jun, Jooyoung Lee, Bo-hyun Jung, Varvara A. Kirchner, Shin Hwang, Gi-Won Song, Sung-Gyu Lee
      Acute liver failure (ALF) is a severe life-threatening disease which usually arises in patients with-irreversible liver illnesses. Although human ectonucleotide triphosphate diphosphohydrolase-1, E-NTPDase1 (CD39) and ecto-5′-nucleotidase, Ecto5′NTase (CD73) are known to protect tissues from ALF, the expression and function of CD39 and CD73 during ALF are currently not fully investigated. We tested whether CD39 and CD73 are upregulated by hypoxia inducible factor (HIF)-1α, and improve ischemic tolerance to ALF. To test our hypothesis, liver biopsies were obtained and we found that CD39 and CD73 mRNA and proteins from human specimens were dramatically elevated in ALF. We investigated that induction of CD39 and CD73 in ALF-related with wild type mice. In contrast, deletion of cd39 and cd73 mice has severe ALF. In this study, we concluded that CD39 and CD73 are molecular targets for the development of drugs for ALF patients care.
      Graphical abstract image

      PubDate: 2016-12-01T08:25:54Z
      DOI: 10.1016/j.taap.2016.11.016
       
  • The regulation of cellular apoptosis by the ROS-triggered PERK/EIF2α/chop
           pathway plays a vital role in bisphenol A-induced male reproductive
           toxicity
    • Authors: Yin Yanlin; Dai Zhihong Cui Xiao Jiang Wenbin Liu Fei
      Abstract: Publication date: 1 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 314
      Author(s): Li Yin, Yanlin Dai, Zhihong Cui, Xiao Jiang, Wenbin Liu, Fei Han, Ao Lin, Jia Cao, Jinyi Liu
      Bisphenol A (2,2-bis(4-hydroxyphenyl)propane, BPA) is ubiquitous in the environment, wildlife, and humans. Evidence from past studies suggests that BPA is associated with decreased semen quality. However, the molecular basis for the adverse effect of BPA on male reproductive toxicity remains unclear. We evaluated the effect of BPA on mouse spermatocytes GC-2 cells and adult mice, and we explored the potential mechanism of its action. The results showed that BPA inhibited cell proliferation and increased the apoptosis rate. The testes from BPA-treated mice showed fewer spermatogenic cells and sperm in the seminiferous tubules. In addition, BPA caused reactive oxygen species (ROS) accumulation. Previous study has verified that mitochondrion was the organelle affected by the BPA-triggered ROS accumulation. We found that BPA induced damage to the endoplasmic reticulum (ER) in addition to mitochondria, and most ER stress-related proteins were activated in cellular and animal models. Knocking down of the PERK/EIF2α/chop pathway, one of the ER stress pathways, partially recovered the BPA-induced cell apoptosis. In addition, an ROS scavenger attenuated the expression of the PERK/EIF2α/chop pathway-related proteins. Taken together, these data suggested that the ROS regulated PERK/EIF2α/chop pathway played a vital role in BPA-induced male reproductive toxicity.
      Graphical abstract image

      PubDate: 2016-12-01T08:25:54Z
       
  • Secretory function of ovarian cells and myometrial contractions in cow are
           affected by chlorinated insecticides (chlordane, heptachlor, mirex) in
           vitro
    • Authors: Michael Hubert Wrobel; Jaroslaw Mlynarczuk
      Abstract: Publication date: Available online 22 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Michael Hubert Wrobel, Jaroslaw Mlynarczuk
      The aim of the study was to investigate the effect of chlordane, heptachlor and mirex, on hormonal regulation of the force of myometrial contractions. Myometrial, endometrial, granulosa and luteal cells as well as strips of myometrium from non-pregnant cows were incubated with three insecticides at environmentally relevant doses (0.1, 1 or 10ng/ml). None of the insecticides affected the viability of studied cells. Chlordane stimulated, while heptachlor and mirex inhibited, secretion of testosterone and estradiol from granulosa cells as well as secretion of progesterone from luteal cells, respectively. Secretion of oxytocin (OT) from granulosa cells was increased after incubation with all studied insecticides. Only mirex stimulated OT secretion from luteal cells, while heptachlor inhibited this effect. None of them affected synthesis of OT in luteal cells and prostaglandins (PGF2 and PGE2) secretion from uterine cells, except PGE2 secretion from endometrial cells was decreased when the cells were incubated with 0.1ng/ml of chlordane. Basal and OT-stimulated myometrial contractions were increased by mirex and decreased by heptachlor. The data show that the insecticides altered secretory function of ovarian cells. Heptachlor and mirex affected also myometrial contractions in vitro, but uterine secretion of prostaglandins were not involved in the mechanism of that adverse effect of insecticides. The data indicate on potential of these insecticides to disturb fertilisation, blastocyst implantation or even the length of gestation.

