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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.593]   [H-I: 135]   [17 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [3031 journals]
  • Dual effect of silymarin on experimental non-alcoholic steatohepatitis
           induced by irinotecan
    • Authors: Eudmar Marcolino; Anielle Torres Melo; Venúcia Bruna Magalhães Pereira; Deysi Viviana Tenazoa Wong; Nathalia Ribeiro Pinho Sousa; Christiane Mendes Gonçalves Oliveira; Lara Raissa Cavalcante Malveira; Leonardo Silva Moreira; Marcellus Henrique Loiola Ponte Souza; Paulo Roberto Carvalho Almeida; Roberto César Pereira Lima
      Abstract: Publication date: 15 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 327
      Author(s): Eudmar Marcolino Assis-Júnior, Anielle Torres Melo, Venúcia Bruna Magalhães Pereira, Deysi Viviana Tenazoa Wong, Nathalia Ribeiro Pinho Sousa, Christiane Mendes Gonçalves Oliveira, Lara Raissa Cavalcante Malveira, Leonardo Silva Moreira, Marcellus Henrique Loiola Ponte Souza, Paulo Roberto Carvalho Almeida, Roberto César Pereira Lima-Júnior
      Irinotecan-based regimens are commonly used for treatment of colorectal cancer, which is limited by mucositis and non-alcoholic steatohepatitis (NASH). Silymarin (SIL) prevents fatty liver disease in the clinical setting and in models of liver damage induced chemically. This study investigated the possible effect of SIL on irinotecan (IRI)-induced NASH. Swiss female mice were injected with saline (SAL 5ml/kg i.p.), IRI (50mg/kg i.p.), SIL (150mg/kg p.o.) or IRI (50mg/kg i.p.)+(SIL 1.5, 15 or 150mg/kg p.o.) thrice/week/7weeks. On the seventh week, blood samples were collected for transaminases assay and livers were collected for histopathology, measurement of the total lipids, malondyadehyde (MDA), non-protein sulfhydryl groups (NPSH), cytokines (IL-1β, IL 6 and IL-10), 3-nitrotyrosine (N-Tyr) and toll-like receptor 4 (TLR4) immunoexpression, quantification of NF-kB, α-smooth muscle actin (α-SMA), and Escherichia coli 16S rRNA gene (RRS) expression. IRI increased liver transaminases, neutrophil infiltration, lipid accumulation, MDA, IL-1β and IL-6 levels, N-Tyr and TLR4 immunostaining, NF-kB, α-SMA expression and RRS versus the SAL group (p<0.05). Additionally, SIL (1.5mg/kg) improved these parameters (p<0.05), except neutrophil infiltration and RSS versus the IRI group. Furthermore, the SIL (15mg/kg) only improved the inflammatory parameters, the expression of α-SMA and RRS versus the IRI group (p<0.05). The higher dose of SIL (150mg/kg) was even more deleterious than the intermediate dose. Therefore, silymarin showed a dual effect on liver damage induced by IRI. Hepatoprotection seems to involve the inhibition of oxidative stress and protein nitrosylation, preventing activation of hepatic fibrosis mechanisms.
      Graphical abstract image

      PubDate: 2017-05-13T15:29:55Z
      DOI: 10.1016/j.taap.2017.04.023
      Issue No: Vol. 327 (2017)
       
  • Loss of Nrf2 promotes rapid progression to heart failure following
           myocardial infarction
    • Authors: Joshua Strom; Qin M. Chen
      Abstract: Publication date: 15 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 327
      Author(s): Joshua Strom, Qin M. Chen
      Nrf2 gene encodes a transcription factor regulating the expression of antioxidant and detoxification genes. We test here whether Nrf2 plays a role for cardiac protection during ischemic injury in an effort to establish Nrf2 as a target for cardiac protection therapies. Cardiac ischemia induced by the left anterior descending (LAD) coronary artery ligation results in myocardial infarction (MI). Young mice surviving MI show minimal signs of heart failure. Mice lacking Nrf2 experience an accelerated progression to heart failure that occurs within 10days following induction of MI. Nrf2 knockout (Nrf2 KO) mice have a survival rate similar to wild type (WT) mice at 24h after MI, but a significantly higher mortality rate within 10days after MI (50% vs 86%). Morphological examination revealed maladaptive remodeling, including cardiac hypertrophy and dilated left ventricle in Nrf2 KO mice, which were absent in WT mice. Measurements of cardiac function revealed increased left ventricular mass and decreases in cardiac output in Nrf2 KO mice. In addition, Nrf2 KO mice show biomarkers of heart failure, such as elevated levels of β-MHC, ANF, and BNP mRNA in the myocardium. These data support that Nrf2 plays an important role in protecting the myocardium from ischemic injury. Lack of Nrf2 leads to rapid development of heart failure.

      PubDate: 2017-05-07T15:17:34Z
      DOI: 10.1016/j.taap.2017.03.025
      Issue No: Vol. 327 (2017)
       
  • Genetic susceptibility to toxicologic lung responses among inbred mouse
           strains following exposure to carbon nanotubes and profiling of underlying
           gene networks
    • Authors: Evan A. Frank; Vinicius S. Carreira; Kumar Shanmukhappa; Mario Medvedovic; Daniel R. Prows; Jagjit S. Yadav
      Abstract: Publication date: 15 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 327
      Author(s): Evan A. Frank, Vinicius S. Carreira, Kumar Shanmukhappa, Mario Medvedovic, Daniel R. Prows, Jagjit S. Yadav
      The risk of human exposure to fiber nanoparticles has risen in recent years due to increases in the manufacture and utilization of carbon nanotubes (CNTs). CNTs are present as airborne particulates in occupational settings and their hazard potential has been demonstrated in experimental lung exposure studies using inbred mouse strains. However, it is not known whether different inbred strains differ in lung responses to CNTs by virtue of their genetics. In this work, common inbred strains (BALB/c, C57Bl/6, DBA/2, and C3H/He) were exposed to CNTs via oropharyngeal aspiration and lung histology and bronchoalveolar lavage (BAL) samples were evaluated over 28days with the objective of evaluating sensitivity/resistance among strains. C57Bl/6 mice developed significantly more extensive type II pneumocyte (T2P) hyperplasia and alveolar infiltrate compared to DBA/2 mice, which were resistant. Surprisingly, DBA/2 but not C57Bl/6 mice were extremely sensitive to increases in leukocytes recovered in BAL fluid. Underlying global gene expression patterns in the two strains were compared using mRNA sequencing to investigate regulatory networks associated with the different effects. The impact of exposure on gene networks regulating various aspects of immune response and cell survival was limited in DBA/2 mice compared to C57Bl/6. Investigation of B6D2F1 (C57Bl/6×DBA/2 hybrid) mice demonstrated inheritance of sensitivity to CNT exposures in regard to toxicologic lung pathology and BAL leukocyte accumulations. These findings demonstrate a genetic basis of susceptibility to CNT particle exposures and both inform the use of inbred mouse models and suggest the likelihood of differences in genetic susceptibility among humans.

      PubDate: 2017-05-07T15:17:34Z
      DOI: 10.1016/j.taap.2017.04.019
      Issue No: Vol. 327 (2017)
       
  • Pulmonary pathobiology induced by zinc oxide nanoparticles in mice: A
           24-hour and 28-day follow-up study
    • Authors: Hsiao-Chi Chuang; Kai-Jen Chuang; Jen-Kun Chen; His-En Hua; Yen-Ling Shen; Wei-Neng Liao; Chii-Hong Lee; Chih-Hong Pan; Kuan-Yuan Chen; Kang-Yun Lee; Ta-Chih Hsiao; Tsun-Jen Cheng
      Pages: 13 - 22
      Abstract: Publication date: Available online 19 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Hsiao-Chi Chuang, Kai-Jen Chuang, Jen-Kun Chen, His-En Hua, Yen-Ling Shen, Wei-Neng Liao, Chii-Hong Lee, Chih-Hong Pan, Kuan-Yuan Chen, Kang-Yun Lee, Ta-Chih Hsiao, Tsun-Jen Cheng
      Inhaled zinc oxide nanoparticles (ZnONPs) have high deposition rates in the alveolar region of the lungs; however, the adverse health effects of ZnONPs on the respiratory system are unclear. Herein, pathobiological responses of the respiratory system of mice that received intratracheal administration of ZnONPs were investigated by a combination of molecular and imaging (SPECT and CT) approaches. Also, normal BEAS-2B and adenocarcinoma A549 cells were used to confirm the results in mice. First, female BALB/c mice were administrated a series of doses of 20-nm ZnONPs and were compared to the phosphate-buffered saline control for 24-h and 28-day follow-up observations. Field emission-scanning electron microscopy and an energy-dispersive X-ray microanalysis were first used to characterize ZnONPs. After 24h, instilled ZnONPs had caused significant increases in lactic dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), caspase-3, and the p63 tumor marker in lung tissues (p <0.05). Airway inflammation was present in a dose-dependent manner from the upper to the lower airway as analyzed by SPECT. After 28days, p63 had significantly increased due to ZnONP exposure in lung tissues (p <0.05). Pulmonary inflammatory infiltration mainly occurred in the left and right subsegments of the secondary bronchial bifurcation as observed by CT. A significant increase in p63 and decrease in TTF1 levels were observed in BEAS-2B cells by ZnONP (p <0.05), but not in A549 cells. Our results demonstrated that regional lung inflammation occurred with ZnONP exposure. We also showed that p63 was consistently overexpressed due to ZnONP exposure in vivo and in vitro. This work provides unique findings on the p63 response and the pathobiology in response to ZnONPs, which could be important to the study of pulmonary toxicity and repair.

      PubDate: 2017-04-25T14:50:47Z
      DOI: 10.1016/j.taap.2017.04.018
      Issue No: Vol. 327 (2017)
       
  • Mono-2-ethylhexyl phthalate inhibits human extravillous trophoblast
           invasion via the PPARγ pathway
    • Authors: Fumei Gao; Wenxin Hu; Yu Li; Huan Shen; Jianying Hu
      Pages: 23 - 29
      Abstract: Publication date: 15 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 327
      Author(s): Fumei Gao, Wenxin Hu, Yu Li, Huan Shen, Jianying Hu
      Concerns over the adverse reproductive outcomes in human have been raised, more evidence including the underlying mechanism are required. Since extravillous trophoblast (EVT) invasion is an important physiological step during early development, the effects of mono-2-ethylhexyl phthalate (MEHP), the bioactive metabolite of DEHP, on EVT invasion were investigated using Matrigel-coated transwell chambers and cell line HTR-8/SVneo. In the transwell-based invasive assay, MEHP exposure inhibited EVT invasion as judged by decreased invasion index. Further analysis showed that MEHP exposure significantly inhibited the activity of matrix metalloproteinase-9 (MMP-9), which is an important positive regulator of EVT invasion. Meanwhile, the protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), one key negative regulator of EVT invasion, were upregulated by MEHP treatment. Finally, inactivation of PPARγ pathway by either PPARγ inhibitors or PPARγ shRNA knockdown rescued the MEHP-induced inhibited invasion of HTR-8/SVneo cells, which is accompanied by the recovery of inhibited MMP-9 expression. The present study provides the evidence that MEHP exposure inhibits trophoblast invasion via PPARγ at concentrations comparable to those found in humans, which provides an insight in understanding the mechanisms of DEHP-associated early pregnancy loss.

