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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.429]   [H-I: 117]   [17 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [2969 journals]
  • Chemopreventive Effect and Angiogenic Activity of Punicalagin Isolated
           from Leaves of Lafoensia pacari A. St.-Hil.
    • Abstract: Publication date: Available online 18 August 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Cristiene Costa Carneiro, Suzana da Costa Santos, Ruy de Souza Lino Junior, Maria Teresa Freitas Bara, Beatriz Abdallah Chaibub, Paulo Roberto de Melo Reis, Dwight Assis Chaves, Antônio Jorge Ribeiro da Silva, Luana Santos Silva, Daniela de Melo e Silva, Lee Chen-Chen
      Punicalagin is the major ellagitannin constituent from leaves of Lafoensia pacari, a Brazilian medicinal plant widely used for the treatment of peptic ulcer and wound healing. Genotoxic, cytotoxic, antigenotoxic, and anticytotoxic effects of punicalagin were assessed using micronucleus (MN) test and comet assay in mice. Due to the extensive use of L. pacari in the wound healing process, we also assessed the angiogenic activity of punicalagin using the chick chorioallantoic membrane (CAM) angiogenic assay. The highest dose of punicalagin (50mg/kg) showed significant cytotoxic effect by MN test and in the co-treatment with cyclophosphamide (CPA), this cytotoxicity was enhanced. Co-treatment, pre-treatment and post-treatment of punicalagin with CPA led to a significant reduction in the number of DNA breaks and in the frequency of CPA-induced MN, indicating antigenotoxic effect. Using the CAM model, punicalagin exhibited angiogenic activity in all doses mainly at the lowest concentration (12.5μg/μL). Therefore, these findings indicate an effective chemopreventive role of punicalagin and a high capacity to induce DNA repair. Also, the angiogenic activity presented by punicalagin in this study could contribute for the processes of tissue repairing and wound healing.


      PubDate: 2016-08-22T11:20:20Z
       
  • Toxicology and Applied Pharmacology (TAAP): Building on the past for the
           new science of the twenty-first century
    • Abstract: Publication date: Available online 20 August 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lawrence H. Lash, Larry Lash



      PubDate: 2016-08-22T11:20:20Z
       
  • PKC-alpha modulation by miR-483-3p in platinum-resistant ovarian carcinoma
           cells
    • Abstract: Publication date: Available online 20 August 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Noemi Arrighetti, Giacomo Cossa, Loris De Cecco, Simone Stucchi, Nives Carenini, Elisabetta Corna, Paolo Gandellini, Nadia Zaffaroni, Paola Perego, Laura Gatti
      The occurrence of drug resistance limits the efficacy of platinum compounds in the cure of ovarian carcinoma. Since microRNAs (miRNAs) may contribute to this phenomenon by regulating different aspects of tumor cell response, the aim of this study was to exploit the analysis of expression of miRNAs in platinum sensitive/resistant cells in an attempt to identify potential regulators of drug response. MiR-483-3p, which may participate in apoptosis and cell proliferation regulation, was found up-regulated in 4 platinum resistant variants, particularly in the IGROV-1/Pt1 subline, versus parental cells. Transfection of a synthetic precursor of miR-483-3p in IGROV-1 parental cells elicited a marked up-regulation of the miRNA levels. Growth-inhibition and colony-forming assays indicated that miR-483-3p over-expression reduced cell growth and conferred mild levels of cisplatin resistance in IGROV-1 cells, by interference with their proliferative potential. Predicted targets of miR-483-3p included PRKCA (encoding PKC-alpha), previously reported to be associated to platinum-resistance in ovarian carcinoma. We found that miR-483-3p directly targeted PRKCA in IGROV-1 cells. In keeping with this finding, cisplatin sensitivity of IGROV-1 cells decreased upon molecular/pharmacological inhibition of PKC-alpha. Overall, our results suggest that overexpression of miR-483-3p by ovarian carcinoma platinum-resistant cells may interfere with their proliferation, thus protecting them from DNA damage induced by platinum compounds and ultimately representing a drug-resistance mechanism. The impairment of cell growth may account for low levels of drug resistance that could be relevant in the clinical setting.
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      PubDate: 2016-08-22T11:20:20Z
       
  • Destabilization of mitochondrial functions as a target against breast
           cancer progression: Role of TPP+-linked-polyhydroxybenzoates
    • Abstract: Publication date: Available online 20 August 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Cristian Sandoval-Acuña, Sebastián Fuentes-Retamal, Daniela Guzmán-Rivera, Liliana Peredo-Silva, Matías Madrid-Rojas, Solange Rebolledo, Vicente Castro-Castillo, Mario Pavani, Mabel Catalán, Juan Diego Maya, José A. Jara, Eduardo Parra, Gloria M. Calaf, Hernán Speisky, Jorge Ferreira
      Mitochondrion is an accepted molecular target in cancer treatment since it exhibits a higher transmembrane potential in cancer cells, making it susceptible to be targeted by lipophilic-delocalized cations of triphenylphosphonium (TPP+). Thus, we evaluated five TPP+-linked decyl polyhydroxybenzoates as potential cytotoxic agents in several human breast cancer cell lines that differ in estrogen receptor and HER2/neu expression, and in metabolic profile. Results showed that all cell lines tested were sensitive to the cytotoxic action of these compounds. The mechanism underlying the cytotoxicity would be triggered by their weak uncoupling effect on the oxidative phosphorylation system, while having a wider and safer therapeutic range than other uncouplers and a significant lowering in transmembrane potential. Noteworthy, while the TPP+-derivatives alone led to almost negligible losses of ATP, when these were added in the presence of an AMP-activated protein kinase inhibitor, the levels of ATP fell greatly. Overall, data presented suggest that decyl polyhydroxybenzoates-TPP+ and its derivatives warrant future investigation as potential anti-tumor agents.
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      PubDate: 2016-08-22T11:20:20Z
       
  • Triptolide disrupts the actin-based Sertoli-germ cells adherens junctions
           by inhibiting Rho GTPases expression
    • Abstract: Publication date: Available online 21 August 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Xiang Wang, Fang Zhao, Zhong-ming Lv, Wei-qin Shi, Lu-yong Zhang, Ming Yan
      Triptolide (TP), derived from the medicinal plant Triterygium wilfordii Hook. f. (TWHF), is a diterpene triepoxide with variety biological and pharmacological activities. However, TP has been restricted in clinical application due to its narrow therapeutic window especially in reproductive system. During spermatogenesis, Sertoli cell cytoskeleton plays an essential role in facilitating germ cell movement and cell-cell actin-based adherens junctions (AJ). At Sertoli cell-spermatid interface, the anchoring device is a kind of AJ, known as ectoplasmic specializations (ES). In this study, we demonstrate that β-actin, an important component of cytoskeleton, has been significantly down-regulated after TP treatment. TP can inhibit the expression of Rho GTPase such as, RhoA, RhoB, Cdc42 and Rac1. Downstream of Rho GTPase, Rho-associated protein kinase (ROCKs) gene expressions were also suppressed by TP. F-actin immunofluorescence proved that TP disrupts Sertoli cells cytoskeleton network. As a result of β-actin down-regulation, TP treatment increased expression of testin, which indicating ES has been disassembled. In summary, this report illustrates that TP induces cytoskeleton dysfunction and disrupts cell-cell adherens junctions via inhibition of Rho GTPases.


      PubDate: 2016-08-22T11:20:20Z
       
  • Chlorpyrifos- and chlorpyrifos oxon-induced neurite retraction in
           pre-differentiated N2a cells is associated with transient
           hyperphosphorylation of neurofilament heavy chain and ERK 1/2
    • Abstract: Publication date: 1 October 2016
      Source:Toxicology and Applied Pharmacology, Volume 308
      Author(s): Ramya A. Sindi, Wayne Harris, Gordon Arnott, John Flaskos, Chris Lloyd Mills, Alan J. Hargreaves
      Chlorpyrifos (CPF) and CPF-oxon (CPO) are known to inhibit neurite outgrowth but little is known about their ability to induce neurite retraction in differentiating neuronal cells. The aims of this study were to determine the ability of these compounds to destabilize neurites and to identify the key molecular events involved. N2a cells were induced to differentiate for 20h before exposure to CPF or CPO for 2–8h. Fixed cell monolayers labeled with carboxyfluorescein succinimidyl ester or immunofluorescently stained with antibodies to tubulin (B512) or phosphorylated neurofilament heavy chain (Ta51) showed time- and concentration-dependent reductions in numbers and length of axon-like processes compared to the control, respectively, retraction of neurites being observed within 2h of exposure by live cell imaging. Neurofilament disruption was also observed in treated cells stained by indirect immunofluorescence with anti-phosphorylated neurofilament heavy chain (NFH) monoclonal antibody SMI34, while the microtubule network was unaffected. Western blotting analysis revealed transiently increased levels of reactivity of Ta51 after 2h exposure and reduced levels of reactivity of the same antibody following 8h treatment with both compounds, whereas reactivity with antibodies to anti-total NFH or anti-tubulin was not affected. The alteration in NFH phosphorylation at 2h exposure was associated with increased activation of extracellular signal-regulated protein kinase ERK 1/2. However, increased levels of phosphatase activity were observed following 8h exposure. These findings suggest for the first time that organophosphorothionate pesticide-induced neurite retraction in N2a cells is associated with transient increases in NFH phosphorylation and ERK1/2 activation.