      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.11.011
       
  • A data-driven weighting scheme for multivariate phenotypic endpoints
           recapitulates zebrafish developmental cascades
    • Authors: Guozhu Zhang; Kyle R. Roell; Lisa Truong; Robert L. Tanguay; David M. Reif
      Abstract: Publication date: Available online 22 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Guozhu Zhang, Kyle R. Roell, Lisa Truong, Robert L. Tanguay, David M. Reif
      Zebrafish have become a key alternative model for studying health effects of environmental stressors, partly due to their genetic similarity to humans, fast generation time, and the efficiency of generating high-dimensional systematic data. Studies aiming to characterize adverse health effects in zebrafish typically include several phenotypic measurements (endpoints). While there is a solid biomedical basis for capturing a comprehensive set of endpoints, making summary judgments regarding health effects requires thoughtful integration across endpoints. Here, we introduce a Bayesian method to quantify the informativeness of 17 distinct zebrafish endpoints as a data-driven weighting scheme for a multi-endpoint summary measure, called weighted Aggregate Entropy (wAggE). We implement wAggE using high-throughput screening (HTS) data from zebrafish exposed to five concentrations of all 1060 ToxCast chemicals. Our results show that our empirical weighting scheme provides better performance in terms of the Receiver Operating Characteristic (ROC) curve for identifying significant morphological effects and improves robustness over traditional curve-fitting approaches. From a biological perspective, our results suggest that developmental cascade effects triggered by chemical exposure can be recapitulated by analyzing the relationships among endpoints. Thus, wAggE offers a powerful approach for analysis of multivariate phenotypes that can reveal underlying etiological processes.

      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.11.010
       
  • SIRT1 protects cardiac cells against apoptosis induced by zearalenone or
           its metabolites α- and β-zearalenol through an autophagy-dependent
           pathway
    • Authors: Intidhar Ben Salem; Manel Boussabbeh; Julie Pires Da Silva; Arnaud Guilbert; Hassen Bacha; Salwa Abid-Essefi; Christophe Lemaire
      Abstract: Publication date: Available online 23 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Intidhar Ben Salem, Manel Boussabbeh, Julie Pires Da Silva, Arnaud Guilbert, Hassen Bacha, Salwa Abid-Essefi, Christophe Lemaire
      Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin produced by several species of Fusarium in cereals and agricultural products. The major ZEN metabolites are α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL). In the present study, we investigated the underlying mechanism of the toxicity induced by ZEN, α-ZOL and β-ZOL in cardiac cells (H9c2). We show that treatment with ZEN or its metabolites induces the activation of the mitochondrial pathway of apoptosis as characterized by an increase in ROS generation, a loss of mitochondrial transmembrane potential (ΔΨm) and an activation of caspases. Besides, we demonstrate that these mycotoxins promote the activation of autophagy before the onset of apoptosis. Indeed, we observed that a short-time (6h) treatment with ZEN, α-ZOL or β-ZOL, increased the level of Beclin-1 and LC3-II and induced the accumulation of the CytoID® autophagy detection probe. Moreover, the inhibition of autophagy by Chloroquine significantly increased cell death induced by ZEN, α-ZOL or β-ZOL, suggesting that the activation of autophagy serves as a cardioprotective mechanism against these mycotoxins. In addition, we found that the inhibition (EX527) or the knockdown of SIRT1 (siRNA) significantly increased apoptosis induced by ZEN or its derivatives whereas SIRT1 activation with RSV greatly prevents the cytotoxic effects of these mycotoxins. By contrast, when autophagy was inhibited by CQ, the activation of SIRT1 by RSV had no protection against the cardiotoxicity of ZEN or its metabolites, suggesting that SIRT1 protects cardiac cells by an autophagy-dependent pathway.

      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.11.012
       
  • Single toxin dose-response models revisited
    • Authors: Eugene Demidenko; Glaholt Kyker-Snowman Shaw Chen
      Abstract: Publication date: Available online 12 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Eugene Demidenko, SP Glaholt, E Kyker-Snowman, JR Shaw, CY Chen
      The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of the four models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48h) toxicity tests with mortality as a function of NiCl or CuSO4 toxin.