      PubDate: 2017-05-02T15:07:11Z
      DOI: 10.1016/j.taap.2017.04.014
      Issue No: Vol. 327 (2017)
       
  • Quercetin, a natural product supplement, impairs mitochondrial
           bioenergetics and locomotor behavior in larval zebrafish (Danio rerio)
    • Authors: Ji-Liang Zhang; Christopher Laurence Souders; Nancy D. Denslow; Christopher J. Martyniuk
      Pages: 30 - 38
      Abstract: Publication date: 15 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 327
      Author(s): Ji-Liang Zhang, Christopher Laurence Souders, Nancy D. Denslow, Christopher J. Martyniuk
      Quercetin is a natural product that is sold as a supplement in health food stores. While there are reported benefits for this flavonoid as a dietary supplement due to antioxidant properties, the full scope of its biological interactions has not been fully addressed. To learn more about the mechanisms of action related to quercetin, we exposed zebrafish (Danio rerio) embryos to 1 and 10μg/L quercetin for 96h starting at 3h post fertilization. Quercetin up to 10μg/L did not induce significant mortality in developing fish, but did increase prevalence of an upward-curved dorsal plane in hatched larvae. To determine whether this developmental defect was potentially related to mitochondrial bioenergetics during development, we measured oxygen consumption rate in whole embryos following a 24-hour exposure to quercetin. Basal mitochondrial and ATP-linked respiration were decreased at 1 and 10μg/L quercetin, and maximal respiration was decreased at 10μg/L quercetin, suggesting that quercetin impairs mitochondrial bioenergetics. This is proposed to be related to the deformities observed during development. Due to the fact that ATP production was affected by quercetin, larval behaviors related to locomotion were investigated, as well as transcriptional responses of six myogenesis transcripts. Quercetin at 10μg/L significantly reduced the swimming velocity of zebrafish larvae. The expression levels of both myostatin A (mstna) and myogenic differentiation (myoD) were also altered by quercetin. Mstna, an inhibitory factor for myogenesis, was significantly increased at 1μg/L quercetin exposure, while myoD, a stimulatory factor for myogenesis, was significantly increased at 10μg/L quercetin exposure. There were no changes in transcripts related to apoptosis (bcl2, bax, casp3, casp7), but we did observe a decrease in mRNA levels for catalase (cat) in fish exposed to each dose, supporting an oxidative stress response. Our data support the hypothesis that quercetin may affect locomotion and induce deformities in zebrafish larvae by diminishing ATP production and by altering the expression of transcripts related to muscle formation and activity.

      PubDate: 2017-05-07T15:17:34Z
      DOI: 10.1016/j.taap.2017.04.024
      Issue No: Vol. 327 (2017)
       
  • Altered ion transport in normal human bronchial epithelial cells following
           exposure to chemically distinct metal welding fume particles
    • Authors: Jeffrey S. Fedan; Janet A. Thompson; Terence G. Meighan; Patti C. Zeidler-Erdely; James M. Antonini
      Pages: 1 - 6
      Abstract: Publication date: 1 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 326
      Author(s): Jeffrey S. Fedan, Janet A. Thompson, Terence G. Meighan, Patti C. Zeidler-Erdely, James M. Antonini
      Welding fume inhalation causes pulmonary toxicity, including susceptibility to infection. We hypothesized that airway epithelial ion transport is a target of fume toxicity, and investigated the effects of fume particulates from manual metal arc-stainless steel (MMA-SS) and gas metal arc-mild steel (GMA-MS) on ion transport in normal human bronchial epithelium (NHBE) cultured in air-interface. MMA-SS particles, more soluble than GMA-MS particles, contain Cr, Ni, Fe and Mn; GMA-MS particles contain Fe and Mn. MMA-SS or GMA-MS particles (0.0167–166.7μg/cm2) were applied apically to NHBEs. After 18h transepithelial potential difference (Vt), resistance (Rt), and short circuit current (I sc) were measured. Particle effects on Na+ and Cl¯ channels and the Na+,K+,2Cl¯-cotransporter were evaluated using amiloride (apical), 5-nitro-2-[(3-phenylpropyl)amino]benzoic acid (NPPB, apical), and bumetanide (basolateral), respectively. MMA-SS (0.0167–16.7μg/cm2) increased basal Vt. Only 16.7μg/cm2 GMA-MS increased basal Vt significantly. MMA-SS or GMA-MS exposure potentiated I sc responses (decreases) to amiloride and bumetanide, while not affecting those to NPPB, GMA-MS to a lesser degree than MMA-SS. Variable effects on Rt were observed in response to amiloride, and bumetanide. Generally, MMA-SS was more potent in altering responses to amiloride and bumetanide than GMA-MS. Hyperpolarization occurred in the absence of LDH release, but decreases in Vt, Rt, and I sc at higher fume particulate doses accompanied LDH release, to a greater extent for MMA-SS. Thus, Na+ transport and Na+,K+,2Cl¯-cotransport are affected by fume exposure; MMA-MS is more potent than GMA-MS. Enhanced Na+ absorption and decreased airway surface liquid could compromise defenses against infection.

      PubDate: 2017-04-18T14:35:59Z
      DOI: 10.1016/j.taap.2017.04.008
      Issue No: Vol. 326 (2017)
       
  • Arsenic activates the expression of 3β-HSD in mouse Leydig cells through
           repression of histone H3K9 methylation
    • Authors: Ambreen Alamdar; Guochen Xi; Qingyu Huang; Meiping Tian; Syed Ali Musstjab Akber Shah Eqani; Heqing Shen
      Pages: 7 - 14
      Abstract: Publication date: 1 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 326
      Author(s): Ambreen Alamdar, Guochen Xi, Qingyu Huang, Meiping Tian, Syed Ali Musstjab Akber Shah Eqani, Heqing Shen
      Arsenic exposure has been associated with male reproductive dysfunction by disrupting steroidogenesis; however, the roles of epigenetic drivers, especially histone methylation in arsenic-induced steroidogenic toxicity remain not well documented. In this study, we investigated the role of histone H3 lysine 9 (H3K9) methylation in steroidogenesis disturbance in mouse Leydig cells (MLTC-1) due to arsenic exposure. Our results indicated that mRNA and protein expression levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) were both significantly up-regulated while the rest of key genes involved in steroidogenesis were down-regulated. Moreover, arsenic exposure significantly decreased the histone H3K9 di- and tri-methylation (H3K9me2/3) levels in MLTC-1 cells. Since H3K9 demethylation leads to gene activation, we further investigated whether the induction of 3β-HSD expression was ascribed to reduced H3K9 methylation. The results showed that H3K9me2/3 demethylase (JMJD2A) inhibitor, quercetin (Que) significantly attenuated the decrease of H3K9me2/3 and increase of 3β-HSD expression induced by arsenic. To further elucidate the mechanism for the activation of 3β-HSD, we determined the histone H3K9 methylation levels in Hsd3b gene promoter, which also showed significant decrease of H3K9me2/3 in the investigated region after arsenic exposure. Considering these results, we conclude that arsenic exposure induced 3β-HSD up-regulation by suppressing H3K9me2/3 status, which is suggested as a compensatory mechanism for steroidogenic disturbance in MLTC-1 cells.

      PubDate: 2017-04-18T14:35:59Z
      DOI: 10.1016/j.taap.2017.04.012
      Issue No: Vol. 326 (2017)
       
  • Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute
           kidney injury
    • Authors: Di Huang; Chuangyuan Wang; Yingjie Duan; Qiang Meng; Zhihao Liu; Xiaokui Huo; Huijun Sun; Xiaodong Ma; Kexin Liu
      Pages: 15 - 24
      Abstract: Publication date: Available online 13 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Di Huang, Chuangyuan Wang, Yingjie Duan, Qiang Meng, Zhihao Liu, Xiaokui Huo, Huijun Sun, Xiaodong Ma, Kexin Liu
      Nephrotoxicity is one of major side effects of cisplatin in chemotherapy. Therefore, there is an urgent medical need to develop drugs that may protect kidney from toxicity. In previous study, we found that it showed the protective effects of formononetin against apoptosis by upregulating Nrf2. In this study, we investigated the renoprotective effect of formononetin against cisplatin-induced AKI and tried to elucidate the possible mechanisms. The amelioration of renal function, histopathological changes, and apoptosis in tubular cells was observed after formononetin treatment. Formononetin decreased expression of organic cation transporter 2 (Oct2) and increased the expressions of multidrug resistance-associated proteins (Mrps), which might result in a decrease accumulation of cisplatin in tubular cells after AKI. 5-Bromo-2-deoxyuridine (BrdU) and Ki-67 staining assay indicated that formononetin could promote the renal tubular cells proliferation after cisplatin nephrotoxicity. Moreover, formononetin regulated cyclins and pro-apoptotic proteins to involve the regulation of cell cycle. Furthermore, formononetin decreased p53 expression via promoting the overexpression of murine double minute 2 (MDM2) and MDMX. Taken together, formononetin provided protective effects by promoting proliferation of surviving renal tubular cells and inhibiting apoptosis after cisplatin-induced AKI.

      PubDate: 2017-04-18T14:35:59Z
      DOI: 10.1016/j.taap.2017.04.013
      Issue No: Vol. 326 (2017)
       
  • Licoricidin inhibits the growth of SW480 human colorectal adenocarcinoma
           cells in vitro and in vivo by inducing cycle arrest, apoptosis and
           autophagy
    • Authors: Shuai Ji; Shunan Tang; Kai Li; Ziwei Li; Wenfei Liang; Xue Qiao; Qi Wang; Siwang Yu; Min Ye
      Pages: 25 - 33
      Abstract: Publication date: Available online 14 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Shuai Ji, Shunan Tang, Kai Li, Ziwei Li, Wenfei Liang, Xue Qiao, Qi Wang, Siwang Yu, Min Ye
      Licorice (Glycyrrhiza uralensis Fisch.) possesses significant anti-cancer activities, but the active ingredients and underlying mechanisms have not been revealed. By screening the cytotoxic activities of 122 licorice compounds against SW480 human colorectal adenocarcinoma cells, we found that licoricidin (LCD) inhibited SW480 cell viability with an IC50 value of 7.2μM. Further studies indicated that LCD significantly induced G1/S cell cycle arrest and apoptosis in SW480 cells, accompanied by inhibition of cyclins/CDK1 expression and activation of caspase-dependent pro-apoptotic signaling. Meanwhile, LCD promoted autophagy in SW480 cells, and activated AMPK signaling and inhibited Akt/mTOR pathway. Overexpression of a dominant-negative AMPKα2 abolished LCD-induced inhibition of Akt/mTOR, autophagic and pro-apoptotic signaling pathways, and significantly reversed loss of cell viability, suggesting activation of AMPK is essential for the anti-cancer activity of LCD. In vivo anti-tumor experiments indicated that LCD (20mg/kg, i.p.) significantly inhibited the growth of SW480 xenografts in nude mice with an inhibitory rate of 43.5%. In addition, we obtained the glycosylated product LCDG by microbial transformation, and found that glycosylation slightly enhanced the in vivo anti-cancer activities of LCD. This study indicates that LCD could inhibit SW480 cells by inducing cycle arrest, apoptosis and autophagy, and is a potential chemopreventive or chemotherapeutic agent against colorectal cancer.