      PubDate: 2016-08-22T11:20:20Z
       
  • Editorial Board
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307




      PubDate: 2016-08-22T11:20:20Z
       
  • Contents
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307




      PubDate: 2016-08-22T11:20:20Z
       
  • 6-Shogaol, an active compound of ginger, alleviates allergic
           dermatitis-like skin lesions via cytokine inhibition by activating the
           Nrf2 pathway
    • Abstract: Publication date: Available online 22 August 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Gunhyuk Park, Dal-Seok Oh, Mi Gi Lee, Chang Eon Lee, Yong-ung Kim
      Allergic dermatitis (AD) clinically presents with skin erythematous plaques, eruption, and elevated serum IgE, and T helper cell type 2 and 1 (Th2 and Th1) cytokine levels. 6-Shogaol [1-(4-hydroxy-methoxyphenyl)-4-decen-one], a pungent compound isolated from ginger, has shown anti-inflammatory effects, but its inhibitory effects on AD are unknown. The aim of this study was to examine whether 6-shogaol inhibits AD-like skin lesions and their underlying mechanism in vivo and in vitro. An AD-like response was induced by tumor necrosis factor-α (TNF-α)+IFN-γ in human keratinocytes or by 2,4-dinitrochlorobenzene (DNCB) in mice. In vivo, 6-shogaol inhibited the development of DNCB-induced AD-like skin lesions and scratching behavior, and showed significant reduction in Th2/1-mediated inflammatory cytokines, IgE, TNF-α, IFN-γ, thymus and activation-regulated chemokine, IL-1, 4, 12, and 13, cyclooxygenase-2, and nitric oxide synthase levels. In vitro, 6-shogaol inhibited reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) signaling, and increased the levels of total glutathione, heme oxygenase-1, and quinone 1 via nuclear factor erythroid 2 related factor 2 (Nrf2) activation. 6-shogaol can alleviate AD-like skin lesions by inhibiting immune mediators via regulating the ROS/MAPKs/Nrf2 signaling pathway, and may be an effective alternative therapy for AD.
      Graphical abstract image

      PubDate: 2016-08-22T11:20:20Z
       
  • Phenotypically anchored transcriptome profiling of developmental exposure
           to the antimicrobial agent, triclosan, reveals hepatotoxicity in embryonic
           zebrafish
    • Abstract: Publication date: 1 October 2016
      Source:Toxicology and Applied Pharmacology, Volume 308
      Author(s): Derik E. Haggard, Pamela D. Noyes, Katrina M. Waters, Robert L. Tanguay
      Triclosan (TCS) is an antimicrobial agent commonly found in a variety of personal care products and cosmetics. TCS readily enters the environment through wastewater and is detected in human plasma, urine, and breast milk due to its widespread use. Studies have implicated TCS as a disruptor of thyroid and estrogen signaling; therefore, research examining the developmental effects of TCS is warranted. In this study, we used embryonic zebrafish to investigate the developmental toxicity and potential mechanism of action of TCS. Embryos were exposed to graded concentrations of TCS from 6 to 120hours post-fertilization (hpf) and the concentration where 80% of the animals had mortality or morbidity at 120hpf (EC80) was calculated. Transcriptomic profiling was conducted on embryos exposed to the EC80 (7.37μM). We identified a total of 922 significant differentially expressed transcripts (FDR adjusted P-value≤0.05; fold change ≥2). Pathway and gene ontology enrichment analyses identified biological networks and transcriptional hubs involving normal liver functioning, suggesting TCS may be hepatotoxic in zebrafish. Tissue-specific gene enrichment analysis further supported the role of the liver as a target organ for TCS toxicity. We also examined the in vitro bioactivity profile of TCS reported by the ToxCast screening program. TCS had a diverse bioactivity profile and was a hit in 217 of the 385 assay endpoints we identified. We observed similarities in gene expression and hepatic steatosis assays; however, hit data for TCS were more concordant with the hypothesized CAR/PXR activity of TCS from rodent and human in vitro studies.


      PubDate: 2016-08-22T11:20:20Z
       
  • SHP-1 is Directly Activated by the Aryl Hydrocarbon Receptor and regulates
           BCL-6 in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
    • Abstract: Publication date: Available online 18 August 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Ashwini S. Phadnis-Moghe, Jinpeng Li, Robert B. Crawford, Norbert E. Kaminski
      The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a strong AHR agonist, causes significant suppression of human B cell activation and differentiation. The current studies describe the identification of Src homology phosphatase 1 (SHP-1) encoded by the gene PTPN6 as a putative regulator of TCDD-mediated suppression of B cell activation. Shp-1 was initially identified through a genome-wide analysis of AHR binding in mouse B cells in the presence of TCDD. The binding of AHR to the PTPN6 promoter was further confirmed using electrophoretic mobility shift assays in which, specific binding of AHR was detected at four putative DRE sites within PTPN6 promoter. Time-course measurements performed in human B cells highlighted a significant increase in SHP-1 mRNA and protein levels in the presence of TCDD. The changes in the protein levels of SHP-1 were also observed in a TCDD concentration-dependent manner. The increase in SHP-1 levels was also seen to occur due to a change in early signaling events in the presence of TCDD. We have shown that BCL-6 regulates B cell activation by repressing activation marker CD80 in the presence of TCDD. TCDD-treatment led to a significant increase in the double positive (SHP-1hi BCL-6hi) population. Interestingly, treatment of naïve human B cells with SHP-1 inhibitor decreased BCL-6 protein levels suggesting possible regulation of BCL-6 by SHP-1 for the first time. Collectively, these results suggest that SHP-1 is regulated by AHR in presence of TCDD and may, in part through BCL-6, regulate TCDD-mediated suppression of human B cell activation.


      PubDate: 2016-08-18T10:57:17Z
       
  • Chronic plus binge ethanol exposure causes more severe pancreatic injury
           and inflammation
    • Abstract: Publication date: 1 October 2016
      Source:Toxicology and Applied Pharmacology, Volume 308
      Author(s): Zhenhua Ren, Fanmuyi Yang, Xin Wang, Yongchao Wang, Mei Xu, Jacqueline A. Frank, Zun-ji Ke, Zhuo Zhang, Xianglin Shi, Jia Luo
      Alcohol abuse increases the risk for pancreatitis. The pattern of alcohol drinking may impact its effect. We tested a hypothesis that chronic ethanol consumption in combination with binge exposure imposes more severe damage to the pancreas. C57BL/6 mice were divided into four groups: control, chronic ethanol exposure, binge ethanol exposure and chronic plus binge ethanol exposure. For the control group, mice were fed with a liquid diet for two weeks. For the chronic ethanol exposure group, mice were fed with a liquid diet containing 5% ethanol for two weeks. In the binge ethanol exposure group, mice were treated with ethanol by gavage (5g/kg, 25% ethanol w/v) daily for 3days. For the chronic plus binge exposure group, mice were fed with a liquid diet containing 5% ethanol for two weeks and exposed to ethanol by gavage during the last 3days. Chronic and binge exposure alone caused minimal pancreatic injury. However, chronic plus binge ethanol exposure induced significant apoptotic cell death. Chronic plus binge ethanol exposure altered the levels of alpha-amylase, glucose and insulin. Chronic plus binge ethanol exposure caused pancreatic inflammation which was shown by the macrophages infiltration and the increase of cytokines and chemokines. Chronic plus binge ethanol exposure increased the expression of ADH1 and CYP2E1. It also induced endoplasmic reticulum stress which was demonstrated by the unfolded protein response. In addition, chronic plus binge ethanol exposure increased protein oxidation and lipid peroxidation, indicating oxidative stress. Therefore, chronic plus binge ethanol exposure is more detrimental to the pancreas.


      PubDate: 2016-08-18T10:57:17Z
       
  • Role of necroptosis in autophagy signaling during hepatic ischemia and
           reperfusion
    • Abstract: Publication date: 1 October 2016
      Source:Toxicology and Applied Pharmacology, Volume 308
      Author(s): Jeong-Min Hong, Seok-Joo Kim, Sun-Mee Lee
      Ischemia and reperfusion (I/R) is a complex phenomenon involving massive inflammation and cell death. Necroptosis refers to a newly described cell death as “programmed necrosis” that is controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, which is involved in the pathogenesis of several inflammatory diseases. Autophagy is an essential cytoprotective system that is rapidly activated in response to various stimuli and involves crosstalk between different modes of cell death and inflammation. In this study, we investigated pattern changes in necroptosis and its role in autophagy signaling during hepatic I/R. Male C57BL/6 mice were subjected to 60min of ischemia followed by 3h reperfusion. Necrostatin-1 (Nec-1, a necroptosis inhibitor; 1.65mg/kg) was administered intraperitoneally 5min before reperfusion. Hepatic I/R significantly increased the level of RIP3, phosphorylated RIP1 and RIP3 protein expression, and RIP1/RIP3 necrosome formation, which were attenuated by Nec-1. I/R also significantly increased serum levels of alanine aminotransferase, tumor necrosis factor-α, and interleukin-6, which were attenuated by Nec-1. Meanwhile, hepatic I/R activated autophagy and mitophagy, as evidenced by increased LC3-II, PINK1, and Parkin, and decreased sequestosome 1/p62 protein expression. Nec-1 attenuated these changes and attenuated the increased levels of autophagy-related protein (ATG) 3, ATG7, Rab7, and cathepsin B protein expression during hepatic I/R. Moreover, hepatic I/R activated the extracellular signal-regulated kinase (ERK) pathway, and Nec-1 attenuated this increase. Taken together, our findings suggest that necroptosis contributes to hepatic damage during I/R, which induces autophagy via ERK activation.


