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  Subjects -> ENVIRONMENTAL STUDIES (Total: 832 journals)
    - ENVIRONMENTAL STUDIES (758 journals)
    - POLLUTION (24 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (40 journals)
    - WASTE MANAGEMENT (10 journals)

ENVIRONMENTAL STUDIES (758 journals)            First | 1 2 3 4 5 6 7 8     

Journal of Sustainable Development Studies     Open Access   (Followers: 9)
Journal of Sustainable Society     Open Access   (Followers: 6)
Journal of the American Planning Association     Hybrid Journal   (Followers: 22)
Journal of the Association of Environmental and Resource Economists     Full-text available via subscription  
Journal of the Atmospheric Sciences     Full-text available via subscription   (Followers: 27)
Journal of the IEST     Full-text available via subscription  
Journal of the North Atlantic     Full-text available via subscription   (Followers: 1)
Journal of Theological Studies     Open Access   (Followers: 10)
Journal of Tropical Ecology     Hybrid Journal   (Followers: 11)
Journal of Urban and Environmental Engineering     Open Access   (Followers: 1)
Journal of Vietnamese Environment     Open Access   (Followers: 2)
Journal of Water Security     Open Access  
Journal of Wetlands Environmental Management     Open Access   (Followers: 1)
Julius-Kühn-Archiv     Open Access  
Kleio     Full-text available via subscription   (Followers: 2)
Knowledge Management Research & Practice     Hybrid Journal   (Followers: 17)
Koedoe : African Protected Area Conservation and Science     Open Access   (Followers: 7)
L1-Educational Studies in Language and Literature     Open Access   (Followers: 2)
Lake and Reservoir Management     Hybrid Journal   (Followers: 5)
Landscape Ecology     Hybrid Journal   (Followers: 44)
Landscapes     Hybrid Journal   (Followers: 18)
Large Marine Ecosystems     Full-text available via subscription  
Latin American and Caribbean Ethnic Studies     Hybrid Journal   (Followers: 5)
Latin American Journal of Management for Sustainable Development     Hybrid Journal   (Followers: 1)
Legal Studies     Hybrid Journal   (Followers: 4)
Letras Verdes. Revista Latinoamericana de Estudios Socioambientales     Open Access  
Leviathan : A Journal of Melville Studies     Full-text available via subscription   (Followers: 2)
Limnological Review     Open Access   (Followers: 6)
Living Reviews in Landscape Research     Open Access   (Followers: 2)
Local Environment: The International Journal of Justice and Sustainability     Hybrid Journal   (Followers: 7)
Low Carbon Economy     Open Access   (Followers: 4)
Luna Azul     Open Access  
M+A. Revista Electrónica de Medioambiente     Open Access  
Macquarie Journal of International and Comparative Environmental Law     Full-text available via subscription   (Followers: 9)
Madagascar Conservation & Development     Open Access  
Management International Review     Hybrid Journal   (Followers: 7)
Management of Environmental Quality: An International Journal     Hybrid Journal   (Followers: 6)
Management of Sustainable Development     Open Access   (Followers: 2)
Marine Ecology     Hybrid Journal   (Followers: 22)
Marine Environmental Research     Hybrid Journal   (Followers: 21)
Marine Pollution Bulletin     Hybrid Journal   (Followers: 21)
Materials for Renewable and Sustainable Energy     Open Access   (Followers: 10)
Mathematical and Computational Forestry & Natural-Resource Sciences     Free  
Mathematical Population Studies: An International Journal of Mathematical Demography     Hybrid Journal   (Followers: 2)
Medieval Sermon Studies     Hybrid Journal   (Followers: 3)
Medio Ambiente y Urbanizacion     Full-text available via subscription  
Membranes     Open Access   (Followers: 6)
Michigan Journal of Sustainability     Open Access  
Midwest Studies In Philosophy     Hybrid Journal   (Followers: 12)
Mine Water and the Environment     Hybrid Journal   (Followers: 6)
Mitigation and Adaptation Strategies for Global Change     Hybrid Journal   (Followers: 12)
Modern Asian Studies     Hybrid Journal   (Followers: 9)
Modern Cartography Series     Full-text available via subscription   (Followers: 4)
Mountain Research and Development     Open Access   (Followers: 4)
Multequina     Open Access  
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis     Hybrid Journal   (Followers: 2)
Mutation Research/Genetic Toxicology and Environmental Mutagenesis     Hybrid Journal   (Followers: 7)
Nativa     Open Access  
Natur und Recht     Hybrid Journal   (Followers: 7)
Natural Areas Journal     Full-text available via subscription   (Followers: 9)
Natural Hazards     Hybrid Journal   (Followers: 114)
Natural Resources     Open Access  
Natural Resources and Environmental Issues     Open Access   (Followers: 5)
Nature and Culture     Full-text available via subscription   (Followers: 11)
NeuroToxicology     Hybrid Journal   (Followers: 1)
Neurotoxicology and Teratology     Hybrid Journal   (Followers: 1)
NEW SOLUTIONS: A Journal of Environmental and Occupational Health Policy     Full-text available via subscription   (Followers: 5)
New Zealand Journal of Environmental Law     Full-text available via subscription   (Followers: 4)
NJAS - Wageningen Journal of Life Sciences     Full-text available via subscription   (Followers: 1)
Noise Mapping     Open Access  
Noise Notes     Full-text available via subscription   (Followers: 3)
Novos Cadernos NAEA     Open Access   (Followers: 2)
Observatorio Medioambiental     Open Access  
Occupational and Environmental Medicine     Full-text available via subscription   (Followers: 10)
Ocean Acidification     Open Access   (Followers: 1)
Ochrona Srodowiska i Zasobów Naturalnych : Environmental Protection and Natural Resources     Open Access  
Oecologia     Hybrid Journal   (Followers: 44)
Oikos     Hybrid Journal   (Followers: 41)
Open Journal of Ecology     Open Access   (Followers: 10)
Open Journal of Marine Science     Open Access   (Followers: 7)
Open Journal of Modern Hydrology     Open Access   (Followers: 4)
Our Nature     Open Access   (Followers: 3)
Oxford Journal of Legal Studies     Hybrid Journal   (Followers: 22)
Pace Environmental Law Review     Open Access   (Followers: 6)
Pace Environmental Law Review Online Companion     Open Access   (Followers: 1)
Packaging, Transport, Storage & Security of Radioactive Material     Hybrid Journal   (Followers: 1)
Palaeobiodiversity and Palaeoenvironments     Hybrid Journal   (Followers: 4)
Particle and Fibre Toxicology     Open Access   (Followers: 2)
Pastos y Forrajes     Open Access  
Pesquisa em Educação Ambiental     Open Access  
Pharmacology & Therapeutics     Hybrid Journal   (Followers: 5)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (Followers: 1)
Philosophical Studies     Hybrid Journal   (Followers: 8)
Physio-Géo     Open Access   (Followers: 2)
Pittsburgh Journal of Environmental and Public Health Law     Open Access   (Followers: 1)
Planet     Open Access   (Followers: 3)
Planning & Environmental Law: Issues and decisions that impact the built and natural environments     Hybrid Journal   (Followers: 7)
Plant Ecology & Diversity     Partially Free   (Followers: 14)
Plant Knowledge Journal     Open Access   (Followers: 3)
Plant, Cell & Environment     Hybrid Journal   (Followers: 5)

  First | 1 2 3 4 5 6 7 8     

Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.429]   [H-I: 117]   [12 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [2801 journals]
  • Development of complex-shaped liver multicellular spheroids as a
           human-based model for nanoparticle toxicity assessment in vitro
    • Abstract: Publication date: Available online 26 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Monika Dubiak-Szepietowska, Aleksandra Karczmarczyk, Martin Jonsson-Niedziolka, Thomas Winckler, Karl-Heinz Feller
      The emergence of human-based models is incontestably required for the study of complex physiological pathways and validation of reliable in vitro methods as alternative for in vivo studies in experimental animals for toxicity assessment. With this objective, we have developed and tested three dimensional environments for cells using different types of hydrogels including transglutaminase-cross-linked gelatin, collagen type I, and growth-factor depleted Matrigel. Cells grown in Matrigel exhibited the greatest cell proliferation and spheroid diameter. Moreover, analysis of urea and albumin biosynthesis revealed that the created system allowed the immortalized liver cell line HepG2 to re-establish normal hepatocyte-like properties which were not observed under the conditions of conventional cell cultures. This study presents a scalable technology for production of complex-shaped liver multicellular spheroids as a system which improves the predictive value of cell-based assays for safety and risk assessment. The time- and dose-dependent toxicity of nanoparticles demonstrates a higher cytotoxic effect when HepG2 cells grown as monolayer than embedded in hydrogels. The experimental setup provided evidence that the cell environment has significant influence on cell sensitivity and that liver spheroid is a useful and novel tool to examine nanoparticle dosing effect even at the level of in vitro studies. Therefore, this system can be applied to a wide variety of potentially hostile compounds in basic screening to provide initial warning of adverse effects and trigger subsequent analysis and remedial actions.


      PubDate: 2016-01-30T07:55:32Z
       
  • Evaluation of nefazodone-induced cardiotoxicity in human induced
           pluripotent stem cell-derived cardiomyocytes
    • Abstract: Publication date: Available online 25 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Sujeong Lee, Hyang-Ae Lee, Sung Woo Choi, Sung Joon Kim, Ki-Suk Kim
      The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which express the major cardiac ion channels and recapitulate spontaneous mechanical and electrical activities, may provide a possible solution for the lack of in vitro human-based cardiotoxicity testing models. Cardiotoxicity induced by the antidepressant nefazodone was previously revealed to cause an acquired QT prolongation by hERG channel blockade. To elucidate the cellular mechanisms underlying the cardiotoxicity of nefazodone beyond hERG, its effects on cardiac action potentials (APs) and ion channels were investigated using hiPSC-CMs with whole-cell patch clamp techniques. In a proof of principle study, we examined the effects of cardioactive channel blockers on the electrophysiological profile of hiPSC-CMs in advance of the evaluation of nefazodone. Nefazodone dose-dependently prolonged the AP duration at 90% (APD90) and 50% (APD50) repolarization, reduced the maximum upstroke velocity (dV/dtmax) and induced early after depolarizations. Voltage-clamp studies of hiPSC-CMs revealed that nefazodone inhibited various voltage-gated ion channel currents including I Kr, I Ks, I Na, and I Ca. Among them, I Kr and I Na showed relatively higher sensitivity to nefazodone, consistent with the changes in the AP parameters. In summary, hiPSC-CMs enabled an integrated approach to evaluate the complex interactions of nefazodone with cardiac ion channels. These results suggest that hiPSC-CMs can be an effective model for detecting drug-induced arrhythmogenicity beyond the current standard assay of heterologously expressed hERG K+ channels.


