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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.593]   [H-I: 135]   [20 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [3049 journals]
  • Effects of pirfenidone in acute and sub-chronic liver fibrosis, and an
           initiation-promotion cancer model in the mouse
    • Authors: Oleksii Seniutkin; Shinji Furuya; Yu-Syuan Luo; Joseph A. Cichocki; Hisataka Fukushima; Yuki Kato; Hiromi Sugimoto; Tomoko Matsumoto; Takeki Uehara; Ivan Rusyn
      Pages: 1 - 9
      Abstract: Publication date: 15 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 339
      Author(s): Oleksii Seniutkin, Shinji Furuya, Yu-Syuan Luo, Joseph A. Cichocki, Hisataka Fukushima, Yuki Kato, Hiromi Sugimoto, Tomoko Matsumoto, Takeki Uehara, Ivan Rusyn
      Liver fibrosis results from chronic tissue damage and excessive regeneration with accumulation of extracellular matrix proteins; it is a precursor of liver cirrhosis and hepatocellular carcinoma. Liver fibrosis treatments are primarily directed at inflammation, with few options to combat fibrogenesis. Pirfenidone is a drug approved for idiopathic pulmonary fibrosis and this study was focused on anti-fibrotic and anti-cancer potential of pirfenidone in the liver of male B6C3F1/J mice. In a dose-finding study, mice were treated with CCl4 (0.2ml/kg ip, 2×wk for 4weeks) while on a pirfenidone-containing (0–600mg/kg) diet. Pirfenidone at doses of 300 and 600mg/kg had significant anti-fibrotic (collagen) and anti-inflammatory (serum transaminases and “ballooning” hepatocyte) effects. In a sub-chronic study (14weeks), mice received CCl4 while on pirfenidone (300mg/kg) diet. Pirfenidone significantly reduced collagen deposition, but had little effect of inflammation and injury. In an initiation-promotion cancer study with N-nitrosodiethylamine and CCl4, pirfenidone (300mg/kg) did not affect incidence, size, or multiplicity of liver tumors. Overall, we conclude that while pirfenidone exhibits strong anti-fibrotic effects in early stage liver fibrosis, it is less effective in advanced liver fibrosis and was not protective in an initiation-promotion liver cancer.

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.11.024
      Issue No: Vol. 339 (2017)
       
  • Flumioxazin metabolism in pregnant animals and cell-based
           protoporphyrinogen IX oxidase (PPO) inhibition assay of fetal metabolites
           in various animal species to elucidate the mechanism of the rat-specific
           developmental toxicity
    • Authors: Jun Abe; Naohiko Isobe; Kazuki Mikata; Hirohisa Nagahori; Yoshikazu Naito; Hideo Saji; Masahiro Ono; Satoshi Kawamura
      Pages: 34 - 41
      Abstract: Publication date: 15 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 339
      Author(s): Jun Abe, Naohiko Isobe, Kazuki Mikata, Hirohisa Nagahori, Yoshikazu Naito, Hideo Saji, Masahiro Ono, Satoshi Kawamura
      Flumioxazin, an N-phenylimide herbicide, inhibits protoporphyrinogen oxidase (PPO), a key enzyme in heme biosynthesis in mammals, and causes rat-specific developmental toxicity. The mechanism has mainly been clarified, but no research has yet focused on the contribution of its metabolites. We therefore conducted in vivo metabolism studies in pregnant rats and rabbits, and found 6 major known metabolites in excreta. There was no major rat-specific metabolite. The most abundant component in rat fetuses was APF, followed by flumioxazin and 5 identified metabolites. The concentrations of flumioxazin and these metabolites in fetuses were lower in rabbits than in rats. In vitro PPO inhibition assays with rat and human liver mitochondria showed that flumioxazin is a more potent PPO inhibitor than the metabolites. There were no species differences in relative intensity of PPO inhibition among flumioxazin and these metabolites. Based on the results of these in vivo and in vitro experiments, we concluded that flumioxazin is the causal substance of the rat-specific developmental toxicity. As a more reliable test system for research on in vitro PPO inhibition, cell-based assays with rat, rabbit, monkey, and human hepatocytes were performed. The results were consistent with those of the mitochondrial assays, and rats were more sensitive to PPO inhibition by flumioxazin than humans, while rabbits and monkeys were almost insensitive. From these results, the species difference in the developmental toxicity was concluded to be due to the difference in sensitivity of PPO to flumioxazin, and rats were confirmed to be the most sensitive of these species.

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.11.028
      Issue No: Vol. 339 (2017)
       
  • Antitumor action of 3-bromopyruvate implicates reorganized tumor growth
           regulatory components of tumor milieu, cell cycle arrest and induction of
           mitochondria-dependent tumor cell death
    • Authors: Saveg Yadav; Praveen Kumar Kujur; Shrish Kumar Pandey; Yugal Goel; Babu Nandan Maurya; Ashish Verma; Ajay Kumar; Rana Pratap Singh; Sukh Mahendra Singh
      Pages: 52 - 64
      Abstract: Publication date: 15 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 339
      Author(s): Saveg Yadav, Praveen Kumar Kujur, Shrish Kumar Pandey, Yugal Goel, Babu Nandan Maurya, Ashish Verma, Ajay Kumar, Rana Pratap Singh, Sukh Mahendra Singh
      Evidences demonstrate that metabolic inhibitor 3-bromopyruvate (3-BP) exerts a potent antitumor action against a wide range of malignancies. However, the effect of 3-BP on progression of the tumors of thymic origin remains unexplored. Although, constituents of tumor microenvironment (TME) plays a pivotal role in regulation of tumor progression, it remains unclear if 3-BP can alter the composition of the crucial tumor growth regulatory components of the external surrounding of tumor cells. Thus, the present investigation attempts to understand the effect of 3-BP administration to a host bearing a progressively growing tumor of thymic origin on tumor growth regulatory soluble, cellular and biophysical components of tumor milieu vis-à-vis understanding its association with tumor progression, accompanying cell cycle events and mode of cell death. Further, the expression of cell survival regulatory molecules and hemodynamic characteristics of the tumor milieu were analysed to decipher mechanisms underlying the antitumor action of 3-BP. Administration of 3-BP to tumor-bearing hosts retarded tumor progression accompanied by induction of tumor cell death, cell cycle arrest, declined metabolism, inhibited mitochondrial membrane potential, elevated release of cytochrome c and altered hemodynamics. Moreover, 3-BP reconstituted the external milieu, in concurrence with deregulated glucose and pH homeostasis and increased tumor infiltration by NK cells, macrophages, and T lymphocytes. Further, 3-BP administration altered the expression of key regulatory molecules involved in glucose uptake, intracellular pH and tumor cell survival. The outcomes of this study will help in optimizing the therapeutic application of 3-BP by targeting crucial tumor growth regulatory components of tumor milieu.
      Graphical abstract image

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.12.004
      Issue No: Vol. 339 (2017)
       
  • Aberrant promoter methylation in genes related to hematopoietic malignancy
           in workers exposed to a VOC mixture
    • Authors: Octavio Jiménez-Garza; Liqiong Guo; Hyang-Min Byun; Mariella Carrieri; Giovanni Battista Bartolucci; Briscia Socorro Barrón-Vivanco; Andrea A. Baccarelli
      Pages: 65 - 72
      Abstract: Publication date: 15 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 339
      Author(s): Octavio Jiménez-Garza, Liqiong Guo, Hyang-Min Byun, Mariella Carrieri, Giovanni Battista Bartolucci, Briscia Socorro Barrón-Vivanco, Andrea A. Baccarelli
      Occupational exposure to volatile organic compounds (VOCs) may cause hematopoietic malignancy, either by single exposure to benzene or possibly due to a concomitant exposure to several VOCs. Since oxidative stress, inflammation and DNA repair pathways are closely involved in cancer development, the effect of VOC exposure on expression of proteins involved in these pathways has been studied, but epigenetic changes have not been well described. Here, DNA methylation status following occupational exposure to a VOC mixture was assessed by bisulfite sequencing of the promoter regions of seven genes involved in the mentioned pathways. Peripheral blood samples and individual-level VOC exposure data were obtained from healthy leather shoe factory workers (LS, n=40) and gas station attendants (GS, n=36), as well as a reference group of university employees (C, n=66). Exposure levels for acetone, ethylbenzene, methyl ethyl ketone, n-hexane, toluene and xylene were higher in LS (p<0.001); benzene and methyl acetate levels were higher in GS (p<0.001). TOP2A, SOD1, and TNF-α promoter methylation status was increased in LS (p<0.05). In LS, we also found significant correlations between GSTP1 promoter methylation and both iNOS (r=0.37, p=0.008) and COX-2 (r=−0.38, p=0.007) methylation. In exposed groups, ethylbenzene exposure levels showed a significant correlation with TOP2A methylation (β=0.33). Our results show early, toxic effects at the epigenetic level caused by occupational exposure to high levels of a VOC mixture. These subcellular modifications may represent the initial mechanism of toxicity leading to hematopoietic malignancy, possibly due to a synergistic, hematotoxic effect of VOC mixtures.

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.12.002
      Issue No: Vol. 339 (2017)
       
  • Genistein and daidzein treatments differently affect uterine homeostasis
           in the ovary-intact middle-aged rats
    • Authors: Ivana Jarić; Jasmina Živanović; Marko Miler; Vladimir Ajdžanović; Duško Blagojević; Nataša Ristić; Verica Milošević; Nataša Nestorović
      Pages: 73 - 84
      Abstract: Publication date: 15 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 339
      Author(s): Ivana Jarić, Jasmina Živanović, Marko Miler, Vladimir Ajdžanović, Duško Blagojević, Nataša Ristić, Verica Milošević, Nataša Nestorović
      This study aimed to investigate the effects of soy isoflavones, genistein (GEN) and daidzein, (DAI) on the uterine function in ovary-intact middle-aged rats. GEN and DAI (35mg/kg) were subcutaneously administrated to acyclic (12-month-old) Wistar females, daily, for 4weeks. Control group received either vehicle (olive oil and ethanol, 9:1) or remained intact. We found that GEN and DAI differently affect uterine morphophysiology. GEN significantly increased the uterine wet weight which was associated with hyperplastic changes, revealed by stereological and histomorphometrical analyses. Also, PCNA immunoexpression was increased, whereas expression of apoptotic marker (caspase-3) was decreased. Protein and gene expressions of ERα were down-regulated, while PR and ERβ were up-regulated after GEN application. Also, GEN caused an increase of LAC and VEGF mRNA expression, together with an up-regulation of Akt activity. In contrast, DAI did not change the uterine wet weight and stereological features of the main uterine compartments as well as LAC and VEGF gene expression. Absence of hyperplastic changes were illustrated by an increase in caspase-3 immunoexpression, associated with reduced PCNA expression. DAI up-regulated only the expression of ERβ, while the expression levels of ERα and PR remain unaffected. Also, DAI inhibited the activation of Akt due to down-regulation of phosphorylated and total form of Akt protein expression. Compared to GEN, DAI did not promote events associated with the endometrial cell proliferation in the conducted study, figuring as the compound with a potential safety profile, which justifies further investigation.

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.12.001
      Issue No: Vol. 339 (2017)
       
  • Synthetic cannabinoid AM2201 induces seizures: Involvement of cannabinoid
           CB1 receptors and glutamatergic transmission
    • Authors: Masahiko Funada; Mika Takebayashi-Ohsawa
      Pages: 1 - 8
      Abstract: Publication date: 1 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 338
      Author(s): Masahiko Funada, Mika Takebayashi-Ohsawa
      Abuse of synthetic cannabinoids is a serious social problem worldwide. Intentional ingestion of synthetic cannabinoids can cause severe toxicity, including seizures. Here we investigated the effects of acute administration of synthetic cannabinoids on the induction of epileptic seizures by monitoring electroencephalographic activity in freely moving mice. The synthetic cannabinoid, AM2201, induced abnormal, high-amplitude (>2-fold baseline amplitude), sharp-wave activity. The abnormal spike-wave discharges were accompanied by epileptiform behavior: rigid posture, tail extension, rearing with forepaws extended, jumping, and intermittent tonic-clonic jerking movements. The abnormal spike-wave discharges and behavioral changes were suppressed by pretreatment with the selective CB1 receptor antagonist AM251, but not with the selective CB2 receptor antagonist AM630 or the vanilloid receptor antagonist, capsazepine. Furthermore, the group 1 metabotropic glutamate receptor antagonist SIB1757 eliminated AM2201-induced spike-wave discharges and episodes of epileptiform behavior. AM2201 markedly increased the extracellular glutamate concentration in the hippocampus during periods of AM2201-induced abnormal spike-wave discharges and behavioral changes. These findings are the first evidence that AM2201 induces epileptic seizures by enhancing glutamatergic transmission in the hippocampus. Our findings demonstrate that induction of epileptic seizures by synthetic cannabinoids is mediated by CB1 receptors, but not by CB2 receptors, and further suggest that rapid elevation of glutamatergic transmission may play an important role in the induction of seizures following intentional ingestion of synthetic cannabinoids.

