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Journal Cover
Toxicology and Applied Pharmacology
Journal Prestige (SJR): 1.275
Citation Impact (citeScore): 4
Number of Followers: 20  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
Published by Elsevier Homepage  [3163 journals]
  • Pesticides and cardiotoxicity. Where do we stand'
    • Authors: Nikolaos Georgiadis; Konstantinos Tsarouhas; Christina Tsitsimpikou; Alexandros Vardavas; Ramin Rezaee; Ioannis Germanakis; Aristides Tsatsakis; Dimitrios Stagos; Demetrios Kouretas
      Pages: 1 - 14
      Abstract: Publication date: 15 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 353
      Author(s): Nikolaos Georgiadis, Konstantinos Tsarouhas, Christina Tsitsimpikou, Alexandros Vardavas, Ramin Rezaee, Ioannis Germanakis, Aristides Tsatsakis, Dimitrios Stagos, Demetrios Kouretas
      Cardiovascular diseases are among the most significant causes of mortality in humans. Pesticides toxicity and risk for human health are controlled at a European level through a well-developed regulatory network, but cardiotoxicity is not described as a separate hazard class. Specific classification criteria should be developed within the frame of Regulation (EC) No 1272/2008 in order to classify chemicals as cardiotoxic, if applicable to avoid long-term cardiovascular complications. The aim of this study was to review the cardiac pathology and function impairment due to exposure to pesticides (i.e. organophosphates, organothiophisphates, organochlorines, carbamates, pyrethroids, dipyridyl herbicides, triazoles, triazines) based on both animal and human data. The majority of human data on cardiotoxicity of pesticides come from poisoning cases and epidemiological data. Several cardiovascular complications have been reported in animal models including electrocardiogram abnormalities, myocardial infarction, impaired systolic and diastolic performance, functional remodeling and histopathological findings, such as haemorrhage, vacuolisation, signs of apoptosis and degeneration.

      PubDate: 2018-06-08T15:48:39Z
      DOI: 10.1016/j.taap.2018.06.004
      Issue No: Vol. 353 (2018)
       
  • Prenatal nicotine exposure intergenerationally programs imperfect
           articular cartilage via histone deacetylation through maternal lineage
    • Authors: Zhe Xie; Zhe Zhao; Xu Yang; Linguo Pei; Hanwen Luo; Qubo Ni; Bin Li; Yongjian Qi; Kai Tie; Jacques Magdalou; Liaobin Chen; Hui Wang
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Zhe Xie, Zhe Zhao, Xu Yang, Linguo Pei, Hanwen Luo, Qubo Ni, Bin Li, Yongjian Qi, Kai Tie, Jacques Magdalou, Liaobin Chen, Hui Wang
      Accumulating evidence has shown that the impact of prenatal environmental factors on the organs of the offspring could last until the adulthood. Here, we aimed to investigate these effects and the potential mechanism of prenatal nicotine exposure (PNE) on the female adult cartilage of the first generation (PNE-F1) and the second generation (PNE-F2). Pregnant Wistar rats were injected with 2.0 mg/kg.d nicotine from gestational day (GD) 9 to 20. Then their F1 generation at GD20 and postnatal week (PW) 12, and F2 generation at PW12 were harvested. The expression of extracellular matrix (ECM) and transforming growth factor β (TGFβ) signaling genes were analyzed by real-time quantitative PCR, and the histone acetylation was examined by chromatin immunoprecipitation assay. The results showed that PNE reduced the ECM and TGFβ signaling gene expressions in both PNE-F1 and PNE-F2 female adult articular cartilage. In the F1 generation, PNE inhibited the acetylation at H3K9 of TGFβ, TGFβ receptor 1 (TGFβR1), SRY-type high mobility group box 9 (SOX9), a1 chain of type II collagen (COL2A1) and aggrecan (ACAN) gene promoters at both GD20 and PW12. In PNE-F2 at PW12, the obvious deacetylation at H3K9 of the TGFβR1 and COL2A1 promoters still existed. Moreover, in rat fetal chondrocytes, corticosterone rather than nicotine directly induced the hypoacetylation of H3K9 of TGFβR1 and COL2A1 genes, which might be the main cause of imperfect cartilage for PNE-F2. This study may be helpful to elucidate the developmental variability of articular cartilage quality and useful for the early prevention of articular damage.

      PubDate: 2018-05-30T15:38:00Z
      DOI: 10.1016/j.taap.2018.03.018
      Issue No: Vol. 352 (2018)
       
  • Behavioral, cellular and molecular maladaptations covary with exposure to
           pyridostigmine bromide in a rat model of gulf war illness pain
    • Authors: B.Y. Cooper; L.D. Flunker; R.D. Johnson; T.J. Nutter
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): B.Y. Cooper, L.D. Flunker, R.D. Johnson, T.J. Nutter
      Many veterans of Operation Desert Storm (ODS) struggle with the chronic pain of Gulf War Illness (GWI). Exposure to insecticides and pyridostigmine bromide (PB) have been implicated in the etiology of this multisymptom disease. We examined the influence of 3 (DEET (N,N-diethyl-meta-toluamide), permethrin, chlorpyrifos) or 4 GW agents (DEET, permethrin, chlorpyrifos, pyridostigmine bromide (PB)) on the post-exposure ambulatory and resting behaviors of rats. In three independent studies, rats that were exposed to all 4 agents consistently developed both immediate and delayed ambulatory deficits that persisted at least 16 weeks after exposures had ceased. Rats exposed to a 3 agent protocol (PB excluded) did not develop any ambulatory deficits. Cellular and molecular studies on nociceptors harvested from 16WP (weeks post-exposure) rats indicated that vascular nociceptor Nav1.9 mediated currents were chronically potentiated following the 4 agent protocol but not following the 3 agent protocol. Muscarinic linkages to muscle nociceptor TRPA1 were also potentiated in the 4 agent but not the 3 agent, PB excluded, protocol. Although Kv7 activity changes diverged from the behavioral data, a Kv7 opener, retigabine, transiently reversed ambulation deficits. We concluded that PB played a critical role in the development of pain-like signs in a GWI rat model and that shifts in Nav1.9 and TRPA1 activity were critical to the expression of these pain behaviors.

      PubDate: 2018-05-30T15:38:00Z
      DOI: 10.1016/j.taap.2018.05.023
      Issue No: Vol. 352 (2018)
       
  • BET-inhibition by JQ1 alleviates streptozotocin-induced diabetic
           cardiomyopathy
    • Authors: Miao Guo; Hong-Xia Wang; Wen-Jun Chen
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Miao Guo, Hong-Xia Wang, Wen-Jun Chen
      Diabetic cardiomyopathy is a cascade of complex events leading to eventual heart failure in diabetes. JQ1, one of Bromodomain and extra-terminal domain (BET) protein inhibitors, has exerted therapeutic effects on cancer proliferation, inflammation and cardiovascular disease. Recently, JQ1 was reported to protect mice from bleomycin-induced lung fibrosis and reverse the fibrotic response in carbon tetrachloride-induced liver fibrosis. However, its role in diabetic cardiomyopathy remains to be clarified. Our results indicated that JQ1 treatment suppressed cardiac fibrosis and improved cardiac function in a STZ-induced diabetic mouse model. We further used both cardiofibroblasts and cardiomyocytes in vitro to investigate the protective mechanism of JQ1. JQ1 significantly suppressed hyperglycemia-induced cardiofibroblasts proliferation and migration, myofibroblast differentiation, and collagen production. Moreover, JQ1 reduced hyperglycemia-induced apoptosis of cardiomyocytes in vitro and in vivo. Mechanistically, JQ1 treatment could reverse the expression of Caveolin-1, which modulates transforming growth factor-β1 (TGF-β1) signaling in cardiofibroblasts and inhibits cardiomyocytes apoptosis. Our findings identify BET inhibitor JQ1 as promising agent for diabetic cardiomyopathy.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.05.018
      Issue No: Vol. 352 (2018)
       