      PubDate: 2016-01-30T07:55:32Z
       
  • Urinary microRNAs as potential biomarkers of pesticide exposure
    • Abstract: Publication date: Available online 27 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Brittany A. Weldon, Sara Pacheco Shubin, Marissa N. Smith, Tomomi Workman, Alexander Artemenko, William C. Griffith, Beti Thompson, Elaine M. Faustman
      MicroRNAs (miRNAs) are post-transcriptional regulators that silence messenger RNAs. Because miRNAs are stable at room temperature and long-lived, they have been proposed as molecular biomarkers to monitor disease and exposure status. While urinary miRNAs have been used clinically as potential diagnostic markers for kidney and bladder cancers and other diseases, their utility in non-clinical settings has yet to be fully developed. Our goal was to investigate the potential of urinary miRNAs to act as biomarkers of pesticide exposure and early biological response by identifying the miRNAs present in urine from 27 parent/child, farmworker/non-farmworker pairs (16FW/11NFW) collected during two agricultural seasons (thinning and post-harvest) and characterizing the between- and within-individual variability of these miRNA epigenetic regulators. MiRNAs were isolated from archived urine samples and identified using PCR arrays. Comparisons were made between age, households, season, and occupation. Of 384 miRNAs investigated, 297 (77%) were detectable in at least one sample. Seven miRNAs were detected in at least 50% of the samples, and one miRNA was present in 96% of the samples. Principal components and hierarchical clustering analyses indicate significant differences in miRNA profiles between farmworker and non-farmworker adults as well as between seasons. Six miRNAs were observed to be positively associated with farmworkers status during the post-harvest season. Expression of five of these miRNA trended towards a positive dose response relationship with organophosphate pesticide metabolites in farmworkers. These results suggest that miRNAs may be novel biomarkers of pesticide exposure and early biological response.


      PubDate: 2016-01-30T07:55:32Z
       
  • DNA damage-inducible transcript 4 (DDIT4) mediates methamphetamine-induced
           autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes
    • Abstract: Publication date: Available online 26 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Rui Chen, Bin Wang, Ling Chen, Dunpeng Cai, Bing Li, Chuanxiang Chen, Enping Huang, Chao Liu, Zhoumeng Lin, Wei-Bing Xie, Huijun Wang
      Methamphetamine (METH) is an amphetamine-like psychostimulant that is commonly abused. Previous studies have shown that METH can induce damages to the nervous system and recent studies suggest that METH can also cause adverse and potentially lethal effects on the cardiovascular system. Recently, we demonstrated that DNA damage-inducible transcript 4 (DDIT4) regulates METH-induced neurotoxicity. However, the role of DDIT4 in METH-induced cardiotoxicity remains unknown. We hypothesized that DDIT4 may mediate METH-induced autophagy and apoptosis in cardiomyocytes. To test the hypothesis, we examined DDIT4 protein expression in cardiomyocytes and in heart tissues of rats exposed to METH with Western blotting. We also determined the effects on METH-induced autophagy and apoptosis after silencing DDIT4 expression with synthetic siRNA with or without pretreatment of a mTOR inhibitor rapamycin in cardiomyocytes using Western blot analysis, fluorescence microscopy and TUNEL staining. Our results showed that METH exposure increased DDIT4 expression and decreased phosphorylation of mTOR that was accompanied with increased autophagy and apoptosis both in vitro and in vivo. These effects were normalized after silencing DDIT4. On the other hand, rapamycin promoted METH-induced autophagy and apoptosis in DDIT4 knockdown cardiomyocytes. These results suggest that DDIT4 mediates METH-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes.


      PubDate: 2016-01-30T07:55:32Z
       
  • A redox proteomics approach to investigate the mode of action of
           nanomaterials
    • Abstract: Publication date: Available online 28 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Christian Riebeling, Martin Wiemann, Jürgen Schnekenburger, Thomas A.J. Kuhlbusch, Wendel Wohlleben, Andreas Luch, Andrea Haase
      Numbers of engineered nanomaterials (ENMs) are steadily increasing. Therefore, alternative testing approaches with reduced costs and high predictivity suitable for high throughput screening and prioritization are urgently needed to ensure a fast and effective development of safe products. In parallel, extensive research efforts are targeted to understanding modes of action of ENMs, which may also support the development of new predictive assays. Oxidative stress is a widely accepted paradigm associated with different adverse outcomes of ENMs. It has frequently been identified in in vitro and in vivo studies and different assays have been developed for this purpose. Fluorescent dye based read-outs are most frequently used for cell testing in vitro but may be limited due to possible interference of the ENMs. Recently, other assays have been put forward such as acellular determination of ROS production potential using methods like electron spin resonance, antioxidant quantification or the use of specific sensors. In addition, Omics based approaches have gained increasing attention. In particular, redox proteomics can combine the assessment of oxidative stress with the advantage of getting more detailed mechanistic information. Here we propose a comprehensive testing strategy for assessing the oxidative stress potential of ENMs, which combines acellular methods and fast in vitro screening approaches, as well as a more involved detailed redox proteomics approach. This allows for screening and prioritization in a first tier and, if required, also for unraveling mechanistic details down to compromised signaling pathways.


      PubDate: 2016-01-30T07:55:32Z
       
  • Partial contribution of the Keap1–Nrf2 system to cadmium-mediated
           metallothionein expression in vascular endothelial cells
    • Abstract: Publication date: Available online 28 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Yasuhiro Shinkai, Tomoki Kimura, Ayaka Itagaki, Chika Yamamoto, Keiko Taguchi, Masayuki Yamamoto, Yoshito Kumagai, Toshiyuki Kaji
      Cadmium is an environmental electrophile that modifies protein reactive thiols such as Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of nuclear factor-erythroid 2-related factor 2 (Nrf2). In the present study, we investigated a role of the Keap1–Nrf2 system in cellular response to cadmium in vascular endothelial cells. Exposure of bovine aortic endothelial cells to cadmium resulted in modification of Keap1 and Nrf2 activation, thereby up-regulating not only its typical downstream proteins but also metallothionein-1/2. Experiments with siRNA-mediated knockdown of Nrf2 or Keap1 supported participation of the Keap1–Nrf2 system in the modulation of metallothionein-1/2 expression. Furthermore, chromatin immunoprecipitation assay showed that Nrf2 was recruited to the antioxidant response element of the promoter region of the bovine metallothionein-2 gene in the presence of cadmium. These results suggest that the transcription factor Nrf2 plays, at least in part, a role in the changes in metallothionein expression mediated by exposure to cadmium.


      PubDate: 2016-01-30T07:55:32Z
       
  • Pathophysiologic mechanisms of biomedical nanomaterials
    • Abstract: Publication date: Available online 29 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Liming Wang, Chunying Chen
      Nanomaterials (NMs) have been widespread used in biomedical fields, daily consuming, and even food industry. It is crucial to understand the safety and biomedical efficacy of NMs. In this review, we summarized the recent progress about the physiological and pathological effects of NMs from several levels: protein-nano interface, NM-subcellular structures, and cell–cell interaction. We focused on the detailed information of nano-bio interaction, especially about protein adsorption, intracellular trafficking, biological barriers, and signaling pathways as well as the associated mechanism mediated by nanomaterials. We also introduced related analytical methods that are meaningful and helpful for biomedical effect studies in the future. We believe that knowledge about pathophysiologic effects of NMs is not only significant for rational design of medical NMs but also helps predict their safety and further improve their applications in the future.


      PubDate: 2016-01-30T07:55:32Z
       
  • Nephron segment specific miRNA biomarkers of pre-clinical drug-induced
           renal toxicity: Opportunities and challenges
    • Abstract: Publication date: Available online 29 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Rounak Nassirpour, Shashi K. Ramaiah, Laurence O. Whiteley
      Drug-induced nephrotoxicity is a common drug development complication for pharmaceutical companies. Sensitive, specific, translatable and non-invasive biomarkers of renal toxicity are urgently needed to diagnose nephron segment specific injury. The currently available gold standard biomarkers for nephrotoxicity are not kidney-specific, lack sensitivity for early detection, and are not suitable for renal damage localization (glomerular vs tubulointerstitial injury). MicroRNAs (miRNAs) are increasingly gaining momentum as promising biomarkers of various organ toxicities, including drug induced renal injury. This is mostly due to their stability in easily accessible biofluids, ease of developing nucleic acids detection compared to protein detection assays, as well as their interspecies translatability. Increasing concordance of miRNA findings by standardizing methodology most suitable for their detection and quantitation, as well as characterization of their expression pattern in a cell type specific manner, will accelerate progress toward validation of these miRNAs as biomarkers in pre-clinical, and clinical settings. This review aims to highlight the current pre-clinical findings surrounding miRNAs as biomarkers in two important segments of the nephron, the glomerulus and tubules.