      PubDate: 2017-11-18T08:53:15Z
      DOI: 10.1016/j.taap.2017.10.007
      Issue No: Vol. 338 (2017)
       
  • Effects of opioid and nonopioid analgesics on canine wheal formation and
           cultured human mast cell degranulation
    • Authors: Eric Schmidt-Rondon; Zhenping Wang; Shelle A. Malkmus; Anna Di Nardo; Keith Hildebrand; Linda Page; Tony L. Yaksh
      Pages: 54 - 64
      Abstract: Publication date: 1 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 338
      Author(s): Eric Schmidt-Rondon, Zhenping Wang, Shelle A. Malkmus, Anna Di Nardo, Keith Hildebrand, Linda Page, Tony L. Yaksh
      Mast cell (MC) degranulation has been implicated in the side effect profile of a variety of clinically useful agents. Thus, after intrathecal delivery, formation of space-occupying, meningeally-derived masses may be related to local MC degranulation. We systematically characterized degranulating effects of opioid and nonopioid analgesics on cutaneous flares in the dog and in primary human MC (hMC) cultures. Methods Dogs were anesthetized with IV propofol and received intradermal (ID) injections (50μL). Flare diameters were measured at 30min. Drugs showing flare responses were tested after intramuscular (IM) cromolyn (10mg/kg), a MC stabilizer. Human primary MCs (human cord blood CD34+/CD45+ cells) were employed and β-hexosaminidase in cell-free supernatants were measured to assess degranulation. Results A significant skin flare for several classes of agents was observed including opioids, ziconotide, ketamine, ST-91, neostigmine, adenosine, bupivacaine, lidocaine, MK-801 and 48/80. Tizanidine, fentanyl, alfentanil, gabapentin and baclofen produced no flare. Flare produced by all ID agents, except adenosine, bupivacaine and lidocaine, was reduced by cromolyn. Naloxone had no effect upon opiate or 48/80 evoked flares. In hMC studies, 48/80 resulted in a concentration-dependent release of β-hexosaminidase. The rank order of drug-induced hMC β-hexosaminidase release was similar to that for flares. Conclusions A variety of therapeutically useful drugs degranulate MCs. This action may account for side effects such as the intrathecal granuloma resulting from spinally-delivered opioids. This degranulating effect may be useful in predicting potential intrathecal toxicity in the development of novel agents.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.10.017
      Issue No: Vol. 338 (2017)
       
  • Pb2+ modulates ryanodine receptors from the endoplasmic reticulum in rat
           brain
    • Authors: Qiyue Jia; Guihua Du; Yu Li; Zhiping Wang; Jie Xie; Junwang Gu; Guangming Yin; Shuyun Zhang; Yanyan Gao; Fankun Zhou; Chang Feng; Guangqin Fan
      Pages: 103 - 111
      Abstract: Publication date: 1 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 338
      Author(s): Qiyue Jia, Guihua Du, Yu Li, Zhiping Wang, Jie Xie, Junwang Gu, Guangming Yin, Shuyun Zhang, Yanyan Gao, Fankun Zhou, Chang Feng, Guangqin Fan
      Although the neurotoxic mechanism of lead (Pb2+) has been extensively studied, it is not well understood. The effects of Pb2+ on free cytosolic calcium (Ca2+) concentration and calcium-regulated events have been suggested to be major mechanisms in Pb2+ toxicity. Based on our previous findings that Pb2+ changes calcium release through ryanodine receptors (RyRs), the modulation of endoplasmic reticulum (ER) vesicular RyRs by Pb2+ was investigated further in the present study. The results of [3H]ryanodine binding assays showed that in the presence of a free Ca2+ concentration ([Ca2+]f) of 100μM, Pb2+ modulated the equilibrium of [3H]ryanodine binding to brain RyRs, with a U-type dose-response curve, where minimal binding was observed at a free Pb2+ concentration ([Pb2+]f) of 0.39μM. This modulation was also observed over a time course. Scatchard analysis indicated that both an increase in Kd and a possible decrease in Bmax were responsible for the decrease in binding induced by low [Pb2+]f. Moreover, the effects of Pb2+ on the function of ER RyRs in neurons might also be controlled by other RyR modulators. Whole-cell patch-clamp experiments revealed that dynamic calcium oscillations evoked by specific RyR agonists were depressed rapidly and reversibly by exposure to 10μM Pb2+. Our study indicates that RyRs are molecular targets of Pb2+, and this interaction disturbs Ca2+ signals and leads to neurotoxicity.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.11.013
      Issue No: Vol. 338 (2017)
       
  • Selective inhibition of CTCF binding by iAs directs TET-mediated
           reprogramming of 5-hydroxymethylation patterns in iAs-transformed cells
    • Authors: Matthew Rea; Tyler Gripshover; Yvonne Fondufe-Mittendorf
      Pages: 124 - 133
      Abstract: Publication date: 1 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 338
      Author(s): Matthew Rea, Tyler Gripshover, Yvonne Fondufe-Mittendorf
      Methylation at cytosine (5mC) is a fundamental epigenetic DNA modification recently associated with iAs-mediated carcinogenesis. In contrast, the role of 5-hydroxymethylcytosine (5hmC), the oxidation product of 5mC in iAs-mediated carcinogenesis is unknown. Here we assess the hydroxymethylome in iAs-transformed cells, showing that dynamic modulation of hydroxymethylated DNA is associated with specific transcriptional networks. Moreover, this pathologic iAs-mediated carcinogenesis is characterized by a shift toward a higher hydroxymethylation pattern genome-wide. At specific promoters, hydroxymethylation correlated with increased gene expression. Furthermore, this increase in hydroxymethylation occurs concurrently with an upregulation of ten-eleven translocation (TET) enzymes that oxidize 5-methylcytosine (5mC) in DNA. To gain an understanding into how iAs might impact TET expression, we found that iAs inhibits the binding of CTCF at the proximal, weak CTCF binding sites of the TET1 and TET2 gene promoters and enhances CTCF binding at the stronger distal binding site. Further analyses suggest that this distal site acts as an enhancer, thus high CTCF occupancy at the enhancer region of TET1 and TET2 possibly drives their high expression in iAs-transformed cells. These results have major implications in understanding the impact of differential CTCF binding, genome architecture and its consequences in iAs-mediated pathogenesis.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.11.015
      Issue No: Vol. 338 (2017)
       
  • Anxiolytic- and antidepressant-like effects of Silymarin compared to
           diazepam and fluoxetine in a mouse model of mild traumatic brain injury
    • Authors: Morteza Kosari-Nasab; Ghaffar Shokouhi; Amir Ghorbanihaghjo; Mehran Mesgari Abbasi; Ali-Akbar Salari
      Pages: 159 - 173
      Abstract: Publication date: 1 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 338
      Author(s): Morteza Kosari-Nasab, Ghaffar Shokouhi, Amir Ghorbanihaghjo, Mehran Mesgari Abbasi, Ali-Akbar Salari
      Clinical and experimental studies have shown that mild traumatic brain injury (mTBI) is associated with increased anxiety- and depression-related behaviors and inflammation in the brain. Unfortunately, there are no specific therapies for long-term behavioral consequences of mTBI. This study set out to determine whether silymarin treatment compared to diazepam (DZP) and fluoxetine (FLX) can reduce neuroinflammation, anxiety- and depression-like behaviors after mTBI induction in mice. We used open field, elevated plus maze, light-dark box, zero maze, sucrose preference, forced swim, and tail suspension tests to assess anxiety and depression-like behaviors in mTBI-induced mice. The levels of tumor necrosis factor (TNF)-α protein, a marker of inflammation, in the prefrontal cortex and hippocampus was also measured. This study identified that the long-term treatment with DZP, FLX or SIL results in decreased anxiety and depression-like behaviors in mTBI-induced mice. The results also showed that these drugs reduced TNF-α levels in the prefrontal cortex and hippocampus. In addition, there were no significant differences between the effects of SIL and DZP or SIL and FLX on behavioral and cytokine levels in mTBI-induced mice. Our findings support the idea that mTBI could be a risk factor for anxiety- and depression-related disorders and neuroinflammation in the brain. Taken together, this study demonstrates that DZP, FLX or SIL can significantly reduce anxiety- and depression-like symptoms, and neuroinflammation after mTBI induction in mice.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.11.012
      Issue No: Vol. 338 (2017)
       
  • Individual serum bile acid profiling in rats aids in human risk assessment
           of drug-induced liver injury due to BSEP inhibition
    • Authors: Steven Cepa; David Potter; Lisa Wong; Leah Schutt; Jacqueline Tarrant; Jodie Pang; Xiaolin Zhang; Roxanne Andaya; Laurent Salphati; Yingqing Ran; Le An; Ryan Morgan; Jonathan Maher
      Pages: 204 - 213
      Abstract: Publication date: 1 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 338
      Author(s): Steven Cepa, David Potter, Lisa Wong, Leah Schutt, Jacqueline Tarrant, Jodie Pang, Xiaolin Zhang, Roxanne Andaya, Laurent Salphati, Yingqing Ran, Le An, Ryan Morgan, Jonathan Maher
      Drug-induced liver injury (DILI) has been the most frequent cause of post-marketing drug withdrawals in the last 50years. The multifactorial nature of events that precede severe liver injury in human patients is difficult to model in rodents due to a variety of confounding or contributing factors that include disease state, concurrent medications, and translational species differences. In retrospective analyses, a consistent risk factor for DILI has been the inhibition of the Bile Salt Export Pump (BSEP). One compound known for potent BSEP inhibition and severe DILI is troglitazone. The purpose of the current study is to determine if serum profiling of 19 individual bile acids by liquid chromatography-mass spectrometry (LC/MS) can detect perturbations in bile acid homeostasis in rats after acute intravenous (IV) administration of vehicle or 5, 25, or 50mg/kg troglitazone. Minimal serum transaminase elevations (approximately two-fold) were observed with no evidence of microscopic liver injury. However, marked changes in individual serum bile acids occurred, with dose-dependent increases in the majority of the bile acids profiled. When compared to predose baseline values, tauromuricholic acid and taurocholic acid had the most robust increase in serum levels and dynamic range, with a maximum fold increase from baseline of 34-fold and 29-fold, respectively. Peak bile acid increases occurred within 2hours (h) after dosing and returned to baseline values before 24h. In conclusion, serum bile acid profiling can potentially identify a mechanistic risk of clinical DILI that could be poorly detected by traditional toxicity endpoints.

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.11.007
      Issue No: Vol. 338 (2017)
       
  • Nanotoxicological and teratogenic effects: A linkage between dendrimer
           surface charge and zebrafish developmental stages
    • Authors: Maria Natalia Calienni; Daniela Agustina Feas; Daniela Edith Igartúa; Nadia Silvia Chiaramoni; Silvia del Valle Alonso; Maria Jimena Prieto
      Pages: 1 - 11
      Abstract: Publication date: 15 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 337
      Author(s): Maria Natalia Calienni, Daniela Agustina Feas, Daniela Edith Igartúa, Nadia Silvia Chiaramoni, Silvia del Valle Alonso, Maria Jimena Prieto
      This article reports novel results about nanotoxicological and teratogenic effects of the PAMAM dendrimers DG4 and DG4.5 in zebrafish (Danio rerio). Zebrafish embryos and larvae were used as a rapid, high-throughput, cost-effective whole-animal model. The objective was to provide a more comprehensive and predictive developmental toxicity screening of DG4 and DG4.5 and test the influence of their surface charge. Nanotoxicological and teratogenic effects were assessed at developmental, morphological, cardiac, neurological and hepatic level. The effect of surface charge was determined in both larvae and embryos. DG4 with positive surface charge was more toxic than DG4.5 with negative surface charge. DG4 and DG4.5 induced teratogenic effects in larvae, whereas DG4 also induced lethal effects in both zebrafish embryos and larvae. However, larvae were less sensitive than embryos to the lethal effects of DG4. The platform of assays proposed and data obtained may contribute to the characterization of hazards and differential effects of these nanoparticles.