      PubDate: 2017-04-18T14:35:59Z
      DOI: 10.1016/j.taap.2017.04.015
      Issue No: Vol. 326 (2017)
       
  • Pre-clinical therapeutic development of a series of metalloporphyrins for
           Parkinson's disease
    • Authors: Li-Ping Liang; Jie Huang; Ruth Fulton; Jennifer N. Pearson-Smith; Brian J. Day; Manisha Patel
      Pages: 34 - 42
      Abstract: Publication date: 1 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 326
      Author(s): Li-Ping Liang, Jie Huang, Ruth Fulton, Jennifer N. Pearson-Smith, Brian J. Day, Manisha Patel
      Reactive oxygen species are a well-defined therapeutic target for Parkinson's disease (PD) and pharmacological agents that catalytically scavenge reactive species are promising neuroprotective strategies for treatment. Metalloporphyrins are synthetic catalytic antioxidants that mimic the body's own antioxidant enzymes i.e. superoxide dismutases and catalase. The goal of this study was to determine if newly designed metalloporphyrins have enhanced pharmacodynamics including oral bioavailability, longer plasma elimination half-lives, penetrate the blood brain barrier, and show promise for PD treatment. Three metalloporphyrins (AEOL 11216, AEOL 11203 and AEOL 11114) were identified in this study as potential candidates for further pre-clinical development. Each of these compounds demonstrated blood brain barrier permeability by the i.p. route and two of three compounds (AEOL 11203 and AEOL 11114) were orally bioavailable. All of these compounds protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, including dopamine depletion in the striatum, dopaminergic neuronal loss in the substantial nigra, and increased oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain of the mice without inhibiting MPTP metabolism. Daily therapeutic dosing of these metalloporphyrins were well tolerated without accumulation of brain manganese levels or behavioral alterations assessed by open field and rotarod tests. The study identified two orally active metalloporphyrins and one injectable metalloporphyrin as clinical candidates for further development in PD.

      PubDate: 2017-04-25T14:50:47Z
      DOI: 10.1016/j.taap.2017.04.004
      Issue No: Vol. 326 (2017)
       
  • Increased seizure susceptibility and other toxicity symptoms following
           acute sulforaphane treatment in mice
    • Authors: Katarzyna Socała; Dorota Nieoczym; Edyta Kowalczuk-Vasilev; Elżbieta Wyska; Piotr Wlaź
      Pages: 43 - 53
      Abstract: Publication date: Available online 13 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Katarzyna Socała, Dorota Nieoczym, Edyta Kowalczuk-Vasilev, Elżbieta Wyska, Piotr Wlaź
      Activation of Nrf2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. It is widely consumed, also by patients suffering from seizure and taking antiepileptic drugs, but no toxicity profile of sulforaphane exists. Since many natural remedies and dietary supplements may increase seizure risk and potentially interact with antiepileptic drugs, the aim of our study was to investigate the acute effects of sulforaphane on seizure thresholds and activity of some first- and second-generation antiepileptic drugs in mice. In addition, some preliminary toxicity profile of sulforaphane in mice after intraperitoneal injection was evaluated. The LD50 value of sulforaphane in mice was estimated at 212.67mg/kg, while the TD50 value – at191.58mg/kg. In seizure tests, sulforaphane at the highest dose tested (at 200mg/kg) significantly decreased the thresholds for the onset of the first myoclonic twitch and generalized clonic seizure in the iv PTZ test as well as the threshold for the 6Hz-induced psychomotor seizure. At doses of 10–200mg/kg, sulforaphane did not affect the threshold for the iv PTZ-induced forelimb tonus or the threshold for maximal electroshock-induced hindlimb tonus. Interestingly, sulforaphane (at 100mg/kg) potentiated the anticonvulsant efficacy of carbamazepine in the maximal electroshock seizure test. This interaction could have been pharmacokinetic in nature, as sulforaphane increased concentrations of carbamazepine in both serum and brain tissue. The toxicity study showed that high doses of sulforaphane produced marked sedation (at 150–300mg/kg), hypothermia (at 150–300mg/kg), impairment of motor coordination (at 200–300mg/kg), decrease in skeletal muscle strength (at 250–300mg/kg), and deaths (at 200–300mg/kg). Moreover, blood analysis showed leucopenia in mice injected with sulforaphane at 200mg/kg. In conclusion, since sulforaphane was proconvulsant at a toxic dose, the safety profile and the risk-to-benefit ratio of sulforaphane usage in epileptic patients should be further evaluated.

      PubDate: 2017-04-18T14:35:59Z
      DOI: 10.1016/j.taap.2017.04.010
      Issue No: Vol. 326 (2017)
       
  • The monoamine oxidase inhibition properties of selected structural
           analogues of methylene blue
    • Authors: Anzelle Delport; Brian H. Harvey; Anél Petzer; Jacobus P. Petzer
      Pages: 1 - 8
      Abstract: Publication date: 15 June 2017
      Source:Toxicology and Applied Pharmacology, Volume 325
      Author(s): Anzelle Delport, Brian H. Harvey, Anél Petzer, Jacobus P. Petzer
      The thionine dye, methylene blue (MB), is a potent inhibitor of monoamine oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO inhibition by MB analogues, the present study investigates the human MAO inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC50 =0.0037μM), Nile blue (IC50 =0.0077μM) and 1,9-dimethyl methylene blue (IC50 =0.018μM) exhibiting higher potency inhibition compared to MB (IC50 =0.07μM). Nile blue also represents a potent MAO-B inhibitor with an IC50 value of 0.012μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST.
      Graphical abstract image

      PubDate: 2017-04-18T14:35:59Z
      DOI: 10.1016/j.taap.2017.03.026
      Issue No: Vol. 325 (2017)
       
  • Improved physiologically based pharmacokinetic model for oral exposures to
           chromium in mice, rats, and humans to address temporal variation and
           sensitive populations
    • Authors: C.R. Kirman; M. Suh; D.M. Proctor; S.M. Hays
      Pages: 9 - 17
      Abstract: Publication date: Available online 5 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): C.R. Kirman, M. Suh, D.M. Proctor, S.M. Hays
      A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment.

      PubDate: 2017-04-11T14:21:40Z
      DOI: 10.1016/j.taap.2017.03.023
      Issue No: Vol. 325 (2017)
       
  • Butyl paraben and propyl paraben modulate bisphenol A and estradiol
           concentrations in female and male mice
    • Authors: Tyler Pollock; Rachel E. Weaver; Ramtin Ghasemi; Denys deCatanzaro
      Pages: 18 - 24
      Abstract: Publication date: Available online 5 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Tyler Pollock, Rachel E. Weaver, Ramtin Ghasemi, Denys deCatanzaro
      People are routinely exposed to the antimicrobial preservatives butyl paraben (BP) and propyl paraben (PP), as well as the monomer of polycarbonate plastics, bisphenol A (BPA). These chemicals are reliably detected in human urine and potentially interact. We investigated whether BP or PP exposure can modulate the concentrations of 14C-BPA and 17β-estradiol (E2). Female and male CF1 mice were each given a subcutaneous injection of oil containing 0 (vehicle), 1, 3, or 9mg BP or PP, then given a dietary supplement containing 50μg/kg 14C-BPA. Radioactivity was measured in tissues through liquid scintillation counting. Significantly elevated 14C-BPA concentrations were observed following BP treatment in blood serum of both sexes, as well as the lungs, uterus, and ovaries of females and the testes and epididymides of males. Treatment with PP significantly elevated 14C-BPA concentrations in the uterus only. In another experiment, female and male CF1 mice were each injected with vehicle, 3mg BP, or 3mg PP, and E2 was measured in urine 2–12h later. Whereas PP did not affect E2, BP significantly elevated E2 6–10h after injection in females and 8h after injection in males. These data indicate that BP and PP can alter the pharmacokinetics of BPA in vivo, and that BP can modulate E2 concentrations. These results are consistent with evidence that parabens inhibit enzymes that are critical for BPA and E2 metabolism, and demonstrate the importance of considering concurrent exposure to multiple chemicals when determining regulatory exposure limits.

      PubDate: 2017-04-11T14:21:40Z
      DOI: 10.1016/j.taap.2017.04.001
      Issue No: Vol. 325 (2017)
       
  • The scaffold protein RACK1 is a target of endocrine disrupting chemicals
           (EDCs) with important implication in immunity
    • Authors: Erica Buoso; Marilisa Galasso; Melania Ronfani; Angela Papale; Valentina Galbiati; Ivano Eberini; Marina Marinovich; Marco Racchi; Emanuela Corsini
      Pages: 37 - 47
      Abstract: Publication date: 15 June 2017
      Source:Toxicology and Applied Pharmacology, Volume 325
      Author(s): Erica Buoso, Marilisa Galasso, Melania Ronfani, Angela Papale, Valentina Galbiati, Ivano Eberini, Marina Marinovich, Marco Racchi, Emanuela Corsini
      We recently demonstrated the existence of a complex hormonal balance between steroid hormones in the control of RACK1 (Receptor for Activated C Kinase 1) expression and immune activation, suggesting that this scaffold protein may also be targeted by endocrine disrupting chemicals (EDCs). As a proof of concept, we investigated the effect of the doping agent nandrolone, an androgen receptor (AR) agonist, and of p,p′DDT (dichlorodiphenyltrichloroethane) and its main metabolite p,p′DDE (dichlorodiphenyldichloroethylene), a weak and strong AR antagonist, respectively, on RACK1 expression and innate immune response. In analogy to endogenous androgens, nandrolone induced a dose-related increase in RACK1 transcriptional activity and protein expression, resulting in increased LPS-induced IL-8 and TNF-α production and proliferation in THP-1 cells. Conversely, p,p′DDT and p,p′DDE significantly decrease RACK1 expression, LPS-induced cytokine production and CD86 expression; with p,p′DDE exerting a stronger repressor effect than p,p′DDT, consistent with its stronger AR antagonistic effect. These results indicate that RACK1 could be a relevant target of EDCs, responding in opposite ways to agonist or antagonist of AR, representing a bridge between the endocrine system and the innate immune system.
      Graphical abstract image

      PubDate: 2017-05-07T15:17:34Z
      DOI: 10.1016/j.taap.2017.04.011
      Issue No: Vol. 325 (2017)
       