      PubDate: 2016-11-17T04:55:33Z
       
  • Obeticholic acid protects against carbon tetrachloride-induced acute liver
           injury and inflammation
    • Authors: Da-Gang Zhang; Cheng Zhang; Jun-Xian Wang; Bi-Wei Wang; Hua Wang; Zhi-Hui Zhang; Yuan-Hua Chen; Yan Lu; Li Tao; Jian-Qing Wang; Xi Chen; De-Xiang Xu
      Abstract: Publication date: Available online 16 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Da-Gang Zhang, Cheng Zhang, Jun-Xian Wang, Bi-Wei Wang, Hua Wang, Zhi-Hui Zhang, Yuan-Hua Chen, Yan Lu, Li Tao, Jian-Qing Wang, Xi Chen, De-Xiang Xu
      The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl4)-induced acute liver injury. Mice were intraperitoneally injected with CCl4 (0.15ml/kg). In CCl4 +OCA group, mice were orally with OCA (5mg/kg) 48, 24 and 1h before CCl4. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl4-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl4-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl4-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl4-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl4-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl4-induced acute liver injury. These results suggest that OCA protects against CCl4-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury.

      PubDate: 2016-11-17T04:55:33Z
      DOI: 10.1016/j.taap.2016.11.006
       
  • Sibutramine provokes apoptosis of aortic endothelial cells through altered
           production of reactive oxygen and nitrogen species
    • Authors: Yoshifumi Morikawa; Akinobu Shibata; Naoko Okumura; Akira Ikari; Yasuhide Sasajima; Koichi Suenami; Kiyohito Sato; Yuji Takekoshi; Ossama El-Kabbani; Toshiyuki Matsunaga
      Abstract: Publication date: Available online 9 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Yoshifumi Morikawa, Akinobu Shibata, Naoko Okumura, Akira Ikari, Yasuhide Sasajima, Koichi Suenami, Kiyohito Sato, Yuji Takekoshi, Ossama El-Kabbani, Toshiyuki Matsunaga
      Overdose administration of sibutramine, a serotonin-noradrenalin reuptake inhibitor, is considered to elicit severe side effects including hypertension, whose pathogenic mechanism remains unclear. Here, we found that 48-h incubation with >10μM sibutramine provokes apoptosis of human aortic endothelial (HAE) cells. Treatment with the lethal concentration of sibutramine facilitated production of reactive oxygen species (ROS), altered expression of endoplasmic reticulum stress response genes (heat shock protein 70 and C/EBP homologous protein), and inactivated 26S proteasome-based proteolysis. The treatment also decreased cellular level of nitric oxide (NO) through lowering of expression and activity of endothelial NO synthase. These results suggest that ROS production and depletion of NO are crucial events in the apoptotic mechanism and may be linked to the pathogenesis of vasoconstriction elicited by the drug. Compared to sibutramine, its metabolites (N-desmethylsibutramine and N-didesmethylsibutramine) were much less cytotoxic to HAE cells, which hardly metabolized sibutramine. In contrast, both the drug and metabolites showed low cytotoxicity to hepatic HepG2 cells with high metabolic potency and expression of cytochrome P450 (CYP) 3A4. The cytotoxicity of sibutramine to HepG2 cells was remarkably augmented by inhibition and knockdown of CYP3A4. This study also suggests an inverse relationship between sibutramine cytotoxicity and CYP3A4-mediated metabolism into the N-desmethyl metabolites.
      Graphical abstract image