      PubDate: 2017-10-29T12:17:20Z
      DOI: 10.1016/j.taap.2017.10.003
      Issue No: Vol. 337 (2017)
       
  • Inhibitory effect of silver nanoparticles on proliferation of
           estrogen-dependent MCF-7/BUS human breast cancer cells induced by butyl
           paraben or di-n-butyl phthalate
    • Authors: Joanna Roszak; Anna Smok-Pieniążek; Katarzyna Domeradzka-Gajda; Jarosław Grobelny; Emilia Tomaszewska; Katarzyna Ranoszek-Soliwoda; Grzegorz Celichowski; Maciej Stępnik
      Pages: 12 - 21
      Abstract: Publication date: 15 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 337
      Author(s): Joanna Roszak, Anna Smok-Pieniążek, Katarzyna Domeradzka-Gajda, Jarosław Grobelny, Emilia Tomaszewska, Katarzyna Ranoszek-Soliwoda, Grzegorz Celichowski, Maciej Stępnik
      In this study the effect of silver nanoparticles (AgNPs) on proliferation of estrogen receptor (ER)-positive human breast cancer MCF-7/BUS cells was assessed by means of in vitro assay. The cells were exposed in the absence of estrogens to AgNPs alone or in combination with aluminum chloride (AlCl3), butyl paraben (BPB) and di-n-butyl phthalate (DBPh). The results revealed that AgNPs at the non-cytotoxic concentrations (up to 2μg/mL) and AlCl3 (up to 500μM) did not induce proliferation of MCF-7/BUS cells whereas BPB and DBPh showed strong estrogenic activity with the highest effect at 16μM and 35μM, respectively. AgNPs inhibited the proliferation of the cells induced by DBPh, BPB or even with 17β-estradiol (E2) during 6-day incubation in the absence of estrogens. ICI 182,780 (10nM), a known estrogen receptor (ER) antagonist, induced strong inhibitory effect. AgNPs also decreased transcription of the estrogen-responsive pS2 and progesterone receptor (PGR) genes but modulated expression neither of ERα nor ERβ in MCF-7/BUS cells exposed to BPB, DBPh or E2 for 6h. Our results indicate that AgNPs may inhibit growth of breast cancer cells stimulated by E2 or estrogenic chemicals, i.e. BPB and DBPh.

      PubDate: 2017-10-29T12:17:20Z
      DOI: 10.1016/j.taap.2017.10.014
      Issue No: Vol. 337 (2017)
       
  • ABC-transporter blockage mediated by xanthotoxin and bergapten is the
           major pathway for chemosensitization of multidrug-resistant cancer cells
    • Authors: Seyed Abbas Mirzaei; Neda Gholamian Dehkordi; Mahsa Ghamghami; Amir Hossein Amiri; Elaheh Dalir Abdolahinia; Fatemeh Elahian
      Pages: 22 - 29
      Abstract: Publication date: 15 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 337
      Author(s): Seyed Abbas Mirzaei, Neda Gholamian Dehkordi, Mahsa Ghamghami, Amir Hossein Amiri, Elaheh Dalir Abdolahinia, Fatemeh Elahian
      Furanocoumarins derived from herbal and citrus extracts can act as antibacterial, antioxidant, immunomodulator, apoptotic, and selective anticancer agents, prompting a biological investigation to determine and predict their clinical therapeutic significance. Here, the cell cytotoxic effects of bergapten and xanthotoxin were analyzed alone and in combination with standard chemotherapeutics on three multidrug resistant cells and their nonresistant parental counterparts. The furanocoumarins modulatory effects on MDR1, BCRP, and MRP pump expression and function were investigated. Although quantitative real time PCR demonstrated that the MDR transcript level changes in a time dependent manner, flow cytometric analyses using fluorescent-labeled antibodies have indicated that bergapten and xanthotoxin had no significant effect on the protein levels. FACS analyses indicated that these prominent anticancer agents significantly blocked MDR1, BCRP, and MRP transporter function. Maximum furanocoumarin-mediated pump activity blockage in the MDR-resistant cells was quantified as 87% of normal and consequently, chemotherapeutic accumulation increased up to 2.7-fold and cytotoxicity tension increased 104-fold. MDR1 efflux kinetics also revealed that the maximum velocity and the pump affinity to daunorubicin were uncompetitively decreased. We conclude that bergapten and xanthotoxin are cytotoxic agents capable of preventing daunorubicin, mitoxantrone, and cisplatin binding to ABC-transporters and subsequently inhibiting their efflux out of cells and they may be a potential combination therapy for malignant cancers.
      Graphical abstract image

      PubDate: 2017-10-29T12:17:20Z
      DOI: 10.1016/j.taap.2017.10.018
      Issue No: Vol. 337 (2017)
       
  • A novel stilbene-like compound that inhibits melanoma growth by regulating
           melanocyte differentiation and proliferation
    • Authors: Noah A. Stueven; Nicholas M. Schlaeger; Aaron P. Monte; Sheng-Ping L. Hwang; Cheng-chen Huang
      Pages: 30 - 38
      Abstract: Publication date: 15 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 337
      Author(s): Noah A. Stueven, Nicholas M. Schlaeger, Aaron P. Monte, Sheng-Ping L. Hwang, Cheng-chen Huang
      Melanoma is the most aggressive form of skin cancer. Current challenges to melanoma therapy include the adverse effects from immunobiologics, resistance to drugs targeting the MAPK pathway, intricate interaction of many signal pathways, and cancer heterogeneity. Thus combinational therapy with drugs targeting multiple signaling pathways becomes a new promising therapy. Here, we report a family of stilbene-like compounds called A11 that can inhibit melanoma growth in both melanoma-forming zebrafish embryos and mouse melanoma cells. The growth inhibition by A11 is a result of mitosis reduction but not apoptosis enhancement. Meanwhile, A11 activates both MAPK and Akt signaling pathways. Many A11-treated mouse melanoma cells exhibit morphological changes and resemble normal melanocytes. Furthermore, we found that A11 causes down-regulation of melanocyte differentiation genes, including Pax3 and MITF. Together, our results suggest that A11 could be a new melanoma therapeutic agent by inhibiting melanocyte differentiation and proliferation.

      PubDate: 2017-10-29T12:17:20Z
      DOI: 10.1016/j.taap.2017.10.008
      Issue No: Vol. 337 (2017)
       
  • Application of gene specific mRNA level determinations in individual cells
           using flow cytometry-based PrimeFlow™ in immunotoxicology
    • Authors: Joseph Henriquez; Jiajun Zhou; Jinpeng Li; Robert Crawford; Norbert Kaminski
      Pages: 39 - 44
      Abstract: Publication date: 15 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 337
      Author(s): Joseph Henriquez, Jiajun Zhou, Jinpeng Li, Robert Crawford, Norbert Kaminski
      Determining changes in gene expression by measuring mRNA levels is an important capability in biological research. Real-Time Quantitative PCR (RT-qPCR) is the most ubiquitous technique for measuring changes in mRNA transcript levels, but heterogeneity of cell populations and low cell number are serious technical limitations. Recent advances in flow cytometric analytical techniques have enabled the quantification of mRNA levels in individual cells. Here, we present examples demonstrating the strength and challenges of concurrently measuring mRNA using PrimeFlow™ with other endpoints in immunotoxicological studies. Specifically, we demonstrate how measuring gene specific mRNA levels on a per cell basis was used to study: 1) markers of activation and differentiation; 2) cell signaling by measuring intracellular proteins in mature and developing cell types; and 3) a cell type that constitutes a minor population in peripheral blood. We also discuss cell type-specific modifications to the parent technique, which facilitated optimal performance in these cells. While the examples provided are focused on immunotoxicological questions and endpoints, this new strategy can be applied to a wide variety of toxicological research problems.

      PubDate: 2017-11-05T10:38:21Z
      DOI: 10.1016/j.taap.2017.10.021
      Issue No: Vol. 337 (2017)
       
  • Natural modulators of nonalcoholic fatty liver disease: Mode of action
           analysis and in silico ADME-Tox prediction
    • Authors: Merilin Al Sharif; Petko Alov; Vessela Vitcheva; Antonia Diukendjieva; Mattia Mori; Bruno Botta; Ivanka Tsakovska; Ilza Pajeva
      Pages: 45 - 66
      Abstract: Publication date: 15 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 337
      Author(s): Merilin Al Sharif, Petko Alov, Vessela Vitcheva, Antonia Diukendjieva, Mattia Mori, Bruno Botta, Ivanka Tsakovska, Ilza Pajeva
      Nonalcoholic fatty liver disease (NAFLD) is considered to be the most common chronic liver disease. The discovery of natural product-based NAFLD modulators requires a more comprehensive study of their modes of action (MoAs). In this study we analysed available in the literature data for 26 naturally-derived compounds associated with experimental evidence for NAFLD alleviation and outlined potential biomolecular targets and a network of pharmacological MoAs for 12 compounds with the highest number of experimentally supported MoA key events, modulated by them. Despite the general perception that the therapeutic agents of natural origin are safe, an evaluation of ADME-Tox properties of these compounds has also been performed in order to estimate their suitability as drug candidates. We evaluated how the investigated structures fit to Lipinski's “Rule of five” and predicted their potential Phase I biotransformation pathways and toxicological effects using the ACD/Percepta platform, and the Meteor Nexus and Derek Nexus knowledge-based systems. Our results revealed the potential of the studied compounds as lead structures and outlined those of them that needed further optimisation of their pharmacokinetic profiles. The presented combined MoA/in silico approach could be extrapolated to naturally-derived and pathology-relevant lead structures with other biological activities. It could direct their optimisation by a mechanistically justified in silico evaluation.
      Graphical abstract image

      PubDate: 2017-11-05T10:38:21Z
      DOI: 10.1016/j.taap.2017.10.013
      Issue No: Vol. 337 (2017)
       
  • Liposomalization of oxaliplatin induces skin accumulation of it, but
           negligible skin toxicity
    • Authors: Kentaro Nishida; Misaki Kashiwagi; Shunsuke Shiba; Kiwamu Muroki; Akihiro Ohishi; Yusuke Doi; Hidenori Ando; Tatsuhiro Ishida; Kazuki Nagasawa
      Pages: 76 - 84
      Abstract: Publication date: 15 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 337
      Author(s): Kentaro Nishida, Misaki Kashiwagi, Shunsuke Shiba, Kiwamu Muroki, Akihiro Ohishi, Yusuke Doi, Hidenori Ando, Tatsuhiro Ishida, Kazuki Nagasawa
      Liposomalization causes alteration of the pharmacokinetics of encapsulated drugs, and allows delivery to tumor tissues through passive targeting via an enhanced permeation and retention (EPR) effect. PEGylated liposomal doxorubicin (Doxil®, Lipo-DXR), a representative liposomal drug, is well-known to reduce cardiotoxicity and increase the anti-tumor activity of DXR, but to induce the hand-foot syndrome (HFS) as a result of skin DXR accumulation, which is one of its severe adverse effects. We have developed a new liposomal preparation of oxaliplatin (l-OHP), an important anti-tumor drug for treatment of colorectal cancer, using PEGylated liposomes (Lipo-l-OHP), and showed that Lipo-l-OHP exhibits increased anti-tumor activity in tumor-bearing mice compared to the original preparation of l-OHP. However, whether Lipo-l-OHP causes HFS-like skin toxicity similar to Lipo-DXR remains to be determined. Administration of Lipo-l-OHP promoted accumulation of platinum in rat hind paws, however, it caused negligible morphological and histological alterations on the plantar surface of the paws. Administration of DiI-labeled empty PEGylated liposomes gave almost the same distribution profile of dyes into the dermis of hind paws with DXR as in the case of Lipo-DXR. Treatment with Lipo-l-OHP, Lipo-DXR, DiI-labeled empty PEGylated liposomes or empty PEGylated liposomes caused migration of CD68+ macrophages into the dermis of hind paws. These findings suggest that the skin toxicity on administration of liposomalized drugs is reflected in the proinflammatory characteristics of encapsulated drugs, and indicate that Lipo-l-OHP with a higher anti-cancer effect and no HFS may be an outstanding l-OHP preparation leading to an improved quality of life of cancer patients.
      Graphical abstract image