  • 4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin
           sensitivity in highly aggressive epithelial cancer through the
           PI3K/Akt/mTOR/p70S6K signaling pathway
    • Authors: Mingche Liu; Oluwaseun Adebayo Bamodu; Wen-Chien Huang; Muhammad Ary Zucha; Yen-Kuang Lin; Alexander T.H. Wu; Chun-Chih Huang; Wei-Hwa Lee; Chiou-Chung Yuan; M. Hsiao; Li Deng; Yew-Min Tzeng; Chi-Tai Yeh
      Pages: 48 - 60
      Abstract: Publication date: 15 June 2017
      Source:Toxicology and Applied Pharmacology, Volume 325
      Author(s): Mingche Liu, Oluwaseun Adebayo Bamodu, Wen-Chien Huang, Muhammad Ary Zucha, Yen-Kuang Lin, Alexander T.H. Wu, Chun-Chih Huang, Wei-Hwa Lee, Chiou-Chung Yuan, M. Hsiao, Li Deng, Yew-Min Tzeng, Chi-Tai Yeh
      Targeting residual self-renewing, chemoresistant cancerous cells may represent the key to overcoming therapy resistance. The entry of these quiescent cells into an activated state is associated with high metabolic demand and autophagic flux. Therefore, modulating the autophagy pathway in aggressive carcinomas may be beneficial as a therapeutic modality. In this study, we evaluated the anti-tumor activities of 4-acetylantroquinonol B (4-AAQB) in chemoresistant ovarian cancer cells, particularly its ability to modulate autophagy through autophagy-related genes (Atg). Atg-5 was overexpressed in invasive ovarian cancer cell lines and tissue (OR: 5.133; P =0.027) and depleting Atg-5 in ES-2 cell lines significantly induced apoptosis. 4-AAQB effectively suppressed viability of various subtypes of ovarian cancer. Cells with higher cisplatin-resistance were more responsive to 4-AAQB. For the first time, we demonstrate that 4-AAQB significantly suppress Atg-5 and Atg-7 expression with decreased autophagic flux in ovarian cancer cells via inhibition of the PI3K/Akt/mTOR/p70S6K signaling pathway. Similar to Atg-5 silencing, 4-AAQB-induced autophagy inhibition significantly enhanced cell death in vitro. These results are comparable to those of hydroxychloroquine (HCQ). In addition, 4-AAQB/cisplatin synergistically induced apoptosis in ovarian cancer cells. In vivo, 4-AAQB/cisplatin also significantly induced apoptosis and autophagy in an ES-2 mouse xenografts model. This is the first report demonstrating the efficacy of 4-AAQB alone or in combination with cisplatin on the suppression of ovarian cancer via Atg-5-dependent autophagy. We believe these findings will be beneficial in the development of a novel anti-ovarian cancer therapeutic strategy.
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      PubDate: 2017-05-07T15:17:34Z
      DOI: 10.1016/j.taap.2017.04.003
      Issue No: Vol. 325 (2017)
       
  • Assessment of the potential activity of major dietary compounds as
           selective estrogen receptor modulators in two distinct cell models for
           proliferation and differentiation
    • Authors: Sylvain Lecomte; Marie Lelong; Gaëlle Bourgine; Theo Efstathiou; Christian Saligaut; Farzad Pakdel
      Pages: 61 - 70
      Abstract: Publication date: 15 June 2017
      Source:Toxicology and Applied Pharmacology, Volume 325
      Author(s): Sylvain Lecomte, Marie Lelong, Gaëlle Bourgine, Theo Efstathiou, Christian Saligaut, Farzad Pakdel
      Estrogen receptors (ERs) α and β are distributed in most tissues of women and men. ERs are bound by estradiol (E2), a natural hormone, and mediate the pleiotropic and tissue-specific effects of E2, such as proliferation of breast epithelial cells or protection and differentiation of neuronal cells. Numerous environmental molecules, called endocrine disrupting compounds, also interact with ERs. Phytoestrogens belong to this large family and are considered potent therapeutic molecules that act through their selective estrogen receptor modulator (SERM) activity. Using breast cancer cell lines as a model of estrogen-dependent proliferation and a stably ER-expressing PC12 cell line as a model of neuronal differentiating cells, we studied the SERM activity of major dietary compounds, such as apigenin, liquiritigenin, daidzein, genistein, coumestrol, resveratrol and zearalenone. The ability of these compounds to induce ER-transactivation and breast cancer cell proliferation and enhance Nerve Growth Factor (NGF) -induced neuritogenesis was assessed. Surprisingly, although all compounds were able to activate the ER through an estrogen responsive element reporter gene, they showed differential activity toward proliferation or differentiation. Apigenin and resveratrol showed a partial or no proliferative effect on breast cancer cells but fully contributed to the neuritogenesis effect of NGF. However, daidzein and zearalenone showed full effects on cellular proliferation but did not induce cellular differentiation. In summary, our results suggest that the therapeutic potential of phytoestrogens can diverge depending on the molecule and the phenotype considered. Hence, apigenin and resveratrol might be used in the development of therapeutics for breast cancer and brain diseases.
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      PubDate: 2017-05-07T15:17:34Z
      DOI: 10.1016/j.taap.2017.04.005
      Issue No: Vol. 325 (2017)
       
  • Interleukin-24 as a target cytokine of environmental aryl hydrocarbon
           receptor agonist exposure in the lung
    • Authors: Yueh-Hsia Luo; Yu-Chun Kuo; Ming-Hsien Tsai; Chia-Chi Ho; Hui-Ti Tsai; Chin-Yu Hsu; Yu-Cheng Chen; Pinpin Lin
      Pages: 1 - 11
      Abstract: Publication date: 1 June 2017
      Source:Toxicology and Applied Pharmacology, Volume 324
      Author(s): Yueh-Hsia Luo, Yu-Chun Kuo, Ming-Hsien Tsai, Chia-Chi Ho, Hui-Ti Tsai, Chin-Yu Hsu, Yu-Cheng Chen, Pinpin Lin
      Exposure to environmental aryl hydrocarbon receptor (AhR) agonists, such as halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs), has great impacts on the development of various lung diseases. As emerging molecular targets for AhR agonists, cytokines may contribute to the inflammatory or immunotoxic effects of environmental AhR agonists. However, general cytokine expression may not specifically indicate environmental AhR agonist exposure. By comparing cytokine and chemokine expression profiles in human lung adenocarcinoma cell line CL5 treated with AhR agonists and the non-AhR agonist polychlorinated biphenyl (PCB) 39, we identified a target cytokine of environmental AhR agonist exposure of in the lungs. Thirteen cytokine and chemokine genes were altered in the AhR agonists-treated cells, but none were altered in the PCB39-treated cells. Interleukin (IL)-24 was the most highly induced gene among AhR-modulated cytokines. Cotreatment with AhR antagonist completely prevented IL-24 induction by AhR agonists in the CL5 cells. Knockdown AhR expression with short-hairpin RNA (shRNA) significantly reduced benzo[a]pyrene (BaP)-induced IL-24 mRNA levels. We further confirmed that gene transcription, but not mRNA stability, was involved in IL-24 upregulation by BaP. Particulate matter (PM) in the ambient air contains some PAHs and is reported to activate AhR. Oropharyngeal aspiration of PM significantly increased IL-24 levels in lung epithelia and in bronchoalveolar lavage fluid of mice 4weeks after treatment. Thus, our data suggests that IL-24 is a pulmonary exposure target cytokine of environmental AhR agonists.
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      PubDate: 2017-04-04T02:33:26Z
      DOI: 10.1016/j.taap.2017.03.019
      Issue No: Vol. 324 (2017)
       
  • Caffeic acid phenethyl ester protects against glucocorticoid-induced
           osteoporosis in vivo: Impact on oxidative stress and RANKL/OPG signals
    • Authors: Mai F. Tolba; Ahmed T. El-Serafi; Hany A. Omar
      Pages: 26 - 35
      Abstract: Publication date: Available online 29 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Mai F. Tolba, Ahmed T. El-Serafi, Hany A. Omar
      Glucocorticoid-induced osteoporosis (GIO) is one of the most common causes of secondary osteoporosis. Given that glucocorticoids are considered a main component of the treatment protocols for a variety of inflammation and immune-mediated diseases in addition to its use as adjuvant with several chemotherapeutic agents, it is crucial to find ways to overcome this critical adverse effect. Caffeic acid phenethyl ester (CAPE), which is a natural compound derived from honeybee propolis displayed promising antiosteoporotic effects against mechanical bone injury in various studies. The current work aimed at investigating the potential protective effect of CAPE against GIO in vivo with emphasis on modulation of oxidative status and receptor activator of NF-kB ligand (RANKL)/osteoprotegrin (OPG) signaling. The results showed that CAPE opposed dexamethasone (DEX)-mediated alterations in bone histology and tartarate-resistant acid phosphatase (TRAP) activity. In addition, CAPE restored oxidative balance, Runt-related transcription factor 2 (RunX2) expression and reduced caspase-3 activity in femur tissues. Co-administration of CAPE with DEX normalized RANKL/OPG ratio and Akt activation indicating a reduction in DEX-osteoclatogenesis. In conclusion, concurrent treatment of CAPE with DEX exhibited promising effects in the protection against DEX-induced osteoporosis through opposing osteoclastogenesis and protecting osteoblasts. The potent antioxidant activity of CAPE is, at least in part, involved in its anti-apoptotic effects and modulation of RunX2 and RANKL/OPG signals. The use of CAPE-enriched propolis formulas is strongly recommended for patients on chronic glucocorticoid therapy to help in attenuation of GIO.
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      PubDate: 2017-04-04T02:33:26Z
      DOI: 10.1016/j.taap.2017.03.021
      Issue No: Vol. 324 (2017)
       
  • TRPA1: Acrolein meets its target
    • Authors: Satyanarayana Achanta; Sven-Eric Jordt
      Pages: 45 - 50
      Abstract: Publication date: 1 June 2017
      Source:Toxicology and Applied Pharmacology, Volume 324
      Author(s): Satyanarayana Achanta, Sven-Eric Jordt


      PubDate: 2017-04-25T14:50:47Z
      DOI: 10.1016/j.taap.2017.03.007
      Issue No: Vol. 324 (2017)
       
  • TRPA1 mediates changes in heart rate variability and cardiac mechanical
           function in mice exposed to acrolein
    • Authors: Nicole Kurhanewicz; Rachel McIntosh-Kastrinsky; Haiyan Tong; Allen Ledbetter; Leon Walsh; Aimen Farraj; Mehdi Hazari
      Pages: 51 - 60
      Abstract: Publication date: 1 June 2017
      Source:Toxicology and Applied Pharmacology, Volume 324
      Author(s): Nicole Kurhanewicz, Rachel McIntosh-Kastrinsky, Haiyan Tong, Allen Ledbetter, Leon Walsh, Aimen Farraj, Mehdi Hazari
      Short-term exposure to ambient air pollution is linked with adverse cardiovascular effects. While previous research focused primarily on particulate matter-induced responses, gaseous air pollutants also contribute to cause short-term cardiovascular effects. Mechanisms underlying such effects have not been adequately described, however the immediate nature of the response suggests involvement of irritant neural activation and downstream autonomic dysfunction. Thus, this study examines the role of TRPA1, an irritant sensory receptor found in the airways, in the cardiac response of mice to acrolein and ozone. Conscious unrestrained wild-type C57BL/6 (WT) and TRPA1 knockout (KO) mice implanted with radiotelemeters were exposed once to 3ppm acrolein, 0.3ppm ozone, or filtered air. Heart rate (HR) and electrocardiogram (ECG) were recorded continuously before, during and after exposure. Analysis of ECG morphology, incidence of arrhythmia and heart rate variability (HRV) were performed. Cardiac mechanical function was assessed using a Langendorff perfusion preparation 24h post-exposure. Acrolein exposure increased HRV independent of HR, as well as incidence of arrhythmia. Acrolein also increased left ventricular developed pressure in WT mice at 24h post-exposure. Ozone did not produce any changes in cardiac function. Neither gas produced ECG effects, changes in HRV, arrhythmogenesis, or mechanical function in KO mice. These data demonstrate that a single exposure to acrolein causes cardiac dysfunction through TRPA1 activation and autonomic imbalance characterized by a shift toward parasympathetic modulation. Furthermore, it is clear from the lack of ozone effects that although gaseous irritants are capable of eliciting immediate cardiac changes, gas concentration and properties play important roles.