  • Cross-linking by epichlorohydrin and diepoxybutane correlates with
           cytotoxicity and leads to apoptosis in human leukemia (HL-60) cells
    • Authors: Phuong M. Le; Vanesa L. Silvestri; Samuel C. Redstone; Jordanne B. Dunn; Julie T. Millard
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Phuong M. Le, Vanesa L. Silvestri, Samuel C. Redstone, Jordanne B. Dunn, Julie T. Millard
      The bifunctional alkylating agents epichlorohydrin (ECH) and diepoxybutane (DEB) have been linked to increased cancer risks in industrial workers. These compounds react with DNA and proteins, leading to genotoxic effects. We used the comet assay to monitor formation of cross-links in HL-60 cells treated with ECH, DEB, and the structurally related anti-cancer drug mechlorethamine (HN2). We report a time- and dose-dependent cytotoxicity that correlated with cross-linking activity, following the order HN2 > DEB > ECH. The rate of cross-link repair also varied with drug, with ECH-induced lesions the fastest to repair. High drug doses led to the formation of saturating amounts of HN2 cross-links that were repaired inefficiently. DEB and ECH produced fewer overall cross-links, but some were also resistant to repair. These persistent cross-links may activate cell-cycle arrest to allow repair of damage, with prolonged arrest triggering apoptosis. Quantitative reverse transcription polymerase chain reaction experiments revealed that treatment of HL-60 cells with DEB and ECH results in up-regulation of several genes involved in the intrinsic (mitochondrial) apoptosis pathway, including BAX, BAK1, CASP-9, APAF-1, and BCL-2. These findings contribute to our understanding of the principles underlying the carcinogenic potentials of these xenobiotics.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.05.020
      Issue No: Vol. 352 (2018)
       
  • Investigation of nonalcoholic fatty liver disease-induced drug metabolism
           by comparative global toxicoproteomics
    • Authors: Ann-Yae Na; Jung Jae Jo; Ok Kwang Kwon; Riya Shrestha; Piljoung Cho; Kyu Min Kim; Sung Hwan Ki; Tae Hee Lee; Tae Won Jeon; Tae Cheon Jeong; Sangkyu Lee
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Ann-Yae Na, Jung Jae Jo, Oh Kwang Kwon, Riya Shrestha, Pil Joung Cho, Kyu Min Kim, Sung Hwan Ki, Tae Hee Lee, Tae Won Jeon, Tae Cheon Jeong, Sangkyu Lee
      Non-alcoholic fatty liver disease (NAFLD) includes conditions such as steatosis, non-alcoholic steatohepatitis, and ultimately hepatocellular carcinoma. Although the pathology of NAFLD is well-established, NAFLD-induced drug metabolism mediated by cytochrome P450 (CYP) in the liver has remained largely unexplored. Therefore, we investigated NAFLD-induced drug metabolism mediated by CYP by quantitative toxicoproteomics analysis. After administration of a methionine-choline deficient (MCD) diet to induce development of NAFLD, tandem mass tags-based liquid chromatography-tandem mass spectrometry analysis was conducted to investigate the dynamics of hepatic proteins. A total of 1295 proteins were identified, of which 934 were quantified by proteomic analysis. Among these proteins, 21 proteins were up-regulated and 51 proteins were down-regulated by the MCD diet. Notably, domain annotation enrichment using InterPro indicated that proteins related to CYPs were significantly decreased. When we investigated CYP activity using in vivo and in vitro CYP cocktail assays, most CYPs were significantly decreased, whereas CYP2D was not changed after administration of the MCD diet. In conclusion, we identified significantly altered levels of CYPs and their activities induced by the MCD diet and confirmed the NAFLD-induced drug metabolism by pharmacokinetic analysis.
      Graphical abstract image

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.05.021
      Issue No: Vol. 352 (2018)
       
  • Membrane cholesterol delays cellular apoptosis induced by ginsenoside Rh2,
           a steroid saponin
    • Authors: Sandrine L. Verstraeten; Marie Albert; Adrien Paquot; Giulio G. Muccioli; Donatienne Tyteca; Marie-Paule Mingeot-Leclercq
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Sandrine L. Verstraeten, Marie Albert, Adrien Paquot, Giulio G. Muccioli, Donatienne Tyteca, Marie-Paule Mingeot-Leclercq
      Saponins exhibit several biological and pharmacological activities, such as antibacterial, anti-inflammatory and anticancer effects. Many studies attribute their activities to their interactions with cholesterol. In this study, we focus on the steroid saponin ginsenoside Rh2, one of the active principles of Panax ginseng root. Some evidence suggests that lipid rafts, defined as nanodomains enriched in cholesterol and sphingolipids, could be involved in the Rh2-induced apoptosis. However, the role of membrane lipids, especially cholesterol, in this process is still poorly understood. Here, we demonstrate that (i) A549, THP-1 and U937 cells are all susceptible to the Rh2-induced apoptosis but to a differential extent and (ii) the cytotoxic effect inversely correlates with the cell membrane cholesterol content. Upon cholesterol depletion via methyl-β-cyclodextrin, those three cells lines become more sensitive to Rh2-induced apoptosis. Then, focusing on the cholesterol-auxotroph U937 cell line, we showed that Rh2 alters plasma membrane fluidity by compacting the hydrophobic core of lipid bilayer (DPH anisotropy) and relaxing the interfacial packaging of the polar head of phospholipids (TMA-DPH anisotropy). The treatment with Rh2 conducts to the dephosphorylation of Akt and the activation of the intrinsic pathway of apoptosis (loss of mitochondrial membrane potential, caspase-9 and -3 activation). All these features are induced faster in cholesterol-depleted cells, which could be explained by faster cell accumulation of Rh2 in these conditions. This work is the first reporting that membrane cholesterol could delay the activity of ginsenoside Rh2, renewing the idea that saponin cytotoxicity is ascribed to an interaction with membrane cholesterol.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.05.014
      Issue No: Vol. 352 (2018)
       
  • Evaluation of kidney injury biomarkers in an adult Mexican population
           environmentally exposed to fluoride and low arsenic levels
    • Authors: Monica I. Jiménez-Córdova; Mariana Cárdenas-González; Guadalupe Aguilar-Madrid; Luz C. Sanchez-Peña; Ángel Barrera-Hernández; Iván A. Domínguez-Guerrero; Carmen González-Horta; Olivier C. Barbier; Luz M. Del Razo
      Pages: 97 - 106
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Monica I. Jiménez-Córdova, Mariana Cárdenas-González, Guadalupe Aguilar-Madrid, Luz C. Sanchez-Peña, Ángel Barrera-Hernández, Iván A. Domínguez-Guerrero, Carmen González-Horta, Olivier C. Barbier, Luz M. Del Razo
      Fluoride (F) is a toxicant widely distributed in the environment. Experimental studies have shown kidney toxicity from F exposure. However, co-exposure to arsenic (As) has not been considered, and epidemiological information remains limited. We evaluated the association between F exposure and urinary kidney injury biomarkers and assessed As co-exposure interactions. A cross-sectional study was conducted in 239 adults (18–77 years old) from three communities in Chihuahua, Mexico. Exposure to F was assessed in urine and drinking water, and As in urine samples. We evaluated the urinary concentrations of albumin (ALB), cystatin-C (Cys-C), kidney injury molecule 1 (KIM-1), clusterin (CLU), osteopontin (OPN), and trefoil factor 3 (TFF-3). The estimated glomerular filtration rate (eGFR) was calculated using serum creatinine (Creat) levels. We observed a positive correlation between water and urine F concentrations (ρ = 0.7419, p < 0.0001), with median values of 1.5 mg/L and 2 μg/mL, respectively, suggesting that drinking water was the main source of F exposure. The geometric mean of urinary As was 18.55 ng/mL, approximately 39% of the urine samples had As concentrations above the human biomonitoring value (15 ng/mL). Multiple linear regression models demonstrated a positive association between urinary F and ALB (β = 0.56, p < 0.001), Cys-C (β = 0.022, p = 0.001), KIM-1 (β = 0.048, p = 0.008), OPN (β = 0.38, p = 0.041), and eGFR (β = 0.49, p = 0.03); however, CLU (β = 0.07, p = 0.100) and TFF-3 (β = 1.14, p = 0.115) did not show significant associations. No interaction with As exposure was observed. In conclusion, F exposure was related to the urinary excretion of early kidney injury biomarkers, supporting the hypothesis of the nephrotoxic role of F exposure.