      PubDate: 2016-01-30T07:55:32Z
       
  • Molybdenum induces pancreatic β-cell dysfunction and apoptosis via
           interdependent of JNK and AMPK activation-regulated mitochondria-dependent
           and ER stress-triggered pathways
    • Abstract: Publication date: Available online 21 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Tsung-Yuan Yang, Cheng-Chieh Yen, Kuan-I Lee, Chin-Chuan Su, Ching-Yao Yang, Chin-Ching Wu, Shang-Shu Hsieh, Kwo-Chang Ueng, Chun-Fa Huang
      Molybdenum (Mo), a well-known toxic environmental and industrial pollutant, causes adverse health effects and diseases in humans and has received attention as a potential risk factor for DM. However, the roles of Mo in the mechanisms of the toxicological effects in pancreatic β-cells are mostly unclear. In this study, the results revealed dysfunction of insulin secretion and apoptosis in the pancreatic β-cell-derived RIN-m5F cells and the isolated mouse islets in response to Mo. These effects were accompanied by a mitochondria-dependent apoptotic signals including a decreased in the MMP, an increase in cytochrome c release, and the activation of caspase cascades and PARP. In addition, ER stress was triggered as indicated by several key molecules of the UPR. Furthermore, exposure to Mo induced the activation of ERK1/2, JNK, AMPKα, and GSK3-α/β. Pretreatment with specific pharmacological inhibitors (in RIN-m5F cells and isolated mouse islets) of JNK (SP600125) and AMPK (Compound C) or transfection with si-RNAs (in RIN-m5F cells) specific to JNK and AMPKα effectively prevented the Mo-induced apoptosis and related signals, but inhibitors of ERK1/2 and GSK3-α/β (PD98059 and LiCl, respectively) did not reverse the Mo-induced effects. Additionally, both the inhibitors and specific si-RNAs could suppress the Mo-induced phosphorylation of JNK and AMPKα each other. Taken together, these results suggest that Mo exerts its cytotoxicity on pancreatic β-cells by inducing dysfunction and apoptosis via interdependent JNK and AMPK activation downstream-regulated mitochondrial-dependent and ER stress-triggered apoptosis pathways.
      Graphical abstract image

      PubDate: 2016-01-24T13:00:29Z
       
  • Pharmacological evaluation of the mechanisms involved in increased
           adiposity in zebrafish triggered by the environmental contaminant
           tributyltin
    • Abstract: Publication date: Available online 23 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Nafia Ouadah-Boussouf, Patrick J. Babin
      One proposed contributing factor to the rise in overweight and obesity is exposure to endocrine disrupting chemicals. Tributyltin chloride (TBT), an organotin, induces adipogenesis in cell culture models and may increases adipose mass in vivo in vertebrate model organisms. It has been hypothesized that TBT acts via the peroxisome proliferator activated receptor (PPAR)γ-dependent pathway. However, the mechanisms involved in the effects of TBT exposure on in vivo adipose tissue metabolism remain unexplored. Semitransparent zebrafish larvae, with their well-developed white adipose tissue, offer a unique opportunity for studying the effects of toxicant chemicals and pharmaceuticals on adipocyte biology and whole-organism adiposity in a vertebrate model. Within hours, zebrafish larvae, treated at environmentally-relevant nanomolar concentrations of TBT, exhibited a remarkable increase in adiposity linked to adipocyte hypertrophy. Under the experimental conditions used, we also demonstrated that zebrafish larvae adipose tissue proved to be highly responsive to selected human nuclear receptor agonists and antagonists. Retinoid X receptor (RXR) homodimers and RXR/liver X receptor heterodimers were suggested to be in vivo effectors of the obesogenic effect of TBT on zebrafish white adipose tissue. RXR/PPARγ heterodimers may be recruited to modulate adiposity in zebrafish but were not a necessary requirement for the short term in vivo TBT obesogenic effect. Together, the present results suggest that TBT may induce the promotion of triacylglycerol storage in adipocytes via RXR-dependent pathways without necessary using PPAR isoforms.
      Graphical abstract image

      PubDate: 2016-01-24T13:00:29Z
       
  • Role of NLRC5 in progression and reversal of hepatic fibrosis
    • Abstract: Publication date: Available online 22 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Xuejiao Liu, Yuting Wu, Yang Yang, Wanxia Li, Cheng Huang, Xiaoming Meng, Jun Li
      Background NLRC5, as the largest member of NLRs family, has recently been identified as a critical regulator of immune responses through negatively regulating NF-κB which is associated with the development of hepatic fibrosis. However, the expression and potential roles of NLRC5 in hepatic fibrosis and its reversal are still to be defined. Methods C57BL/6 mice were treatment with carbon tetrachloride (CCl4) induce hepatic fibrosis and its reversal. In vitro, models of hepatic fibrosis and its reversal are established by the treatment with TGF-β and MDI. The expression of NLRC5 was determined by RT-PCR, Western blot and immunohistochemistry. Consequently, NLRC5 was overexpressed or knockdown by transfecting PEGFP-C2-NLRC5 or NLRC5-siRNA respectively in the reversal of hepatic fibrosis, and the expression of fibrogenic genes such as α-SMA and Col1α1 was quantified. The NF-κB activity was detected as well. Results Immunohistochemistry, RT-PCR and Western blot analysis with liver tissues and primary HSCs showed that NLRC5 was highly expressed in hepatic fibrosis and correspondingly decreased in the reversal stage. The differential expression of NLRC5 was confirmed in vitro. Enforced NLRC5 expression increased the expression of α-SMA and Col1α1, and blockade of NLRC5 reduced the fibrotic response. While the opposite expression of phosphorylated NF-кB p65 and phospho-IκBα was found. Conclusion NLRC5 is differentially expressed in hepatic tissues and hepatic stellate cells during hepatic fibrosis and its reversal. All the data indicated that NLRC5 may play a crucial role in regulating the reversal of hepatic fibrosis through NF-κB signaling pathway.
      Graphical abstract image

      PubDate: 2016-01-24T13:00:29Z
       
  • Protective effect of Ac-SDKP on alveolar epithelial cells through
           inhibition of EMT via TGF-β1/ROCK1 pathway in silicosis in rat
    • Abstract: Publication date: Available online 16 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Haijing Deng, Hong Xu, Xianghong Zhang, Yue Sun, Ruimin Wang, Darrell Brann, Fang Yang
      The epithelial–mesenchymal transition (EMT) is a critical stage during the development of silicosis fibrosis. In the current study, we hypothesized that the anti-fibrotic tetrapeptide, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) may exert its anti-fibrotic effects via activation of the TGF-β1/ROCK1 pathway, leading to inhibition of EMT. To address this hypothesis, we first examined the effect of Ac-SDKP upon EMT using an in vivo rat silicosis model, as well as in an in vitro model of TGF-β1-induced EMT. Confocal laser scanning microscopy was used to examine colocalization of surfactant protein A (SP-A), fibroblast specific protein-1 (FSP-1) and α-smooth muscle actin (α-SMA) in vivo. Western blot analysis was used to examine for changes in the protein levels of E-cadherin (E-cad) and SP-A (epithelial cell markers), vimentin (mesenchymal cell marker), α-SMA (active myofibroblast marker), and collagen I and III in both in vivo and in vitro experiments. Secondly, we utilized Western blot analysis and confocal laser scanning microscopy to examine the protein expression of TGF-β1 and ROCK1 in in vivo and in vitro studies. The results revealed that Ac-SDKP treatment prevented increases in the expression of mesenchymal markers as well as TGF-β1, ROCK1, collagen I and III. Furthermore, Ac-SDKP treatment prevented decreases in the expression of epithelial cell markers in both in vivo and in vitro experiments. Based on the results, we conclude that Ac-SDKP inhibits the transition of epithelial cell-myofibroblast in silicosis via activation of the TGF-β1/ROCK1 signaling pathway, which may serve as a novel mechanism by which it exerts its anti-fibrosis properties.


      PubDate: 2016-01-20T12:57:08Z
       
  • Table of Contents
    • Abstract: Publication date: 1 February 2016
      Source:Toxicology and Applied Pharmacology, Volume 292




      PubDate: 2016-01-20T12:57:08Z
       
  • PBPK modeling of the cis- and trans-permethrin isomers and their major
           urinary metabolites in rats
    • Abstract: Publication date: Available online 20 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Marie-Emilie Willemin, Sophie Desmots, Rozenn Le Grand, François Lestremau, Florence A. Zeman, Eric Leclerc, Christian Moesch, Céline Brochot
      Permethrin, a pyrethroid insecticide, is suspected to induce neuronal and hormonal disturbances in humans. The widespread exposure of the populations has been confirmed by the detection of the urinary metabolites of permethrin in biomonitoring studies. Permethrin is a chiral molecule presenting two forms, the cis and the trans isomers. Because in vitro studies indicated a metabolic interaction between the trans and cis isomers of permethrin, we adapted and calibrated two PBPK models for trans- and cis-permethrin in rats. The models also describe the toxicokinetics of three urinary metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA), 3-phenoxybenzoic acid (3-PBA) and 4′OH-phenoxybenzoic acid (4′-OH-PBA). In vivo experiments performed in Sprague–Dawley rats were used to calibrate the PBPK models in a Bayesian framework. The model captured well the toxicokinetics of permethrin isomers and their metabolites including the rapid absorption, the accumulation in fat and the extensive metabolism of the parent compounds, and the rapid elimination of metabolites in urine. Average hepatic clearances in rats were estimated to be 2.4 and 5.7L/h/kg for cis- and trans-permethrin, respectively. High concentrations of the metabolite 4′-OH-PBA were measured in urine compared to cis- and trans-DCCA and 3-PBA. The confidence in the extended PBPK model was then confirmed by good predictions of published experimental data obtained using the isomers mixture. The extended PBPK model could be extrapolated to humans to predict the internal dose of exposure to permethrin from biomonitoring data in urine.


      PubDate: 2016-01-20T12:57:08Z
       
  • Editorial Board
    • Abstract: Publication date: 1 February 2016
      Source:Toxicology and Applied Pharmacology, Volume 292




      PubDate: 2016-01-20T12:57:08Z
       
  • Bisphenol A sulfonation is impaired in metabolic and liver disease
    • Abstract: Publication date: 1 February 2016
      Source:Toxicology and Applied Pharmacology, Volume 292
      Author(s): Emine B. Yalcin, Supriya R. Kulkarni, Angela L. Slitt, Roberta King
      Background Bisphenol A (BPA) is a widely used industrial chemical and suspected endocrine disruptor to which humans are ubiquitously exposed. The liver metabolizes and facilitates BPA excretion through glucuronidation and sulfonation. The sulfotransferase enzymes contributing to BPA sulfonation (detected in human and rodents) is poorly understood. Objectives To determine the impact of metabolic and liver disease on BPA sulfonation in human and mouse livers. Methods The capacity for BPA sulfonation was determined in human liver samples that were categorized into different stages of metabolic and liver disease (including obesity, diabetes, steatosis, and cirrhosis) and in livers from ob/ob mice. Results In human liver tissues, BPA sulfonation was substantially lower in livers from subjects with steatosis (23%), diabetes cirrhosis (16%), and cirrhosis (18%), relative to healthy individuals with non-fatty livers (100%). In livers of obese mice (ob/ob), BPA sulfonation was lower (23%) than in livers from lean wild-type controls (100%). In addition to BPA sulfonation activity, Sult1a1 protein expression decreased by 97% in obese mouse livers. Conclusion Taken together these findings establish a profoundly reduced capacity of BPA elimination via sulfonation in obese or diabetic individuals and in those with fatty or cirrhotic livers versus individuals with healthy livers.