      PubDate: 2017-04-25T14:50:47Z
      DOI: 10.1016/j.taap.2016.10.008
      Issue No: Vol. 324 (2017)
       
  • Role of TRPA1 in acute cardiopulmonary toxicity of inhaled acrolein
    • Authors: Daniel J. Conklin; Petra Haberzettl; Ganapathy Jagatheesan; Maiying Kong; Gary W. Hoyle
      Pages: 61 - 72
      Abstract: Publication date: 1 June 2017
      Source:Toxicology and Applied Pharmacology, Volume 324
      Author(s): Daniel J. Conklin, Petra Haberzettl, Ganapathy Jagatheesan, Maiying Kong, Gary W. Hoyle
      Acrolein is a highly toxic, volatile, unsaturated aldehyde generated during incomplete combustion as in tobacco smoke and indoor fires. Because the transient receptor potential ankyrin 1 (TRPA1) channel mediates tobacco smoke-induced lung injury, we assessed its role in high-level acrolein-induced toxicity in mice. Acrolein (100–275ppm, 10–30min) caused upper airway epithelial sloughing, bradypnea and oral gasping, hypothermia, cardiac depression and mortality. Male wild-type mice (WT, C57BL/6; 5–52weeks) were significantly more sensitive to high-level acrolein than age-matched, female WT mice. Both male and female TRPA1-null mice were more sensitive to acrolein-induced mortality than age- and sex-matched WT mice. Acrolein exposure increased lung weight:body weight ratios and lung albumin and decreased plasma albumin to a greater extent in TRPA1-null than in WT mice. Lung and plasma protein-acrolein adducts were not increased in acrolein-exposed TRPA1-null mice compared with WT mice. To assess TRPA1-dependent protective mechanisms, respiratory parameters were monitored by telemetry. TRPA1-null mice had a slower onset of breathing rate suppression (‘respiratory braking’) than WT mice suggesting TRPA1 mediates this protective response. Surprisingly, WT male mice treated either with a TRPA1 antagonist (HC030031; 200mg/kg) alone or with combined TRPA1 (100mg/kg) and TRPV1 (capsazepine, 10mg/kg) antagonists at 30min post-acrolein exposure (i.e., “real world” delay in treatment) were significantly protected from acrolein-induced mortality. These data show TRPA1 protects against high-level acrolein-induced toxicity in a sex-dependent manner. Post-exposure TRPA1 antagonism also protected against acrolein-induced mortality attesting to a complex role of TRPA1 in cardiopulmonary injury.
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      PubDate: 2017-04-25T14:50:47Z
      DOI: 10.1016/j.taap.2016.08.028
      Issue No: Vol. 324 (2017)
       
  • Genipin protects the liver from ischemia/reperfusion injury by modulating
           mitochondrial quality control
    • Abstract: Publication date: 1 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 328
      Author(s): Jun-Kyu Shin, Sun-Mee Lee
      Hepatic ischemia and reperfusion (IR) injury is closely linked to oxidative mitochondrial damage. Since mitochondrial quality control (QC) plays a pivotal role in the recovery of impaired mitochondrial function, mitochondrial QC has emerged as a potential therapeutic target. Genipin, an iridoid compound from Gardenia jasminoides, has been showed antioxidant and anti-inflammatory properties. In this study, we investigated the hepatoprotective mechanism of genipin against IR-induced hepatic injury, particularly focusing on mitochondrial QC. Male C57BL/6 mice underwent liver ischemia for 60min, followed by reperfusion for 6h. Genipin (100mg/kg, i.p.) or vehicle (10% Tween 80 in saline) was administrated to mice 1h before ischemia. Liver and blood samples were collected 6h after reperfusion. Hepatic IR increased hepatocellular oxidative damage and induced mitochondrial dysfunction. These phenomena were ameliorated by genipin. Hepatic IR also increased the level of mitochondrial fission, such as dynamin-related protein 1 and the level of PINK1 protein expression. In contrast, hepatic IR decreased the levels of mitochondrial biogenesis related proteins (e.g., peroxisome proliferator-activated receptor gamma coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A), mitophagy related proteins (e.g., Parkin), and fusion related protein (e.g., mitofusin 2). Furthermore, hepatic IR decreased the levels of sirtuin1 protein and phosphorylation of AMP-activated protein kinase. Genipin alleviated these IR-induced changes. These data indicate that genipin protects against IR-induced hepatic injury via regulating mitochondrial QC. (225/250).

      PubDate: 2017-05-22T19:08:11Z
       
  • HMGA2, a driver of inflammation, is associated with hypermethylation in
           acute liver injury
    • Abstract: Publication date: 1 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 328
      Author(s): Huimin Huang, Haidi Li, Xin Chen, Yang Yang, Xiaofeng Li, Wanxia Li, Cheng Huang, Xiaoming Meng, Lei Zhang, Jun Li
      Acute liver injury (ALI) is characteristic of abrupt hepatic dysfunction and inflammatory response. Activaion of Kupffer cells (KCs) plays a central role in the pathogenesis of ALI. Since the High Mobility Group A protein2 (HMGA2) occurs as a driver at critical stage of hepatocellular carcinoma, herein, we investigated the role of HMGA2 in macrophage activation during ALI. Our study found that the expression of HMGA2 decreased dramatically both in KCs isolated from the liver in mice with ALI and in LPS-induced RAW264.7 cell lines. Moreover, loss- and gain-of-function studies suggested that HMGA2 could enhance the expression of pro-inflammatory cytokines including TNF-α, IL-6 and IL-1β. These results indicated that HMGA2 may play an essential role in macrophage activation during ALI. Additionally, our results showed the expression of HMGA2 was up-regulated when LPS-induced RAW264.7 cells were treated with 5-aza-2-deoxycytidine. Furthermore, silencing of DNMT1, DNMT3a, DNMT3b could respectively prevent the down-expression of HMGA2 in LPS-induced RAW264.7 cells. In conclusion, HMGA2 promotes the release of pro-inflammatory cytokines through NF-κB pathway, and the dysregulation of HMGA2 may involve with hypermethylation.

      PubDate: 2017-05-22T19:08:11Z
       
  • Effects of monocrotophos pesticide on cholinergic and dopaminergic
           neurotransmitter systems during early development in the sea urchin
           Hemicentrotus pulcherrimus
    • Abstract: Publication date: 1 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 328
      Author(s): Xiaona Zhang, Shuman Li, Cuicui Wang, Hua Tian, Wei Wang, Shaoguo Ru
      During early development in sea urchins, classical neurotransmitters, including acetylcholine (ACh), dopamine (DA), and serotonin (5-HT), play important roles in the regulation of morphogenesis and swimming behavior. However, the underlying mechanisms of how organophosphate pesticides cause developmental neurotoxicity by interfering with different neurotransmitter systems are unclear. In this study, we investigated the effects of 0.01, 0.10, and 1.00mg/L monocrotophos (MCP) pesticide on the activity of acetyltransferase (ChAT), acetylcholinesterase (AChE), monoamine oxidase, the concentration of DA, dopamine transporter, and the transcription activity of DA receptor D1 and tyrosine hydroxylase, during critical periods in cholinergic and dopaminergic nervous system development in sea urchin (Hemicentrotus pulcherrimus) embryos and larvae. At the blastula stages, MCP disrupted DA metabolism but not 5-HT metabolism, resulting in abnormal development. High ChAT and AChE activity were observed at the gastrulation-completed stage and the two-armed pluteus stage, respectively, MCP inhibited ChAT activity and AChE activity/distribution and resulted in developmental defects of the plutei. From the gastrula stage to the two-armed pluteus stage, we found ubiquitous disrupting effects of MCP on ACh, DA, and 5-HT metabolism, particularly at critical periods during the development of these neurotransmitter systems. Therefore, we propose that this disruption is one of the main mechanisms of MCP-related developmental neurotoxicity, which would contribute better understanding insight into the mechanism of MCP pesticide's toxic effects.

      PubDate: 2017-05-22T19:08:11Z
       
  • An impedance-based approach using human iPSC-derived cardiomyocytes
           significantly improves in vitro prediction of in vivo cardiotox
           liabilities
    • Abstract: Publication date: Available online 22 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Bryan Koci, Gregory Luerman, Anika Duenbostell, Ralf Kettenhofen, Heribert Bohlen, Luke Coyle, Brian Knight, Warren Ku, Walter Volberg, Joseph R. Woska, Martha P. Brown
      Current in vitro approaches to cardiac safety testing typically focus on mechanistic ion channel testing to predict in vivo proarrhythmic potential. Outside of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, structural and functional cardiotoxicity related to chronic dosing effects are of great concern as these effects can impact compound attrition. Development and implementation of an in vitro cardiotoxicity screening platform that effectively identifies these liabilities early in the discovery process should reduce costly attrition and decrease preclinical development time. Impedence platforms have the potential to accurately identify structural and functional cardiotoxicity and have sufficient throughput to be included in a multi-parametric optimization approach. Human induced pluripotent stem cell cardiomyocytes (hIPSC-CMs) have demonstrated utility in cardiac safety and toxicity screening. The work described here leverages these advantages to assess the predictive value of data generated by two impedance platforms. The response of hIPSC-CMs to compounds with known or predicted cardiac functional or structural toxicity was determined. The compounds elicited cardiac activities and/or effects on “macro” impedance often associated with overt structural or cellular toxicity, detachment, or hypertrophy. These assays correctly predicted in vivo cardiotox findings for 81% of the compounds tested and did not identify false positives. In addition, internal or literature Cmax values from in vivo studies correlated within 4 fold of the in vitro observations. The work presented here demonstrates the predictive power of impedance platforms with hIPSC-CMs and provides a means toward accelerating lead candidate selection by assessing preclinical cardiac safety earlier in the drug discovery process.