      PubDate: 2016-08-18T10:57:17Z
       
  • A simple physiologically based pharmacokinetic model evaluating the effect
           of anti-nicotine antibodies on nicotine disposition in the brains of rats
           and humans
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Kyle Saylor, Chenming Zhang
      Physiologically based pharmacokinetic (PBPK) modeling was applied to investigate the effects of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans. Successful construction of both rat and human models was achieved by fitting model outputs to published nicotine concentration time course data in the blood and in the brain. Key parameters presumed to have the most effect on the ability of these antibodies to prevent nicotine from entering the brain were selected for investigation using the human model. These parameters, which included antibody affinity for nicotine, antibody cross-reactivity with cotinine, and antibody concentration, were broken down into different, clinically-derived in silico treatment levels and fed into the human PBPK model. Model predictions suggested that all three parameters, in addition to smoking status, have a sizable impact on anti-nicotine antibodies' ability to prevent nicotine from entering the brain and that the antibodies elicited by current human vaccines do not have sufficient binding characteristics to reduce brain nicotine concentrations. If the antibody binding characteristics achieved in animal studies can similarly be achieved in human studies, however, nicotine vaccine efficacy in terms of brain nicotine concentration reduction is predicted to meet threshold values for alleviating nicotine dependence.


      PubDate: 2016-08-13T04:31:48Z
       
  • Hepatocyte-protective effect of nectandrin B, a nutmeg lignan, against
           oxidative stress: Role of Nrf2 activation through ERK phosphorylation and
           AMPK-dependent inhibition of GSK-3β
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Jae-Sook Song, Eun-Kyung Kim, Yong-Won Choi, Won Keun Oh, Young-Mi Kim
      Oxidative stress can contribute to the development and progression of liver diseases, such as drug-induced or alcoholic liver injury, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. Nectandrin B is a bioactive lignan isolated from nutmeg extract. To date, little information is available about its pharmacological activities in the liver. This study investigated the hepatocyte-protective effect of nectandrin B against tert-butylhydroperoxide-induced oxidative injury and the underlying molecular mechanism. The cell viability assay revealed that nectandrin B prevents apoptosis stimulated by tert-butylhydroperoxide in both HepG2 cells and primary mouse hepatocytes. Nectandrin B also attenuated ROS production and restored the depleted glutathione level. Real-time PCR and immunoblot analyses showed that the expression of glutamate-cysteine ligase, an enzyme responsible for the glutathione biosynthesis, was induced by nectandrin B, indicating its indirect antioxidative effect. The NF-E2-related factor-2 (Nrf2) regulates gene expression of an array of antioxidant enzymes in hepatocytes. Nectandrin B stimulated Nrf2 activation as evidenced by its enhanced nuclear accumulation and increased antioxidant response element (ARE)-luciferase activity. Intriguingly, the hepatocyte-protective effect of nectandrin B against oxidative damage was completely abrogated by Nrf2 knockdown using Nrf2 specific siRNA. Nectandrin B promoted ERK activation, but inactivated GSK-3β through the AMPK-mediated inhibitory phosphorylation. The enforced overexpression of dominant-negative mutant of MEK1 or AMPKα, or wild-type GSK-3β inhibited the increase in the NQO1-ARE-luciferase activity stimulated by nectandrin B, suggesting that both ERK and AMPK-GSK-3β signalings are involved in the activation of Nrf2/ARE pathway by nectandrin B. Consistent with this, cytoprotection and restoration of glutathione level by nectandrin B was also blocked by the overexpression of dominant-negative MEK1 or wild-type GSK-3β. Finally, our data demonstrate that nectandrin B has the ability to protect hepatocytes against oxidative injury through the activation of Nrf2/ARE pathway mediated by ERK phosphorylation and AMPK-dependent inactivation of GSK-3β.


      PubDate: 2016-08-13T04:31:48Z
       
  • Disruption of motor behavior and injury to the CNS induced by
           3-thienylboronic acid in mice
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): E.D. Farfán-García, M. Pérez-Rodríguez, C. Espinosa-García, N.T. Castillo-Mendieta, M. Maldonado-Castro, E. Querejeta, J.G. Trujillo-Ferrara, M.A. Soriano-Ursúa
      The scarcity of studies on boron containing compounds (BCC) in the medicinal field is gradually being remedied. Efforts have been made to explore the effects of BCCs due to the properties that boron confers to molecules. Research has shown that the safety of some BCCs is similar to that found for boron-free compounds (judging from the acute toxicological evaluation). However, it has been observed that the administration of 3-thienylboronic acid (3TB) induced motor disruption in CD1 mice. In the current contribution we studied in deeper form the disruption of motor performance produced by the intraperitoneal administration of 3TB in mice from two strains (CD1 and C57BL6). Disruption of motor activity was dependent not only on the dose of 3TB administered, but also on the DMSO concentration in the vehicle. The ability of 3TB to enter the Central Nervous System (CNS) was evidenced by Raman spectroscopy as well as morphological effects on the CNS, such as loss of neurons yielding biased injury to the substantia nigra and striatum at doses ≥200mg/kg, and involving granular cell damage at doses of 400mg/kg but less injury in the motor cortex. Our work acquaints about the use of this compound in drug design, but the interesting profile as neurotoxic agent invite us to study it regarding the damage on the motor system.
      Graphical abstract image

      PubDate: 2016-08-09T04:06:59Z
       
  • DEHP exposure in utero disturbs sex determination and is potentially
           linked with precocious puberty in female mice
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Yongan Wang, Qing Yang, Wei Liu, Mingxi Yu, Zhou Zhang, Xiaoyu Cui
      Human's ubiquitous exposure to di (2-ethylhexyl) phthalate (DEHP) is thought to be associated with female reproductive toxicity. Previous studies found that DEHP inhibited follicle growth and decreased estradiol levels in adult female mice. However, limited information is available on the link between in utero DEHP exposure and ovarian development in female mouse offspring. The present study evaluates the disturbances in regulatory genes involved in female sex determination and the ovarian outcomes in fetal and postnatal female mice treated with in utero DEHP exposure. Pregnant mice were exposed to DEHP by gavage, with the dosage regime beginning at human relevant exposure levels. After in utero DEHP exposure, increased follicular atresia was observed in the female pups at postnatal days (PND) 21. Foxl2 expression was significantly upregulated, and Fst was significantly downregulated by DEHP above 2mg/kg/d at PND 1 and 21. This suggests that lesion of granulosa cell differentiation and disturbance of follicle development in postnatal female mice. The expression of Cyp11a1 and Star were significantly downregulated by in utero DEHP exposure, indicating effects on estradiol biosynthesis. The female sex determination pathway was disturbed in fetus by DEHP at 2mg/kg/d and above during the critical time window of sex determination causing significant upregulation of Foxl2, Wnt4, β-catenin and Fst. Furthermore, the increased expression of Wnt4 was supported by whole-mount in situ hybridization (WISH). These results suggest a possible association between in utero DEHP exposure and precocious puberty in the postnatal life of mice offspring, where disturbance of the sex determination regulating pathway acted as an important mechanism.