      PubDate: 2016-01-16T12:50:13Z
       
  • Mice housed on coal dust-contaminated sand: A model to evaluate the
           impacts of coal mining on health
    • Abstract: Publication date: Available online 13 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Karina Caballero-Gallardo, Jesus Olivero-Verbel
      Coal dust is the most important air pollutant in coal mining in regards to producing deleterious health effects. It permeates the surrounding environment threatening public health. The aim of this study was to evaluate the toxic effects associated with exposure to sand contaminated with coal dust particles below 38μm in diameter, obtained from a mineral sample collected in the largest coal mine in South America, La Loma, Cesar, Colombia. Sterilized sand was spiked with coal dust to obtain concentrations ranging from zero to 4% coal dust. To model natural exposure, mice were housed for eight weeks in boxes containing this mixture as bedding after which, they were euthanized and blood and tissue samples were collected. Real time PCR analysis revealed an increase in Cyp1A1 mRNA for living on sand with coal dust concentrations greater than 2% compared to mice living on sand without coal dust. Unexpectedly, for mice on coal dust-polluted sand, Sod1, Scd1 and Nqo1 hepatic mRNA were downregulated. The Comet assay in peripheral blood cells and the micronucleus test in blood smears, showed a significant potential genotoxic effect only at the highest coal dust concentration. Histopathological analysis revealed vascular congestion and peribronchial inflammation in the lungs. A dose–response relationship for the presence of hepatic steatosis, vacuolization and nuclei enlargements was observed in the exposed animals. The data suggest living on a soil polluted with coal dust induces molecular, cellular and histopathological changes in mice. Accordingly, the proposed model can be used to identify deleterious effects of exposure to coal dust deposited in soils that may pose health risks for surrounding wildlife populations.


      PubDate: 2016-01-16T12:50:13Z
       
  • Short-term toxicity assessments of an antibiotic metabolite in wistar rats
           and its metabonomics analysis by ultra-high performance liquid
           chromatography coupled to quadrupole time-of-flight mass spectrometry
    • Abstract: Publication date: Available online 9 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Hongxing Han, Hailong Xiao, Zhenmei Lu
      4-epi-oxytetracycline (4-EOTC), one of main oxytetracycline (OTC) metabolites, can be commonly detected in food and environment. The toxicity and effects of OTC on animals have been well characterized; however, its metabolites have never been studied systemically. This study aims to investigate 15-day oral dose toxicity and urine metabonomics changes of 4-EOTC after repeated administration in Wistar rats at daily doses of 0.5, 5.0 and 50.0mg/kg bw (bodyweight). Hematology and clinical chemistry parameters, including white blood cell count, red blood cell count, total protein, globulin and albumin/globulin, were obviously altered in rats of 5.0 and 50.0mg/kg bw. Histopathology changes of kidney and liver tissues were also observed in high-dose groups. Urinary metabolites from all groups were analyzed using ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Seventeen metabolites contributing to the clusters were identified as potential biomarkers from multivariate analysis, including aminoadipic acid, 6-phosphogluconate, sebacic acid, pipecolic acid, etc. The significant changes of these biomarkers demonstrated metabonomic variations in treated rats, especially lysine and purine metabolism. For the first time in this paper, we combined the results of toxicity and metabonomics induced by 4-EOTC for the serious reconsideration of the safety and potential risks of antibiotics and its degradation metabolites.
      Graphical abstract image

      PubDate: 2016-01-12T12:49:09Z
       
  • Inflammatory mediators in a short-time mouse model of doxorubicin-induced
           cardiotoxicity
    • Abstract: Publication date: Available online 11 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Michela Pecoraro, Mariagiovanna Del Pizzo, Stefania Marzocco, Rosalinda Sorrentino, Michele Ciccarelli, Guido Iaccarino, Aldo Pinto, Ada Popolo
      Doxorubicin (DOXO) is commonly used to treat a wide range of malignant tumors, but its clinical use is limited by acute and chronic cardiotoxicity. The precise mechanism underlying DOXO-induced cardiotoxicity is still not completely elucidated, but cardiac inflammation seems to be involved. Effects of DOXO on proinflammatory cytokines, inflammatory cell infiltration, and necrosis have been proven only when a functional impairment has already occurred, so this study aimed to investigate the acute effect of DOXO administration in mouse heart. The results of our study demonstrated alterations in cardiac function parameters assessed by ultrasound within 24h after a single injection of DOXO, with a cumulative effect along the increase of the dose and the number of DOXO administrations. At the same time, DOXO causes a significant production of proinflammatory cytokines (such as TNF-α and IL-6) with a concomitant reduction of IL-10, a well-known antiinflammatory cytokine. Furthermore, overexpression of inducible nitric oxide synthase (iNOS) in heart tissue and increased levels of serum nitrite in DOXO-treated mice were detected. Notably, DOXO administration significantly increased nitrotyrosine expression in mouse heart. Our data support the hypothesis that these early events, could be responsible for the later onset of more severe deleterious remodeling leading to DOXO induced cardiomyopathy.


      PubDate: 2016-01-12T12:49:09Z
       
  • SATB2 expression increased anchorage-independent growth and cell migration
           in human bronchial epithelial cells
    • Abstract: Publication date: Available online 11 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Feng Wu, Ashley Jordan, Thomas Kluz, Steven Shen, Hong Sun, Laura A. Cartularo, Max Costa
      The special AT-rich sequence-binding protein 2 (SATB2) is a protein that binds to the nuclear matrix attachment region of the cell and regulates gene expression by altering chromatin structure. In our previous study, we reported that SATB2 gene expression was induced in human bronchial epithelial BEAS-2B cells transformed by arsenic, chromium, nickel and vanadium. In this study, we show that ectopic expression of SATB2 in the normal human bronchial epithelial cell-line BEAS-2B increased anchorage-independent growth and cell migration, meanwhile, shRNA-mediated knockdown of SATB2 significantly decreased anchorage-independent growth in Ni transformed BEAS-2B cells. RNA sequencing analyses of SATB2 regulated genes revealed the enrichment of those involved in cytoskeleton, cell adhesion and cell-movement pathways. Our evidence supports the hypothesis that SATB2 plays an important role in BEAS-2B cell transformation.


      PubDate: 2016-01-12T12:49:09Z
       
  • Genistein exposure inhibits growth and alters steroidogenesis in adult
           mouse antral follicles
    • Abstract: Publication date: Available online 12 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Shreya Patel, Jackye Peretz, Yuan-Xiang Pan, William G. Helferich, Jodi A. Flaws
      Genistein is a naturally occurring isoflavone phytoestrogen commonly found in plant products such as soybeans, lentils, and chickpeas. Genistein, like other phytoestrogens, has the potential to mimic, enhance, or impair the estradiol biosynthesis pathway, thereby potentially altering ovarian follicle growth. Previous studies have inconsistently indicated that genistein exposure may alter granulosa cell proliferation and hormone production, but no studies have examined the effects of genistein on intact antral follicles. Thus, this study was designed to test the hypothesis that genistein exposure inhibits follicle growth and steroidogenesis in intact antral follicles. To test this hypothesis, antral follicles isolated from CD-1 mice were cultured with vehicle (dimethyl sulfoxide; DMSO) or genistein (6.0 and 36μM) for 18–96h (h). Every 24h, follicle diameters were measured to assess growth. At the end of each culture period, the media were pooled to measure hormone levels, and the cultured follicles were collected to measure expression of cell cycle regulators and steroidogenic enzymes. The results indicate that genistein (36μM) inhibits growth of mouse antral follicles. Additionally, genistein (6.0 and 36μM) increases progesterone, testosterone, and dehydroepiandrosterone (DHEA) levels, but decreases estrone and estradiol levels. The results also indicate that genistein alters the expression of steroidogenic enzymes at 24, 72 and 96h, and the expression of cell cycle regulators at 18h. These data indicate that genistein exposure inhibits antral follicle growth by inhibiting the cell cycle, alters sex steroid hormone levels, and dysregulates steroidogenic enzymes in cultured mouse antral follicles.


      PubDate: 2016-01-12T12:49:09Z
       
  • Relationship of antioxidant and oxidative stress markers in different
           organs following copper toxicity in a rat model
    • Abstract: Publication date: Available online 11 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Vijay Kumar, Jayantee Kalita, Himangsu K. Bora, Usha K. Misra
      Copper (Cu) at a higher level becomes toxic and it can catalyze the formation of highly reactive hydroxyl radical. We report the vulnerability of liver, kidney and brain to different dose of copper sulfate (CuSO4) induced oxidative stress at different time duration. Fifty-four male Wistar rats (weight range=205±10g) were equally divided into three groups. CuSO4 was administered orally to the experimental groups (Group-II and III) up to 90days in a dose of 100 and 200mg/Kg body weight per day. Saline water was given to the control group (Group-I). At the end of 30, 60 and 90days of administration, neurobehavioral studies were done and six rats from each group were sacrificed. Their liver, kidney and brain tissues were subjected for Cu, glutathione (GSH), malondialdehyde (MDA) and total antioxidant capacity (TAC) assay. Blood urea nitrogen (BUN), serum creatinine, bilirubin and transaminases were measured. GSH, TAC and MDA levels were correlated with the markers of respective organ dysfunction. Administration of CuSO4 resulted in increased free Cu and MDA level, and decrease GSH and TAC levels in group-II and III compared with group-I. In experimental groups, the reduction in TAC and GSH levels was maximum in liver tissue followed by brain and kidney; whereas increase in MDA level was highest in liver followed by brain and kidney at 30, 60 and 90days. TAC and GSH levels in the liver inversely correlated with serum transaminases and bilirubin, and tissue free Cu, and positively correlated with MDA levels. Free Cu level in kidney tissue and BUN inversely correlated with TAC and GSH, and positively with MDA level. Grip-strength, rotarod and Y-maze findings were inversely correlated with brain free Cu and MDA levels and positively with GSH and TAC levels. The oxidative stress was highest in liver followed by brain and kidney after oral CuSO4 exposure in a rat model. These levels correlated with the respective organ dysfunction and tissue free Cu concentration.