      PubDate: 2017-05-22T19:08:11Z
       
  • Zuotai and HgS differ from HgCl2 and methyl mercury in Hg accumulation and
           toxicity in weanling and aged rats
    • Abstract: Publication date: Available online 20 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Bin-Bin Zhang, Wen-Kai Li, Wei-Yu Hou, Ya Luo, Jing-Zhen Shi, Cen Li, Li-Xin Wei, Jie Liu
      Mercury sulfides are used in Ayurvedic medicines, Tibetan medicines, and Chinese medicines for thousands of years and are still used today. Cinnabar (α-HgS) and metacinnabar (β-HgS) are different from mercury chloride (HgCl2) and methylmercury (MeHg) in their disposition and toxicity. Whether such scenario applies to weanling and aged animals is not known. To address this question, weanling (21d) and aged (450d) rats were orally given Zuotai (54% β-HgS, 30mg/kg), HgS (α-HgS, 30mg/kg), HgCl2 (34.6mg/kg), or MeHg (MeHgCl, 3.2mg/kg) for 7days. Accumulation of Hg in kidney and liver, and the toxicity-sensitive gene expressions were examined. Animal body weight gain was decreased by HgCl2 and to a lesser extent by MeHg, but unaltered after Zuotai and HgS. HgCl2 and MeHg produced dramatic tissue Hg accumulation, increased kidney (kim-1 and Ngal) and liver (Ho-1) injury-sensitive gene expressions, but such changes are absent or mild after Zuotai and HgS. Aged rats were more susceptible than weanling rats to Hg toxicity. To examine roles of transporters in Hg accumulation, transporter gene expressions were examined. The expression of renal uptake transporters Oat1, Oct2, and Oatp4c1 and hepatic Oatp2 was decreased, while the expression of renal efflux transporter Mrp2, Mrp4 and Mdr1b was increased following HgCl2 and MeHg, but unaffected by Zuotai and HgS. Thus, Zuotai and HgS differ from HgCl2 and MeHg in producing tissue Hg accumulation and toxicity, and aged rats are more susceptible than weanling rats. Transporter expression could be adaptive means to reduce tissue Hg burden.
      Graphical abstract image

      PubDate: 2017-05-22T19:08:11Z
       
  • Ochratoxin A transport by the human breast cancer resistance protein
           (BCRP), multidrug resistance protein 2 (MRP2), and organic
           anion-transporting polypeptides 1A2, 1B1 and 2B1
    • Abstract: Publication date: Available online 19 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Xiaozhe Qi, Els Wagenaar, Wentao Xu, Kunlun Huang, Alfred H. Schinkel
      Ochratoxin A (OTA) is a fungal secondary metabolite that can contaminate various foods. OTA has several toxic effects like nephrotoxicity, hepatotoxicity, and neurotoxicity in different animal species, but its mechanisms of toxicity are still unclear. How OTA accumulates in kidney, liver, and brain is as yet unknown, but transmembrane transport proteins are likely involved. We studied transport of OTA in vitro, using polarized MDCKII cells transduced with cDNAs of the efflux transporters mouse (m)Bcrp, human (h)BCRP, mMrp2, or hMRP2, and HEK293 cells overexpressing cDNAs of the human uptake transporters OATP1A2, OATP1B1, OATP1B3, or OATP2B1 at pH7.4 and 6.4. MDCKII-mBcrp cells were more resistant to OTA toxicity than MDCKII parental and hBCRP-transduced cells. Transepithelial transport experiments showed some apically directed transport by MDCKII-mBcrp cells at pH7.4, whereas both mBcrp and hBCRP clearly transported OTA at pH6.4. There was modest transport of OTA by mMrp2 and hMRP2 only at pH6.4. OATP1A2 and OATP2B1 mediated uptake of OTA both at pH7.4 and 6.4, but OATP1B1 only at pH7.4. There was no detectable transport of OTA by OATP1B3. Our data indicate that human BCRP and MRP2 can mediate elimination of OTA from cells, thus reducing OTA toxicity. On the other hand, human OATP1A2, OATP1B1, and OATP2B1 can mediate cellular uptake of OTA, which could aggravate OTA toxicity.

      PubDate: 2017-05-22T19:08:11Z
       
  • Molecular insights into the differences in anti-inflammatory activities of
           green tea catechins on IL-1β signaling in rheumatoid arthritis synovial
           fibroblasts
    • Abstract: Publication date: Available online 19 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Sabrina Fechtner, Anil Singh, Mukesh Chourasia, Salahuddin Ahmed
      In this study, we found that catechins found in green tea (EGCG, EGC, and EC) differentially interfere with the IL-1β signaling pathway which regulates the expression of pro-inflammatory mediators (IL-6 and IL-8) and Cox-2 in primary human rheumatoid arthritis synovial fibroblasts (RASFs). EGCG and EGC inhibited IL-6, IL-8, and MMP-2 production and selectively inhibited Cox-2 expression. EC did not exhibit any inhibitory effects. When we looked at the expression of key signaling proteins in the IL-1β signaling pathway, we found all the tested catechins could inhibit TAK-1 activity. Therefore, the consumption of green tea offers an overall anti-inflammatory effect. Molecular docking analysis confirms that EGCG, EGC, and EC all occupy the active site of the TAK1 kinase domain. However, EGCG occupies the majority of the TAK1 active site. In addition to TAK1 inhibition, EGCG can also inhibit P38 and nuclear NF-κB expression whereas EC and EGC were not effective inhibitors. Our findings suggest one of the main health benefits associated with the consumption of green tea are due to the activity of EGCG and EGC which are both present at higher amounts. Although EGCG is the most effective catechin at inhibiting downstream inflammatory signaling, its effectives could be hindered by the presence of EC. Therefore, varying EC content in green tea may reduce the anti-inflammatory effects of other potential catechins in green tea.
      Graphical abstract image

      PubDate: 2017-05-22T19:08:11Z
       
  • Early life allergen and air pollutant exposures alter longitudinal blood
           immune profiles in infant rhesus monkeys
    • Abstract: Publication date: Available online 18 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Candace M. Crowley, Justin H. Fontaine, Joan E. Gerriets, Edward S. Schelegle, Dallas M. Hyde, Lisa A. Miller
      Early life is a critical period for the progressive establishment of immunity in response to environmental stimuli; the impact of airborne challenges on this process is not well defined. In a longitudinal fashion, we determined the effect of episodic house dust mite (HDM) aerosol and ozone inhalation, both separately and combined, on peripheral blood immune cell phenotypes and cytokine expression from 4 to 25weeks of age in an infant rhesus monkey model of childhood development. Immune profiles in peripheral blood were compared with lung lavage at 25weeks of age. Independent of exposure, peripheral blood cell counts fluctuated with chronologic age of animals, while IFNγ and IL-4 mRNA levels increased over time in a linear fashion. At 12weeks of age, total WBC, lymphocyte numbers, FoxP3 mRNA and IL-12 mRNA were dramatically reduced relative to earlier time points, but increased to a steady state with age. Exposure effects were observed for monocyte numbers, as well as CCR3, FoxP3, and IL-12 mRNA levels in peripheral blood. Significant differences in cell surface marker and cytokine expression were detected following in vitro HDM or PMA/ionomycin stimulation of PBMC isolated from animals exposed to either HDM or ozone. Lavage revealed a mixed immune phenotype of FoxP3, IFNγ and eosinophilia in association with combined HDM plus ozone exposure, which was not observed in blood. Collectively, our findings show that airborne challenges during postnatal development elicit measureable cell and cytokine changes in peripheral blood over time, but exposure-induced immune profiles are not mirrored in the lung.

      PubDate: 2017-05-22T19:08:11Z
       
  • Impact of hepatic P450-mediated biotransformation on the disposition and
           respiratory tract toxicity of inhaled naphthalene
    • Abstract: Publication date: Available online 18 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Nataliia Kovalchuk, Jacklyn Kelty, Lei Li, Matthew Hartog, Qing-Yu Zhang, Patricia Edwards, Laura Van Winkle, Xinxin Ding
      We determined whether a decrease in hepatic microsomal cytochrome P450 activity would impact lung toxicity induced by inhalation exposure to naphthalene (NA), a ubiquitous environmental pollutant. The liver-Cpr-null (LCN) mouse showed decreases in microsomal metabolism of NA in liver, but not lung, compared to wild-type (WT) mouse. Plasma levels of NA and NA-glutathione conjugates (NA-GSH) were both higher in LCN than in WT mice after a 4-h nose-only NA inhalation exposure at 10ppm. Levels of NA were also higher in lung and liver of LCN, compared to WT, mice, following exposure to NA at 5 or 10ppm. Despite the large increase in circulating and lung tissue NA levels, the level of NA-GSH, a biomarker of NA bioactivation, was either not different, or only slightly higher, in lung and liver tissues of LCN mice, relative to that in WT mice. Furthermore, the extent of NA-induced acute airway injury, judging from high-resolution lung histopathology and morphometry at 20h following NA exposure, was not higher, but lower, in LCN than in WT mice. These results, while confirming the ability of extrahepatic organ to bioactivate inhaled NA and mediate NA's lung toxicity, suggest that liver P450-generated NA metabolites also have a significant, although relatively small, contribution to airway toxicity of inhaled NA. This hepatic contribution to the airway toxicity of inhaled NA may be an important risk factor for individuals with diminished bioactivation activity in the lung.

      PubDate: 2017-05-22T19:08:11Z
       
  • Cadmium stimulates metastasis-associated phenotype in triple-negative
           breast cancer cells through integrin and β-catenin signaling
    • Abstract: Publication date: Available online 17 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Zhengxi Wei, Zahir A. Shaikh
      Cadmium (Cd) is a carcinogenic heavy metal which is implicated in breast cancer development. While the mechanisms of Cd-induced breast cancer initiation and promotion have been studied, the molecular processes involved in breast cancer progression remain to be investigated. The purpose of the present study was to evaluate the influence of Cd on metastasis-associated phenotypes, such as cell adhesion, migration, and invasion in triple-negative breast cancer cells. Treatment of MDA-MB-231 cells with 1μM Cd increased cell spreading and cell migration. This was associated with the activation of integrin β1, FAK, Src, and Rac1. Treatment with Cd also inhibited GSK3β activity and induced T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription, indicating the involvement of β-catenin signaling. Furthermore, treatment with 3μM Cd for 4weeks increased the expression of β-catenin and enhanced TCF/LEF-mediated transcription. Furthermore, enhanced expressions of integrins α5 and β1, paxillin, and vimentin indicated that prolonged Cd treatment reorganized the cytoskeleton, which aided malignancy, as evidenced by enhanced matrix metalloprotease 2/9 (MMP2/9) secretion and cell invasion. Prolonged Cd treatment also caused an increase in cell growth. Together, these results indicate that Cd alters key signaling processes involved in the regulation of cytoskeleton to enhance cancer cell migration, invasion, adhesion, and proliferation.