      PubDate: 2016-08-09T04:06:59Z
       
  • Andrographolide inhibits adipogenesis of 3T3-L1 cells by suppressing
           C/EBPβ expression and activation
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Ching-Chu Chen, Wei-Ting Chuang, Ai-Hsuan Lin, Chia-Wen Tsai, Chin-Shiu Huang, Yun-Ting Chen, Haw-Wen Chen, Chong-Kuei Lii
      Andrographolide, a diterpenoid, is the most abundant terpenoid in Andrographis paniculata, a popular Chinese herbal medicine. Andrographolide displays diverse biological activities including hypoglycemia, hypolipidemia, anti-inflammation, and anti-tumorigenesis. Recent evidence indicates that andrographolide displays anti-obesity property by inhibiting lipogenic gene expression, however, the underlying mechanisms remain to be elucidated. In this study, the effects of andrographolide on transcription factor cascade and mitotic clonal expansion in 3T3-L1 preadipocyte differentiation into adipocyte were determined. Andrographolide dose-dependently (0–15μM) inhibited CCAAT/enhancer-binding protein α (C/EBPα) and C/EBPβ mRNA and protein expression as well as peroxisome proliferator-activated receptor γ (PPARγ) protein level during the adipogenesis of 3T3-L1 cells. Concomitantly, fatty acid synthase and stearoyl-CoA desaturase expression and lipid accumulation were attenuated by andrographolide. Oil-red O staining further showed that the first 48h after the initiation of differentiation was critical for andrographolide inhibition of adipocyte formation. Andrographolide inhibited the phosphorylation of PKA and the activation of cAMP response element-binding protein (CREB) in response to a differentiation cocktail, which led to attenuated C/EBPβ expression. In addition, ERK and GSK3β-dependent C/EBPβ phosphorylation was attenuated by andrographolide. Moreover, andrographolide suppressed cyclin A, cyclin E, and CDK2 expression and impaired the progression of mitotic clonal expansion (MCE) by arresting the cell cycle at the Go/G1 phase. Taken together, these results indicate that andrographolide has a potent anti-obesity action by inhibiting PKA-CREB-mediated C/EBPβ expression as well as C/EBPβ transcriptional activity, which halts MCE progression and attenuates C/EBPα and PPARγ expression.
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      PubDate: 2016-08-09T04:06:59Z
       
  • Additive effects of levonorgestrel and ethinylestradiol on brain aromatase
           (cyp19a1b) in zebrafish specific in vitro and in vivo bioassays
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): N. Hinfray, C. Tebby, C. Garoche, B. Piccini, G. Bourgine, S. Aït-Aïssa, O. Kah, F. Pakdel, F. Brion
      Estrogens and progestins are widely used in combination in human medicine and both are present in aquatic environment. Despite the joint exposure of aquatic wildlife to estrogens and progestins, very little information is available on their combined effects. In the present study we investigated the effect of ethinylestradiol (EE2) and Levonorgestrel (LNG), alone and in mixtures, on the expression of the brain specific ER-regulated cyp19a1b gene. For that purpose, recently established zebrafish-derived tools were used: (i) an in vitro transient reporter gene assay in a human glial cell line (U251-MG) co-transfected with zebrafish estrogen receptors (zfERs) and the luciferase gene under the control of the zebrafish cyp19a1b gene promoter and (ii) an in vivo bioassay using a transgenic zebrafish expressing GFP under the control of the zebrafish cyp19a1b gene promoter (cyp19a1b-GFP). Concentration-response relationships for single chemicals were modeled and used to design the mixture experiments following a ray design. The results from mixture experiments were analyzed to predict joint effects according to concentration addition and statistical approaches were used to characterize the potential interactions between the components of the mixtures (synergism/antagonism). We confirmed that some progestins could elicit estrogenic effects in fish brain. In mixtures, EE2 and LNG exerted additive estrogenic effects both in vitro and in vivo, suggesting that some environmental progestin could exert effects that will add to those of environmental (xeno-)estrogens. Moreover, our zebrafish specific assays are valuable tools that could be used in risk assessment for both single chemicals and their mixtures.
      Graphical abstract image

      PubDate: 2016-08-09T04:06:59Z
       
  • Reduction of hexavalent chromium by fasted and fed human gastric fluid.
           II. Ex vivo gastric reduction modeling
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Christopher R. Kirman, Mina Suh, Sean M. Hays, Hakan Gürleyük, Russ Gerads, Silvio De Flora, William Parker, Shu Lin, Laurie C. Haws, Mark A. Harris, Deborah M. Proctor
      To extend previous models of hexavalent chromium [Cr(VI)] reduction by gastric fluid (GF), ex vivo experiments were conducted to address data gaps and limitations identified with respect to (1) GF dilution in the model; (2) reduction of Cr(VI) in fed human GF samples; (3) the number of Cr(VI) reduction pools present in human GF under fed, fasted, and proton pump inhibitor (PPI)-use conditions; and (4) an appropriate form for the pH-dependence of Cr(VI) reduction rate constants. Rates and capacities of Cr(VI) reduction were characterized in gastric contents from fed and fasted volunteers, and from fasted pre-operative patients treated with PPIs. Reduction capacities were first estimated over a 4-h reduction period. Once reduction capacity was established, a dual-spike approach was used in speciated isotope dilution mass spectrometry analyses to characterize the concentration-dependence of the 2nd order reduction rate constants. These data, when combined with previously collected data, were well described by a three-pool model (pool 1 = fast reaction with low capacity; pool 2 = slow reaction with higher capacity; pool 3 = very slow reaction with higher capacity) using pH-dependent rate constants characterized by a piecewise, log-linear relationship. These data indicate that human gastric samples, like those collected from rats and mice, contain multiple pools of reducing agents, and low concentrations of Cr(VI) (<0.7 mg/L) are reduced more rapidly than high concentrations. The data and revised modeling results herein provide improved characterization of Cr(VI) gastric reduction kinetics, critical for Cr(VI) pharmacokinetic modeling and human health risk assessment.


      PubDate: 2016-08-04T03:56:33Z
       
  • Reduction of hexavalent chromium by fasted and fed human gastric fluid. I.
           Chemical reduction and mitigation of mutagenicity
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Silvio De Flora, Anna Camoirano, Rosanna T. Micale, Sebastiano La Maestra, Vincenzo Savarino, Patrizia Zentilin, Elisa Marabotto, Mina Suh, Deborah M. Proctor
      Evaluation of the reducing capacity of human gastric fluid from healthy individuals, under fasted and fed conditions, is critical for assessing the cancer hazard posed by ingested hexavalent chromium [Cr(VI)] and for developing quantitative physiologically-based pharmacokinetic models used in risk assessment. In the present study, the patterns of Cr(VI) reduction were evaluated in 16 paired pre- and post-meal gastric fluid samples collected from 8 healthy volunteers. Human gastric fluid was effective both in reducing Cr(VI), as measured by using the s-diphenylcarbazide colorimetric method, and in attenuating mutagenicity in the Ames test. The mean (±SE) Cr(VI)-reducing ability of post-meal samples (20.4±2.6μgCr(VI)/mL gastric fluid) was significantly higher than that of pre-meal samples (10.2±2.3μgCr(VI)/mL gastric fluid). When using the mutagenicity assay, the decrease of mutagenicity produced by pre-meal and post-meal samples corresponded to reduction of 13.3±1.9 and 25.6±2.8μgCr(VI)/mL gastric fluid, respectively. These data are comparable to parallel results conducted by using speciated isotope dilution mass spectrometry. Cr(VI) reduction was rapid, with >70% of total reduction occurring within 1min and 98% of reduction is achieved within 30min with post-meal gastric fluid at pH2.0. pH dependence was observed with decreasing Cr(VI) reducing capacity at higher pH. Attenuation of the mutagenic response is consistent with the lack of DNA damage observed in the gastrointestinal tract of rodents following administration of ≤180ppm Cr(VI) for up to 90days in drinking water. Quantifying Cr(VI) reduction kinetics in the human gastrointestinal tract is necessary for assessing the potential hazards posed by Cr(VI) in drinking water.
      Graphical abstract image

      PubDate: 2016-08-04T03:56:33Z
       
  • Editorial Board
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306




      PubDate: 2016-08-04T03:56:33Z
       
  • Terbinafine inhibits gap junctional intercellular communication
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Ju Yeun Lee, Sei Mee Yoon, Eun Ju Choi, Jinu Lee
      Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca2+ concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action.
      Graphical abstract image

      PubDate: 2016-08-04T03:56:33Z
       
  • TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen
           receptor regulation in response to mutations associated with prostate
           cancer
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Joubert Banjop Kharlyngdoh, Solomon Asnake, Ajay Pradhan, Per-Erik Olsson
      Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the ART877A mutation, which is frequently detected mutation in PCa tumors and the ARW741C that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression. In the present study we investigated the effect of AR mutations (ARW741C and ART877A) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The ART877A mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (ART877A) compared to T-47D cells (ARWT) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of ART877A and ARW741C to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters.


      PubDate: 2016-08-04T03:56:33Z
       
  • Different roles of ROS and Nrf2 in Cr(VI)-induced inflammatory responses
           in normal and Cr(VI)-transformed cells
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Ram Vinod Roy, Poyil Pratheeshkumar, Yong-Ok Son, Lei Wang, John Andrew Hitron, Sasidharan Padmaja Divya, Zhuo Zhang, Xianglin Shi
      Hexavalent chromium (Cr(VI)) is classified as a human carcinogen. Cr(VI) has been associated with adenocarcinomas and squamous cell carcinoma of the lung. The present study shows that acute Cr(VI) treatment in human bronchial epithelial cells (BEAS-2B) increased inflammatory responses (TNF-α, COX-2, and NF-кB/p65) and expression of Nrf2. Cr(VI)-induced generation of reactive oxygen species (ROS) are responsible for increased inflammation. Despite the fact that Nrf2 is a master regulator of response to oxidative stress, silencing of Nrf2 in the acute Cr(VI) treatment had no effect on Cr(VI)-induced inflammation. In contrast, in Cr(VI)-transformed (CrT) cells, Nrf2 is constitutively activated. Knock-down of this protein resulted in decreased inflammation, while silencing of SOD2 and CAT had no effect in the expression of these inflammatory proteins. Results obtained from the knock-down of Nrf2 in CrT cells are very different from the results obtained in the acute Cr(VI) treatment. In BEAS-2B cells, knock-down of Nrf2 had no effect in the inflammation levels, while in CrT cells a decrease in the expression of inflammation markers was observed. These results indicate that before transformation, ROS plays a critical role while Nrf2 not in Cr(VI)-induced inflammation, whereas after transformation (CrT cells), Nrf2 is constitutively activated and this protein maintains inflammation while ROS not. Constitutively high levels of Nrf2 in CrT binds to the promoter regions of COX-2 and TNF-α, leading to increased inflammation. Collectively, our results demonstrate that before cell transformation ROS are important in Cr(VI)-induced inflammation and after transformation a constitutively high level of Nrf2 is important.