      PubDate: 2018-05-30T15:38:00Z
      DOI: 10.1016/j.taap.2018.05.027
      Issue No: Vol. 352 (2018)
       
  • TRAIL attenuates sulforaphane-mediated Nrf2 and sustains ROS generation,
           leading to apoptosis of TRAIL-resistant human bladder cancer cells
    • Authors: Cheng-Yun Jin; Ilandarage Menu Neelaka Molagoda; Wisurumuni Arachchilage Hasitha Maduranga Karunarathne; Sang-Hyuck Kang; Cheol Park; Gi-Young Kim; Yung Hyun Choi
      Pages: 132 - 141
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Cheng-Yun Jin, Ilandarage Menu Neelaka Molagoda, Wisurumuni Arachchilage Hasitha Maduranga Karunarathne, Sang-Hyuck Kang, Cheol Park, Gi-Young Kim, Yung Hyun Choi
      Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) can preferentially initiate apoptosis in malignant cells with minimal toxicity to normal cells. Unfortunately, many human cancer cells are refractory to TRAIL-induced apoptosis through many unknown mechanisms. Here, we report that TRAIL resistance can be reversed in human bladder cancer cell lines by treatment with sulforaphane (SFN), a well-known chemopreventive isothiocyanate in various cruciferous vegetables. Combined treatment with SFN and TRAIL (SFN/TRAIL) significantly induced apoptosis concomitant with activation of caspases, loss of mitochondrial membrane potential (MMP), Bid truncation, and induction of death receptor 5. Transient knockdown of Bid prevented collapse of MMP induced by SFN/TRAIL, consequently reducing apoptotic effects. Furthermore, SFN increased both the generation of reactive oxygen species (ROS) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is an anti-oxidant enzyme. Interestingly, TRAIL effectively suppressed SFN-mediated nuclear translocation of Nrf2, and the period of ROS generation was more extended compared to that of treatment with SFN alone. In addition, silencing of Nrf2 increased apoptosis in cells treated with SFN/TRAIL; however, blockade of ROS generation inhibited apoptotic activity. These data suggest that SFN-induced ROS generation promotes TRAIL sensitivity and SFN can be used for the management of TRAIL-resistant cancer.

      PubDate: 2018-06-02T15:40:14Z
      DOI: 10.1016/j.taap.2018.05.022
      Issue No: Vol. 352 (2018)
       
  • Incorporation of the glutathione conjugation pathway in an updated
           
    • Authors: Chimeddulam Dalaijamts; Joseph A. Cichocki; Yu-Syuan Luo; Ivan Rusyn; Weihsueh A. Chiu
      Pages: 142 - 152
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Chimeddulam Dalaijamts, Joseph A. Cichocki, Yu-Syuan Luo, Ivan Rusyn, Weihsueh A. Chiu
      Background Perchloroethylene (perc) induced target organ toxicity has been associated with tissue-specific metabolic pathways. Previous physiologically-based pharmacokinetic (PBPK) modeling of perc accurately predicted oxidative metabolites but suggested the need to better characterize glutathione (GSH) conjugation as well as toxicokinetic uncertainty and variability. Objectives We updated the previously published “harmonized” perc PBPK model in mice to better characterize GSH conjugation metabolism as well as the uncertainty and variability of perc toxicokinetics. Methods The updated PBPK model includes expanded models for perc and its oxidative metabolite trichloroacetic acid (TCA), and physiologically-based sub-models for conjugative metabolites. Previously compiled mouse kinetic data in B6C3F1 and Swiss-Webster mice were augmented to include data from a recent study in male C57BL/6J mice that measured perc and metabolites in serum and multiple tissues. Hierarchical Bayesian population analysis using Markov chain Monte Carlo was conducted to characterize uncertainty and inter-strain variability in perc metabolism. Results The updated model fit the data as well or better than the previously published “harmonized” PBPK model. Tissue dosimetry for both oxidative and conjugative metabolites was successfully predicted across the three strains of mice, with estimated residuals errors of 2-fold for majority of data. Inter-strain variability across three strains was evident for oxidative metabolism; GSH conjugation data were only available for one strain. Conclusions This updated PBPK model fills a critical data gap in quantitative risk assessment by predicting the internal dosimetry of perc and its oxidative and GSH conjugation metabolites and lays the groundwork for future studies to better characterize toxicokinetic variability.
      Graphical abstract image

      PubDate: 2018-06-08T15:48:39Z
      DOI: 10.1016/j.taap.2018.05.033
      Issue No: Vol. 352 (2018)
       
  • Neuroprotective effect of linagliptin against cuprizone-induced
           demyelination and behavioural dysfunction in mice: A pivotal role of
           AMPK/SIRT1 and JAK2/STAT3/NF-κB signalling pathway modulation
    • Authors: Eman M. Elbaz; Mahmoud A. Senousy; Dalia M. El-Tanbouly; Rabab H. Sayed
      Pages: 153 - 161
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Eman M. Elbaz, Mahmoud A. Senousy, Dalia M. El-Tanbouly, Rabab H. Sayed
      Multiple sclerosis is a chronic inflammatory demyelinating central nervous system disorder leading to serious neurological deficits. Linagliptin, a dipeptidyl peptidase-4 inhibitor, recently showed neuroprotective properties against neurodegenerative diseases. This study investigated the possible neuroprotective effect of linagliptin against cuprizone-induced demyelination in mice and its potential early-remyelinating properties. C57Bl/6 mice were fed chow containing 0.7% cuprizone for 1 week, followed by 3 weeks of a 0.2% cuprizone diet. Linagliptin (10 mg/kg/day, p.o.) was given for 3 weeks starting from the second week. Linagliptin treatment improved behavioural and motor abnormalities induced by cuprizone, as demonstrated by open field, rotarod and grip strength tests. In parallel, linagliptin lessened the demyelination through enhancing Olig2 gene expression, as shown by increased myelin basic protein, myelin proteolipid protein levels and Luxol fast blue-staining intensity. Linagliptin attenuated cuprizone-induced oxidative stress by decreasing brain thiobarbituric acid reactive substances along with restoring reduced glutathione levels. Linagliptin exerted an anti-inflammatory effect by reducing brain tumor necrosis factor-alpha. Interestingly, linagliptin diminished phosphorylated JAK2, phosphorylated STAT3 and NF-κB p65 protein expression while up-regulating phosphorylated AMP-activated protein kinase (p-AMPK) protein and SIRT1 gene expression levels. In conclusion, linagliptin exerted a neuroprotective effect in mice with cuprizone-induced demyelination possibly by modulating AMPK/SIRT1 and JAK2/STAT3/NF-κB signalling pathways.

      PubDate: 2018-06-08T15:48:39Z
      DOI: 10.1016/j.taap.2018.05.035
      Issue No: Vol. 352 (2018)
       
  • Toxicological study of a new doxorubicin-loaded pH-sensitive liposome: A
           preclinical approach
    • Authors: Juliana de Oliveira Silva; Sued Eustáquio Mendes Miranda; Elaine Amaral Leite; Adriano de Paula Sabino; Karina Braga Gomes Borges; Valbert Nascimento Cardoso; Geovanni Dantas Cassali; Andrea Grabe Guimarães; Mônica Cristina Oliveira; André Luis Branco de Barros
      Pages: 162 - 169
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Juliana de Oliveira Silva, Sued Eustáquio Mendes Miranda, Elaine Amaral Leite, Adriano de Paula Sabino, Karina Braga Gomes Borges, Valbert Nascimento Cardoso, Geovanni Dantas Cassali, Andrea Grabe Guimarães, Mônica Cristina Oliveira, André Luis Branco de Barros
      Doxorubicin (DOX) is widely used in cancer treatment, however, the use of this drug is often limited due to its cardiotoxic side effects. In order to avoid these adverse effects, the encapsulation of DOX into nanosystems has been used in the last decades. In this context, pH-sensitive liposomes have been shown promising for delivering cytotoxic agents into tumor cells, however, the lack of information about in vivo toxicity of this nanocarrier has impaired translational studies. Therefore, the aim of this work was to investigate the acute toxicity and cardiotoxicity of DOX-loading pH-sensitive liposomes (SpHL-DOX). To achieve this, female BALB/c mice, after intravenous administration, were monitored by means of clinical, laboratory, histopathological and electrocardiographic (ECG) analyses. Results indicate that SpHL was able to prevent renal toxicity and the hepatic injury was less extensive than free DOX. In addition, lower body weight loss was associated with less ECG QT interval prolongation to animals receiving SpHL-DOX (14.6 ± 5.2%) compared to animals receiving free DOX (35.7 ± 4.0%) or non-pH-sensitive liposomes (nSpHL-DOX) (47.0 ± 9.8%). These results corroborate with SpHL-DOX biodistribution studies published by our group. In conclusion, the SpHL-DOX showed less toxic effects on mice compared to free DOX or nSpHL-DOX indicating that SpHL-DOX is a promising strategy to reduce the serious cardiotoxic effects of DOX.