      PubDate: 2017-05-22T19:08:11Z
       
  • Von Willebrand factor deficiency reduces liver fibrosis in mice
    • Abstract: Publication date: Available online 17 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Nikita Joshi, Anna K. Kopec, Jessica L. Ray, Holly Cline-Fedewa, Dafna J. Groeneveld, Ton Lisman, James P. Luyendyk
      Liver diseases are associated with complex changes in the hemostatic system and elevated levels of the platelet-adhesive protein Von Willebrand factor (VWF) are reported in patients with acute and chronic liver damage. Although elevated levels of VWF are associated with fibrosis in the general population, the role of VWF in acute and chronic liver injury has not been examined in depth in experimental settings. We tested the hypothesis that VWF deficiency inhibits experimental liver injury and fibrosis. Wild-type (WT) and VWF-deficient mice were challenged with carbon tetrachloride (CCl4) and the impact of VWF deficiency on acute liver injury and chronic liver fibrosis was determined. VWF deficiency did not significantly affect acute CCl4-induced hepatocellular necrosis in mice. Chronic CCl4 challenge, twice weekly for 6weeks, significantly increased hepatic stellate cell activation and collagen deposition in livers of WT mice. Interestingly, hepatic induction of several profibrogenic and stellate cell activation genes was attenuated in VWF-deficient mice. Moreover, birefringent sirius red staining (indicating type I and III collagens) and type I collagen immunofluorescence indicated a reduction in hepatic collagen deposition in CCl4-exposed VWF-deficient mice compared to CCl4-exposed WT mice. The results indicate that VWF deficiency attenuates chronic CCl4-induced liver fibrosis without affecting acute hepatocellular necrosis. The results are the first to demonstrate that VWF deficiency reduces the progression of liver fibrosis, suggesting a mechanistic role of elevated plasma VWF levels in cirrhosis.

      PubDate: 2017-05-22T19:08:11Z
       
  • Methylparaben and butylparaben alter multipotent mesenchymal stem cell
           fates towards adipocyte lineage
    • Abstract: Publication date: Available online 17 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Pan Hu, Haley Overby, Emily Heal, Shu Wang, Jiangang Chen, Chwan-li Shen, Ling Zhao
      Paraben esters and their salts are widely used as preservatives in cosmetics, personal care products, pharmaceuticals, and foods. We previously reported that parabens promoted adipocyte differentiation in vitro and increased adiposity but suppressed serum marker of bone formation in vivo. Here, we investigated the effects of parabens (methylparaben and butylparaben) on modulating cell fate of multipotent stem cell line C3H10T1/2. Both parabens modulated adipogenic, osteogenic, and chondrogenic differentiation of C3H10T1/2 cells in vitro. Butylparaben markedly promoted adipogenic differentiation, but suppressed osteogenic and chondrogenic differentiation whereas methylparaben showed similar but less pronounced effects. Moreover, butylparaben, but not methylparaben, was shown to activate peroxisome proliferator-activated receptor (PPAR) γ whereas neither of the paraben was shown to activate glucocorticoid receptor (GR) responsive reporter in C3H10T1/2 cells. The adipogenic effects of butylparaben were significantly attenuated by PPARγ knockdown, but not by GR knockdown. In contrast, paraben's effects on osteoblast differentiation were affected by both knockdowns. Collectively, the results demonstrate opposing effects of parabens on adipogenic and osteoblastogenic/chondrogenic differentiation of multipotent stem cells. In light of the recent findings that parabens are detected in human placenta and milk, our studies provide rationales to study paraben exposure during early development of life in the future.

      PubDate: 2017-05-22T19:08:11Z
       
  • Content
    • Abstract: Publication date: 1 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 326


      PubDate: 2017-05-13T15:29:55Z
       
  • Impact of common clandestine structural modifications on synthetic
           cathinone “bath salt” pharmacokinetics
    • Authors: Gregory G. Grecco; David F. Kisor; Joseph S. Magura; Jon E. Sprague
      Abstract: Publication date: Available online 12 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Gregory G. Grecco, David F. Kisor, Joseph S. Magura, Jon E. Sprague
      Since 2009, the synthetic cathinones (“bath salts”) have risen in popularity as drugs of abuse. However, there are a paucity of studies that have determined the impact of functional group modifications in the synthetic cathinone chemical structures on plasma and central nervous system (CNS) pharmacokinetics. In the present study, we investigated the in vivo plasma and CNS pharmacokinetics of three synthetic cathinones whose structures differ by lengthening of the α-alkyl chain: methylone (-CH3), butylone (-CH2CH3), and pentylone (-CH2CH2CH3). Male Sprague-Dawley rats were treated with a 20mg/kg subcutaneous dose of the individual synthetic cathinone. Blood samples were obtained at specific times from a jugular vein cannula over an 8hour period. Over a separate three-hour period, CNS samples were obtained using a microdialysis cannula surgically implanted into the lateral ventricle. In the plasma, pentylone, with the longest α-alkyl chain, displayed the highest Cmax and AUC0–∞, and the longest t1/2. Decreasing the α-alkyl chain length as in butylone and methylone significantly decreased the Cmax, AUC0–∞, and t1/2. The plasma pharmacokinetic values are consistent with the greater lipophilicity associated with α-alkyl side chain lengthening. Conversely, in the CNS, methylone and butylone displayed higher Cmax and AUC0–∞ values than pentylone. These contrary findings in the CNS and plasma demonstrate that lengthening of the α-alkyl chain of methylone, butylone, and pentylone yields differential pharmacokinetic properties in the CNS as compared to the plasma.
      Graphical abstract image

      PubDate: 2017-05-13T15:29:55Z
      DOI: 10.1016/j.taap.2017.05.010
       
  • Safety evaluation of dermal exposure to phthalates: Metabolism-dependent
           percutaneous absorption
    • Authors: Masahiro Sugino; Tomomi Hatanaka; Hiroaki Todo; Yuko Mashimo; Takamasa Suzuki; Miho Kobayashi; Osamu Hosoya; Hideto Jinno; Kazuhiko Juni; Kenji Sugibayashi
      Abstract: Publication date: Available online 12 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Masahiro Sugino, Tomomi Hatanaka, Hiroaki Todo, Yuko Mashimo, Takamasa Suzuki, Miho Kobayashi, Osamu Hosoya, Hideto Jinno, Kazuhiko Juni, Kenji Sugibayashi
      Phthalates, known as reproductive toxicants and endocrine disruptors, are widely used as plasticizers in polyvinyl chloride products. The present study was conducted for risk identification of dermal exposure to phthalates. When dibutyl phthalate was applied to the skin of hairless rats and humans, only monobutyl phthalate appeared through the skin, and the permeability of the skin was higher than that after the application of the monoester directly. The inhibition of skin esterases made the skin impermeable to the metabolite following dermal exposure to dibutyl ester, whereas removal of the stratum corneum from the skin did not change the skin permeation behavior. Similar phenomena were observed for benzyl butyl phthalate. The skin permeability of monobenzyl phthalate was higher than that of monobutyl phthalate in humans, although the reverse was observed in rats. Species difference in skin permeation profile corresponded to the esterase activity of the skin homogenate. Di(2-ethylhexyl) phthalate, which was not metabolized by esterases in the skin, was not transported across the skin. These results suggest that highly lipophilic phthalates may be transported easily across the stratum corneum lipids. The water-rich viable layer may become permeable to these phthalates by their metabolism into monoesters, which are relatively hydrophilic. Skin metabolism is essential to the percutaneous absorption of phthalates. Because esterase activity has large inter-individual differences, further study will be needed for individual risk identification of dermal exposure to phthalates.
      Graphical abstract image

      PubDate: 2017-05-13T15:29:55Z
      DOI: 10.1016/j.taap.2017.05.009
       
  • Curcumin improves alcoholic fatty liver by inhibiting fatty acid
           biosynthesis
    • Authors: Chang Guo; Jingfan Ma; Qionghong Zhong; Mengyuan Zhao; Tianxing Hu; Tong Chen; Longxin Qiu; Longping Wen
      Abstract: Publication date: Available online 2 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Chang Guo, Jingfan Ma, Qionghong Zhong, Mengyuan Zhao, Tianxing Hu, Tong Chen, Longxin Qiu, Longping Wen
      Alcoholic fatty liver is a threat to human health. It has been long known that abstinence from alcohol is the most effective therapy, other effective therapies are not available for the treatment in humans. Curcumin has a great potential for anti-oxidation and anti-inflammation, but the effect on metabolic reconstruction remains little known. Here we performed metabolomic analysis by gas chromatography/mass spectrometry and explored ethanol pathogenic insight as well as curcumin action pattern. We identified seventy-one metabolites in mouse liver. Carbohydrates and lipids were characteristic categories. Pathway analysis results revealed that ethanol-induced pathways including biosynthesis of unsaturated fatty acids, fatty acid biosynthesis and pentose and glucuronate interconversions were suppressed by curcumin. Additionally, ethanol enhanced galactose metabolism and pentose phosphate pathway. Glyoxylate and dicarboxylate metabolism and pyruvate metabolism were inhibited in mice fed ethanol diet plus curcumin. Stearic acid, oleic acid and linoleic acid were disease biomarkers and therapical biomarkers. These results reflect the landscape of hepatic metabolism regulation. Our findings illustrate ethanol pathological pathway and metabolic mechanism of curcumin therapy.
      Graphical abstract image

      PubDate: 2017-05-07T15:17:34Z
      DOI: 10.1016/j.taap.2017.05.001
       
  • Structure-toxicity relationship of cefoperazone and its impurities to
           developing zebrafish by transcriptome and Raman analysis
    • Authors: Ying Han; Jianqin Qian; Jingpu Zhang; Changqin Hu; Chen Wang
      Abstract: Publication date: Available online 29 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Ying Han, Jianqin Qian, Jingpu Zhang, Changqin Hu, Chen Wang
      Cefoperazone (CFP) is a potent antibacterial agent that is widely used for the treatment of bacterial infections. Previously, we found that both the C-7 and C-3 substituents of CFP are toxic functional groups, and two groups could affect gene expression in zebrafish embryos, thereby resulting in variable abnormal phenotypes. (6R, 7S)-cefoperazone (7S-CFP) is the 7-epimer of CFP and 1-methyl-1H-tetrazole-5-thiol (MTT) is the C-3 substituent of CFP. Both molecules are impurities isolated from CFP that can induce adverse effects. Transcriptome analysis was performed in the present study to identify differentially expressed genes (DEGs), coupled with Raman mapping of individual organ regions to detect changes in the biochemical composition of zebrafish embryos, which reflect the differences in distribution of the compounds. CFP, 7S–CFP, and MTT exposure altered the expression of 254, 368, and 1153 genes, respectively. Gene ontology analysis revealed that various processes related to development, growth, and morphology of tissues were significantly enriched with DEGs. We integrated seven co-DEGs with protein-protein interaction networks and identified various developmental processes that were regulated by the three compounds, including vasodilation, eye, brain, melanogenesis, and heart looping. Our findings suggested that Calca and Ptger4a may be potentially utilized as novel biomarkers for CFP, which causes bleeding. Raman analysis indicated that CFP, 7S-CFP, and MTT exhibited abnormal maps in tissues, which coincided with changes in their expression and morphological features. This study may provide bioinformatics and spectral information that may be used in further investigations on the relationship between structure and toxicity of drugs and impurities.
      Graphical abstract image