      PubDate: 2017-11-11T10:58:30Z
      DOI: 10.1016/j.taap.2017.10.006
      Issue No: Vol. 337 (2017)
       
  • Xanthatin triggers Chk1-mediated DNA damage response and destabilizes
           Cdc25C via lysosomal degradation in lung cancer cells
    • Authors: Li Tao; Yuzhu Cao; Zhonghong Wei; Qi Jia; Suyun Yu; Jinqiu Zhong; Ainyun Wang; James R. Woodgett; Yin Lu
      Pages: 85 - 94
      Abstract: Publication date: 15 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 337
      Author(s): Li Tao, Yuzhu Cao, Zhonghong Wei, Qi Jia, Suyun Yu, Jinqiu Zhong, Ainyun Wang, James R. Woodgett, Yin Lu
      Previous studies had shown that xanthatin, a natural xanthanolide sesquiterpene lactone, could induce mitotic arrest and apoptosis in non-small cell lung cancer (NSCLC) cells. Here, we examined whether the DNA damage response (DDR) could be a primary cytotoxic event underlying xanthatin-mediated anti-tumor activity. Using EdU incorporation assay in combination with novel imaging flow cytometry, our data indicated that xanthatin suppressed DNA replication, prevented cells from G2/M entry and increased the spot count of γH2AX nuclear foci. Given that checkpoint kinase 1 (Chk1) represents a core component in DDR-mediated cell cycle transition and the phosphorylation on Ser-345 is essential for kinase activation and function, we surprisingly found xanthatin distinctly modulated Ser-345 phosphorylation of Chk1 in A549 and H1299 cells. Further investigation on Cdc25C/CDK1/CyclinB1 signaling cascade in the absence or presence of pharmacological DDR inhibitors showed that xanthatin directly destabilized the protein levels of Cdc25C, and recovery of p53 expression in p53-deficient H1299 cells further intensified xanthatin-mediated inhibition of Cdc25C, suggesting p53-dependent regulation of Cdc25C in a DDR machinery. Moreover, exogenous expression of Cdc25C was also substantially repressed by xanthatin and partially impaired xanthatin-induced G2 arrest. In addition, xanthatin could induce accumulation of ubiquitinated Cdc25C without undergoing further proteasomal degradation. However, an alternative lysosomal proteolysis of Cdc25C was observed. Interestingly, lysosome-like vesicles were produced upon xanthatin treatment, accompanied by rapid accumulation of lysosomal associated membrane protein LAPM-1. Furthermore, vacuolar proton (V)-ATPases inhibitor bafilomycin A1 and lysosomal proteases inhibitor leupeptin could remarkably overturn the levels of Cdc25C in xanthatin-treated H1299 cells. Altogether, these data provide insight into how xanthatin can be effectively targeted DDR molecules towards certain tumors.
      Graphical abstract image

      PubDate: 2017-11-11T10:58:30Z
      DOI: 10.1016/j.taap.2017.10.015
      Issue No: Vol. 337 (2017)
       
  • Chronic treatment with caffeine and its withdrawal modify the
           antidepressant-like activity of selective serotonin reuptake inhibitors in
           the forced swim and tail suspension tests in mice. Effects on Comt,
           Slc6a15 and Adora1 gene expression
    • Authors: Aleksandra Szopa; Urszula Doboszewska; Mariola Herbet; Sylwia Wośko; Elżbieta Wyska; Katarzyna Świąder; Anna Serefko; Agnieszka Korga; Aleksandra Wlaź; Andrzej Wróbel; Marta Ostrowska; Joanna Terlecka; Adam Kanadys; Ewa Poleszak; Jarosław Dudka; Piotr Wlaź
      Pages: 95 - 103
      Abstract: Publication date: 15 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 337
      Author(s): Aleksandra Szopa, Urszula Doboszewska, Mariola Herbet, Sylwia Wośko, Elżbieta Wyska, Katarzyna Świąder, Anna Serefko, Agnieszka Korga, Aleksandra Wlaź, Andrzej Wróbel, Marta Ostrowska, Joanna Terlecka, Adam Kanadys, Ewa Poleszak, Jarosław Dudka, Piotr Wlaź
      Recent preclinical and clinical data suggest that low dose of caffeine enhances the effects of common antidepressants. Here we investigated the effects of chronic administration of caffeine (5mg/kg, twice daily for 14days) and its withdrawal on day 15th on the activity of per se ineffective doses of fluoxetine (5mg/kg) and escitalopram (2mg/kg) given on day 15th. We found decreased immobility time in the forced swim and tail suspension tests in mice in which caffeine was administered simultaneously with antidepressants on day 15th following a 14-day caffeine treatment and no alterations in the spontaneous locomotor activity. A decrease in the level of escitalopram and an increase in the level of caffeine in serum were observed after concomitant administration of these compounds, while the joint administration of caffeine and fluoxetine was not associated with changes in their levels in serum or brain. Caffeine withdrawal caused a decrease in Adora1 mRNA level in the cerebral cortex (Cx). Administration of escitalopram or fluoxetine followed by caffeine withdrawal caused an increase in this gene expression, whereas administration of escitalopram, but not fluoxetine, on day 15th together with caffeine caused a decrease in Adora1 mRNA level in the Cx. Furthermore, antidepressant-like activity observed after joint administration of the tested drugs with caffeine was associated with decreased Slc6a15 mRNA level in the Cx. The results show that withdrawal of caffeine after its chronic intake may change activity of antidepressants with concomitant alterations within monoamine, adenosine and glutamate systems.

      PubDate: 2017-11-11T10:58:30Z
      DOI: 10.1016/j.taap.2017.10.020
      Issue No: Vol. 337 (2017)
       
  • Altered gene expression profiles in the lungs of benzo[a]pyrene-exposed
           
    • Authors: Q. Shi; R.R. Fijten; D. Spina; Y. Riffo Vasquez; V.M. Arlt; R.W. Godschalk; F.J. Van Schooten
      Pages: 8 - 19
      Abstract: Publication date: 1 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 336
      Author(s): Q. Shi, R.R. Fijten, D. Spina, Y. Riffo Vasquez, V.M. Arlt, R.W. Godschalk, F.J. Van Schooten
      Patients with inflammatory lung diseases are often additionally exposed to polycyclic aromatic hydrocarbons like B[a]P and B[a]P-induced alterations in gene expression in these patients may contribute to the development of lung cancer. Mice were intra-nasally treated with lipopolysaccharide (LPS, 20μg/mouse) to induce pulmonary inflammation and subsequently exposed to B[a]P (0.5mg/mouse) by intratracheal instillation. Gene expression changes were analyzed in mouse lungs by RNA microarrays. Analysis of genes that are known to be involved in the cellular response to B[a]P indicated that LPS significantly inhibited gene expression of various enzymes linked to B[a]P metabolism, which was confirmed by phenotypic analyses of enzyme activity. Ultimately, these changes resulted in higher levels of B[a]P-DNA adducts in the lungs of mice exposed to B[a]P with prior LPS treatment compared to the lungs of mice exposed to B[a]P alone. Using principle component analysis (PCA), we found that of all the genes that were significantly altered in their expression, those that were able to separate the different exposure conditions were predominantly related to immune-response. Moreover, an overall analysis of differentially expressed genes indicated that cell-cell adhesion and cell-cell communication was inhibited in lungs of mice that received both B[a]P and LPS. Our results indicate that pulmonary inflammation increased the genotoxicity of B[a]P via inhibition of both phase I and II metabolism. Therefore, inflammation could be a critical contributor to B[a]P-induced carcinogenesis in humans.

      PubDate: 2017-10-29T12:17:20Z
      DOI: 10.1016/j.taap.2017.09.023
      Issue No: Vol. 336 (2017)
       
  • Long-enduring primary hepatocyte-based co-cultures improve prediction of
           hepatotoxicity
    • Authors: Eric I. Novik; Jacquelyn Dwyer; James K. Morelli; Amit Parekh; Cheul Cho; Eitan Pludwinski; Anil Shrirao; Robert M. Freedman; James S. MacDonald; Zaid Jayyosi
      Pages: 20 - 30
      Abstract: Publication date: 1 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 336
      Author(s): Eric I. Novik, Jacquelyn Dwyer, James K. Morelli, Amit Parekh, Cheul Cho, Eitan Pludwinski, Anil Shrirao, Robert M. Freedman, James S. MacDonald, Zaid Jayyosi
      The failure of drug candidates during clinical trials and post-marketing withdrawal due to Drug Induced Liver Injury (DILI), results in significant late-stage attrition in the pharmaceutical industry. Animal studies have proven insufficient to definitively predict DILI in the clinic, therefore a variety of in vitro models are being tested in an effort to improve prediction of human hepatotoxicity. The model system described here consists of cryopreserved primary rat, dog or human hepatocytes co-cultured together with a fibroblast cell line, which aids in the hepatocytes' maintenance of more in vivo-like characteristics compared to traditional hepatic mono-cultures, including long term viability and retention of activity of cytochrome P450 isozymes. Cell viability was assessed by measurement of ATP following treatment with 29 compounds having known hepatotoxic liabilities. Hμrelrat™, Hμreldog™, and Hμrelhuman™ hepatic co-cultures were treated for 24h, or under repeat-dosing for 7 or 13days, and compared to rat and human hepatic mono-cultures following single-dose exposure for 24h. The results allowed for a comparison of cytotoxicity, species-specific responses and the effect of repeat compound exposure on the prediction of hepatotoxic potential in each model. Results show that the co-culture model had greater sensitivity compared to that of the hepatic mono-cultures. In addition, “time-based ratios” were determined by dividing the compounds' 24-hour TC50/Cmax values by TC50/Cmax values measured after dosing for either 7 or 13days. The results suggest that this approach may serve as a useful adjunct to traditional measurements of hepatotoxicity, improving the predictive value of early screening studies.

      PubDate: 2017-10-29T12:17:20Z
      DOI: 10.1016/j.taap.2017.09.013
      Issue No: Vol. 336 (2017)
       
  • The disturbed redox-balance in pulmonary fibrosis is modulated by the
           plant flavonoid quercetin
    • Authors: C. Veith; M. Drent; A. Bast; F.J. van Schooten; A.W. Boots
      Pages: 40 - 48
      Abstract: Publication date: 1 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 336
      Author(s): C. Veith, M. Drent, A. Bast, F.J. van Schooten, A.W. Boots
      Idiopathic pulmonary fibrosis (IPF) is characterized by a disturbed pulmonary redox balance associated with inflammation. To restore this balance, antioxidants are often suggested as therapy for IPF but previous clinical trials with these compounds and their precursors have not been successful in the clinic. The exogenous antioxidant quercetin, which has a versatile antioxidant profile and is effective in restoring a disturbed redox balance, might be a better candidate. The aim of this study was to evaluate the protective effect of quercetin on oxidative and inflammatory markers in IPF. Here, we demonstrate that IPF patients have a significantly reduced endogenous antioxidant defense, shown by a reduced total antioxidant capacity and lowered glutathione and uric acid levels compared to healthy controls. This confirms that the redox balance is disturbed in IPF. Ex vivo incubation with quercetin in blood of both IPF patients and healthy controls reduces LPS-induced production of the pro-inflammatory cytokines IL-8 and TNFα. This anti-inflammatory effect was more pronounced in the blood of the patients. Our pro-fibrotic in vitro model, consisting of bleomycin-triggered BEAS-2B cells, shows that quercetin boosts the antioxidant response, by increasing Nrf2 activity, and decreases pro-inflammatory cytokine production in a concentration-dependent manner. Collectively, our findings implicate that IPF patients may benefit from the use of quercetin to restore the disturbed redox balance and reduce inflammation.