      PubDate: 2016-01-12T12:49:09Z
       
  • Gossypol induces pyroptosis in mouse macrophages via a non-canonical
           inflammasome pathway
    • Abstract: Publication date: Available online 4 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Qiu-Ru Lin, Chen-Guang Li, Qing-Bing Zha, Li-Hui Xu, Hao Pan, Gao-Xiang Zhao, Dong-Yun Ouyang, Xian-Hui He
      Gossypol, a polyphenolic compound isolated from cottonseeds, has been reported to possess many pharmacological activities, but whether it can influence inflammasome activation remains unclear. In this study, we found that in mouse macrophages, gossypol induced cell death characterized by rapid membrane rupture and robust release of HMGB1 and pro-caspase-11 comparable to ATP treatment, suggesting an induction of pyroptotic cell death. Unlike ATP, gossypol induced much low levels of mature interleukin-1β (IL-1β) secretion from mouse peritoneal macrophages primed with LPS, although it caused pro-IL-1β release similar to that of ATP. Consistent with this, activated caspase-1 responsible for pro-IL-1β maturation was undetectable in gossypol-treated peritoneal macrophages. Besides, RAW 264.7 cells lacking ASC expression and caspase-1 activation also underwent pyroptotic cell death upon gossypol treatment. In further support of pyroptosis induction, both pan-caspase inhibitor and caspase-1 subfamily inhibitor, but not caspase-3 inhibitor, could sharply suppress gossypol-induced cell death. Other canonical pyroptotic inhibitors, including potassium chloride and N-acetyl-l-cysteine, could suppress ATP-induced pyroptosis but failed to inhibit or even enhanced gossypol-induced cell death, whereas nonspecific pore-formation inhibitor glycine could attenuate this process, suggesting involvement of a non-canonical pathway. Of note, gossypol treatment eliminated thioglycollate-induced macrophages in the peritoneal cavity with recruitment of other leukocytes. Moreover, gossypol administration markedly decreased the survival of mice in a bacterial sepsis model. Collectively, these results suggested that gossypol induced pyroptosis in mouse macrophages via a non-canonical inflammasome pathway, which raises a concern for its in vivo cytotoxicity to macrophages.


      PubDate: 2016-01-08T12:39:55Z
       
  • Cover 4--TOC
    • Abstract: Publication date: 15 January 2016
      Source:Toxicology and Applied Pharmacology, Volume 291




      PubDate: 2016-01-08T12:39:55Z
       
  • Enzymatic oxidative biodegradation of nanoparticles: Mechanisms,
           significance and applications
    • Abstract: Publication date: Available online 6 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Irina I. Vlasova, Alexandr A. Kapralov, Zachary P. Michael, Seth C. Burkert, Michael R. Shurin, Alexander Star, Anna A. Shvedova, Valerian E. Kagan
      Biopersistence of carbon nanotubes, graphene oxide (GO) and several other types of carbonaceous nanomaterials is an essential determinant of their health effects. Successful biodegradation is one of the major factors defining the life span and biological responses to nanoparticles. Here, we review the role and contribution of different oxidative enzymes of inflammatory cells – myeloperoxidase, eosinophil peroxidase, lactoperoxidase, hemoglobin, and xanthine oxidase – to the reactions of nanoparticle biodegradation. We further focus on interactions of nanomaterials with hemoproteins dependent on the specific features of their physico-chemical and structural characteristics. Mechanistically, we highlight the significance of immobilized peroxidase reactive intermediates vs diffusible small molecule oxidants (hypochlorous and hypobromous acids) for the overall oxidative biodegradation process in neutrophils and eosinophils. We also accentuate the importance of peroxynitrite-driven pathways realized in macrophages via the engagement of NADPH oxidase- and NO synthase-triggered oxidative mechanisms. We consider possible involvement of oxidative machinery of other professional phagocytes such as microglial cells, myeloid-derived suppressor cells, in the context of biodegradation relevant to targeted drug delivery. We evaluate the importance of genetic factors and their manipulations for the enzymatic biodegradation in vivo. Finally, we emphasize a novel type of biodegradation realized via the activation of the “dormant” peroxidase activity of hemoproteins by the nano-surface. This is exemplified by the binding of GO to cyt c causing the unfolding and ‘unmasking’ of the peroxidase activity of the latter. We conclude with the strategies leading to safe by design carbonaceous nanoparticles with optimized characteristics for mechanism-based targeted delivery and regulatable life-span of drugs in circulation.


      PubDate: 2016-01-08T12:39:55Z
       
  • The enhancing effect of genistein on apoptosis induced by trichostatin A
           in lung cancer cells with wild type p53 genes is associated with
           upregulation of histone acetyltransferase
    • Abstract: Publication date: Available online 6 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Tzu-Chin Wu, Yi-Chin Lin, Hsiao-Ling Chen, Pei-Ru Huang, Shang-Yu Liu, Shu-Lan Yeh
      Genistein has been shown to enhance the antitumor activity of trichostatin A (TSA) in human lung carcinoma A549 cells. However, whether the combined treatment exerts the same effect in other lung cancer cells is unclear. In the present study we first compared the enhancing effect of genistein on the antitumor effect of TSA in ABC-1, NCI-H460 (H460) and A549 cells. Second, we investigated whether the effects of genistein are associated with increased histone/non-histone protein acetylation. We found that the enhancing effect of genistein on cell-growth-arrest in ABC-1 cells (p53 mutant) was less than in A549 and H460 cells. Genistein enhanced TSA induced apoptosis in A549 and H460 cells rather than in ABC-1 cells. After silencing p53 expression in A549 and H460 cells, the enhancing effect of genistein was diminished. In addition, genistein increased TSA-induced histone H3/H4 acetylation in A549 and H460 cells. Genistein also increased p53 acetylation in H460 cells. The inhibitor of acetyltransferase, anacardic acid, diminished the enhancing effect of genistein on all TSA-induced histone/p53 acetylation and apoptosis. Genistein in combination with TSA increased the expression of p300 protein, an acetyltransferase, in A549 and NCI-H460 cells. Furthermore, we demonstrated that genistein also enhanced the antitumor effect of genistein in A549-tumor-bearing mice. Taken together, these results suggest that the enhancing effects of genistein on TSA-induced apoptosis in lung cancer cells were p53-dependent and were associated with histone/non-histone protein acetylation.
      Graphical abstract image

      PubDate: 2016-01-08T12:39:55Z
       
  • Inhibition of human anthracycline reductases by emodin - a possible remedy
           for anthracycline resistance
    • Abstract: Publication date: Available online 7 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Jan Hintzpeter, Jan Moritz Seliger, Jakub Hofman, Hans-Joerg Martin, Vladimir Wsol, Edmund Maser
      The clinical application of anthracyclines, like daunorubicin and doxorubicin, is limited by two factors: dose-related cardiotoxicity and drug resistance. Both have been linked to reductive metabolism of the parent drug to their metabolites daunorubicinol and doxorubicinol, respectively. These metabolites show significantly less anti-neoplastic properties as their parent drugs and accumulate in cardiac tissue leading to chronic cardiotoxicity. Therefore, we aimed to identify novel and potent natural inhibitors for anthracycline reductases, which enhance the anticancer effect of anthracyclines by preventing the development of anthracycline resistance. Human enzymes responsible for the reductive metabolism of daunorubicin were tested for their sensitivity towards anthrachinones, in particular emodin and anthraflavic acid. Intense inhibition kinetic data for the most effective daunorubicin reductases, including IC50- and Ki-values, the mode of inhibition, as well as molecular docking, were compiled. Subsequently, a cytotoxicity profile and the ability of emodin to reverse daunorubicin resistance were determined using multiresistant A549 lung cancer and HepG2 liver cancer cells. Emodin potently inhibited the four main human daunorubicin reductases in vitro. Further, we could demonstrate that emodin is able to synergistically sensitize human cancer cells towards daunorubicin at clinically relevant concentrations. Therefore, emodin may yield the potential to enhance the therapeutic effectiveness of anthracyclines by preventing anthracycline resistance via inhibition of the anthracycline reductases. In symphony with its known pharmacological properties, emodin might be a compound of particular interest in the management of anthracycline chemotherapy efficacy and their adverse effects.


      PubDate: 2016-01-08T12:39:55Z
       
  • Understanding the immunogenicity and antigenicity of nanomaterials: Past,
           present and future
    • Abstract: Publication date: Available online 7 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Anna N. Ilinskaya, Marina A. Dobrovolskaia
      Nanoparticle immunogenicity and antigenicity have been under investigation for many years. During the past decade, significant progress has been made in understanding what makes a nanoparticle immunogenic, how immune cells respond to nanoparticles, what consequences of nanoparticle-specific antibody formation exist and how they challenge the application of nanoparticles for drug delivery. Moreover, it has been recognized that accidental contamination of therapeutic protein formulations with nanosized particulate materials may contribute to the immunogenicity of this type of biotechnology products. While the immunological properties of engineered nanomaterials and their application as vaccine carriers and adjuvants have been given substantial consideration in the current literature, little attention has been paid to nanoparticle immuno- and antigenicity. To fill in this gap, we herein provide an overview of this subject to highlight the current state of the field, review past and present research, and discuss future research directions.
      Graphical abstract image

      PubDate: 2016-01-08T12:39:55Z
       
  • Effects of defined mixtures of persistent organic pollutants (POPs) on
           multiple cellular responses in the human hepatocarcinoma cell line, HepG2,
           using high content analysis screening
    • Abstract: Publication date: Available online 7 January 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Jodie Wilson, Hanne Friis Berntsen, Karin Elisabeth Zimmer, Caroline Frizzell, Steven Verhaegen, Erik Ropstad, Lisa Connolly
      Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential. Most studies focus on single compound effects, however as humans are exposed to several POPs simultaneously, investigating exposure effects of real life POP mixtures on human health is necessary. A defined mixture of POPs was used, where the compound concentration reflected its contribution to the levels seen in Scandinavian human serum (total mix). Several sub mixtures representing different classes of POP were also constructed. The perfluorinated (PFC) mixture contained six perfluorinated compounds, brominated (Br) mixture contained seven brominated compounds, chlorinated (Cl) mixture contained polychlorinated biphenyls and also p,p’-dichlorodiphenyldichloroethylene, hexachlorobenzene, three chlordanes, three hexachlorocyclohexanes and dieldrin. Human hepatocarcinoma (HepG2) cells were used for 2h and 48h exposures to the seven mixtures and analysis on a CellInsight™ NXT High Content Screening platform. Multiple cytotoxic endpoints were investigated: cell number, nuclear intensity and area, mitochondrial mass and membrane potential (MMP) and reactive oxygen species (ROS). Both the Br and Cl mixtures induced ROS production but did not lead to apoptosis. The PFC mixture induced the ROS production and likely induced cell apoptosis accompanied by the dissipation of MMP. Synergistic effects were evident for ROS induction when cells were exposed to the PFC+Br mixture. No significant effects were detected in the Br+Cl, PFC+Cl or total mixtures, which contain the same concentrations of chlorinated compounds as the Cl mixture plus additional compounds; highlighting the need for further exploration of POP mixtures in risk assessment.