      PubDate: 2016-08-04T03:56:33Z
       
  • Epigenetic modification of miR-10a regulates renal damage by targeting
           CREB1 in type 2 diabetes mellitus
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Qun Shan, Guihong Zheng, Aihua Zhu, Li Cao, Jun Lu, Dongmei Wu, ZiFeng Zhang, Shaohua Fan, Chunhui Sun, Bin Hu, Yuanlin Zheng
      Emerging evidence has shown that microRNA-mediated gene expression modulation plays a crucial role in the pathogenesis of type 2 diabetes mellitus, but the novel miRNAs involved in type 2 diabetes and its functional regulatory mechanisms still need to be determined. In this study, we assessed the role of miR-10a in extracellular matrix accumulation in the kidney of diabetic mellitus induced by combining administration of chronic high fat diet (HFD) and low dosage of streptozotocin (STZ, 35mg/kg). Here, we found that HFD/STZ administration decreased the level of microRNA (miR-10a) expression in ICR strain mice. Overexpression of miR-10a alleviated the increased ratio of urine albumin-to-creatinine (ACR) ratio of HFD/STZ mice. In contrast, knockdown of miR-10a increased the ratio of kidney ACR in naïve mice. Furthermore, cAMP response element binding protein 1 (CREB1) was validated as a target of miR-10a in vitro and in vivo. CREB1 and its downstream fibronectin (FN, extracellular matrix) were increased in HFD/STZ-treated mice, which was reversed by kidney miR-10a overexpression. The content of CREB1 and FN was increased by miR-10a knockdown in kidney of naïve mice. Furthermore, histone deacetylase 3 (HDAC3) was revealed to be increased in kidney of HFD/STZ mice, accompanied with the augmentation of ACR ratio and FN level. Knockdown of HDAC3 with siRNA significantly caused the increase of miR-10a, resulting in the decrease in CREB1 and FN expression in kidney of HFD/STZ mice. Contrarily, HDAC3 overexpression mediated by lentivirus decreased miR-10a content, and enhanced ACR value, CREB1 and FN formation in naïve mice. Collectively, these results elucidate that HDAC3/miR-10a/CREB1 serves as a new mechanism underlying kidney injury, providing potential therapeutic targets in type 2 diabetes.


      PubDate: 2016-08-04T03:56:33Z
       
  • Cover 4--TOC
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306




      PubDate: 2016-08-04T03:56:33Z
       
  • A newly synthesized macakurzin C-derivative attenuates acute and chronic
           skin inflammation: The Nrf2/heme oxygenase signaling as a potential target
           
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Muhammad Akram, Iljin Shin, Kyeong-A Kim, Dabi Noh, Seung-Hoon Baek, Sun-Young Chang, Hyoungsu Kim, Ok-Nam Bae
      Impaired immune responses in skin play a pivotal role in the development and progression of chemical-associated inflammatory skin disorders. In this study, we synthesized new flavonoid derivatives from macakurzin C, and identified in vitro and in vivo efficacy of a potent anti-inflammatory flavonoid, Compound 14 (CPD 14), with its underlying mechanisms. In lipopolysaccharide (LPS)-stimulated murine macrophages and IFN-γ/TNF-α-stimulated human keratinocytes, CPD 14 significantly inhibited the release of inflammatory mediators including nitric oxide (NO), prostaglandins, and cytokines (IC50 for NO inhibition in macrophages: 4.61μM). Attenuated NF-κB signaling and activated Nrf2/HO-1 pathway were responsible for the anti-inflammatory effects of CPD 14. The in vivo relevance was examined in phorbol 12-myristate 13-acetate (TPA)-induced acute skin inflammation and oxazolone-induced atopic dermatitis models. Topically applied CPD 14 significantly protected both irritation- and sensitization-associated skin inflammation by suppressing the expression of inflammatory mediators. In summary, we demonstrated that a newly synthesized flavonoid, CPD 14, has potent inhibitory effects on skin inflammation, suggesting it is a potential therapeutic candidate to treat skin disorders associated with excessive inflammation.


      PubDate: 2016-07-30T03:36:45Z
       
  • Lack of TAK1 in dendritic cells inhibits the contact hypersensitivity
           response induced by trichloroethylene in local lymph node assay
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Pan Yao, Chu Hongqian, Meng Qinghe, Shang Lanqin, Jiang Jianjun, Yang Xiaohua, Wei Xuetao, Hao Weidong
      Trichloroethylene (TCE) is a ubiquitous environmental contaminant. Occupational TCE exposure has been associated with severe, generalized contact hypersensitivity (CHS) skin disorder. The development of CHS depends on innate and adaptive immune functions. Transforming growth factor-β activated kinase-1 (TAK1) controls the survival of dendritic cells (DCs) that affect the immune system homeostasis. We aimed to investigate the role of TAK1 activity in DC on TCE-induced CHS response. Control mice and DC-specific TAK1 deletion mice were treated with 80% (v/v) TCE using local lymph node assay (LLNA) to establish a TCE-induced CHS model. The draining lymph nodes (DLNs) were excised and the lymphocytes were measure for proliferation by BrdU-ELISA, T-cell phenotype analysis by flow cytometry and signaling pathway activation by western blot. The ears were harvested for histopathological analysis. Control mice in the 80% TCE group displayed an inflammatory response in the ears, increased lymphocyte proliferation, elevated regulatory T-cell and activated T-cell percentages, and more IFN-γ producing CD8+ T cells in DLNs. In contrast to control mice, DC-specific TAK1 deletion mice in the 80% TCE group showed an abolished CHS response and this was associated with defective T-cell expansion, activation and IFN-γ production. This effect may occur through Jnk and NF-κB signaling pathways. Overall, this study demonstrates a pivotal role of TAK1 in DCs in controlling TCE-induced CHS response and suggests that targeting TAK1 function in DCs may be a viable approach to preventing and treating TCE-related occupational health hazards.


      PubDate: 2016-07-30T03:36:45Z
       
  • The study of the mechanism of arsenite toxicity in respiration-deficient
           cells reveals that NADPH oxidase-derived superoxide promotes the same
           downstream events mediated by mitochondrial superoxide in
           respiration-proficient cells
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Andrea Guidarelli, Mara Fiorani, Silvia Carloni, Liana Cerioni, Walter Balduini, Orazio Cantoni
      We herein report the results from a comparative study of arsenite toxicity in respiration-proficient (RP) and -deficient (RD) U937 cells. An initial characterization of these cells led to the demonstration that the respiration-deficient phenotype is not associated with apparent changes in mitochondrial mass and membrane potential. In addition, similar levels of superoxide (O2 .-) were generated by RP and RD cells in response to stimuli specifically triggering respiratory chain-independent mitochondrial mechanisms or extramitochondrial, NADPH-oxidase dependent, mechanisms. At the concentration of 2.5μM, arsenite elicited selective formation of O2 .- in the respiratory chain of RP cells, with hardly any contribution of the above mechanisms. Under these conditions, O2 .- triggered downstream events leading to endoplasmic reticulum (ER) stress, autophagy and apoptosis. RD cells challenged with similar levels of arsenite failed to generate O2 .- because of the lack of a functional respiratory chain and were therefore resistant to the toxic effects mediated by the metalloid. Their resistance, however, was lost after exposure to four fold greater concentrations of arsenite, coincidentally with the release of O2 .- mediated by NADPH oxidase. Interestingly, extramitochondrial O2 .- triggered the same downstream events and an identical mode of death previously observed in RP cells. Taken together, the results obtained in this study indicate that arsenite toxicity is strictly dependent on O2 .- availability that, regardless of whether generated in the mitochondrial or extramitochondrial compartments, triggers similar downstream events leading to ER stress, autophagy and apoptosis.