      PubDate: 2017-10-29T12:17:20Z
      DOI: 10.1016/j.taap.2017.10.001
      Issue No: Vol. 336 (2017)
       
  • Intestinal exposure to PCB 153 induces inflammation via the ATM/NEMO
           pathway
    • Authors: Matthew C. Phillips; Rishu Dheer; Rebeca Santaolalla; Julie Davies; Juan F. Burgueno; Jessica K. Lang; Michal Toborek; Maria T. Abreu
      Abstract: Publication date: Available online 29 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Matthew C. Phillips, Rishu Dheer, Rebeca Santaolalla, Julie M. Davies, Juan Burgueño, Jessica K. Lang, Michal Toborek, Maria T. Abreu
      Background Polychlorinated biphenyls (PCBs) are persistent organic pollutants that adversely affect human health. PCBs bio-accumulate in organisms important for human consumption. PCBs accumulation in the body leads to activation of the transcription factor NF-κB, a major driver of inflammation. Despite dietary exposure being one of the main routes of exposure to PCBs, the gut has been widely ignored when studying the effects of PCBs. Objectives We investigated the effects of PCB 153 on the intestine and addressed whether PCB 153 affected intestinal permeability or inflammation and the mechanism by which this occurred. Methods Mice were orally exposed to PCB 153 and gut permeability was assessed. Intestinal epithelial cells (IECs) were collected and evaluated for evidence of genotoxicity and inflammation. A human IEC line (SW480) was used to examine the direct effects of PCB 153 on epithelial function. NF-кB activation was measured using a reporter assay, DNA damage was assessed, and cytokine expression was ascertained with real-time PCR. Results Mice orally exposed to PCB 153 had an increase in intestinal permeability and inflammatory cytokine expression in their IECs; inhibition of NF-кB ameliorated both these effects. This inflammation was associated with genotoxic damage and NF-кB activation. Exposure of SW480 cells to PCB 153 led to similar effects as seen in vivo. We found that activation of the ATM/NEMO pathway by genotoxic stress was upstream of NF-kB activation. Conclusions These results demonstrate that oral exposure to PCB 153 is genotoxic to IECs and induces downstream inflammation and barrier dysfunction in the intestinal epithelium.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/s0016-5085(17)33272-9
      Issue No: Vol. 152, No. 5 (2017)
       
  • Trans-resveratrol mitigates type 1 diabetes-induced oxidative DNA damage
           and accumulation of advanced glycation end products in glomeruli and
           tubules of rat kidneys
    • Authors: Heba Al-Hussaini; Narayana Kilarkaje
      Abstract: Publication date: Available online 8 December 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Heba Al-Hussaini, Narayana Kilarkaje
      Hyperglycemia induces the formation of advanced glycation end products (AGEs) and their receptors (RAGEs), which alter several intracellular signaling mechanisms leading to the onset and progression of diabetic nephropathy. The present study focused on, i) modulatory effects of trans-resveratrol (3,5,4′-trihydroxy-trans-stilbene) on structural changes, AGE (NƐ-carboxymethyl-lysine), RAGE, oxidative stress and DNA damage, and apoptosis, and ii) localization of fibrotic changes, AGE, RAGE, 8-oxo-dG and 4-hydroxynonenal (4-HNE) in diabetic rat kidneys. Resveratrol (5mg/kg; po, administered during last 45days of 90-day-long hyperglycemic period) administration to streptozotocin-induced type 1 diabetic male Wistar rats reduced renal hypertrophy and structural changes (tubular atrophy, mesangial expansion or shrinkage, diffuse glomerulonephritis, and fibrosis), AGE accumulation, oxidative stress and DNA damage (8-oxo-dG), 4-HNE, caspase-3, and cleaved-caspase-3, but not the RAGE expression. The AGE accumulated in the mesangium, vascular endothelium, and proximal convoluted tubules and less intensely in distal convoluted tubules of diabetic rat kidneys. The RAGE expression increased in the convoluted tubules and collecting ducts of diabetic rat kidneys, but not in the mesangium. Diabetes increased the expression of 8-oxo-dG in nuclei and cytoplasm of renal cells, and 4-HNE in glomeruli, convoluted tubules, the loops of Henle and collecting ducts. Hyperglycemia-induced AGE-RAGE axis and oxidative stress in turn induced apoptosis in diabetic kidneys. Resveratrol mitigated all diabetic effects except the RAGE expression. In conclusion, Resveratrol significantly alleviates diabetes-induced glycation, oxidative damage, and apoptosis to inhibit the progression of diabetic nephropathy. Resveratrol supplementation may be useful to hinder the onset and progression of diabetic kidney diseases.
      Graphical abstract image

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.11.025
       
  • Valproic acid disrupts the oscillatory expression of core circadian rhythm
           transcription factors
    • Authors: Chanel A. Griggs; Scott W. Malm; Rosa Jaime-Frias; Catharine L. Smith
      Abstract: Publication date: Available online 8 December 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Chanel A. Griggs, Scott W. Malm, Rosa Jaime-Frias, Catharine L. Smith
      Valproic acid (VPA) is a well-established therapeutic used in treatment of seizure and mood disorders as well as migraines and a known hepatotoxicant. About 50% of VPA users experience metabolic disruptions, including weight gain, hyperlipidemia, and hyperinsulinemia, among others. Several of these metabolic abnormalities are similar to the effects of circadian rhythm disruption. In the current study, we examine the effect of VPA exposure on the expression of core circadian transcription factors that drive the circadian clock via a transcription-translation feedback loop. In cells with an unsynchronized clock, VPA simultaneously upregulated the expression of genes encoding core circadian transcription factors that regulate the positive and negative limbs of the feedback loop. Using low dose glucocorticoid, we synchronized cultured fibroblast cells to a circadian oscillatory pattern. Whether VPA was added at the time of synchronization or 12h later at CT12, we found that VPA disrupted the oscillatory expression of multiple genes encoding essential transcription factors that regulate circadian rhythm. Therefore, we conclude that VPA has a potent effect on the circadian rhythm transcription-translation feedback loop that may be linked to negative VPA side effects in humans. Furthermore, our study suggests potential chronopharmacology implications of VPA usage.

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.12.005
       
  • Total particulate matter from cigarette smoke disrupts vascular
           development in zebrafish brain (Danio rerio)
    • Authors: Andrey Massarsky; G.L. Prasad Richard Giulio
      Abstract: Publication date: Available online 6 December 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Andrey Massarsky, G.L. Prasad, Richard T. Di Giulio
      Several studies have demonstrated zebrafish as a useful high-throughput in-vivo model to study the effects of cigarette smoke on early development. It has been shown previously that exposure of zebrafish to cigarette smoke total particulate matter (TPM) leads to several adverse physiological aberrations, including heart deformities and improper angiogenesis. Consequently, this study investigated the effects of TPM on cardiovascular development in zebrafish that were exposed to increasing concentrations of TPM based upon nicotine content from 6h post fertilization (hpf) up to 72hpf. We show that TPM exposure in wild-type embryos led to a dose-dependent increase in fluorescence, especially in the yolk and head regions, suggesting bioaccumulation of cyclic compounds in TPM, such as polycyclic aromatic hydrocarbons (PAHs). Similarly, the incidence of cranial hemorrhage, pericardial edema, and string heart was increased with TPM exposure in a dose-dependent manner. Additionally, TPM exposure in transgenic (Flk1:eGFP) zebrafish showed a decrease in vascular abundance in the brain, but the transcript abundance of key angiogenic genes Tie-2, Angpt1, Notch3, and Flk1 remained largely unchanged and that of Vegf actually increased with TPM. The study also investigated aspects of a proposed crosstalk between the activation of the aryl hydrocarbon receptor (AhR) pathway and subsequent inhibition of the Wnt signaling pathway, resulting in cardiac malformations. In an effort to reduce the occurrence of cardiovascular malformations, larvae were co-treated with CHIR99021 (CHIR), which should promote Wnt signaling. However, co-treatment with CHIR did not significantly affect the TPM-induced cardiovascular toxicity. Overall, results from this study demonstrate that exposure to TPM leads to several cardiovascular deformities and disrupted vascular development in the brain, and that these effects are associated with downregulation of Wnt signaling.

      PubDate: 2017-12-11T15:52:50Z
       
  • Cover 2--Ed Board
    • Abstract: Publication date: 15 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 337


      PubDate: 2017-11-30T12:44:11Z
       
  • Cover 4--TOC
    • Abstract: Publication date: 15 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 337


      PubDate: 2017-11-30T12:44:11Z
       
  • Association between inefficient arsenic methylation capacity and
           demographic characteristics on the risk of skin lesions
    • Authors: Hifza Rasheed; Paul Kay; Rebecca Slack; Yun Yun Gong
      Abstract: Publication date: Available online 29 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Hifza Rasheed, Paul Kay, Rebecca Slack, Yun Yun Gong
      This study was conducted in rural Pakistan to assess the dose-response relationship between skin lesions and arsenic exposure and their variation by demographic characteristics. The study included 398 participants (66 participants with skin lesions and 332 without) residing in six previously unstudied villages exposed to ground water arsenic in the range of <1 to 3090μgL−1. The skin lesions identification process involved interview and physical examinations of participants followed by confirmation by a physician according to UNICEF criteria. Urinary inorganic arsenic (iAs), total arsenic (tAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were analysed to determine methylation capacity, methylation efficiency and the dose-response relationship with skin lesions. Study participants with skin lesions were found to be exposed to arsenic >10μgL−1 with a daily arsenic intake of 0.78±2.01mgday−1 from household ground water sources for an exposure duration of 10–20years. The participants with skin lesions compared to those without skin lesions showed higher levels of urinary iAs (133.40±242.48 vs. 44.24±86.48μgg−1 Cr), MMA (106.38±135.04 vs. 35.43±39.97μgg−1 Cr), MMA% (15.26±6.31 vs.12.11±4.68) and lower levels of DMA% (66.99±13.59 vs. 73.39±10.44) and secondary methylation index (SMI) (0.81±0.11 vs. 0.86±0.07). Study participants carrying a lower methylation capacity characterized by higher MMA% (OR 5.06, 95% CI: 2.09–12.27), lower DMA% (OR 0.64, 95% CI: 0.33–1.26), primary methylation index (PMI) (OR 0.56, 95% CI: 0.28–1.12) and SMI (OR 0.43, 95% CI: 0.21–0.88) had a significantly higher risk of skin lesions compared to their corresponding references after adjusting for occupation categories. The findings confirmed that inefficient arsenic methylation capacity was significantly associated with increased skin lesion risks and the effect might be modified by labour intensive occupations.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.11.026
       
  • Asiatic acid ameliorates hepatic ischemia/reperfusion injury in rats via
           mitochondria-targeted protective mechanism
    • Authors: Yapeng Lu; Huiwen Kan; Ying Wang; Dan Wang; Xueting Wang; Jing Gao; Li Zhu
      Abstract: Publication date: Available online 28 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Yapeng Lu, Huiwen Kan, Ying Wang, Dan Wang, Xueting Wang, Jing Gao, Li Zhu
      It has been proved that asiatic acid (AA) directly targets mitochondria and acts as a mild mitochondrial uncoupler. In this study, we aim to investigate the protective effects of AA against ischemia/reperfusion (I/R)-induced liver injury in rats and some underlying mechanisms involved were elucidated. The results showed that 50mg/kg AA pre-treatment significantly reduced I/R-induced liver damage, characterized by the decreased release of aspartate aminotransferase (AST) and TNF-α. Furthermore, AA pre-treatment dramatically inhibited the production of MDA and increased the hepatic SOD, catalase activities and GSH levels in liver tissue of I/R rats which indicated that AA ameliorated I/R-induced liver damage by reducing oxidative stress. In isolated liver mitochondria in I/R rats, AA improved mitochondrial respiration, decreased mitochondrial MDA level, prevented I/R-induced drop of mitochondrial membrane potential (MMP) and increased ATP content, indicating the protective effect of AA against I/R-induced mitochondrial oxidative damage. In isolated liver mitochondria from normal rats, AA was found to effectively block succinate-driven H2O2 production no matter of the presence or absence of rotenone. In addition, AA showed a clear protective effect against anoxia/reoxygenation (A/R)-induced injury in isolated rat liver mitochondria when malate/glutamate were used as respiratory substrates. After AA treatment, mitochondrial respiratory dysfunction induced by A/R was ameliorated. Also, A/R-induced mitochondrial ROS generation was significantly inhibited by AA. In conclusion, AA can attenuate I/R-induced liver damage in rats and A/R-induced mitochondrial injury in isolated rat liver mitochondria by inhibiting oxidative stress and restoring mitochondrial function. Therefore, AA might have potential as a mitochondrial protective agent for use in clinical treatment of hepatic I/R injury.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.11.023
       