      PubDate: 2016-01-08T12:39:55Z
       
  • Editorial Board
    • Abstract: Publication date: 15 January 2016
      Source:Toxicology and Applied Pharmacology, Volume 291




      PubDate: 2016-01-08T12:39:55Z
       
  • The role of heme oxygenase-1 in drug metabolizing dysfunction in the
           alcoholic fatty liver exposed to ischemic injury
    • Abstract: Publication date: Available online 31 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Sang Won Park, Jung-Woo Kang, Sun-Mee Lee
      This study was designed to investigate the role of heme oxygenase-1 (HO-1) in hepatic drug metabolizing dysfunction after ischemia/reperfusion (IR) in alcoholic fatty liver (AFL). Rats were fed a Lieber–DeCarli diet for five weeks to allow for development of AFL and were then subjected to 90min of hepatic ischemia and 5h of reperfusion. Rats were pretreated with hemin (HO-1 inducer) or ZnPP (HO-1 inhibitor) for 16h and 3h before hepatic ischemia. After hepatic IR, ethanol diet (ED)-fed rats had higher serum aminotransferase activities and more severe hepatic necrosis compared to the control diet (CD)-fed rats. These changes were attenuated by hemin and exacerbated by ZnPP. The activity and gene expression of HO-1 and its transcription factor (Nrf2) level increased significantly after 5h of reperfusion in CD-fed rats but not in ED-fed rats. After reperfusion, cytochrome P450 (CYP) 1A1, 1A2, and 2B1 activities were reduced to levels lower than those observed in sham group, whereas CYP2E1 activity increased. The decrease in CYP2B1 activity and the increase in CYP2E1 activity were augmented after hepatic IR in ED-fed animals. These changes were significantly attenuated by hemin but aggravated by ZnPP. Finally, CHOP expression and PERK phosphorylation, microsomal lipid peroxidation, and levels of proinflammatory mediators increased in ED-fed rats compared to CD-fed rats after reperfusion. These increases were attenuated by hemin. Our results suggest that AFL exacerbates hepatic drug metabolizing dysfunction during hepatic IR via endoplasmic reticulum stress and lipid peroxidation and this is associated with impaired HO-1 induction.


      PubDate: 2016-01-03T12:14:52Z
       
  • Dioscin alleviates BDL- and DMN-induced hepatic fibrosis via
           Sirt1/Nrf2-mediated inhibition of p38 MAPK pathway
    • Abstract: Publication date: Available online 30 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Lina Gu, Xufeng Tao, Youwei Xu, Xu Han, Yan Qi, Lina Xu, Lianhong Yin, Jinyong Peng
      Oxidative stress is involved in hepatic stellate cells (HSCs) activation and extracellular matrix overproduction. We previously reported the promising effects of dioscin against CCl4-induced liver fibrosis, but its effects and mechanisms on BDL- and DMN-induced liver fibrosis remain unknown. The results in the present study indicated that dioscin significantly inhibited HSCs activation and attenuated hepatic fibrosis in rats. Furthermore, dioscin markedly up-regulated the levels of sirtuin 1 (Sirt1), HO-1, GST, GCLC and GCLM via increasing the nuclear translocation of nuclear erythroid factor 2-related factor 2 (Nrf2), which in turn inhibited mitogen-activated protein kinase 14 (p38 MAPK) phosphorylation and reduced the levels of COL1A1, COL3A1, α-SMA and fibronectin. These results were further validated by knockdown of Sirt1 and Nrf2 using siRNAs silencing, and abrogation of p38 MAPK using SB-203580 (a p38 MAPK inhibitor) in HSC-T6 and LX-2 cells. Collectively, our findings confirmed the potent effects of dioscin against liver fibrosis and also provided novel insights into the mechanisms of this compound as a candidate for the prevention of liver fibrosis in the future.
      Graphical abstract image

      PubDate: 2016-01-03T12:14:52Z
       
  • PTP1B confers liver fibrosis by regulating the activation of hepatic
           stellate cells
    • Abstract: Publication date: Available online 29 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Pei-Jie Chen, Shuang-Peng Cai, Yang Yang, Wan-Xia Li, Cheng Huang, Xiao-Ming Meng, Jun Li
      Liver fibrosis is a reversible wound-healing response to chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) plays a pivotal role in the development of hepatic fibrosis. The currently accepted mechanism for the resolution of liver fibrosis is the apoptosis and inactivation of activated HSCs. Protein tyrosine phosphatase 1B (PTP1B), a prototype of non-receptor protein tyrosine phosphatase, is proved to be a vital modulator in cardiac fibrogenesis. However, the precise role of PTP1B on liver fibrosis and HSC activation is still unclear. Our study showed that the expression of PTP1B was elevated in fibrotic liver but reduced after spontaneous recovery. Moreover, stimulation of HSC-T6 cells with transforming growth factor-β1 (TGF-β1) resulted in a dose/time-dependent increase of PTP1B mRNA and protein. Co-incubation of HSC-T6 cells with PTP1B-siRNA inhibited the cell proliferation and activation induced by TGF-β1. Additionally, both mRNA and protein of PTP1B were dramatically decreased in inactivated HSCs after treated with adipogenic differentiation mixture (MDI). Overexpression of PTP1B hindered the inactivation of HSC-T6 cells induced by MDI. These observations revealed a regulatory role of PTP1B in liver fibrosis and implied PTP1B as a potential therapeutic target.


      PubDate: 2015-12-30T12:04:50Z
       
  • A cellular model to study drug-induced liver injury in nonalcoholic fatty
           liver disease: application to acetaminophen
    • Abstract: Publication date: Available online 29 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Anaïs Michaut, Dounia Le Guillou, Caroline Moreau, Simon Bucher, Mitchell R. McGill, Sophie Martinais, Thomas Gicquel, Isabelle Morel, Marie-Anne Robin, Hartmut Jaeschke, Bernard Fromenty
      Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity.


      PubDate: 2015-12-30T12:04:50Z
       
  • The combination of ethanol with mephedrone increases the signs of
           neurotoxicity and impairs neurogenesis and learning in adolescent CD-1
           mice
    • Abstract: Publication date: Available online 30 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Andrés Ciudad-Roberts, Leticia Duart-Castells, Jorge Camarasa, David Pubill, Elena Escubedo
      A new family of psychostimulants, under the name of cathinones, has broken into the market in the last decade. In light of the fact that around 95% of cathinone consumers have been reported to combine them with alcoholic drinks, we sought to study the consequences of the concomitant administration of ethanol on mephedrone ­induced neurotoxicity. Adolescent male Swiss­CD1 mice were administered four times in one day, every 2h, with saline, mephedrone (25mg/kg), ethanol (2; 1.5; 1.5; 1g/kg) and their combination at a room temperature of 26±2°C. The combination with ethanol impaired mephedrone­induced decreases in dopamine transporter and tyrosine hydroxylase in the frontal cortex; and in serotonin transporter and tryptophan hydroxylase in the hippocampus by approximately 2­fold, 7days post­treatment. Furthermore, these decreases correlated with a 2­fold increase in lipid peroxidation, measured as concentration of malondialdehyde (MDA), 24h post-treatment, and were accompanied by changes in oxidative stress-related enzymes. Ethanol also notably potentiated mephedrone-induced negative effects on learning and memory, as well as hippocampal neurogenesis, measured through the Morris water maze (MWM) and 5-bromo-2′-deoxyuridine staining, respectively. These results are of special significance, since alcohol is widely co­abused with amphetamine derivatives such as mephedrone, especially during adolescence, a crucial stage in brain maturation. Given that the hippocampus is greatly involved in learning and memory processes, normal brain development in young adults could be affected with permanent behavioral consequences after this type of drug co-abuse.
      Graphical abstract image

      PubDate: 2015-12-30T12:04:50Z
       
  • Lovastatin prevents cisplatin-induced activation of pro-apoptotic DNA
           damage response (DDR) of renal tubular epithelial cells
    • Abstract: Publication date: Available online 29 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Katharina Krüger, Verena Ziegler, Christina Hartmann, Christian Henninger, Jürgen Thomale, Nicole Schupp, Gerhard Fritz
      The platinating agent cisplatin (CisPt) is commonly used in the therapy of various types of solid tumors. The anticancer efficacy of CisPt largely depends on the formation of bivalent DNA intrastrand crosslinks, which stimulate mechanisms of the DNA damage response (DDR), thereby triggering checkpoint activation, gene expression and cell death. The clinically most relevant adverse effect associated with CisPt treatment is nephrotoxicity that results from damage to kidney tubular epithelial cells. Here, we addressed the question whether the HMG-CoA-reductase inhibitor lovastatin affects the DDR of renal cells by employing rat renal proximal tubular epithelial (NRK-52E) cells as in vitro model. The data show that lovastatin has extensive inhibitory effects on CisPt-stimulated DDR of NRK-52E cells as reflected on the levels of phosphorylated ATM, Chk1, Chk2, p53 and Kap1. Mitigation of CisPt-induced DDR by lovastatin was independent of the formation of DNA damage as demonstrated by (i) the analysis of Pt-(GpG) intrastrand crosslink formation by Southwestern blot analyses and (ii) the generation of DNA strand breaks as analyzed on the level of nuclear γH2AX foci and employing the alkaline Comet assay. Lovastatin protected NRK-52E cells from the cytotoxicity of high CisPt doses as shown by measuring cell viability, cellular impedance and flow cytometry-based analyses of cell death. Importantly, the statin also reduced the level of kidney DNA damage and apoptosis triggered by CisPt treatment of mice. The data show that the lipid-lowering drug lovastatin extensively counteracts pro-apoptotic signal mechanisms of the DDR of tubular epithelial cells following CisPt injury.