      PubDate: 2018-06-08T15:48:39Z
      DOI: 10.1016/j.taap.2018.05.037
      Issue No: Vol. 352 (2018)
       
  • Course-, dose-, and stage-dependent toxic effects of prenatal
           dexamethasone exposure on long bone development in fetal mice
    • Authors: Ze Chen; Xin Zhao; Yunzepeng Li; Rui Zhang; Zaihui Nie; Xiang Cheng; Xianrong Zhang; Hui Wang
      Abstract: Publication date: 15 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 351
      Author(s): Ze Chen, Xin Zhao, Yunzepeng Li, Rui Zhang, Zaihui Nie, Xiang Cheng, Xianrong Zhang, Hui Wang
      Dexamethasone is routinely used for treating those mothers at risk for preterm delivery. However, overexposure to exogenous glucocorticoids induces bone loss in offspring, and the “critical window” and safe dose of this treatment are largely unknown. In this study, we found that femoral length, and the length of the primary ossification center were significantly reduced in fetal mice after repeated prenatal dexamethasone exposure (PDE). Compared with single-course exposure on gestational day (GD)15, newborn mice with repeated PDE (3 times, from GD15 to 17) showed a significant decrease in femoral trabecular bone mass with decreased trabecular number and thickness. For those newborn mice treated after repeated PDE at different doses (0, 0.2, 0.8, and 1.2 mg/kg/d), the toxic effect of dexamethasone on bone development was observed at 0.8 and 1.2 mg/kg/d. More severe retardation in bone development was observed in the fetal mice after PDE at 0.8 mg/kg/d during GD12–14, compared with that during GD15–17. Interestingly, stronger toxic effects were observed in male newborn mice after PDE than were observed in female newborn mice. In conclusion, PDE with multiple course, higher dose, or exposure at an early stage of pregnancy have stronger toxic effects on bone development of fetal mice.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.05.005
      Issue No: Vol. 351 (2018)
       
  • Aggregate exposure of the adult French population to pyrethroids
    • Authors: Keyvin Darney; Laurent Bodin; Michèle Bouchard; Jonathan Côté; Jean-Luc Volatier; Virginie Desvignes
      Abstract: Publication date: 15 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 351
      Author(s): Keyvin Darney, Laurent Bodin, Michèle Bouchard, Jonathan Côté, Jean-Luc Volatier, Virginie Desvignes
      The French Nutrition and Health Survey (ENNS) reported higher biomarker levels of exposure to pyrethroids than those observed in North American and German biomonitoring studies. The authors therefore investigated aggregate exposure to permethrin as an initial case study because this compound is one of the most widely-used pyrethroid insecticides. We assessed several contamination sources—such as indoor and outdoor air, settled dust and diet—and several pathways, including oral, inhalation and dermal routes. We used permethrin exposure level estimations (computed from ENNS data) and a PBPK model calibrated with human kinetic data (from 6 individuals) to simulate an internal dose of cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- or trans-DCCA) in a population of 219 individuals. The urinary concentrations of cis- and trans -DCCA predicted by the PBPK model according to three permethrin exposure scenarios (“lower”, “intermediate”, and “upper”), were compared to the urinary levels measured in the ENNS study. The ENNS levels were between the levels simulated according to permethrin exposure scenarios “lower” and “intermediate”. The “upper” scenario led to an overestimation of the predicted urinary concentration levels of cis - and trans -DCCA compared to those measured in the ENNS study. The most realistic scenario was the “lower” one (permethrin concentration of left-censored data considered as 0). Using PBPK modeling, we estimated the contribution of each pathway and source to the internal dose. The main route of permethrin exposure was oral (98%), diet being the major source (87%) followed by dust (11%) then the dermal route (1.5%) and finally inhalation (0.5%).

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.05.007
      Issue No: Vol. 351 (2018)
       
  • Evaluation of the dose-response and fate in the lung and pleura of
           chrysotile-containing brake dust compared to chrysotile or crocidolite
           asbestos in a 28-day quantitative inhalation toxicology study
    • Authors: D.M. Bernstein; B. Toth; R.A. Rogers; R. Sepulveda; P. Kunzendorf; J.I. Phillips; H. Ernst
      Abstract: Publication date: 15 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 351
      Author(s): D.M. Bernstein, B. Toth, R.A. Rogers, R. Sepulveda, P. Kunzendorf, J.I. Phillips, H. Ernst
      This study provides an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake-dust (brakes manufactured with chrysotile). The design included a 28-day repeated multi-dose inhalation exposure (6 h/d, 5 d/wk, 4 wks) followed by 28-days without exposure. Fiber control groups included a similar grade chrysotile as used in the brakes and a commercial crocidolite asbestos. Aerosol fiber distributions of the chrysotile and crocidolite were similar (fiber-length > 20 μm/cm3: Chrysotile-low/high 42/62; Crocidolite-low/high 36/55; WHO-fibers/cm3: Chrysotile-low/high 192/219; Crocidolite-low/high 211/255). The total number of aerosol particles/cm3 in the brake-dust was similar to that in the chrysotile (Brake-dust 710–1065; Chrysotile 532–1442). Brake-dust at particle exposure levels equal to or greater than chrysotile or crocidolite caused no indication of microgranulomas, epithelial hyperplasia, or fibrosis (Wagner score < 1.7) or changes in bronchoalveolar lavage (BAL) indices from the air control. Chrysotile BAL indices did not differ from the air control. Pathologically, there was low level of inflammation and epithelial hyperplasia, but no fibrosis (Wagner score ≤ 3). Crocidolite induced elevated neutrophils and cell damage (BAL), persistent inflammation, microgranulomas, and fibrosis (Wagner scores 4) which persisted through the post exposure period. Confocal microscopy of snap-frozen chestwalls showed no difference between control, brake-dust and chrysotile-HD groups or in thickness of visceral or parietal pleural. The crocidolite exposure resulted in extensive inflammatory response, collagen development and adhesions between the visceral and parietal surfaces with double the surface thickness. These results provide essential information for the design of a subsequent subchronic study.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.04.033
      Issue No: Vol. 351 (2018)
       
  • Inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine
           ameliorates monosodium urate crystal-induced inflammation
    • Authors: Yanzhuo Liu; Chenfan Duan; Honglei Chen; Chenlong Wang; Xiaoxiao Liu; Miao Qiu; Honglin Tang; Feng Zhang; Xiaoyang Zhou; Jing Yang
      Pages: 1 - 11
      Abstract: Publication date: 15 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 351
      Author(s): Yanzhuo Liu, Chenfan Duan, Honglei Chen, Chenlong Wang, Xiaoxiao Liu, Miao Qiu, Honglin Tang, Feng Zhang, Xiaoyang Zhou, Jing Yang
      Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and microsomal prostaglandin E synthase-1 (mPGES-1)-derived eicosanoids play an essential role in human inflammatory disorders. Here, we investigated whether inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine ameliorates monosodium urate (MSU) crystal-induced inflammation. Virtual screening assay and in vitro enzyme inhibition assay showed that leonurine was a potential inhibitor of COX-2, mPGES-1 and 5-LOX. Compared with COX-2 inhibitor celecoxib, leonurine (30 mg/kg) significantly decreased ankle perimeter, gait score and neutrophil number in synovial fluid in MSU crystal-treated rats, accompanied with the decreased expression of COX-2, mPGES-1 and 5-LOX and production of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the synovial fluid macrophages. In addition, leonurine decreased representative M1 marker (iNOS and CD86) expression, NLRP3 inflammasome activation and M1 cytokine (TNF-α and IL-1β) production. In the in vitro cultured RAW264.7 and human monocyte-derived macrophages (MDMs), blockade of COX-2/mPGES-1 and 5-LOX by leonurine inhibited macrophage M1 polarization and NLRP3 inflammasome activation in response to MSU crystals, and thus down-regulated IL-1β and TNF-α with STAT1 and NF-κB inactivation. Conversely, these effects were partially abolished by overexpression of COX-2, mPGES-1, 5-LOX or STAT1. Furthermore, leonurine prevented a positive feedback loop between COX-2/mPGES-1/5-LOX and IL-1β/TNF-α in MSU crystal-induced inflammation. Together, simultaneous down-regulation of COX-2/mPGES-1 and 5-LOX by leonurine ameliorates MSU crystal-induced inflammation through decreasing IL-1β and TNF-α production. Our study may provide novel multi-target agents toward the arachidonic acid (AA) network for gouty arthritis therapy.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.05.010
      Issue No: Vol. 351 (2018)
       