      PubDate: 2016-07-30T03:36:45Z
       
  • Chronic preclinical safety evaluation of EPO-018B, a pegylated peptidic
           erythropoiesis-stimulating agent in monkeys and rats
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Xue-Lian Gong, Xiao-Lei Gu, Yong-Chun Chen, Hai Zhu, Zhen-Na Xia, Jian-Zhong Li, Guo-Cai Lu
      EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is mainly designed for treatment of anemia caused by chronic renal failure and chemotherapy against cancer. It overcomes the deficiencies of currently approved ESA, including the frequent administration of temperature-sensitive recombinant protein and anti-EPO antibody-mediated pure red cell aplasia (PRCA). This study was designed to evaluate the potential chronic toxicity of EPO-018B. Subcutaneous administration doses were designed as 0, 0.2, 1 and 10mg/kg for six months for 160 rats (20/gender/group) and 0, 0.3, 3 and 20mg/kg for nine months for 32 monkeys (4/gender/group) once every three weeks. The vehicles received the same volume of physiological saline injection. All animals survived to the scheduled necropsies after six weeks (for rats) and fourteen weeks (for monkeys) recovery period, except for the two high-dose female rats and two high-dose male monkeys, which were considered related to the increased RBCs, chronic blood hyperviscosity and chronic cardiac injury. EPO-018B is supposed to be subcutaneously injected once every month and the intended human therapeutic dose is 0.025mg/kg. The study findings at 0.2mg/kg for rats and 0.3mg/kg for monkeys were considered to be the study NOAEL (the no observed adverse effect level), which were more than ten times the intended human therapeutic dose. Higher doses caused adverse effects related to the liver toxicity, cardiotoxicity, appearance of neutralizing antibodies of EPO-018B and the decrease of serum glucose and cholesterol. Most treatment-induced effects were reversible or revealed ongoing recovery upon the discontinuation of treatment. The sequelae occurred in rats and monkeys were considered secondary to exaggerated pharmacology and would less likely occur in the intended patient population. As to the differences between human beings and animals, the safety of EPO-018B need to be further confirmed in the future clinical studies.


      PubDate: 2016-07-30T03:36:45Z
       
  • Mangiferin, a novel nuclear factor kappa B-inducing kinase inhibitor,
           suppresses metastasis and tumor growth in a mouse metastatic melanoma
           model
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Tomoya Takeda, Masanobu Tsubaki, Kotaro Sakamoto, Eri Ichimura, Aya Enomoto, Yuri Suzuki, Tatsuki Itoh, Motohiro Imano, Genzoh Tanabe, Osamu Muraoka, Hideaki Matsuda, Takao Satou, Shozo Nishida
      Advanced metastatic melanoma, one of the most aggressive malignancies, is currently without reliable therapy. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone and exerts many beneficial biological activities. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we evaluated the effect of mangiferin on metastasis and tumor growth in a mouse metastatic melanoma model. We found that mangiferin inhibited spontaneous metastasis and tumor growth. Furthermore, mangiferin suppressed the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated NF-κB-inducing kinase (NIK), inhibitor of kappa B kinase (IKK), and inhibitor of kappa B (IκB) and increases the expression of IκB protein in vivo. In addition, we found that mangiferin inhibited the expression of matrix metalloproteinases (MMPs) and very late antigens (VLAs) in vivo. Mangiferin treatment also increased the expression of cleaved caspase-3, cleaved Poly ADP ribose polymerase-1 (PARP-1), p53 upregulated modulator of apoptosis (PUMA), p53, and phosphorylated p53 proteins, and decreased the expression of Survivin and Bcl-associated X (Bcl-xL) proteins in vivo. These results indicate that mangiferin selectivity suppresses the NF-κB pathway via inhibition of NIK activation, thereby inhibiting metastasis and tumor growth. Importantly, the number of reported NIK selective inhibitors is limited. Taken together, our data suggest that mangiferin may be a potential therapeutic agent with a new mechanism of targeting NIK for the treatment of metastatic melanoma.


      PubDate: 2016-07-25T03:11:40Z
       
  • Development of a PBPK model of thiocyanate in rats with an extrapolation
           to humans: A computational study to quantify the mechanism of action of
           thiocyanate kinetics in thyroid
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Marie-Emilie Willemin, Annie Lumen
      Thyroid homeostasis can be disturbed due to thiocyanate exposure from the diet or tobacco smoke. Thiocyanate inhibits both thyroidal uptake of iodide, via the sodium-iodide symporter (NIS), and thyroid hormone (TH) synthesis in the thyroid, via thyroid peroxidase (TPO), but the mode of action of thiocyanate is poorly quantified in the literature. The characterization of the link between intra-thyroidal thiocyanate concentrations and dose of exposure is crucial for assessing the risk of thyroid perturbations due to thiocyanate exposure. We developed a PBPK model for thiocyanate that describes its kinetics in the whole-body up to daily doses of 0.15mmol/kg, with a mechanistic description of the thyroidal kinetics including NIS, passive diffusion, and TPO. The model was calibrated in a Bayesian framework using published studies in rats. Goodness-of-fit was satisfactory, especially for intra-thyroidal thiocyanate concentrations. Thiocyanate kinetic processes were quantified in vivo, including the metabolic clearance by TPO. The passive diffusion rate was found to be greater than NIS-mediated uptake rate. The model captured the dose-dependent kinetics of thiocyanate after acute and chronic exposures. Model behavior was evaluated using a Morris screening test. The distribution of thiocyanate into the thyroid was found to be determined primarily by the partition coefficient, followed by NIS and passive diffusion; the impact of the latter two mechanisms appears to increase at very low doses. Extrapolation to humans resulted in good predictions of thiocyanate kinetics during chronic exposure. The developed PBPK model can be used in risk assessment to quantify dose-response effects of thiocyanate on TH.


      PubDate: 2016-07-25T03:11:40Z
       
  • Editorial Board
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305




      PubDate: 2016-07-25T03:11:40Z
       
  • Triazine herbicides inhibit relaxin signaling and disrupt nitric oxide
           homeostasis
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Si Eun Park, Sa Rang Lim, Hyung-kyoon Choi, Jeehyeon Bae
      Triazines are herbicides that are widely used worldwide, and we previously observed that the maternal exposure of mice to simazine (50 or 500μg/kg) resulted in smaller ovaries and uteri of their female offspring. Here, we investigated the underlying mechanism that may account for the reproductive dysfunction induced by simazine. We found that following maternal exposure, simazine is transmitted to the offspring, as evidenced by its presence in the offspring ovaries. Analyses of the simazine-exposed offspring revealed that the expression of the relaxin hormone receptor, relaxin-family peptide receptor 1 (RXFP1), prominently decreased in their ovaries and uteri. In addition, downstream target genes of the relaxin pathway including nitric oxide (NO) synthase 2 (Nos2), Nos3, matrix metallopeptidase 9 (Mmp9), and vascular endothelial growth factor (Vegf) were downregulated in their ovaries. Moreover, AKT and extracellular signal-regulated kinases (ERK) levels and their phosphorylated active forms decreased in simazine-exposed ovaries. In vitro exposure of the human ovarian granulosa cells (KGN) and uterine endometrium cells (Hec-1A) to very low concentrations (0.001 to 1nM) of triazines including atrazine, terbuthylazine, and propazine repressed NO production with a concurrent reduction in RXFP1, NOS2, and NOS3. The inhibitory action of triazines on NO release was dependent on RXFP1, phosphoinositol 3-kinase (PI3K)/AKT, and ERK. Radioligand-binding assay also confirmed that triazines competitively inhibited the binding of relaxin to its receptor. Therefore, the present study suggests that triazine herbicides act as endocrine disrupters by interfering with relaxin hormone signaling. Thus, further evaluation of their impact on human health is imperative.


      PubDate: 2016-07-25T03:11:40Z
       
  • MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in
           mice
    • Abstract: Publication date: 15 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 307
      Author(s): Yasuaki Uematsu, Sho Akai, Tomoaki Tochitani, Shingo Oda, Toru Yamada, Tsuyoshi Yokoi
      MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury.
      Graphical abstract image

      PubDate: 2016-07-20T03:03:31Z
       
  • Low doses of arsenic, via perturbing p53, promotes tumorigenesis
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Suthakar Ganapathy, Ping Li, Johan Fagman, Tianqi Yu, Jean Lafontant, Guojun Zhang, Changyan Chen
      In drinking water and in workplace or living environments, low doses of arsenic can exist and operate as a potent carcinogen. Due to insufficient understanding and information on the pervasiveness of environmental exposures to arsenic, there is an urgent need to elucidate the underlying molecular mechanisms of arsenic regarding its carcinogenic effect on human health. In this study, we demonstrate that low doses of arsenic exposure mitigate or mask p53 function and further perturb intracellular redox state, which triggers persistent endoplasmic reticulum (ER) stress and activates UPR (unfolded protein response), leading to transformation or tumorigenesis. Thus, the results suggest that low doses of arsenic exposure, through attenuating p53-regulated tumor suppressive function, change the state of intracellular redox and create a microenvironment for tumorigenesis. Our study also provides the information for designing more effective strategies to prevent or treat human cancers initiated by arsenic exposure.