      PubDate: 2015-12-30T12:04:50Z
       
  • Genetically obese (ob/ob) mice are resistant to the lethal effects of
           thioacetamide hepatotoxicity
    • Abstract: Publication date: 15 January 2016
      Source:Toxicology and Applied Pharmacology, Volume 291
      Author(s): Young-Suk Won, Ji-Won Song, Jong-Hwan Lim, Mee-Young Lee, Og-Sung Moon, Hyoung-Chin Kim, Hwa-Young Son, Hyo-Jung Kwon
      Obesity increases the risk of chronic liver diseases, including viral hepatitis, alcohol-induced liver disease, and non-alcoholic steatohepatitis. In this study, we investigated the effects of obesity in acute hepatic failure using a murine model of thioacetamide (TA)-induced liver injury. Genetically obese ob/ob mice, together with non-obese ob/+ littermates, were subjected to a single intraperitoneal injection of TA, and examined for signs of hepatic injury. ob/ob mice showed a significantly higher survival rate, lower levels of serum alanine aminotransferase and aspartate aminotransferase, and less hepatic necrosis and apoptosis, compared with ob/+ mice. In addition, ob/ob mice exhibited significantly lower levels of malondialdehyde and significantly higher levels of glutathione and antioxidant enzyme activities compared with their ob/+ counterparts. Bioactivation analyses revealed reduced plasma clearance of TA and covalent binding of [14C]TA to liver macromolecules in ob/ob mice. Together, these data demonstrate that genetically obese mice are resistant to TA-induced acute liver injury through diminished bioactivation of TA and antioxidant effects.


      PubDate: 2015-12-30T12:04:50Z
       
  • Zebrafish embryos as a screen for DNA methylation modifications after
           compound exposure
    • Abstract: Publication date: Available online 19 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Manon C. Bouwmeester, Sander Ruiter, Tobias Lommelaars, Josefine Sippel, Hennie M. Hodemaekers, Evert-Jan van den Brandhof, Jeroen L.A.; Pennings, Jorke H. Kamstra, Jaroslav Jelinek, Jean-Pierre J. Issa, Juliette Legler, Leo T.M. van der Ven
      Modified epigenetic programming early in life is proposed to underlie the development of an adverse adult phenotype, known as the Developmental Origins of Health and Disease (DOHaD) concept. Several environmental contaminants have been implicated as modifying factors of the developing epigenome. This underlines the need to investigate this newly recognized toxicological risk and systematically screen for the epigenome modifying potential of compounds. In this study, we examined the applicability of the zebrafish embryo as a screening model for DNA methylation modifications. Embryos were exposed from 0 to 72h post fertilization (hpf) to bisphenol-A (BPA), diethylstilbestrol, 17α-ethynylestradiol, nickel, cadmium, tributyltin, arsenite, perfluoroctanoic acid, valproic acid, flusilazole, 5-azacytidine (5AC) in subtoxic concentrations. Both global and site-specific methylation was examined. Global methylation was only affected by 5AC. Genome wide locus-specific analysis was performed for BPA exposed embryos using Digital Restriction Enzyme Analysis of Methylation DREAM, which showed minimal wide scale effects on the genome, whereas potential informative markers were not confirmed by pyrosequencing. Site-specific methylation was examined in the promoter regions of three selected genes vasa, vtgI and cyp19a2, of which vasa (ddx4) was the most responsive. This analysis distinguished estrogenic compounds from metals by direction and sensitivity of the effect compared to embryotoxicity. In conclusion, the zebrafish embryo is a potential screening tool to examine DNA methylation modifications after xenobiotic exposure. The next step is to examine the adult phenotype of exposed embryos and to analyze molecular mechanisms that potentially link epigenetic effects and altered phenotypes, to support the DOHaD hypothesis.


      PubDate: 2015-12-22T11:57:29Z
       
  • Suppression of NRF2–ARE activity sensitizes chemotherapeutic
           agent-induced cytotoxicity in human acute monocytic leukemia cells
    • Abstract: Publication date: Available online 18 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Hui Peng, Huihui Wang, Peng Xue, Yongyong Hou, Jian Dong, Tong Zhou, Weidong Qu, Shuangqing Peng, Jin Li, Paul L. Carmichael, Bud Nelson, Rebecca Clewell, Qiang Zhang, Melvin E. Andersen, Jingbo Pi
      Nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the antioxidant response element (ARE)-dependent transcription, plays a pivotal role in chemical detoxification in normal and tumor cells. Consistent with previous findings that NRF2–ARE contributes to chemotherapeutic resistance of cancer cells, we found that stable knockdown of NRF2 by lentiviral shRNA in human acute monocytic leukemia (AML) THP-1 cells enhanced the cytotoxicity of several chemotherapeutic agents, including arsenic trioxide (As2O3), etoposide and doxorubicin. Using an ARE-luciferase reporter expressed in several human and mouse cells, we identified a set of compounds, including isonicotinic acid amides, isoniazid and ethionamide, that inhibited NRF2–ARE activity. Treatment of THP-1 cells with ethionamide, for instance, significantly reduced mRNA expression of multiple ARE-driven genes under either basal or As2O3-challenged conditions. As determined by cell viability and cell cycle, suppression of NRF2–ARE by ethionamide also significantly enhanced susceptibility of THP-1 and U937 cells to As2O3-induced cytotoxicity. In THP-1 cells, the sensitizing effect of ethionamide on As2O3-induced cytotoxicity was highly dependent on NRF2. To our knowledge, the present study is the first to demonstrate that ethionamide suppresses NRF2–ARE signaling and disrupts the transcriptional network of the antioxidant response in AML cells, leading to sensitization to chemotherapeutic agents.


      PubDate: 2015-12-22T11:57:29Z
       
  • Small structural changes on a hydroquinone scaffold determine the complex
           I inhibition or uncoupling of tumoral oxidative phosphorylation
    • Abstract: Publication date: Available online 19 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Félix A. Urra, Miguel Córdova-Delgado, Michel Lapier, Andrea Orellana-Manzano, Luis Acevedo-Arévalo, Hernán Pessoa-Mahana, Jaime M. González-Vivanco, Maximiliano Martínez-Cifuentes, Oney Ramírez-Rodríguez, Juan Pablo Millas-Vargas, Boris Weiss-López, Mario Pavani, Jorge Ferreira, Ramiro Araya-Maturana

      Graphical abstract image

      PubDate: 2015-12-22T11:57:29Z
       
  • Effects of the β1 auxiliary subunit on modification of Rat Nav1.6
           sodium channels expressed in HEK293 cells by the pyrethroid insecticides
           tefluthrin and deltamethrin
    • Abstract: Publication date: Available online 19 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Bingjun He, David M. Soderlund
      We expressed rat Nav1.6 sodium channels with or without the rat β1 subunit in human embryonic kidney (HEK293) cells and evaluated the effects of the pyrethroid insecticides tefluthrin and deltamethrin on whole-cell sodium currents. In assays with the Nav1.6 α subunit alone, both pyrethroids prolonged channel inactivation and deactivation and shifted the voltage dependence of channel activation and steady-state inactivation toward hyperpolarization. Maximal shifts in activation were ~18mV for tefluthrin and ~24mV for deltamethrin. These compounds also caused hyperpolarizing shifts of ~10–14mV in the voltage dependence of steady-state inactivation and increased in the fraction of sodium current that was resistant to inactivation. The effects of pyrethroids on the voltage-dependent gating greatly increased the size of sodium window currents compared to unmodified channels; modified channels exhibited increased probability of spontaneous opening at membrane potentials more negative than the normal threshold for channel activation and incomplete channel inactivation. Coexpression of Nav1.6 with the β1 subunit had no effect on the kinetic behavior of pyrethroid-modified channels but had divergent effects on the voltage-dependent gating of tefluthrin- or deltamethrin-modified channels, increasing the size of tefluthrin-induced window currents but decreasing the size of corresponding deltamethrin-induced currents. Unexpectedly, the β1 subunit did not confer sensitivity to use-dependent channel modification by either tefluthrin or deltamethrin. We conclude from these results that functional reconstitution of channels in vitro requires careful attention to the subunit composition of channel complexes to ensure that channels in vitro are faithful functional and pharmacological models of channels in neurons.


      PubDate: 2015-12-22T11:57:29Z
       
  • Human dermal absorption of chlorinated organophosphate flame retardants;
           implications for human exposure
    • Abstract: Publication date: Available online 19 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Mohamed Abou-Elwafa Abdallah, Gopal Pawar, Stuart Harrad
      Tris-2-chloroethyl phosphate (TCEP), tris (1-chloro-2-propyl) phosphate (TCIPP) and tris-1,3-dichloropropyl phosphate (TDCIPP) are organophosphate flame retardants (PFRs) widely applied in a plethora of consumer products despite their carcinogenic potential. Human dermal absorption of these PFRs is investigated for the first time using human ex vivo skin and EPISKIN™ models. Results of human ex vivo skin experiments revealed 28%, 25% and 13% absorption of the applied dose (500ng/cm2, finite dose) of TCEP, TCIPP and TDCIPP, respectively after 24h exposure. The EPISKIN™ model showed enhanced permeability values (i.e. weaker barrier), that were respectively 16%, 11% and 9% for TCEP, TCIPP and TDCIPP compared to human ex vivo skin. However, this difference was not significant (P>0.05). Estimated permeability constants (K p , cm/h) showed a significant negative correlation with log Kow for the studied contaminants. The effect of hand-washing on dermal absorption of PFRs was investigated. Washing reduced overall dermal absorption, albeit to varying degrees depending on the physicochemical properties of the target PFRs. Moreover, slight variations of the absorbed dose were observed upon changing the dosing solution from acetone to 20% Tween 80 in water, indicating the potential influence of the dose vehicle on the dermal absorption of PFRs. Finally, estimated dermal uptake of the studied PFRs via contact with indoor dust was higher in UK toddlers (median ΣPFRs=36ng/kgbwday) than adults (median ΣPFRs=4ng/kgbwday). More research is required to fully elucidate the toxicological implications of such exposure.