      PubDate: 2016-11-10T14:09:26Z
      DOI: 10.1016/j.taap.2016.11.003
       
  • Estimation of iodine nutrition and thyroid function status in
           late-gestation pregnant women in the United States: Development and
           application of a population-based pregnancy model
    • Authors: A. Lumen; N.I. George
      Abstract: Publication date: Available online 3 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): A. Lumen, N.I. George
      Previously, a deterministic biologically-based dose-response (BBDR) pregnancy model was developed to evaluate moderate thyroid axis disturbances with and without thyroid-active chemical exposure in a near-term pregnant woman and fetus.In the current study, the existing BBDR model was adapted to include a wider functional range of iodine nutrition, including more severe iodine deficiency conditions, and to incorporate empirically the effects of homeostatic mechanisms. The extended model was further developed into a population-based model and was constructed using a Monte Carlo-based probabilistic framework. In order to characterize total (T4) and free (fT4) thyroxine levels for a given iodine status at the population-level, the distribution of iodine intake for late-gestation pregnant women in the U.S was reconstructed using various reverse dosimetry methods and available biomonitoring data. The range of median (mean) iodine intake values resulting from three different methods of reverse dosimetry tested was 196.5–219.9μg of iodine/day (228.2–392.9μg of iodine/day). There was minimal variation in model-predicted maternal serum T4 and ft4 thyroxine levels from use of the three reconstructed distributions of iodine intake; the range of geometric mean for T4 and fT4, was 138–151.7nmol/L and 7.9–8.7pmol/L, respectively. The average value of the ratio of the 97.5th percentile to the 2.5th percentile equaled 3.1 and agreed well with similar estimates from recent observations in third-trimester pregnant women in the U.S. In addition, the reconstructed distributions of iodine intake allowed us to estimate nutrient inadequacy for late-gestation pregnant women in the U.S. via the probability approach. The prevalence of iodine inadequacy for third-trimester pregnant women in the U.S. was estimated to be between 21% and 44%. Taken together, the current work provides an improved tool for evaluating iodine nutritional status and the corresponding thyroid function status in pregnant women in the U.S. This model enables future assessments of the relevant risk of thyroid hormone level perturbations due to exposure to thyroid-active chemicals at the population-level.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.026
       
  • Proteomics analysis of dendritic cell activation by contact allergens
           reveals possible biomarkers regulated by Nrf2
    • Authors: Franz Mussotter; Janina Melanie Tomm; Zeina El Ali; Marc Pallardy; Saadia Kerdine-Römer; Mario Götz; Martin von Bergen; Andrea Haase; Andreas Luch
      Abstract: Publication date: Available online 3 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Franz Mussotter, Janina Melanie Tomm, Zeina El Ali, Marc Pallardy, Saadia Kerdine-Römer, Mario Götz, Martin von Bergen, Andrea Haase, Andreas Luch
      Allergic contact dermatitis is a widespread disease with high clinical relevance affecting approximately 20% of the general population. Typically, contact allergens are low molecular weight electrophilic compounds which can activate the Keap1/Nrf2 pathway. We performed a proteomics study to reveal possible biomarkers for dendritic cell (DC) activation by contact allergens and to further elucidate the role of Keap1/Nrf2 signaling in this process. We used bone marrow derived dendritic cells (BMDCs) of wild-type (nrf2 +/+ ) and Nrf2 knockout (nrf2 −/− ) mice and studied their response against the model contact sensitizers 2,4-dinitrochlorobenzene (DNCB), cinnamaldehyde (CA) and nickel(II) sulfate by 2-dimensional polyacrylamide gel electrophoresis (2D–PAGE) in combination with electrospray ionization tandem mass spectrometry (ESI-MS/MS). Sodium dodecyl sulfate (SDS, 100μM) served as irritant control. While treatment with nickel(II) sulfate and SDS had only little effects, CA and DNCB led to significant changes in protein expression. We found 18 and 30 protein spots up-regulated in wild-type cells treated with 50 and 100μM CA, respectively. For 5 and 10μM DNCB, 32 and 37 spots were up-regulated, respectively. Almost all of these proteins were not differentially expressed in nrf2 −/− BMDCs, indicating an Nrf2-dependent regulation. Among them proteins were detected which are involved in oxidative stress and heat shock responses, as well as in signal transduction or basic cellular pathways. The applied approach allowed us to differentiate between Nrf2-dependent and Nrf2-independent cellular biomarkers differentially regulated upon allergen-induced DC activation. The data presented might contribute to the further development of suitable in vitro testing methods for chemical-mediated sensitization.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.11.001
       
  • Role of dietary fatty acids in liver injury caused by vinyl chloride
           metabolites in mice
    • Authors: Lisanne C Anders; Heegook Yeo; Brenna R Kaelin; Anna L Lang; Adrienne M Bushau; Amanda N Douglas; Matt Cave; Gavin E Arteel; Craig J McClain; Juliane I Beier
      Abstract: Publication date: Available online 28 September 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lisanne C Anders, Heegook Yeo, Brenna R Kaelin, Anna L Lang, Adrienne M Bushau, Amanda N Douglas, Matt Cave, Gavin E Arteel, Craig J McClain, Juliane I Beier
      Background Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels.The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD).It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied. Methods Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10weeks after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA). Results In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated. Conclusions Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH.

      PubDate: 2016-09-30T10:25:49Z
      DOI: 10.1016/j.taap.2016.09.026
       
 
 
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