  • Disposition and metabolism of the bisphenol analogue, bisphenol S, in
           Harlan Sprague Dawley rats and B6C3F1/N mice and in vitro in hepatocytes
           from rats, mice, and humans
    • Authors: Suramya Waidyanatha; Sherry R. Black; Rodney W. Snyder; Yun Lan Yueh; Vicki Sutherland; Purvi R. Patel; Scott L. Watson; Timothy R. Fennell
      Pages: 32 - 45
      Abstract: Publication date: 15 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 351
      Author(s): Suramya Waidyanatha, Sherry R. Black, Rodney W. Snyder, Yun Lan Yueh, Vicki Sutherland, Purvi R. Patel, Scott L. Watson, Timothy R. Fennell
      With the removal of bisphenol A (BPA) from many consumer products, the potential use of alternatives such as bisphenol S (BPS) and its derivatives is causing some concerns. These studies investigated the comparative in vitro hepatic clearance and metabolism of BPS and derivatives and the disposition and metabolism of BPS in rats and mice following gavage and intravenous administration. The clearance of BPS and its derivatives was slower in human hepatocytes than in rodents. In male rats following gavage administration of 50, 150, and 500 mg/kg [14C]BPS the main route of excretion was via urine; the urinary excretion decreased (72 to 48%) and the fecal excretion increased (16 to 30%) with increasing dose. The disposition was similar in female rats and male and female mice following gavage administration. Radioactivity remaining in tissues at 72 h in both species and sexes was ≤2.4%. In bile duct cannulated rats 53% of a gavage dose was secreted in bile suggesting extensive enterohepatic recirculation of [14C]BPS. Following an intravenous dose in rats and mice, the pattern of excretion was similar to gavage. These data suggest that the dose excreted in feces folowing gavage administration is likely the absorbed dose. Urinary metabolites included the glucuronide and sulfate conjugates with a moderate amount of parent. The pattern of in vitro hepatic metabolsim was similar to in vivo with some difference among derivatives. These data suggest that similar to other bisphenol analogues, BPS was well absorbed following oral expsosure and extensively excreted with minimal tissue retention.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.05.008
      Issue No: Vol. 351 (2018)
       
  • Effects of phenidone (DuCLOX-2/5 inhibitor) against N-methyl-N-nitrosourea
           induced mammary gland carcinoma in albino rats
    • Authors: Swetlana Gautam; Soniya Rani; Sara A. Aldossary; Abdulaziz S. Saeedan; Mohd. Nazam Ansari; Gaurav Kaithwas
      Pages: 57 - 63
      Abstract: Publication date: 15 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 351
      Author(s): Swetlana Gautam, Soniya Rani, Sara A. Aldossary, Abdulaziz S. Saeedan, Mohd. Nazam Ansari, Gaurav Kaithwas
      The present study was designed to evaluate the effects of phenidone (Dual inhibitor of COX-2 and 5-LOX, DuCLOX-2/5 inhibitor) on various aspects of cancer chemoprevention. Treatment with the phenidone was inquested to validate the implications of dual inhibition of arachidonic acid (AA) metabolism against MNU induced mammary gland carcinogenesis. MNU treated rat showed altered hemodynamic profile, distorted cellular architecture, upregulated inflammatory enzyme markers (COX, LOX, Nitric oxide and hydrogen sulfide) and distorted oxidative stress markers (thiobarbituric acid reactive substances, protein carbonyl, superoxide dismutase, catalase and glutathione). Phenidone treatment regulated histological architecture in the experimental animals similar to control. The treatment with phenidone favorably regulated the levels of inflammatory markers, and oxidative stress markers against toxic treatment. Our findings emphasize the potential role of phenidone in suppression of mammary gland carcinoma against the deleterious effects of MNU.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.04.019
      Issue No: Vol. 351 (2018)
       
  • Monosodium glutamate induced nociception and oxidative stress dependent on
           time of administration, age of rats and susceptibility of spinal cord and
           brain regions
    • Authors: Suzan Gonçalves Rosa; Pietro Maria Chagas; Ana Paula Pesarico; Cristina Wayne Nogueira
      Pages: 64 - 73
      Abstract: Publication date: 15 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 351
      Author(s): Suzan Gonçalves Rosa, Pietro Maria Chagas, Ana Paula Pesarico, Cristina Wayne Nogueira
      Monosodium glutamate (MSG), a food flavor enhancer used worldwide, has been studied because it may cause neurotoxicity, which is associated with oxidative stress. The aim of this study was to investigate whether spinal cord and brain regions are affected by oxidative stress and the temporal profile of nociceptive responses induced by MSG in newborn and adult rats. The newborn (post natal day, PND 1) Wistar rats received ten subcutaneous injections of MSG (4.0 g/kg) or saline solution. At PND 3, 11 or 90, the rats performed nociceptive tests and parameters of oxidative stress were evaluated in samples of spinal cord and brain regions. Adult rats (PND 90) were injected with MSG (4.0 g/kg, 10 injections) or saline solution, but MSG did not induce nociception or oxidative stress. The neonatal administration of MSG increased nociceptive behavior in the tail immersion, hot plate and formalin tests and decreased the SOD activity in spinal cord of PND 3 rats. In rats at PND 11 and 90, the neonatal administration of MSG increased mechanical allodynia and nociceptive behavior in the hot plate and formalin tests. The neonatal administration of MSG induced oxidative stress in the hippocampus of rats at PND 11 and in the cerebral cortex at PND 90. These findings demonstrate that nociception and oxidative stress was induced in rats dependent on the time of MSG administration, susceptibility of spinal cord and brain regions and the age of rats.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.05.019
      Issue No: Vol. 351 (2018)
       
  • N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) attenuates silicotic
           fibrosis by suppressing apoptosis of alveolar type II epithelial cells via
           mediation of endoplasmic reticulum stress
    • Authors: Lijuan Zhang; Dingjie Xu; Qian Li; Yi Yang; Hong Xu; Zhongqiu Wei; Ruimin Wang; Wenli Zhang; Yan Liu; Yucong Geng; Shifeng Li; Xuemin Gao; Fang Yang
      Pages: 1 - 10
      Abstract: Publication date: 1 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 350
      Author(s): Lijuan Zhang, Dingjie Xu, Qian Li, Yi Yang, Hong Xu, Zhongqiu Wei, Ruimin Wang, Wenli Zhang, Yan Liu, Yucong Geng, Shifeng Li, Xuemin Gao, Fang Yang
      Damage to alveolar epithelial cells (AECs) caused by long-term inhalation of large amounts of silica dust plays a significant role in the pathology of silicosis. The present study was undertaken to investigate the regulatory mechanism(s) involved in type II AEC damage from silicon dioxide (SiO2) as well as the mechanism(s) related to the prevention of silicosis by the antifibrotic tetra peptide, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). The 2-DE results showed that SiO2 induced endoplasmic reticulum (ER) stress in A549 cells. In addition, typical apoptotic characteristics were observed using a transmission electron microscope (TEM) in A549 cells stimulated by SiO2 and in type II AECs from silicotic rats. Mechanistic study showed that both Ac-SDKP and 4-phenylbutyrate (4-PBA), an inhibiter of ER stress, attenuated GRP78, phosphor–PERK, phosphor-eIF2α, CHOP and Caspase-12 protein expression in A549 cells stimulated by SiO2 and in type II AECs from silicotic rats. Treatment with Ac-SDKP and 4-PBA in vivo effectively inhibited collagen deposition in the lungs of silicotic rats. In summary, ER stress is involved in the apoptosis of type II AECs both in vitro and in vivo. Ac-SDKP effectively suppresses SiO2-induced apoptosis in type II AECs by attenuating the Caspase-12 and PERK/eIF2α/CHOP pathway activation caused by ER stress, thus preventing silicotic fibrosis.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.04.025
      Issue No: Vol. 350 (2018)
       