  • Fullerene (C60) particle size implications in neurotoxicity following
           infusion into the hippocampi of Wistar rats
    • Authors: Ândrea Barbosa Kraemer; Gustavo Morrone Parfitt; Daiane da Silva Acosta; Gisele Eva Bruch; Marcos Freitas Cordeiro; Luis Fernando Marins; Juliane Ventura-Lima; José María Monserrat; Daniela Martí Barros
      Abstract: Publication date: Available online 27 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Ândrea Barbosa Kraemer, Gustavo Morrone Parfitt, Daiane da Silva Acosta, Gisele Eva Bruch, Marcos Freitas Cordeiro, Luis Fernando Marins, Juliane Ventura-Lima, José María Monserrat, Daniela Martí Barros
      The buckminsterfullerene (C60) is considered as a relevant candidate for drug and gene delivery to the brain, once it has the ability to cross the blood-brain barrier. However, the biological implications of this nanomaterial are not fully understood, and its safety for intracerebral delivery is still debatable. In this study, we investigated if C60 particle size could alter its biological effects. For this, two aqueous C60 suspensions were used with maximum particle size up to 200nm and 450nm. The suspensions were injected in the hippocampus, the main brain structure involved in memory processing and spatial localization. In order to assess spatial learning, male Wistar rats were tested in Morris water maze, and the hippocampal BDNF protein levels and gene expression were analyzed. Animals treated with C60 up to 450nm demonstrated impaired spatial memory with a significant decrease in BDNF protein levels and gene expression. However, an enhanced antioxidant capacity was observed in both C60 treatments. A decrease in reactive oxygen species levels was observed in the treatments with suspensions containing particles measuring with up to 450nm. Thiobarbituric acid reactive substances, glutamate cysteine ligase, and glutathione levels showed no alterations among the different treatments. In conclusion, different particle sizes of the same nanomaterial can lead to different behavioral outcomes and biochemical parameters in brain tissue.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.11.022
       
  • Phosphodiesterase 4B plays a role in benzophenone-3-induced phototoxicity
           in normal human keratinocytes
    • Authors: Hyoung-June Kim; Eunyoung Lee; Moonyoung Lee; Sungjin Ahn; Jungmin Kim; Jingjing Liu; Sun Hee Jin; Jaehyoun Ha; Il Hong Bae; Tae Ryong Lee; Minsoo Noh
      Abstract: Publication date: Available online 26 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Hyoung-June Kim, Eunyoung Lee, Moonyoung Lee, Sungjin Ahn, Jungmin Kim, Jingjing Liu, Sun Hee Jin, Jaehyoun Ha, Il Hong Bae, Tae Ryong Lee, Minsoo Noh
      Benzophenone-3 (BP-3), which is extensively used in organic sunscreen, has phototoxic potential in human skin. Phosphodiesterase 4B (PDE4B) has a well-established role in inflammatory responses in immune cells. Currently, it is unknown if PDE4B is associated with BP-3-induced phototoxicity in normal human keratinocytes (NHKs). We found that BP-3 significantly increased PDE4B expression in ultraviolet B (UVB)-irradiated NHKs. Notably, BP-8, a sunscreen agent that shares the 2-hydroxy-4-methoxyphenyl methanone moiety with BP-3, also upregulated PDE4B expression in NHKs. Upon UVB irradiation, BP-3 upregulated the expression of pro-inflammatory factors, such as prostaglandin endoperoxide synthase 2, tumor necrosis factor α, interleukin 8, and S100A7, and downregulated the level of cornified envelope associated proteins, which are important in the development of the epidermal permeability barrier. The additive effects of UVB-activated BP-3 on the expression of both pro-inflammatory mediators and cornified envelope associated proteins were antagonized by treatment with the PDE4 inhibitor rolipram. The BP-3 and UVB co-stimulation-induced PDE4B upregulation and its association with the upregulation of pro-inflammatory mediators and the downregulation of epidermal differentiation markers were confirmed in a reconstituted three dimensional human epidermis model. Therefore, PDE4B has a role in the mechanism of BP-3-induced phototoxicity.
      Graphical abstract image

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.11.021
       
  • Inhibition of estrogen receptor reduces connexin 43 expression in breast
           cancers
    • Authors: Cheng-Fang Tsai; Yu-Kai Cheng; Dah-Yuu Lu; Shu-Lin Wang; Chen-Ni Chang; Pei-Chun Chang; Wei-Lan Yeh
      Abstract: Publication date: Available online 24 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Cheng-Fang Tsai, Yu-Kai Cheng, Dah-Yuu Lu, Shu-Lin Wang, Chen-Ni Chang, Pei-Chun Chang, Wei-Lan Yeh
      Connexins are widely supported as tumor suppressors due to their downregulation in cancers, nevertheless, more recent evidence suggests roles for connexins in facilitating tumor progression in later stages, including metastasis. One of the key factors regulating the expression, modification, stability, and localization of connexins is hormone receptors in hormone-dependent cancers. It is reasonable to consider that hormones/hormone receptors may modulate connexins expression and play critical roles in the cellular control of connexins during breast cancer progression. In estrogen receptor (ER)-positive breast cancers, tamoxifen and fulvestrant are widely used therapeutic agents and are considered to alter ER signaling. In this present study, we investigated the effects of fulvestrant and tamoxifen in Cx43 expression, and we also explored the role of Cx43 in ER-positive breast cancer migration and the relationship between Cx43 and ER. The involvement of estrogen/ER in Cx43 modulation was further verified by administering tyrosine kinase inhibitors and chemotherapeutic agents. We found that inhibition of ER promoted the binding of E3 ligase Nedd4 to Cx43, leading to Cx43 ubiquitination. Furthermore, inhibition of ER by fulvestrant and tamoxifen phosphorylated p38 MAPK, and inhibition of Rac, MKK3/6, and p38 reversed fulvestrant-reduced Cx43 expression. These findings suggest that Cx43 expression which may positively regulate cell migration is ER-dependent in ER-positive breast cancer cells.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.11.020
       
  • Evaluating the evidence for non-monotonic dose-response relationships: A
           systematic literature review and (re-)analysis of in vivo toxicity data in
           the area of food safety
    • Authors: C. Varret; A. Beronius; L. Bodin; B.G.H. Bokkers; P.E. Boon; M. Burger; L. De Wit-Bos; A. Fischer; A. Hanberg; S. Litens-Karlsson; W. Slob; G. Wolterink; J. Zilliacus; C. Beausoleil; C. Rousselle
      Abstract: Publication date: Available online 24 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): C. Varret, A. Beronius, L. Bodin, B.G.H. Bokkers, P.E. Boon, M. Burger, L. De Wit-Bos, A. Fischer, A. Hanberg, S. Litens-Karlsson, W. Slob, G. Wolterink, J. Zilliacus, C. Beausoleil, C. Rousselle
      This study aims to evaluate the evidence for the existence of non-monotonic dose-responses (NMDRs) of substances in the area of food safety. This review was performed following the systematic review methodology with the aim to identify in vivo studies published between January 2002 and February 2015 containing evidence for potential NMDRs. Inclusion and reliability criteria were defined and used to select relevant and reliable studies. A set of six checkpoints was developed to establish the likelihood that the data retrieved contained evidence for NMDR. In this review, 49 in vivo studies were identified as relevant and reliable, of which 42 were used for dose-response analysis. These studies contained 179 in vivo dose-response datasets with at least five dose groups (and a control group) as fewer doses cannot provide evidence for NMDR. These datasets were extracted and analyzed using the PROAST software package. The resulting dose-response relationships were evaluated for possible evidence of NMDRs by applying the six checkpoints. In total, 10 out of the 179 in vivo datasets fulfilled all six checkpoints. While these datasets could be considered as providing evidence for NMDR, replicated studies would still be needed to check if the results can be reproduced to rule out that the non-monotonicity was caused by incidental anomalies in that specific study. This approach, combining a systematic review with a set of checkpoints, is new and appears useful for future evaluations of the dose response datasets regarding evidence of non-monotonicity.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.11.018
       
  • Exposure to bisphenol-S alters the expression of microRNA in male
           zebrafish
    • Authors: Jiyun Lee; Younglim Kho; Pan-Gyi Kim; Kyunghee Ji
      Abstract: Publication date: Available online 24 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Jiyun Lee, Younglim Kho, Pan-Gyi Kim, Kyunghee Ji
      Bisphenol S (BPS), an alternative compound of bisphenol A, has been found to affect reproduction, development, and immune system. Although microRNAs (miRNAs) play an important role in many metabolic activities, whether and how they are involved in the process of BPS-induced toxicity is unknown. In the present study, BPS-induced changes in miRNAs and target gene expression in male zebrafish gonad, and the potential mechanism was investigated. Male zebrafish were exposed to 0, 5, and 50μg/L BPS for 21 d. miRNA was isolated from the gonad pool and the expression profiles of 255 known zebrafish miRNAs were analyzed using microarrays. Quantitative real-time polymerase chain reaction was used to validate the expression of several miRNAs in the microarray data. The GO term analysis revealed that miRNAs significantly affected by BPS exposure were involved in hematopoiesis, lymphoid organ development, and immune system development. Among 14 miRNAs that were significantly regulated after exposure to 5 and 50μg/L BPS, six targeted cyp19a1b gene, suggesting the role of BPS-induced toxicity via the interference with the aromatization process. Our findings provide novel insight into the epigenetic regulatory mechanisms of BPS-induced toxicity in male zebrafish, and identification of novel miRNA biomarkers for exposure to BPS.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.11.019
       
  • Cover 2--Ed Board
    • Abstract: Publication date: 1 December 2017
      Source:Toxicology and Applied Pharmacology, Volume 336


      PubDate: 2017-11-18T08:53:15Z
       
  • Capsaicin reduces genotoxicity, colonic cell proliferation and
           preneoplastic lesions induced by 1,2-dimethylhydrazine in rats
    • Authors: Brunno Felipe Ramos Caetano; Mariana Baptista Tablas; Natália Elias Ferreira Pereira; Nelci Antunes de Moura; Robson Francisco Carvalho; Maria Aparecida Marchesan Rodrigues; Luis Fernando Barbisan
      Abstract: Publication date: Available online 16 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Brunno Felipe Ramos Caetano, Mariana Baptista Tablas, Natália Elias Ferreira Pereira, Nelci Antunes de Moura, Robson Francisco Carvalho, Maria Aparecida Marchesan Rodrigues, Luis Fernando Barbisan
      Capsaicin (8-Methyl-N-vanillyl-(trans)-6-nonenamide) is the major pungent ingredient found in chili peppers consumed worldwide. Most reports on capsaicin potential carcinogenicity have yielded inconsistent findings. Some studies have shown that capsaicin exerts anti-proliferative and pro-apoptotic effects on different cancer cell lines, while others have reported an association between capsaicin at high doses with mutagenicity and carcinogenicity. Thus, this study aimed at assessing the effects of capsaicin administration on 1,2-dimethyl-hydrazine (DMH)-induced colon carcinogenesis in male Wistar rats. Our results show that capsaicin administration, before and during carcinogen exposure, modified DMH-induced cytotoxicity and genotoxicity, promoting anti-proliferative and pro-apoptotic responses through the expression of the genes involved in apoptosis, cell cycle suppression and cell/tissue differentiation. Furthermore, capsaicin reduced aberrant crypt foci (ACF) number and multiplicity, although there were no differences in tumor incidence and multiplicity among the groups. Taken together, the results suggest that capsaicin may have a preventive effect against DMH-induced colorectal carcinogenesis.