      PubDate: 2015-12-22T11:57:29Z
       
  • Concurrent acetylation of FoxO1/3a and p53 due to sirtuins inhibition
           elicit Bim/PUMA mediated mitochondrial dysfunction and apoptosis in
           berberine-treated HepG2 cells
    • Abstract: Publication date: Available online 19 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Shatrunajay Shukla, Ankita Sharma, Vivek Kumar Pandey, Sheikh Raisuddin, Poonam Kakkar
      Post-translational modifications i.e. phosphorylation, and acetylation are pivotal requirements for proper functioning of eukaryotic proteins. The current study aimed to decode the impact of acetylation/deacetylation of non-histone targets i.e. FoxO1/3a and p53 of sirtuins (NAD+ dependent enzymes with lysine deacetylase activity) in berberine treated human hepatoma cells. Berberine (100μM) inhibited sirtuins significantly (P <0.05) at transcriptional level as well as at translational level. Combination of nicotinamide (sirtuin inhibitor) with berberine potentiated sirtuins inhibition and increased the expression of FoxO1/3a and phosphorylation of p53 tumor suppressor protein. As sirtuins deacetylate non-histone targets including FoxO1/3a and p53, berberine increased the acetylation load of FoxO1/3a and p53 proteins. Acetylated FoxO and p53 proteins transcriptionally activate BH3-only proteins Bim and PUMA (3.89 and 3.87 fold respectively, P <0.001), which are known as direct activator of pro-apoptotic Bcl-2 family protein Bax that culminated into mitochondria mediated activation of apoptotic cascade. Bim/PUMA knock-down showed no changes in sirtuins' expression while cytotoxicity induced by berberine and nicotinamide was curtailed up to 28.3% (P <0.001) and it restored pro/anti apoptotic protein ratio in HepG2 cells. Sirtuins inhibition was accompanied by decline in NAD+/NADH ratio, ATP generation, enhanced ROS production and decreased mitochondrial membrane potential. TEM analysis confirmed mitochondrial deterioration and cell damage. SRT-1720 (1–10μM), a SIRT-1 activator, when pre-treated with berberine (25μM), reversed sirtuins expression comparable to control and significantly restored the cell viability (P <0.05). Thus, our findings suggest that berberine mediated sirtuins inhibition resulting into FoxO1/3a and p53 acetylation followed by BH3-only protein Bim/PUMA activation may in part be responsible for mitochondria-mediated apoptosis.
      Graphical abstract image

      PubDate: 2015-12-22T11:57:29Z
       
  • Effects of acute ethanol exposure on cytokine production by primary airway
           smooth muscle cells
    • Abstract: Publication date: Available online 22 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Lata Kaphalia, Mridul Kalita, Bhupendra S. Kaphalia, William J. Calhoun
      Both chronic and binge alcohol abuse can be significant risk factors for inflammatory lung diseases such as acute respiratory distress syndrome and chronic obstructive pulmonary disease. However, metabolic basis of alcohol-related lung disease is not well defined, and may include key metabolites of ethanol [EtOH] in addition to EtOH itself. Therefore, we investigated the effects of EtOH, acetaldehyde [ACE], and fatty acid ethyl esters [FAEEs] on oxidative stress, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and nuclear translocation of phosphorylated (p)-NF-kB p65 in primary human airway smooth muscle (HASM) cells stimulated to produce cytokines using LPS exposure. Both FAEEs and ACE induced evidence of cellular oxidative stress and ER stress, and increased p-NF-kB in nuclear extracts. EtOH and its metabolites decreased p-AMPKα activation, and induced expression of fatty acid synthase, and decreased expression of sirtuin 1. In general, EtOH decreased secretion of IP-10, IL-6, eotaxin, GCSF, and MCP-1. However, FAEEs and ACE increased these cytokines, suggesting that both FAEEs and ACE as compared to EtOH itself are proinflammatory. A direct effect of EtOH could be consistent with blunted immune response. Collectively, these two features of EtOH exposure, coupled with the known inhibition of innate immune response in our model might explain some clinical manifestations of EtOH exposure in the lung.
      Graphical abstract image

      PubDate: 2015-12-22T11:57:29Z
       
  • The ovarian DNA damage repair response is induced prior to phosphoramide
           mustard-induced follicle depletion, and ataxia telangiectasia mutated
           inhibition prevents PM-induced follicle depletion
    • Abstract: Publication date: Available online 19 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Shanthi Ganesan, Aileen F. Keating
      Phosphoramide mustard (PM) is an ovotoxic metabolite of cyclophosphamide and destroys primordial and primary follicles potentially by DNA damage induction. The temporal pattern by which PM induces DNA damage and initiation of the ovarian response to DNA damage has not yet been well characterized. This study investigated DNA damage initiation, the DNA repair response, as well as induction of follicular demise using a neonatal rat ovarian culture system. Additionally, to delineate specific mechanisms involved in the ovarian response to PM exposure, utility was made of PKC delta (PKCδ) deficient mice as well as an ATM inhibitor (KU 55933; AI). Fisher 344 PND4 rat ovaries were cultured for 12, 24, 48 or 96 h in medium containing DMSO ±60 μM PM or KU 55933 (48 h; 10 nM). PM-induced activation of DNA damage repair genes was observed as early as 12 h post-exposure. ATM, PARP1, E2F7, P73 and CASP3 abundance were increased but RAD51 and BCL2 protein decreased after 96 h of PM exposure. PKCδ deficiency reduced numbers of all follicular stages, but did not have an additive impact on PM-induced ovotoxicity. ATM inhibition protected all follicle stages from PM-induced depletion. In conclusion, the ovarian DNA damage repair response is active post-PM exposure, supporting that DNA damage contributes to PM-induced ovotoxicity.


      PubDate: 2015-12-22T11:57:29Z
       
  • Irinotecan (CPT-11)-induced elevation of bile acids potentiates
           suppression of IL-10 expression
    • Abstract: Publication date: Available online 17 December 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Zhong-Ze Fang, Dunfang Zhang, Yun-Feng Cao, Cen Xie, Dan Lu, Dong-Xue Sun, Naoki Tanaka, Changtao Jiang, Qianming Chen, Yu Chen, Haina Wang, Frank J. Gonzalez
      Irinotecan (CPT-11) is a first-line anti-colon cancer drug, however; CPT-11-induced toxicity remains a key factor limiting its clinical application. To search for clues to the mechanism of CPT-11-induced toxicity, metabolomics was applied using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Intraperitoneal injection of 50mg/kg of CPT-11 induced loss of body weight, and intestine toxicity. Changes in gallbladder morphology suggested alterations in bile acid metabolism, as revealed at the molecular level by analysis of the liver, bile, and ileum metabolomes between the vehicle-treated control group and the CPT-11-treated group. Analysis of immune cell populations further showed that CPT-11 treatment significantly decreased the IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes, but not in spleen or mesenteric lymph nodes. In vitro cell culture studies showed that the addition of bile acids deoxycholic acid and taurodeoxycholic acid accelerated the CPT-11-induced suppression of IL-10 secretion by activated CD4+ naive T cells isolated from mouse splenocytes. These results showed that CPT-11 treatment caused metabolic changes in the composition of bile acids that altered CPT-11-induced suppression of IL-10 expression.
      Graphical abstract image

      PubDate: 2015-12-18T11:53:47Z
       
  • Cover 2--Ed Board
    • Abstract: Publication date: 1 January 2016
      Source:Toxicology and Applied Pharmacology, Volume 290




      PubDate: 2015-12-18T11:53:47Z
       
  • Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium
    • Abstract: Publication date: 15 January 2016
      Source:Toxicology and Applied Pharmacology, Volume 291
      Author(s): Karen L. Cooper, Erica J. Dashner, Ranalda Tsosie, Young Mi Cho, Johnnye Lewis, Laurie G. Hudson
      Uranium has radiological and non-radiological effects within biological systems and there is increasing evidence for genotoxic and carcinogenic properties attributable to uranium through its heavy metal properties. In this study, we report that low concentrations of uranium (as uranyl acetate; <10μM) is not cytotoxic to human embryonic kidney cells or normal human keratinocytes; however, uranium exacerbates DNA damage and cytotoxicity induced by hydrogen peroxide, suggesting that uranium may inhibit DNA repair processes. Concentrations of uranyl acetate in the low micromolar range inhibited the zinc finger DNA repair protein poly(ADP-ribose) polymerase (PARP)-1 and caused zinc loss from PARP-1 protein. Uranyl acetate exposure also led to zinc loss from the zinc finger DNA repair proteins Xeroderma Pigmentosum, Complementation Group A (XPA) and aprataxin (APTX). In keeping with the observed inhibition of zinc finger function of DNA repair proteins, exposure to uranyl acetate enhanced retention of induced DNA damage. Co-incubation of uranyl acetate with zinc largely overcame the impact of uranium on PARP-1 activity and DNA damage. These findings present evidence that low concentrations of uranium can inhibit DNA repair through disruption of zinc finger domains of specific target DNA repair proteins. This may provide a mechanistic basis to account for the published observations that uranium exposure is associated with DNA repair deficiency in exposed human populations.


      PubDate: 2015-12-18T11:53:47Z
       
  • Immunotoxicological and neurotoxicological profile of health effects
           following subacute exposure to geogenic dust from sand dunes at the Nellis
           Dunes Recreation Area, Las Vegas, NV
    • Abstract: Publication date: 15 January 2016
      Source:Toxicology and Applied Pharmacology, Volume 291
      Author(s): Deborah Keil, Brenda Buck, Dirk Goossens, Yuanxin Teng, Mallory Leetham, Lacey Murphy, James Pollard, Margaret Eggers, Brett McLaurin, Russell Gerads, Jamie DeWitt
      Exposure to geogenic particulate matter (PM) comprised of mineral particles has been linked to human health effects. However, very little data exist on health effects associated with geogenic dust exposure in natural settings. Therefore, we characterized particulate matter size, metal chemistry, and health effects of dust collected from the Nellis Dunes Recreation Area (NDRA), a popular off-road vehicle area located near Las Vegas, NV. Adult female B6C3F1 mice were exposed to several concentrations of mineral dust collected from active and vegetated sand dunes in NDRA. Dust samples (median diameter: 4.4μm) were suspended in phosphate-buffered saline and delivered at concentrations ranging from 0.01 to 100mg dust/kg body weight by oropharyngeal aspiration. ICP-MS analyses of total dissolution of the dust resulted in aluminum (55,090μg/g), vanadium (70μg/g), chromium (33μg/g), manganese (511μg/g), iron (21,600μg/g), cobalt (9.4μg/g), copper (69μg/g), zinc (79μg/g), arsenic (62μg/g), strontium (620μg/g), cesium (13μg/g), lead 25μg/g) and uranium (4.7μg/g). Arsenic was present only as As(V). Mice received four exposures, once/week over 28-days to mimic a month of weekend exposures. Descriptive and functional assays to assess immunotoxicity and neurotoxicity were performed 24h after the final exposure. The primary observation was that 0.1 to 100mg/kg of this sand dune derived dust dose-responsively reduced antigen-specific IgM antibody responses, suggesting that dust from this area of NDRA may present a potential health risk.
      Graphical abstract image

      PubDate: 2015-12-09T11:27:06Z
       
  • Experimental models of hepatotoxicity related to acute liver failure
    • Abstract: Publication date: 1 January 2016
      Source:Toxicology and Applied Pharmacology, Volume 290
      Author(s): Michaël Maes, Mathieu Vinken, Hartmut Jaeschke
      Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposure or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure.


      PubDate: 2015-12-05T11:19:50Z
       
 
 
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