  • Salvianolic acid A alleviates chronic ethanol-induced liver injury via
           promotion of β-catenin nuclear accumulation by restoring SIRT1 in rats
    • Authors: Xue Shi; Yan Zhao; Chunchun Ding; Zhecheng Wang; Anlong Ji; Zhenlu Li; Dongcheng Feng; Yang Li; Dongyan Gao; Junjun Zhou; Xiaofeng Tian; Jihong Yao
      Pages: 21 - 31
      Abstract: Publication date: 1 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 350
      Author(s): Xue Shi, Yan Zhao, Chunchun Ding, Zhecheng Wang, Anlong Ji, Zhenlu Li, Dongcheng Feng, Yang Li, Dongyan Gao, Junjun Zhou, Xiaofeng Tian, Jihong Yao
      In recent years, alcoholic liver disease (ALD) has emerged as a growing public health problem worldwide. β-catenin plays an important role in the growth, development, regeneration and metabolic activity of the liver. Salvianolic acid A (SalA) is a water-soluble component from the root extract of Salvia miltiorrhiza Bunge, and its effect on ALD has not yet been investigated. This study aimed to investigate the effect of SalA on chronic alcohol-induced liver injury and to explore the role of SIRT1-mediated β-catenin deacetylation in such an effect. In this study, SalA treatment significantly alleviated the accumulation of lipid droplets and reduced the plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), alcohol and ammonia levels in rats. SalA enhanced ethanol and ammonia metabolism and maintained mitochondrial homeostasis. Moreover, SalA restored the activity of the major ethanol-metabolizing enzymes and oxidative stress functions in the liver. Importantly, we found that SalA treatment effectively inhibited the ethanol-mediated decrease in nuclear β-catenin by upregulating SIRT1 in the liver. SIRT1 then deacetylated β-catenin to promote its accumulation in the nucleus, thereby preventing alcohol-induced liver injury. The results demonstrate that the SIRT1/β-catenin pathway is a key therapeutic target in liver injury caused by chronic alcohol exposure and that SalA protects against alcohol-induced liver injury via the SIRT1-mediated deacetylation of β-catenin.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.04.036
      Issue No: Vol. 350 (2018)
       
  • Sodium tanshinone IIA sulfonate promotes endothelial integrity via
           regulating VE-cadherin dynamics and RhoA/ROCK-mediated cellular
           contractility and prevents atorvastatin-induced intracerebral hemorrhage
           in zebrafish
    • Authors: Zhong-Yan Zhou; Bin Huang; Shang Li; Xiao-Hui Huang; Jing-Yi Tang; Yiu Wa Kwan; Pui Man Hoi; Simon Ming-Yuen Lee
      Pages: 32 - 42
      Abstract: Publication date: 1 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 350
      Author(s): Zhong-Yan Zhou, Bin Huang, Shang Li, Xiao-Hui Huang, Jing-Yi Tang, Yiu Wa Kwan, Pui Man Hoi, Simon Ming-Yuen Lee
      Impaired vascular integrity leads to serious cerebral vascular diseases such as intracerebral hemorrhage (ICH). In addition, high-dose statin therapy is suggested to cause increased ICH risk due to unclear effects of general inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) on the vascular system. Here we evaluated the protective effects of sodium tanshinone IIA sulfonate (STS), which has high efficacy and safety in clinical studies of ischemic stroke, by using atorvastatin (Ator) induced ICH zebrafish embryos and human umbilical vein endothelial cells (HUVECs). By using double transgenic Tg(fli1a:EGFP)y1 & Tg(gata1a:dsRed)sd2 zebrafish, we demonstrated that STS effectively reduced the occurrence and area of hemorrhage induced by Ator in zebrafish and restored impairment in motor function. We further demonstrated that Ator-induced disruption in VE-cadherin (VEC)-containing cell-cell adherens junctions (AJs) in HUVECs by enhancing Src-induced VEC internalization and RhoA/ROCK-mediated cellular contraction. STS inhibited Ator-induced Src activation and subsequent VEC internalization and actin depolymerization near cell borders, reducing lesions between neighboring cells and increasing barrier functions. STS also inhibited the Ator-induced RhoA/ROCK-mediated cellular contraction by regulating downstream LIMK/cofilin and MYPT1/MLC phosphatase signaling. These results showed that STS significantly promoted the stability of cell junctions and vascular integrity. Moreover, we observed that regulations of both Src and RhoA/ROCK are required for the maintenance of vascular integrity, and Src inhibitor (PP2) or ROCK inhibitors (fasudil and H1152) alone could not reduce the occurrence Ator-induced ICH. Taken together, we investigated the underlying mechanisms of Ator-induced endothelial instability, and provided scientific evidences of STS as potential ICH therapeutics by promoting vascular integrity.
      Graphical abstract image

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.04.037
      Issue No: Vol. 350 (2018)
       
  • Feraheme® suppresses immune function of human T lymphocytes through
           mitochondrial damage and mitoROS production
    • Authors: Ankit Shah; Cassandra I. Mankus; Alison M. Vermilya; Ferri Soheilian; Jeffrey D. Clogston; Marina A. Dobrovolskaia
      Pages: 52 - 63
      Abstract: Publication date: 1 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 350
      Author(s): Ankit Shah, Cassandra I. Mankus, Alison M. Vermilya, Ferri Soheilian, Jeffrey D. Clogston, Marina A. Dobrovolskaia
      Despite attractive properties for both therapeutic and diagnostic applications, the clinical use of iron oxide nanoparticles (IONPs) is limited to iron replacement in severely anemic patient populations. While several studies have reported about the immunotoxicity of IONPs, the mechanisms of this toxicity are mostly unknown. We conducted a mechanistic investigation using an injectable form of IONP, Feraheme®. In the cultures of primary human T cells, Feraheme induced miotochondrial oxidative stress and resulted in changes in mitochondrial dynamics, architecture, and membrane potential. These molecular events were responsible for the decrease in cytokine production and proliferation of mitogen-activated T cells. The induction of mitoROS by T cells in response to Feraheme was insufficient to induce total redox imbalance at the cellular level. Consequently, we resolved this toxicity by the addition of the mitochondria-specific antioxidant MitoTEMPO. We further used these findings to develop an experimental framework consisting of critical assays that can be used to estimate IONP immunotoxicity. We explored this framework using several immortalized T-cell lines and found that none of them recapitulate the toxicity observed in the primary cells. Next, we compared the immunotoxicity of Feraheme to that of other FDA-approved iron-containing complex drug formulations and found that the mitochondrial damage and the resulting suppression of T-cell function are specific to Feraheme. The framework, therefore, can be used for comparing the immunotoxicity of Feraheme with that of its generic versions, while other iron-based complex drugs require case-specific mechanistic investigation.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.04.028
      Issue No: Vol. 350 (2018)
       
  • Increased butyrate priming in the gut stalls microbiome
           associated-gastrointestinal inflammation and hepatic metabolic
           reprogramming in a mouse model of Gulf War Illness
    • Authors: Ratanesh Kumar Seth; Diana Kimono; Firas Alhasson; Sutapa Sarkar; Muayad Albadrani; Stephen K. Lasley; Ronnie Horner; Patricia Janulewicz; Mitzi Nagarkatti; Prakash Nagarkatti; Kimberly Sullivan; Saurabh Chatterjee
      Pages: 64 - 77
      Abstract: Publication date: 1 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 350
      Author(s): Ratanesh Kumar Seth, Diana Kimono, Firas Alhasson, Sutapa Sarkar, Muayad Albadrani, Stephen K. Lasley, Ronnie Horner, Patricia Janulewicz, Mitzi Nagarkatti, Prakash Nagarkatti, Kimberly Sullivan, Saurabh Chatterjee
      Most of the associated pathologies in Gulf War Illness (GWI) have been ascribed to chemical and pharmaceutical exposures during the war. Since an increased number of veterans complain of gastrointestinal (GI), neuroinflammatory and metabolic complications as they age and there are limited options for a cure, the present study was focused to assess the role of butyrate, a short chain fatty acid for attenuating GWI-associated GI and metabolic complications. Results in a GWI-mouse model of permethrin and pyridostigmine bromide (PB) exposure showed that oral butyrate restored gut homeostasis and increased GPR109A receptor copies in the small intestine (SI). Claudin-2, a protein shown to be upregulated in conditions of leaky gut was significantly decreased following butyrate administration. Butyrate decreased TLR4 and TLR5 expressions in the liver concomitant to a decrease in TLR4 activation. GW-chemical exposure showed no clinical signs of liver disease but a significant alteration of metabolic markers such as SREBP1c, PPAR-α, and PFK was evident. Liver markers for lipogenesis and carbohydrate metabolism that were significantly upregulated following GW chemical exposure were attenuated by butyrate priming in vivo and in human primary hepatocytes. Further, Glucose transporter Glut-4 that was shown to be elevated following liver complications were significantly decreased in these mice after butyrate administration. Finally, use of TLR4 KO mice completely attenuated the liver metabolic changes suggesting the central role of these receptors in the GWI pathology. In conclusion, we report a butyrate specific mechanistic approach to identify and treat increased metabolic abnormalities in GWI veterans with systemic inflammation, chronic fatigue, GI disturbances, metabolic complications and weight gain.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.05.006
      Issue No: Vol. 350 (2018)
       