      PubDate: 2017-11-18T08:53:15Z
      DOI: 10.1016/j.taap.2017.11.008
       
  • Systemic exposure of vinpocetine in pregnant Sprague Dawley rats following
           repeated oral exposure: An investigation of fetal transfer
    • Authors: Suramya Waidyanatha; Heather Troy; Natalie South; Seth Gibbs; Esra Mutlu; Brian Burback; Barry S. McIntyre; Natasha Catlin
      Abstract: Publication date: Available online 15 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Suramya Waidyanatha, Heather Troy, Natalie South, Seth Gibbs, Esra Mutlu, Brian Burback, Barry S. McIntyre, Natasha Catlin
      Vinpocetine is being used worldwide by people of all ages, including pregnant women, for its purported multiple health benefits. However, limited data is available addressing the safety/toxicity of vinpocetine. The National Toxicology Program conducted studies to examine potential effects of vinpocetine on the developing rat. Disposition data is helpful to put the fetal findings into context and provide information on the potential risk for humans. The current study reports the systemic exposure and toxicokinetic (TK) parameters of vinpocetine and metabolite, apovincaminic acid (AVA), in pregnant Harlan Sprague Dawley rats, fetuses and amniotic fluid following oral gavage exposure of dams to 5 and 20mg/kg vinpocetine from gestational day 6 to 18. Vinpocetine was absorbed rapidly in dams with a maximum plasma concentration (Cmax) reaching ≤1.37h. Predicted Cmax and area under the concentration versus time curve (AUC) increased less than proportionally to the dose. Vinpocetine was rapidly distributed to the peripheral compartment. More importantly, significant transfer of vinpocetine from dam to fetuses was observed with fetal Cmax and AUC≥55% of dams. Vinpocetine was cleared rapidly from dam plasma with an elimination half-life of ≤4.02h with no apparent dose-related effect. Vinpocetine was rapidly and highly metabolized to AVA with AVA plasma levels in dams ≥2.7-fold higher than vinpocetine, although in the fetuses, AVA levels were much lower than vinpocetine. Comparison of current rat data with literature human data demonstrates that systemic exposure to vinpocetine in rats following repeated exposure to 5mg/kg is similar to that following a single human relevant dose of 10mg suggesting that the findings from the toxicology study may be relevant to humans.

      PubDate: 2017-11-18T08:53:15Z
      DOI: 10.1016/j.taap.2017.11.011
       
  • Age dependent in vitro metabolism of bifenthrin in rat and human hepatic
           microsomes
    • Authors: Gopinath Nallani; Appavu Chandrasekaran Kelem Kassahun Shen Shaaban ElNaggar Zhiwei
      Abstract: Publication date: Available online 13 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Gopinath C. Nallani, Appavu Chandrasekaran, Kelem Kassahun, Li Shen, Shaaban F. ElNaggar, Zhiwei Liu
      Bifenthrin, a pyrethroid insecticide, undergoes oxidative metabolism leading to the formation of 4′-hydroxy-bifenthrin (4′-OH-BIF) and hydrolysis leading to the formation of TFP acid in rat and human hepatic microsomes. In this study, age-dependent metabolism of bifenthrin in rats and humans were determined via the rates of formation of 4′-OH-BIF and TFP acid following incubation of bifenthrin in juvenile and adult rat (PND 15 and PND 90) and human (<5years and >18years) liver microsomes. Furthermore, in vitro hepatic intrinsic clearance (CLint) of bifenthrin was determined by substrate consumption method in a separate experiment. The mean Vmax(±SD) for the formation of 4′-OH-BIF in juvenile rat hepatic microsomes was 25.0±1.5pmol/min/mg which was significantly lower (p<0.01) compared to that of adult rats (86.0±17.7pmol/min/mg). However, the mean Km values for juvenile (19.9±6.6μM) and adult (23.9±0.4μM) rat liver microsomes were similar. On the other hand, in juvenile human hepatic microsomes, Vmax for the formation of 4′-OH-BIF (73.9±7.5pmol/min/mg) was significantly higher (p<0.05) than that of adults (21.6±0.6pmol/min/mg) albeit similar Km values (10.5±2.8μM and 8.9±0.6μM) between the two age groups. The trends in the formation kinetics of TFP acid were similar to those of 4′-OH-BIF between the species and age groups, although the differences between juveniles and adults were less pronounced. The data also show that metabolism of bifenthrin occurs primarily via oxidative pathway with relatively lesser contribution (~30%) from hydrolytic pathway in both rat and human liver microsomes. The CLint values for bifenthrin, determined by monitoring the consumption of substrate, in juvenile and adult rat liver microsomes fortified with NADPH were 42.0±7.2 and 166.7±20.5μL/min/mg, respectively, and the corresponding values for human liver microsomes were 76.0±4.0 and 21.3±1.2μL/min/mg, respectively. The data suggest a major species difference in the age dependent metabolism of bifenthrin. In human liver microsomes, bifenthrin is metabolized at a much higher rate in juveniles than in adults, while the opposite appears to be true in rat liver microsomes.

      PubDate: 2017-11-18T08:53:15Z
       
  • Trichloroethylene metabolite S-(1,2-dichlorovinyl)-l-cysteine induces
           lipid peroxidation-associated apoptosis via the intrinsic and extrinsic
           apoptosis pathways in a first-trimester placental cell line
    • Authors: Elana R. Elkin; Sean M. Harris; Rita Loch-Caruso
      Abstract: Publication date: Available online 10 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Elana R. Elkin, Sean M. Harris, Rita Loch-Caruso
      Trichloroethylene (TCE), a prevalent environmental contaminant, is a potent renal and hepatic toxicant through metabolites such as S-(1, 2-dichlorovinyl)-l-cysteine (DCVC). However, effects of TCE on other target organs such as the placenta have been minimally explored. Because elevated apoptosis and lipid peroxidation in placenta have been observed in pregnancy morbidities involving poor placentation, we evaluated the effects of DCVC exposure on apoptosis and lipid peroxidation in a human extravillous trophoblast cell line, HTR-8/SVneo. We exposed the cells in vitro to 10–100μM DCVC for various time points up to 24h. Following exposure, we measured apoptosis using flow cytometry, caspase activity using luminescence assays, gene expression using qRT-PCR, and lipid peroxidation using a malondialdehyde quantification assay. DCVC significantly increased apoptosis in time- and concentration-dependent manners (p<0.05). DCVC also significantly stimulated caspase 3, 7, 8 and 9 activities after 12h (p<0.05), suggesting that DCVC stimulates the activation of both the intrinsic and extrinsic apoptotic signaling pathways simultaneously. Pre-treatment with the tBID inhibitor Bl-6C9 partially reduced DCVC-stimulated caspase 3 and 7 activity, signifying crosstalk between the two pathways. Additionally, DCVC treatment increased lipid peroxidation in a concentration-dependent manner. Co-treatment with the antioxidant peroxyl radical scavenger (±)-α-tocopherol attenuated caspase 3 and 7 activity, suggesting that lipid peroxidation mediates DCVC-induced apoptosis in extravillous trophoblasts. Our findings suggest that DCVC-induced apoptosis and lipid peroxidation in extravillous trophoblasts could contribute to poor placentation if similar effects occur in vivo in response to TCE exposure, indicating that further studies into this mechanism are warranted.
      Graphical abstract image

      PubDate: 2017-11-11T10:58:30Z
      DOI: 10.1016/j.taap.2017.11.006
       
  • Deferiprone inhibits iron overload-induced tissue factor bearing
           endothelial microparticle generation by inhibition oxidative stress
           induced mitochondrial injury, and apoptosis
    • Authors: Shing Chan; Qizhou Lian; Mei-Pian Chen; Dan Jiang; Jolie T.K. Ho; Yiu-Fai Cheung; Godfrey C.F. Chan
      Abstract: Publication date: Available online 10 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Shing Chan, Qizhou Lian, Mei-Pian Chen, Dan Jiang, Jolie T.K. Ho, Yiu-Fai Cheung, Godfrey C.F. Chan
      Iron overload-induced cardiovascular toxicity is one of the most common causes of morbidity and mortality in beta-thalassemia major patients. We have previously shown that iron overload-induced systemic arterial changes characterized by endothelial dysfunction are associated with increased endothelial microparticle (EMP) release. In this study, we further demonstrate how EMP release is associated with iron-induced mitochondrial injury and apoptosis of endothelial cells. Iron increased the production of reactive oxygen species (ROS) and calcium influx into mitochondria [Ca2+]m. Iron also disturbed mitochondrial respiration function and eventually led to loss of mitochondrial membrane potential (ΔΨm). A significant increase in apoptotic cells and EMPs were found under iron treatment. EMPs contained tissue factor (TF), which has potential clinical impact on thromboembolic phenomenon. Then, we investigated the salvaging effect of deferiprone (L1) on endothelial cell damage and EMP release. We found that L1 could inhibit iron-induced ROS generation, and decrease mitochondrial damage with the resultant effect of less endothelial cell apoptosis and EMP release. L1 could protect endothelial cells from iron-induced toxic effects and minimize EMP release, which could be potentially helpful in a subgroup of thalassemia patients who have increased thromboembolic complications.

      PubDate: 2017-11-11T10:58:30Z
      DOI: 10.1016/j.taap.2017.11.005
       
  • An anti-inflammatory chalcone derivative prevents heart and kidney from
           hyperlipidemia-induced injuries by attenuating inflammation
    • Authors: Xiong Chen; Weihui Yu; Weixin Li; Hailing Zhang; Weijian Huang; Jingying Wang; Weiwei Zhu; Qilu Fang; Chao Chen; Xiaokun Li; Guang Liang
      Abstract: Publication date: Available online 8 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Xiong Chen, Weihui Yu, Weixin Li, Hailing Zhang, Weijian Huang, Jingying Wang, Weiwei Zhu, Qilu Fang, Chao Chen, Xiaokun Li, Guang Liang
      Obesity is a growing pandemic in both developed and developing countries. Lipid overload in obesity generates a chronic, low-grade inflammation state. Increased inflammation in heart and renal tissues has been shown to promote the progression of heart and renal damage in obesity. Previously, we found that a novel chalcone derivative, L6H21, inhibited lipopolysaccharide-induced inflammatory response. In the present study, we investigated the effects of L6H21 on inflammatory responses in culture and in animal models of lipid overload. We utilized palmitic acid (PA) challenging in mouse peritoneal macrophages and apolipoprotein E knockout (ApoE−/−) mice fed a high fat diet (HFD) to study whether L6H21 mitigates the inflammatory response. Our studies show that L6H21 significantly reduced PA-induced expression of inflammatory cytokines in macrophages by inhibiting mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NFκB) signaling pathways. L6H21 also reduced fibrosis in the kidney and heart tissues, and indices of inflammatory response in the ApoE−/− mice fed a HFD. These effects in vivo were also associated with inhibition of MAPK and NFκB signaling by L6H21. These findings strongly suggest that L6H21 may be a potential agent for high fat diet-induced injuries in heart and kidney.