      PubDate: 2017-05-02T15:07:11Z
      DOI: 10.1016/j.taap.2017.04.025
       
  • Cover 4--TOC
    • Abstract: Publication date: 1 June 2017
      Source:Toxicology and Applied Pharmacology, Volume 324


      PubDate: 2017-04-25T14:50:47Z
       
  • In vivo inhibitory activity of andrographolide derivative ADN-9 against
           liver cancer and its mechanisms involved in inhibition of tumor
           angiogenesis
    • Authors: Wei Yang; Jin Zhao; Yake Wang; Haiwei Xu; Zhenwei Wu; Yangyang Hu; Kunkun Jiang; Pengpeng Shen; Cuiyun Ma; Zhenzhen Guan; Yan Zhang; Jiahui Ma; Ning Shang; Guangming Yan; Zhenji Wang; Guifu Dai
      Abstract: Publication date: Available online 22 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Wei Yang, Jin Zhao, Yake Wang, Haiwei Xu, Zhenwei Wu, Yangyang Hu, Kunkun Jiang, Pengpeng Shen, Cuiyun Ma, Zhenzhen Guan, Yan Zhang, Jiahui Ma, Ning Shang, Guangming Yan, Zhenji Wang, Guifu Dai
      It is well known that liver cancer is a highly aggressive malignancy with poor prognosis. Andrographolide (AD), a major bioactive component of Andrographis paniculata (Burm. F.), is a potential anti-cancer pharmacophore and the synthesis of AD derivatives with better cytotoxicity to cancer cells has attracted considerable attentions. In the present study, we evaluated the in vivo inhibitory effects of ADN-9, a 15-benzylidene substituted derivative of AD, on the growth and metastasis of murine hepatoma H22 using an orthotopic xenograft model and a subcutaneous xenograft model, and we further studied the anti-angiogenic action and the related mechanisms of ADN-9 in vivo and in vitro. Importantly, ADN-9 remarkably suppressed the growth and metastasis of both orthotopic and subcutaneous xenograft tumors, and the serum AFP level in orthotopic hepatoma-bearing mice treated with 100mg/kg ADN-9 (ig.) was decreased to the normal level. We also found that ADN-9 showed stronger abilities than AD in shrinking tumors, suppressing the invasion and metastasis of H22 cells, decreasing the MVD and promoting tumor cell apoptosis in subcutaneous xenograft of mice. Additionally, ADN-9 exhibited stronger inhibitory activity than AD against the migration and VEGF-induced capillary-like tube formation in HUVECs, which was further proved to be associated with attenuating VEGF/VEGFR2/AKT signaling pathway. The present research provides the first evidence that a 15-substituted AD derivative is more promising than the parent compound in therapeutic treatment of liver cancer.

      PubDate: 2017-04-25T14:50:47Z
      DOI: 10.1016/j.taap.2017.04.022
       
  • Toxicological characterisation of two novel selective aryl hydrocarbon
           receptor modulators in Sprague-Dawley rats
    • Authors: Selma Mahiout; Jere Lindén; Javier Esteban; Ismael Sánchez-Pérez; Satu Sankari; Lars Pettersson; Helen Håkansson; Raimo Pohjanvirta
      Abstract: Publication date: Available online 20 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Selma Mahiout, Jere Lindén, Javier Esteban, Ismael Sánchez-Pérez, Satu Sankari, Lars Pettersson, Helen Håkansson, Raimo Pohjanvirta
      The aryl hydrocarbon receptor (AHR) mediates the toxicity of dioxins, but also plays important physiological roles. Selective AHR modulators, which elicit some effects imparted by this receptor without causing the marked toxicity of dioxins, are presently under intense scrutiny. Two novel such compounds are IMA-08401 (N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-07101 (N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). They represent, as diacetyl prodrugs, AHR-active metabolites of the drug compounds laquinimod and tasquinimod, respectively, which are intended for the treatment of autoimmune diseases and cancer. Here, we toxicologically assessed the novel compounds in Sprague-Dawley rats, after a single dose (8.75–92.5mg/kg) and 5-day repeated dosing at the highest doses achievable (IMA-08401: 100mg/kg/day; and IMA-07101: 75mg/kg/day). There were no overt clinical signs of toxicity, but body weight gain was marginally retarded, and the treatments induced minimal hepatic extramedullary haematopoiesis. Further, both the absolute and relative weights of the thymus were significantly decreased. Cyp1a1 gene expression was substantially increased in all tissues examined. The hepatic induction profile of other AHR battery genes was distinct from that caused by TCDD. The only marked alterations in serum clinical chemistry variables were a reduction in triglycerides and an increase in 3-hydroxybutyrate. Liver and kidney retinol and retinyl palmitate concentrations were affected largely in the same manner as reported for TCDD. In vitro, the novel compounds activated CYP1A1 effectively in H4IIE cells. Altogether, these novel compounds appear to act as potent activators of the AHR, but lack some major characteristic toxicities of dioxins. They therefore represent promising new selective AHR modulators.

      PubDate: 2017-04-25T14:50:47Z
      DOI: 10.1016/j.taap.2017.04.020
       
  • Developmental neurotoxicity of different classes of biocides in PC-12
           cells in vitro
    • Authors: Verena Christen; Manuel Rusconi; Pierre Crettaz; Karl Fent
      Abstract: Publication date: Available online 3 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Verena Christen, Manuel Rusconi, Pierre Crettaz, Karl Fent
      The detection of developmental neurotoxicity (DNT) of chemicals has high relevance for protection of human health. However, DNT of many biocides is only little known. Furthermore, validated in vitro systems for assessment of DNT are not well established. Here we employed the rat phaeochromocytoma cell line PC-12 to evaluate DNT of 18 frequently used biocides of different classes, including neonicotinoids, pyrethroids, organophosphates, organochlorines, quaternary ammonium compounds, the biocidal active substance piperonylbutoxide, as well as the insect repellent DEET. We determined the outgrowth of neurites in PC-12 cells co-treated with nerve growth factor and different concentrations of biocides for 5days. Furthermore, we determined transcriptional alterations of selected genes that may be associated with DNT, such as camk2α and camk2β, gap-43, neurofilament-h, tubulin-α and tubulin-β. Strong and dose dependent inhibition of neurite outgrowth was induced by azamethiphos and chlorpyrifos, dieldrin and heptachlor, which was correlated with up-regulation of gap-43. No or only weak effects on neurite outgrowth and transcriptional alterations occurred for neonicotinoids acetamiprid, clothianidin, imidacloprid and thiamethoxam, pyrethroids λ-cyhalothrin, cyfluthrin, deltamethrin, and permethrin, the biocidal disinfectants C12-C14-alkyl(ethylbenzyl)dimethylammonium (BAC), benzalkonium chloride and barquat (dimethyl benzyl ammonium chloride), and piperonylbutoxide and diethyltoluamide (DEET). Our study confirms potential developmental neurotoxicity of some biocides and provides first evidence that azamethiphos has the potential to act as a developmental neurotoxic compound. We also demonstrate that inhibition of neurite outgrowth and transcriptional alterations of gap-43 expression correlate, which suggests the employment of gap-43 expression as a biomarker for detection and initial evaluation of potential DNT of chemicals.
      Graphical abstract image

      PubDate: 2017-04-04T02:33:26Z
      DOI: 10.1016/j.taap.2017.03.027
       
  • Valproate induced hepatic steatosis by enhanced fatty acid uptake and
           triglyceride synthesis
    • Authors: Xupeng Bai; Weipeng Hong; Peiheng Cai; Yibei Chen; Chuncao Xu; Di Cao; Weibang Yu; Zhongxiang Zhao; Min Huang; Jing Jin
      Abstract: Publication date: Available online 31 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Xupeng Bai, Weipeng Hong, Peiheng Cai, Yibei Chen, Chuncao Xu, Di Cao, Weibang Yu, Zhongxiang Zhao, Min Huang, Jing Jin
      Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36), an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) – extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity.
      Graphical abstract image

      PubDate: 2017-04-04T02:33:26Z
      DOI: 10.1016/j.taap.2017.03.022
       
  • Formaldehyde and co-exposure with benzene induce compensation of bone
           marrow and hematopoietic stem/progenitor cells in BALB/c mice during
           post-exposure period
    • Authors: Chenxi Wei; Mouying Chen; Huihui You; Feng Qiu; Huaxiao Wen; Junlin Yuan; Shuanglin Xiang; Xu Yang
      Abstract: Publication date: Available online 31 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Chenxi Wei, Mouying Chen, Huihui You, Feng Qiu, Huaxiao Wen, Junlin Yuan, Shuanglin Xiang, Xu Yang
      Formaldehyde (FA) is a human leukemogen. Since there is a latency period between initial FA exposure and the development of leukemia, the subsequent impact of FA on hematopoietic stem or progenitor cells (HSCs/HPCs) in post-exposure stage is crucial for a deep understanding of FA-induced hematotoxicity. BALB/c mice were exposed to 3mg/m3 FA for 2weeks, mimicking occupational exposure, and were monitored for another 7days post-exposure. Meanwhile, we included benzene as a positive control, separately and together with FA because co-exposure occurs frequently. After 7-day recovery, colonies of progenitors for CFU-GM and BFU-E, and nucleated bone marrow cells in FA-exposed mice were comparable to controls, although they were significantly reduced during exposure. Levels of reactive oxygen species (ROS) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in CFU-GM and BFU-E from FA-exposed mice were higher than controls, although the increase in 8-OHdG was not significant. Granulocyte-macrophage colony stimulating factor (GM-CSF) level in the FA group was lower than controls, but the expression level for the receptor was not upregulated. It suggests that HSCs/HPCs in FA-exposed mice respond to a small amount of GM-CSF and proliferate rapidly, which may cause a possible risk of expansion of abnormal stem/progenitor cell clones. FA co-exposure with benzene was more potent for promoting CFU-GM formation and inducing ROS in BFU-E and 8-OHdG in CFU-GM during the post-exposure period. The compensation of myeloid progenitors with elevated ROS and 8-OHdG may lead to a risk of transforming normal HSCs/HPCs to leukemic stem/progenitor cells. Thus, co-exposure may pose a greater leukemia risk.
      Graphical abstract image

      PubDate: 2017-04-04T02:33:26Z
      DOI: 10.1016/j.taap.2017.03.024
       
 
 
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