  • Differentiation of sow and mouse ovarian granulosa cells exposed to
           zearalenone in vitro using RNA-seq gene expression
    • Authors: Guo-Liang Zhang; Jun-Lin Song; Yi Zhou; Rui-Qian Zhang; Shun-Feng Cheng; Xiao-Feng Sun; Guo-Qing Qin; Wei Shen; Lan Li
      Pages: 78 - 90
      Abstract: Publication date: 1 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 350
      Author(s): Guo-Liang Zhang, Jun-Lin Song, Yi Zhou, Rui-Qian Zhang, Shun-Feng Cheng, Xiao-Feng Sun, Guo-Qing Qin, Wei Shen, Lan Li
      Zearalenone (ZEA), a natural contaminant found in feed, has been shown to have a negative impact on domestic animal reproduction, particularly in pigs. There are species-specific differences in the ZEA-induced toxicity pattern. Here, we investigated the different biological effects of ZEA exposure on porcine and mouse granulosa cells, using RNA-seq analysis. We treated murine and porcine granulosa cells with 10 μM and 30 μM ZEA during 72 h of culturing, in vitro. The results showed that 10 μM ZEA exposure significantly altered mitosis associated genes in porcine granulosa cells, while the same treatment significantly altered the steroidogenesis associated genes in mouse granulosa cells. Exposure to 30 μM ZEA resulted in significantly up-regulated expression of inflammatory related genes in porcine granulosa cells as well as the cancer related genes in mouse granulosa cells. Similarly, 30 μM ZEA exposure significantly decreased the expression of tumor suppressor factors in the mouse granulosa cells. Furthermore, immunofluorescence, RT-qPCR as well as western-blot analysis verified the different expression of related genes in ZEA exposed porcine and mouse granulosa cells. Collectively, these results illustrate the presence of species differences with regards to ZEA effects between porcine and mouse ovarian granulosa cells, in vitro.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.05.003
      Issue No: Vol. 350 (2018)
       
  • Pharmacologic inhibition of S1P attenuates ATF6 expression, causes ER
           stress and contributes to apoptotic cell death
    • Authors: Paul Lebeau; Jae Hyun Byun; Tamana Yousof; Richard C. Austin
      Pages: 1 - 7
      Abstract: Publication date: 15 June 2018
      Source:Toxicology and Applied Pharmacology, Volume 349
      Author(s): Paul Lebeau, Jae Hyun Byun, Tamana Yousof, Richard C. Austin
      Mammalian cells express unique transcription factors embedded in the endoplasmic reticulum (ER) membrane, such as the sterol regulatory element-binding proteins (SREBPs), that promote de novo lipogenesis. Upon their release from the ER, the SREBPs require proteolytic activation in the Golgi by site-1-protease (S1P). As such, inhibition of S1P, using compounds such as PF-429242 (PF), reduces cholesterol synthesis and may represent a new strategy for the management of dyslipidemia. In addition to the SREBPs, the unfolded protein response (UPR) transducer, known as the activating transcription factor 6 (ATF6), is another ER membrane-bound transcription factor that requires S1P-mediated activation. ATF6 regulates ER protein folding capacity by promoting the expression of ER chaperones such as the 78-kDa glucose-regulated protein (GRP78). ER-resident chaperones like GRP78 prevent and/or resolve ER polypeptide accumulation and subsequent ER stress-induced UPR activation by folding nascent polypeptides. Here we report that pharmacological inhibition of S1P reduced the expression of ATF6 and GRP78 and induced the activation of UPR transducers inositol-requiring enzyme-1α (IRE1α) and protein kinase RNA-like ER kinase (PERK). As a consequence, S1P inhibition also increased the susceptibility of cells to ER stress-induced cell death. Our findings suggest that S1P plays a crucial role in the regulation of ER folding capacity and also identifies a compensatory cross-talk between UPR transducers in order to maintain adequate ER chaperone expression and activity.

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.04.020
      Issue No: Vol. 349 (2018)
       
  • Effects of selective serotonin-reuptake inhibitors (SSRIs) on human
           villous trophoblasts syncytialization
    • Authors: Hélène Clabault; Denis Flipo; Jean Guibourdenche; Thierry Fournier; J. Thomas Sanderson; Cathy Vaillancourt
      Pages: 8 - 20
      Abstract: Publication date: 15 June 2018
      Source:Toxicology and Applied Pharmacology, Volume 349
      Author(s): Hélène Clabault, Denis Flipo, Jean Guibourdenche, Thierry Fournier, J. Thomas Sanderson, Cathy Vaillancourt
      Selective serotonin-reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants during pregnancy. The human placenta is a highly specialized organ supporting normal growth and development of the fetus. Therefore, this study aims to analyze the effects of SSRIs on villous cytotrophoblasts cells, using BeWo cells and human placental trophoblast cells in primary culture. The SSRIs fluoxetine and its metabolite norfluoxetine, sertraline and venlafaxine did not affect BeWo cell proliferation and viability, nor the percentage of M30-positive (apoptotic) primary trophoblast cells. None of the SSRIs affected basal or forskolin-stimulated BeWo cell fusion, whereas sertraline and venlafaxine increased the fusion of primary villous trophoblasts. Sertraline and venlafaxine also modified human chorionic gonadotropin beta (β-hCG) secretion by BeWo cells, whereas none of the SSRIs affected β-hCG secretion in primary trophoblasts. Norfluoxetine increased CGB (chorionic gonadotropin beta) and GJA1 (gap junction protein alpha 1) levels of gene expression (biomarkers of syncytialization) in BeWo cells, whereas in primary trophoblasts none of the SSRIs tested affected the expression of these genes. This study shows that SSRIs affect villous trophoblast syncytialization in a structure- and concentration-dependent manner and suggests that certain SSRIs may compromise placental health. In addition, it highlights the importance of using primary trophoblast cells instead of “trophoblast -like” cell lines to assess the effects of medications on human villous trophoblast function.
      Graphical abstract image

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.04.018
      Issue No: Vol. 349 (2018)
       
  • Dichlorophenyl piperazines, including a recently-approved atypical
           antipsychotic, are potent inhibitors of DHCR7, the last enzyme in
           cholesterol biosynthesis
    • Authors: Thiago C. Genaro-Mattos; Keri A. Tallman; Luke B. Allen; Allison Anderson; Karoly Mirnics; Zeljka Korade; Ned A. Porter
      Pages: 21 - 28
      Abstract: Publication date: 15 June 2018
      Source:Toxicology and Applied Pharmacology, Volume 349
      Author(s): Thiago C. Genaro-Mattos, Keri A. Tallman, Luke B. Allen, Allison Anderson, Karoly Mirnics, Zeljka Korade, Ned A. Porter
      While antipsychotic medications provide important relief from debilitating psychotic symptoms, they also have significant adverse side effects, which might have relevant impact on human health. Several research studies, including ours, have shown that commonly used antipsychotics such as haloperidol and aripiprazole affect cholesterol biosynthesis at the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol. This transformation is promoted by the enzyme DHCR7 and its inhibition causes increases in plasma and tissue levels of 7-DHC. The inhibition of this enzymatic step by mutations in the Dhcr7 gene leads to Smith-Lemli-Opitz syndrome, a devastating human condition that can be replicated in rats by small molecule inhibitors of DHCR7. The fact that two compounds, brexpiprazole and cariprazine, that were recently approved by the FDA have substructural elements in common with the DHCR7 inhibitor aripiprazole, prompted us to evaluate the effect of brexpiprazole and cariprazine on cholesterol biosynthesis. We report that cariprazine affects levels of 7-DHC and cholesterol in cell culture incubations at concentrations as low as 5 nM. Furthermore, a common metabolite of cariprazine and aripiprazole, 2,3-(dichlorophenyl) piperazine, inhibits DHCR7 activity at concentrations comparable to those of the potent teratogen AY9944. The cell culture experiments were corroborated in mice in studies showing that treatment with cariprazine elevated 7-DHC in brain and serum. The consequences of sterol inhibition by antipsychotics in the developing nervous system and the safety of their use during pregnancy remains to be established.
      Graphical abstract image