      PubDate: 2016-07-20T03:03:31Z
       
  • Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell
           death
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Kuo-Liang Wei, Fei-Yun Chen, Chih-Yi Lin, Guan-Lun Gao, Wen-Ya Kao, Chi-Hui Yeh, Chang-Rong Chen, Hao-Chun Huang, Wei-Ren Tsai, Koa-Jen Jong, Wan-Jung Li, Jyan-Gwo Joseph Su
      Carbendazim inhibits microtubule assembly, thus blocking mitosis and inhibiting cancer cell proliferation. Accordingly, carbendazim is being explored as an anticancer drug. Data show that carbendazim increased mRNA and protein expressions and promoter activity of CYP1A1. In addition, carbendazim activated transcriptional activity of the aryl hydrocarbon response element, and induced nuclear translocation of the aryl hydrocarbon receptor (AhR), a sign the AhR is activated. Carbendazim-induced CYP1A1 expression was blocked by AhR antagonists, and was abolished in AhR signal-deficient cells. Results demonstrated that carbendazim activated the AhR, thereby stimulating CYP1A1 expression. In order to understand whether AhR-induced metabolic enzymes turn carbendazim into less-toxic metabolites, Hoechst 33342 staining to reveal carbendazim-induced nuclear changes and flow cytometry to reveal the subG0/G1 population were applied to monitor carbendazim-induced cell apoptosis. Carbendazim induced less apoptosis in Hepa-1c1c7 cells than in AhR signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with β-NF, an AhR agonist that highly induces CYP1A1 expression, decreased carbendazim-induced cell death. In addition, the lower the level of AhR was, the lower the vitality present in carbendazim-treated cells, including hepatoma cells and their derivatives with AhR RNA interference, also embryonic kidney cells, bladder carcinoma cells, and AhR signal-deficient Hepa-1c1c7 cells. In summary, carbendazim is an AhR agonist. The toxicity of carbendazim was lower in cells with the AhR signal. This report provides clues indicating that carbendazim is more potent at inducing cell death in tissues without than in those with the AhR signal, an important reference for applying carbendazim in cancer chemotherapy.


      PubDate: 2016-07-20T03:03:31Z
       
  • Cadmium-induced neural tube defects and fetal growth restriction:
           Association with disturbance of placental folate transport
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Gui-Bin Zhang, Hua Wang, Jun Hu, Min-Yin Guo, Ying Wang, Yan Zhou, Zhen Yu, Lin Fu, Yuan-Hua Chen, De-Xiang Xu
      Previous studies found that maternal Cd exposure on gestational day (GD)9 caused forelimb ectrodactyly and tail deformity, the characteristic malformations. The aim of the present study was to investigate whether maternal Cd exposure on GD8 induces fetal neural tube defects (NTDs). Pregnant mice were intraperitoneally injected with CdCl2 (2.5 or 5.0mg/kg) on GD8. Neither forelimb ectrodactyly nor tail deformity was observed in mice injected with CdCl2 on GD8. Instead, maternal Cd exposure on GD8 resulted in the incidence of NTDs. Moreover, maternal Cd exposure on GD8 resulted in fetal growth restriction. In addition, maternal Cd exposure on GD8 reduced placental weight and diameter. The internal space of maternal and fetal blood vessels in the labyrinth layer was decreased in the placentas of mice treated with CdCl2. Additional experiment showed that placental PCFT protein and mRNA, a critical folate transporter, was persistently decreased when dams were injected with CdCl2 on GD8. Correspondingly, embryonic folate content was markedly decreased in mice injected with CdCl2 on GD8, whereas Cd had little effect on folate content in maternal serum. Taken together, these results suggest that maternal Cd exposure during organogenesis disturbs transport of folate from maternal circulation to the fetuses through down-regulating placental folate transporters.
      Graphical abstract image

      PubDate: 2016-07-16T03:00:43Z
       
  • Systemic metabolic derangement, pulmonary effects, and insulin
           insufficiency following subchronic ozone exposure in rats
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Desinia B. Miller, Samantha J. Snow, Andres Henriquez, Mette C. Schladweiler, Allen D. Ledbetter, Judy E. Richards, Debora L. Andrews, Urmila P. Kodavanti
      Acute ozone exposure induces a classical stress response with elevated circulating stress hormones along with changes in glucose, protein and lipid metabolism in rats, with similar alterations in ozone-exposed humans. These stress-mediated changes over time have been linked to insulin resistance. We hypothesized that acute ozone-induced stress response and metabolic impairment would persist during subchronic episodic exposure and induce peripheral insulin resistance. Male Wistar Kyoto rats were exposed to air or 0.25ppm or 1.00ppm ozone, 5h/day, 3 consecutive days/week (wk) for 13wks. Pulmonary, metabolic, insulin signaling and stress endpoints were determined immediately after 13wk or following a 1wk recovery period (13wk+1wk recovery). We show that episodic ozone exposure is associated with persistent pulmonary injury and inflammation, fasting hyperglycemia, glucose intolerance, as well as, elevated circulating adrenaline and cholesterol when measured at 13wk, however, these responses were largely reversible following a 1wk recovery. Moreover, the increases noted acutely after ozone exposure in non-esterified fatty acids and branched chain amino acid levels were not apparent following a subchronic exposure. Neither peripheral or tissue specific insulin resistance nor increased hepatic gluconeogenesis were present after subchronic ozone exposure. Instead, long-term ozone exposure lowered circulating insulin and severely impaired glucose-stimulated beta-cell insulin secretion. Thus, our findings in young-adult rats provide potential insights into epidemiological studies that show a positive association between ozone exposures and type 1 diabetes. Ozone-induced beta-cell dysfunction may secondarily contribute to other tissue-specific metabolic alterations following chronic exposure due to impaired regulation of glucose, lipid, and protein metabolism.


      PubDate: 2016-07-12T02:48:27Z
       
  • Valproic acid exposure decreases Cbp/p300 protein expression and histone
           acetyltransferase activity in P19 cells
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Christina L. Lamparter, Louise M. Winn
      The teratogenicity of the antiepileptic drug valproic acid (VPA) is well established and its inhibition of histone deacetylases (HDAC) is proposed as an initiating factor. Recently, VPA-mediated HDAC inhibition was demonstrated to involve transcriptional downregulation of histone acetyltransferases (HATs), which was proposed to compensate for the increased acetylation resulting from HDAC inhibition. Cbp and p300 are HATs required for embryonic development and deficiencies in either are associated with congenital malformations and embryolethality. The objective of the present study was to characterize Cbp/p300 following VPA exposure in P19 cells. Consistent with previous studies, exposure to 5mM VPA over 24h induced a moderate decrease in Cbp/p300 mRNA, which preceded a strong decrease in total cellular protein mediated by ubiquitin-proteasome degradation. Nuclear Cbp/p300 protein was also decreased following VPA exposure, although to a lesser extent. Total cellular and nuclear p300 HAT activity was reduced proportionately to p300 protein levels, however while total cellular HAT activity also decreased, nuclear HAT activity was unaffected. Using the Cbp/p300 HAT inhibitor C646, we demonstrated that HAT inhibition similarly affected many of the same endpoints as VPA, including increased reactive oxygen species and caspase-3 cleavage, the latter of which could be attenuated by pre-treatment with the antioxidant catalase. C646 exposure also decreased NF-κB/p65 protein, which was not due to reduced mRNA and was not attenuated with catalase pre-treatment. This study provides support for an adaptive HAT response following VPA exposure and suggests that reduced Cbp/p300 HAT activity could contribute to VPA-mediated alterations.


      PubDate: 2016-07-12T02:48:27Z
       
  • Role of histone deacetylases(HDACs) in progression and reversal of liver
           fibrosis
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Xing Li, Xiao-Qin Wu, Tao Xu, Xiao-Feng Li, Yang Yang, Wan-Xia Li, Cheng Huang, Xiao-Ming Meng, Jun Li
      Liver fibrosis refers to a reversible wound healing process response to chronic liver injuries. Activation of hepatic stellate cells (HSCs) is closely correlated with the development of liver fibrosis. Histone deacetylases(HDACs) determine the acetylation levels of core histones to modulate expression of genes. To demonstrate the link between HDACs and liver fibrosis, CCl4-induced mouse liver fibrosis model and its spontaneous reversal model were established. Results of the current study demonstrated that deregulation of liver HDACs may involved in the development of liver fibrosis. Among 11 HDACs tested in our study (Class I, II, and IV HDACs), expression of HDAC2 was maximally increased in CCl4-induced fibrotic livers but decreased after spontaneous recovery. Moreover, expression of HDAC2 was elevated in human liver fibrotic tissues. In this regard, the potential role of HDAC2 in liver fibrosis was further evaluated. Our results showed that administration of HSC-T6 cells with transforming growth factor-beta1 (TGF-β1) resulted in an increase of HDAC2 protein expression in dose- and time-dependent manners. Moreover, HDAC2 deficiency inhibited HSC-T6 cell proliferation and activation induced by TGF-β1. More importantly, the present study showed HDAC2 may regulate HSCs activation by suppressing expression of Smad7, which is a negative modulator in HSCs activation and liver fibrosis. Collectively, these observations revealed that HDAC2 may play a pivotal role in HSCs activation and liver fibrosis while deregulation of HDACs may serve as a novel mechanism underlying liver fibrosis.