      PubDate: 2017-11-11T10:58:30Z
      DOI: 10.1016/j.taap.2017.11.003
       
  • H2S protects lipopolysaccharide-induced inflammation by blocking NFκB
           transactivation in endothelial cells
    • Authors: Caitlyn Bourque; Yanjie Zhang; Ming Fu; Mélanie Racine; Adam Greasley; Yanxi Pei; Lingyun Wu; Rui Wang; Guangdong Yang
      Abstract: Publication date: Available online 8 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Caitlyn Bourque, Yanjie Zhang, Ming Fu, Mélanie Racine, Adam Greasley, Yanxi Pei, Lingyun Wu, Rui Wang, Guangdong Yang
      Hydrogen sulfide (H2S) is a novel gasotransmitter and acts as a multifunctional regulator in various cellular functions. Past studies have demonstrated a significant role of H2S and its generating enzyme cystathionine gamma-lyase (CSE) in the cardiovascular system. Lipopolysaccharide (LPS), a major pathogenic factor, is known to initiate the inflammatory immune response. The cross talk between LPS-induced inflammation and the CSE/H2S system in vascular cells has not yet been elucidated in detail. Here we showed that LPS decreased CSE mRNA and protein expression in human endothelial cells and blocked H2S production in mouse aorta tissues. Transfection of the cells with TLR4-specific siRNA knockdown TLR4 mRNA expression and abolished the inhibitory role of LPS on CSE expression. Higher dose of LPS (100μg/mL) decreased cell viability, which was reversed by exogenously applied H2S at physiologically relevant concentration (30μM). Lower dose of LPS (10μg/ml) had no effect on cell viability, but significantly induced inflammation gene expressions and cytokines secretion and stimulated cell hyper-permeability. H2S treatment prevented LPS-induced inflammation and hyper-permeability. Lower VE-cadherin expression in LPS-incubated cells would contribute to cell hyper-permeability, which was reversed by H2S co-incubation. In addition, H2S treatment blocked LPS-induced NFκB transactivation. We further validated that LPS-induced hyper-permeability was reversed by CSE overexpression but further deteriorated by CRISPR/Cas9-mediated knockout of CSE. In vivo, deficiency of CSE sensitized the mice to LPS-induced inflammation in vascular tissues. Take together, these data suggest that CSE/H2S system protects LPS-induced inflammation and cell hyper-permeability by blocking NFκB transactivation.
      Graphical abstract image

      PubDate: 2017-11-11T10:58:30Z
      DOI: 10.1016/j.taap.2017.11.004
       
  • Temporal cytokine and lymphoid responses to an inhaled TLR7 antedrug
           agonist in the cynomolgus monkey demonstrates potential safety and
           tolerability of this approach
    • Authors: John Bell; Mike Dymond; Mark Biffen; Stephen Delaney; David Keeling; Hui Zhang; Ian Robinson
      Abstract: Publication date: Available online 6 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): John Bell, Mike Dymond, Mark Biffen, Stephen Delaney, David Keeling, Hui Zhang, Ian Robinson
      AZD8848 is a TLR7 agonist antedrug developed for administration by inhalation dosing for the treatment of allergic diseases, such as asthma. Allergic asthma is associated with increased levels of Th2 cytokines which are suppressed for extended periods by TLR7 agonists in a number of preclinical models of allergic airway inflammation. However, TLRs form a central part of innate immunity and their activation often results in proinflammatory responses. Whilst AZD8848's antedrug mechanism is designed to restrict its pharmacological action beyond the lung, the effect of chronic, supramaximal dosing to the target tissue has yet to be defined. To support clinical development of this potentially disease modifying approach the nonclinical safety and pharmacodynamics of AZD8848 were evaluated in cynomolgus monkeys in studies examining single or multiple weekly inhaled doses. Here we show that following a single dose nearly all responses returned to baseline within a week. During multiple dosing serum biomarkers were quantified over the dosing period and indicated a limited systemic response. The dose at which maximal interferon responses were seen was dependent on dose. Thorough histopathological examination revealed a dose related increase of size and cells of lymphoid tissues in the lung and nose. Local lymphoid responses were recovered after the treatment free period. These studies are the first to evaluate safety of an inhaled TLR7 agonist and demonstrate AZD8848 is safe with a no observed adverse effect level at 26μg/kg allowing progression to man with weekly inhalation dosing.

      PubDate: 2017-11-11T10:58:30Z
      DOI: 10.1016/j.taap.2017.11.002
       
  • Effects of Nrf2 deficiency on arsenic metabolism in mice
    • Authors: Huihui Wang; Jiayu Zhu; Lu Li; Yongfang Li; Hang Lv; Yuanyuan Xu; Guifan Sun; Jingbo Pi
      Abstract: Publication date: Available online 3 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Huihui Wang, Jiayu Zhu, Lu Li, Yongfang Li, Hang Lv, Yuanyuan Xu, Guifan Sun, Jingbo Pi
      Inorganic arsenic (iAs) is a known toxicant and carcinogen. Worldwide arsenic exposure has become a threat to human health. The severity of arsenic toxicity is strongly correlated with the speed of arsenic metabolism (methylation) and clearance. Furthermore, oxidative stress is recognized as a major mechanism for arsenic-induced toxicity. Nuclear factor-E2-related factor 2 (Nrf2), a key regulator in cellular adaptive antioxidant response, is clearly involved in alleviation of arsenic-induced oxidative damage. Multiple studies demonstrate that Nrf2 deficiency mice are more vulnerable to arsenic-induced intoxication. However, what effect Nrf2 deficiency might have on arsenic metabolism in mice is still unknown. In the present study, we measured the key enzymes involved in arsenic metabolism in Nrf2-WT and Nrf2-KO mice. Our results showed that basal transcript levels of glutathione S-transferase omega 2 (Gsto2) were significantly higher and GST mu 1 (Gstm1) lower in Nrf2-KO mice compared to Nrf2-WT control. Arsenic speciation and methylation rate in liver and urine was then studied in mice treated with 5mg/kg sodium arsenite for 12h. Although there were some alterations in arsenic metabolism enzymes between Nrf2-WT and Nrf2-KO mice, the Nrf2 deficiency had no significant effect on arsenic methylation. These results suggest that the Nrf2-KO mice are more sensitive to arsenic than Nrf2-WT mainly because of differences in adaptive antioxidant detoxification capacity rather than arsenic methylation capacity.

      PubDate: 2017-11-05T10:38:21Z
      DOI: 10.1016/j.taap.2017.11.001
       
  • Oxytocin inhibits ox-LDL-induced adhesion of monocytic THP-1 cells to
           human brain microvascular endothelial cells
    • Authors: Shuyan Liu; Shengying Pan; Jing Tan; Weina Zhao; Fengguo Liu
      Abstract: Publication date: Available online 2 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Shuyan Liu, Shengying Pan, Jing Tan, Weina Zhao, Fengguo Liu
      The attachment of monocytes to human brain microvascular endothelial cells (HBMVEs) caused by oxidized low-density lipoprotein (ox-LDL) is associated with an early event and the pathological progression of cerebrovascular diseases. Oxytocin (OT) is a human peptide hormone that is traditionally used as a medication to facilitate childbirth. However, little information is available regarding the physiological function of OT in brain endothelial dysfunction. In the present study, our results indicate that the oxytocin receptor (OTR) was expressed in human brain microvascular endothelial cells (HBMVEs) and was upregulated in response to ox-LDL in a concentration-dependent manner. Notably, OT significantly suppressed ox-LDL-induced attachment of THP-1 monocytes to HBMVEs. Furthermore, we found that OT reduced the expression of adhesion molecules, such as VCAM-1 and E-selectin. Interestingly, it was shown that OT could restore ox-LDL-induced reduction of KLF4 in HBMVEs. Importantly, knockdown of KLF4 abolished the inhibitory effects of OT on ox-LDL-induced expressions of VCAM-1 and E-selectin as well as the adhesion of human monocytic THP-1 cells to endothelial HBMVEs. Mechanistically, we found that the stimulatory effects of OT on KLF4 expression are mediated by the MEK5/MEF2A pathway.

      PubDate: 2017-11-05T10:38:21Z
      DOI: 10.1016/j.taap.2017.10.022
       
  • Effects of acute exposure to chlorpyrifos on cholinergic and
           non-cholinergic targets in normal and high-fat fed male C57BL/6J mice
    • Authors: Sandeep Kondakala; Jung Hwa Lee; Matthew K. Ross; George E. Howell
      Abstract: Publication date: Available online 31 October 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Sandeep Kondakala, Jung Hwa Lee, Matthew K. Ross, George E. Howell
      The prevalence of obesity is increasing at an alarming rate in the United States with 36.5% of adults being classified as obese. Compared to normal individuals, obese individuals have noted pathophysiological alterations which may alter the toxicokinetics of xenobiotics and therefore alter their toxicities. However, the effects of obesity on the toxicity of many widely utilized pesticides has not been established. Therefore, the present study was designed to determine if the obese phenotype altered the toxicity of the most widely used organophosphate (OP) insecticide, chlorpyrifos (CPS). Male C57BL/6J mice were fed normal or high-fat diet for 4weeks and administered a single dose of vehicle or CPS (2.0mg/kg; oral gavage) to assess cholinergic (acetylcholinesterase activities) and non-cholinergic (carboxylesterase and endocannabinoid hydrolysis) endpoints. Exposure to CPS significantly decreased red blood cell acetylcholinesterase (AChE) activity, but not brain AChE activity, in both diet groups. Further, CPS exposure decreased hepatic carboxylesterase activity and hepatic hydrolysis of a major endocannabinoid, anandamide, in a diet-dependent manner with high-fat diet fed animals being more sensitive to CPS-mediated inhibition. These in vivo studies were corroborated by in vitro studies using rat primary hepatocytes, which demonstrated that fatty acid amide hydrolase and CES activities were more sensitive to CPS-mediated inhibition than 2-arachidonoylglycerol hydrolase activity. These data demonstrate hepatic CES and FAAH activities in high-fat diet fed mice were more potently inhibited than those in normal diet fed mice following CPS exposure, which suggests that the obese phenotype may exacerbate some of the non-cholinergic effects of CPS exposure.

      PubDate: 2017-11-05T10:38:21Z
      DOI: 10.1016/j.taap.2017.10.019
       
  • 6-Hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside potentiates the
           anti-proliferative effect of interferon α/β by promoting activation of
           the JAK/STAT signaling by inhibiting SOCS3 in hepatocellular carcinoma
           cells
    • Authors: Orawan Wonganan; Yu-jiao He; Xiao-fei Shen; Kanjana Wongkrajang; Apichart Suksamrarn; Guo-lin Zhang; Fei Wang
      Abstract: Publication date: Available online 12 October 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Orawan Wonganan, Yu-jiao He, Xiao-fei Shen, Kanjana Wongkrajang, Apichart Suksamrarn, Guo-lin Zhang, Fei Wang
      Suppressor of cytokine signaling 3 (SOCS3) is a key negative regulator of type I interferon (IFN α/β) signaling. Inhibition of SOCS3 by small molecules may be a new strategy to enhance the efficacy of type I IFN and reduce its side effects. We established a cell-based screening assay using human hepatoma HepG2 cells stably transfected with a plasmid wherein the luciferase reporter activity was propelled by interferon α-stimulated response element (ISRE), which is a motif specifically recognized by type I IFN-induced activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. After screening our chemical library, 6-hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside (K6G) was identified to be a potent activator of type I IFN with EC50 value of 3.33±0.04μM. K6G enhanced the phosphorylation of JAK1, Tyk2, and STAT1/2 but decreased the phosphorylation of STAT3. K6G also promoted endogenous IFN-α-regulated genes expression. More interestingly, K6G significantly decreased the expression of SOCS3 without affecting the expression of SOCS1. Furthermore, K6G enhanced the anti-proliferative effect of IFN-α on hepatocellular carcinoma (HCC) cells. These results suggested that K6G potentiated the inhibitory effect of IFN-α on HCC cell proliferation through activation of the JAK/STAT signaling pathway by inhibiting SOCS3 expression. K6G warrants further investigation as a novel therapeutic method to enhance the efficacy of IFN-α/β.

      PubDate: 2017-10-14T02:12:11Z
      DOI: 10.1016/j.taap.2017.10.004
       
  • Arginine methyltransferase inhibitor 1 inhibits gastric cancer by
           downregulating eIF4E and targeting PRMT5
    • Authors: Baolai Zhang; Zhang Lijuan Zhu Xue Chen Yunfeng Zhao Chao
      Abstract: Publication date: Available online 4 October 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Baolai Zhang, Su Zhang, Lijuan Zhu, Xue Chen, Yunfeng Zhao, Li Chao, Juanping Zhou, Xing Wang, Xinyang Zhang, Nengqian Ma
      Arginine methylation is carried out by protein arginine methyltransferase (PRMTs) family. Arginine methyltransferase inhibitor 1 (AMI-1) is mainly used to inhibit type I PRMT activity in vitro. However, the effects of AMI-1 on type II PRMT5 activity and gastric cancer (GC) remain unclear. In this study, we provided the first evidence that AMI-1 significantly inhibited GC cell proliferation and migration while induced GC cell apoptosis, and reduced the expression of PRMT5, eukaryotic translation initiation factor 4E (eIF4E), symmetric dimethylation of histone 3 (H3R8me2s) and histone 4 (H4R3me2s). In addition, AMI-1 inhibited tumor growth, downregulated eIF4E, H4R3me2s and H3R8me2s expression in mice xenografts model of GC. Collectively, our results suggest that AMI-1 inhibits GC by downregulating eIF4E and targeting type II PRMT5.

      PubDate: 2017-10-08T11:22:08Z
       
 
 
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