      PubDate: 2016-07-12T02:48:27Z
       
  • Involvement of the histamine H4 receptor in clozapine-induced
           hematopoietic toxicity: Vulnerability under granulocytic differentiation
           of HL-60 cells
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Aya Goto, Akihiro Mouri, Tomoko Nagai, Akira Yoshimi, Mako Ukigai, Tomomi Tsubai, Hirotake Hida, Norio Ozaki, Yukihiro Noda
      Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100μM) and doxorubicin (0.2µM) decreased the cell survival rate, but olanzapine (1–100µM) did not. Under granulocytic differentiation for 5days, clozapine, even at a concentration of 25μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation.


      PubDate: 2016-07-08T01:58:32Z
       
  • P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between
           resveratrol and methotrexate
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Yongming Jia, Zhihao Liu, Changyuan Wang, Qiang Meng, Xiaokui Huo, Qi Liu, Huijun Sun, Pengyuan Sun, Xiaobo Yang, Xiaodong Ma, Kexin Liu
      The purpose of present study was to investigate the effect of resveratrol (Res) on altering methotrexate (MTX) pharmacokinetics and clarify the related molecular mechanism. Res significantly increased rat intestinal absorption of MTX in vivo and in vitro. Simultaneously, Res inhibited MTX efflux transport in MDR1-MDCK and MRP2-MDCK cell monolayers, suggesting that the target of drug interaction was MDR1 and MRP2 in the intestine during the absorption process. Furthermore, there was a significant decrease in renal clearance of MTX after simultaneous intravenous administration. Similarly, MTX uptake was markedly inhibited by Res in rat kidney slices and hOAT1/3-HEK293 cell, indicating that OAT1 and OAT3 were involved in the drug interaction in the kidney. Additionally, concomitant administration of Res decreased cytotoxic effects of MTX in hOAT1/3-HEK293 cells, and ameliorated nephrotoxicity caused by MTX in rats. Conversely, intestinal damage caused by MTX was not exacerbated after Res treatment. In conclusion, Res enhanced MTX absorption in intestine and decreased MTX renal elimination by inhibiting P-gp, MRP2, OAT1 and OAT3 in vivo and in vitro. Res improved MTX-induced renal damage without increasing intestinal toxicity.


      PubDate: 2016-07-08T01:58:32Z
       
  • Statin-induced myotoxicity is exacerbated by aging: A biophysical and
           molecular biology study in rats treated with atorvastatin
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Giulia Maria Camerino, Michela De Bellis, Elena Conte, Antonella Liantonio, Kejla Musaraj, Maria Cannone, Adriano Fonzino, Arcangela Giustino, Annamaria De Luca, Rossella Romano, Claudia Camerino, Antonio Laghezza, Fulvio Loiodice, Jean-Francois Desaphy, Diana Conte Camerino, Sabata Pierno
      Statin-induced skeletal muscle damage in rats is associated to the reduction of the resting sarcolemmal chloride conductance (gCl) and ClC-1 chloride channel expression. These drugs also affect the ClC-1 regulation by increasing protein kinase C (PKC) activity, which phosphorylate and close the channel. Also the intracellular resting calcium (restCa) level is increased. Similar alterations are observed in skeletal muscles of aged rats, suggesting a higher risk of statin myotoxicity. To verify this hypothesis, we performed a 4–5-weeks atorvastatin treatment of 24-months-old rats to evaluate the ClC-1 channel function by the two-intracellular microelectrodes technique as well as transcript and protein expression of different genes sensitive to statins by quantitative real-time-PCR and western blot analysis. The restCa was measured using FURA-2 imaging, and histological analysis of muscle sections was performed. The results show a marked reduction of resting gCl, in agreement with the reduced ClC-1 mRNA and protein expression in atorvastatin-treated aged rats, with respect to treated adult animals. The observed changes in myocyte-enhancer factor-2 (MEF2) expression may be involved in ClC-1 expression changes. The activity of PKC was also increased and further modulate the gCl in treated aged rats. In parallel, a marked reduction of the expression of glycolytic and mitochondrial enzymes demonstrates an impairment of muscle metabolism. No worsening of restCa or histological features was found in statin-treated aged animals. These findings suggest that a strong reduction of gCl and alteration of muscle metabolism coupled to muscle atrophy may contribute to the increased risk of statin-induced myopathy in the elderly.
      Graphical abstract image

      PubDate: 2016-07-08T01:58:32Z
       
  • Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic
           airway inflammation in rat asthma model
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Vaibhav Shrirang Dhawale, Venkateswara Rao Amara, Pinakin Arun Karpe, Vajir Malek, Deep Patel, Kulbhushan Tikoo
      Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2weeks. 48h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocyte count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1β, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers.


      PubDate: 2016-07-08T01:58:32Z
       
  • Endogenous glucocorticoids exacerbate cholestasis-associated liver injury
           and hypercholesterolemia in mice
    • Abstract: Publication date: 1 September 2016
      Source:Toxicology and Applied Pharmacology, Volume 306
      Author(s): Rick van der Geest, Amber B. Ouweneel, Ronald J. van der Sluis, Albert K. Groen, Miranda Van Eck, Menno Hoekstra
      Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18±5ng/ml vs 472±58ng/ml; P <0.001) and disrupted the metabolic and anti-inflammatory glucocorticoid function. Adrenal removal did not exacerbate the cholestasis extent. In contrast, the cholestasis-associated liver injury was markedly lower in adrenalectomized mice as compared to controls as evidenced by a 84%–93% decrease in liver necrosis and plasma alanine aminotransferase and bile acid levels (P <0.001 for all). Gene expression analysis on livers from adrenalectomized mice suggested the absence of bile acid toxicity-associated farnesoid X receptor signaling in the context of a 44% (P <0.01) and 82% (P <0.001) reduction in sodium/bile acid cotransporter member 1 transcript level as compared to respectively control and non-diseased mice. Adrenalectomy reduced the expression of the cholesterol synthesis gene HMG-CoA reductase by 70% (P <0.05), which translated into a 73% lower plasma total cholesterol level (P <0.05). Treatment of C57BL/6 mice with the glucocorticoid receptor antagonist RU-486 recapitulated the protective effect of adrenalectomy on indices of liver injury and hypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice.
      Graphical abstract image

      PubDate: 2016-07-03T01:24:48Z
       
  • Mitragynine and its potential blocking effects on specific cardiac
           potassium channels
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Yea Lu Tay, Yi Fan Teah, Yoong Min Chong, Mohd Fadzly Amar Jamil, Sina Kollert, Mohd Ilham Adenan, Habibah Abdul Wahab, Frank Döring, Erhard Wischmeyer, Mei Lan Tan
      Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac IKr current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, IK1, a Kir current mediated by Kir2.1 channel and IKACh, a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC50 value of 1.62μM and 1.15μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit IKACh current with an IC50 value of 3.32μM but has no significant effects on IK1. Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks.


      PubDate: 2016-06-15T19:57:29Z
       
  • Several synthetic progestins disrupt the glial cell specific-brain
           aromatase expression in developing zebra fish
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Joel Cano-Nicolau, Clémentine Garoche, Nathalie Hinfray, Elisabeth Pellegrini, Noureddine Boujrad, Farzad Pakdel, Olivier Kah, François Brion
      The effects of some progestins on fish reproduction have been recently reported revealing the hazard of this class of steroidal pharmaceuticals. However, their effects at the central nervous system level have been poorly studied until now. Notwithstanding, progesterone, although still widely considered primarily a sex hormone, is an important agent affecting many central nervous system functions. Herein, we investigated the effects of a large set of synthetic ligands of the nuclear progesterone receptor on the glial-specific expression of the zebrafish brain aromatase (cyp19a1b) using zebrafish mechanism-based assays. Progesterone and 24 progestins were first screened on transgenic cyp19a1b-GFP zebrafish embryos. We showed that progesterone, dydrogesterone, drospirenone and all the progesterone-derived progestins had no effect on GFP expression. Conversely, all progestins derived from 19-nortesterone induced GFP in a concentration-dependent manner with EC50 ranging from the low nM range to hundreds nM. The 19-nortestosterone derived progestins levonorgestrel (LNG) and norethindrone (NET) were further tested in a radial glial cell context using U251-MG cells co-transfected with zebrafish ER subtypes (zfERα, zfERβ1 or zfERβ2) and cyp19a1b promoter linked to luciferase. Progesterone had no effect on luciferase activity while NET and LNG induced luciferase activity that was blocked by ICI 182,780. Zebrafish-ERs competition assays showed that NET and LNG were unable to bind to ERs, suggesting that the effects of these compounds on cyp19a1b require metabolic activation prior to elicit estrogenic activity. Overall, we demonstrate that 19-nortestosterone derived progestins elicit estrogenic activity by inducing cyp19a1b expression in radial glial cells. Given the crucial role of radial glial cells and neuro-estrogens in early development of brain, the consequences of exposure of fish to these compounds require further investigation.
      Graphical abstract image

      PubDate: 2016-06-10T00:33:52Z
       
  • Mustard Vesicant-induced Lung Injury: Advances in Therapy
    • Abstract: Publication date: Available online 19 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Barry Weinberger, Rama Malaviya, Vasanthi Sunil, Alessandro Venosa, Diane E. Heck, Jeffrey D. Laskin, Debra L. Laskin
      Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant.


      PubDate: 2016-05-21T00:25:53Z
       
 
 
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