      PubDate: 2018-05-28T15:37:07Z
      DOI: 10.1016/j.taap.2018.04.029
      Issue No: Vol. 349 (2018)
       
  • Sex differences in effects of gestational polychlorinated biphenyl
           exposure on hypothalamic neuroimmune and neuromodulator systems in
           neonatal rats
    • Abstract: Publication date: 15 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 353
      Author(s): Margaret R. Bell, Ariel Dryden, Ryan Will, Andrea C. Gore
      Polychlorinated biphenyls (PCBs) are ubiquitous in the environment and exposure to them is associated with immune, endocrine and neural dysfunction. Effects of PCBs on inflammation and immunity are best described in spleen and blood, with fewer studies on neural tissues. This is an important gap in knowledge, as molecules typically associated with neuroinflammation also serve neuromodulatory roles and interact with hormones in normal brain development. The current study used Sprague-Dawley rats to assess whether gestational PCB exposure altered hypothalamic gene expression and serum cytokine concentration in neonatal animals given an immune challenge. Dams were fed wafers containing a mixture of PCBs at an environmentally relevant dose and composition (20 μg/kg, 1:1:1 Aroclor 1242:1248:1254) or oil vehicle control throughout their pregnancy. One day old male and female offspring were treated with an inflammatory challenge (lipopolysaccharide, LPS, 50 μg/kg, sc) or saline vehicle control approximately 3.5 h prior to tissue collection. Across both basal and activated inflammatory states, PCB exposure caused greater expression of a subset of inflammatory genes in the hypothalamus and lower expression of genes involved in dopamine, serotonin, and opioid systems compared to oil controls. PCB exposure also altered reactions to inflammatory challenge: it reversed the normal decrease in Esr2 hypothalamic expression and induced an abnormal increase in IL-1b and IL-6 serum concentration in response to LPS. Many of these effects were sex specific. Given the potential long-term consequences of neuroimmune disruption, our findings demonstrate the need for further research.

      PubDate: 2018-06-20T08:17:29Z
       
  • Prompt treatment with uridine triacetate improves survival and reduces
           toxicity due to fluorouracil and capecitabine overdose or
           dihydropyrimidine dehydrogenase deficiency
    • Abstract: Publication date: 15 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 353
      Author(s): Rolando A.G. Garcia, Joel A. Saydoff, Michael K. Bamat, Reid W. von Borstel
      Uridine triacetate has been shown to be an effective antidote against mortality and toxicity caused by either overdoses or exaggerated susceptibility to the widely used anticancer agents 5-fluorouracil (5-FU) and capecitabine. However, a direct assessment of efficacy based on when emergency treatment was initiated was not clinically feasible. In this study we used mouse models of 5-FU overdose and of dihydropyrimidine dehydrogenase (DPD) deficiency to compare the efficacy of uridine triacetate in reducing toxicity and mortality when treatment was initiated at time points from 4 to 144 h after administration of 5-FU. We found that uridine triacetate was effective both in the 5-FU overdose and DPD deficiency models. Starting treatment within 24 h was most effective at reducing toxicity and mortality in both models, while treatment starting more than 96 to 120 h after 5-FU was far less effective. Uridine triacetate also reduced mortality in the DPD deficiency model when mice were treated with the 5-FU prodrug capecitabine. The results of this study are supportive of clinical observations and practice, indicating that efficacy declined progressively with later and later treatment initiation. Prompt treatment with uridine triacetate, within 24 h, conferred the greatest protection against 5-FU overexposure.

      PubDate: 2018-06-20T08:17:29Z
       
  • Biological mechanisms of non-linear dose-response for respirable mineral
           fibers
    • Abstract: Publication date: Available online 20 June 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Louis Anthony (Tony) Cox
      Sufficiently high and prolonged inhalation exposures to some respirable elongated mineral particles (REMPs), notably including amphibole asbestos fibers, can increase risk of inflammation-mediated diseases including malignant mesothelioma, pleural diseases, fibrosis, and lung cancer. Chronic inflammation involves ongoing activation of the NLRP3 inflammasome, which enables immune cells to produce potent proinflammatory cytokines IL-1β and IL-18. Reactive oxygen species (ROS) (in particular, mitochondrial ROS) contribute to NRLP3 activation via a well-elucidated mechanism involving oxidation of reduced thioredoxin and association of thioredoxin-interacting protein with NLRP3. Lysosomal destabilization, efflux of cytosolic potassium ions and influx of calcium ions, signals from damaged mitochondria, both translational and post-translational controls, and prion-like polymerization have increasingly clear roles in regulating NLRP3 activation. As the molecular biology of inflammation-mediated responses to REMP exposure becomes clearer, a practical question looms: What do these mechanisms imply for the shape of the dose-response function relating exposure concentrations and durations for EMPs to risk of pathological responses' Dose-response thresholds or threshold-like nonlinearities can arise from (a) Cooperativity in assembly of supramolecular signaling complexes; (b) Positive feedback loops and bistability in regulatory networks; (c) Overwhelming of defensive barriers maintaining homeostasis; and (d) Damage thresholds, as in lysosome destabilization-induced activation of NLRP3. Each of these mechanisms holds for NLRP3 activation in response to stimuli such as REMP exposures. It is therefore timely to consider the implications of these advances in biological understanding for human health risk assessment with dose-response thresholds.

      PubDate: 2018-06-20T08:17:29Z
       
  • Broad spectrum proteomics analysis of the inferior colliculus following
           acute hydrogen sulfide exposure
    • Abstract: Publication date: Available online 19 June 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Dong-Suk Kim, Poojya Anantharam, Andrea Hoffmann, Mitchell L. Meade, Nadja Grobe, Jeffery M. Gearhart, Elizabeth M. Whitley, Belinda Mahama, Wilson K. Rumbeiha
      Acute exposure to high concentrations of H2S causes severe brain injury and long-term neurological disorders, but the mechanisms involved are not known. To better understand the cellular and molecular mechanisms involved in acute H2S-induced neurodegeneration we used a broad-spectrum proteomic analysis approach to identify key molecules and molecular pathways involved in the pathogenesis of acute H2S-induced neurotoxicity and neurodegeneration. Mice were subjected to acute inhalation exposure of up to750 ppm of H2S. H2S induced behavioral deficits and severe lesions including hemorrhage in the inferior colliculus (IC). The IC was microdissected for proteomic analysis. Tandem mass tags (TMT) liquid chromatography mass spectrometry (LC-MS/MS)-based quantitative proteomics was applied for protein identification and quantitation. LC-MS/MS identified 598, 562, and 546 altered proteomic changes at 2 h, and on days 2 and 4 post-H2S exposure, respectively. Of these, 77 proteomic changes were statistically significant at any of the 3 time points. Mass spectrometry data were subjected to Perseus 1.5.5.3 statistical analysis, and gene ontology heat map clustering. Expressions of several key molecules were verified to confirm H2S-dependent proteomics changes. Webgestalt pathway overrepresentation enrichment analysis with Panther engine revealed H2S exposure disrupted several biological processes including metabotropic glutamate receptor group 1 and inflammation mediated by chemokine and cytokine signaling pathways among others. Further analysis showed that energy metabolism, integrity of blood-brain barrier, hypoxic, and oxidative stress signaling pathways were also implicated. Collectively, this broad-spectrum proteomics data has provided important clues to follow up in future studies to further elucidate mechanisms of H2S-induced neurotoxicity.

      PubDate: 2018-06-20T08:17:29Z
       
  • The modifying effect of kidney function on the association of cadmium
           exposure with blood pressure and cardiovascular mortality: NHANES
           1999–2010
    • Abstract: Publication date: 15 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 353
      Author(s): Yi Gao, Xiangzhu Zhu, Martha J. Shrubsole, Lei Fan, Zhaolin Xia, Raymond C. Harris, Lifang Hou, Qi Dai
      Objective We hypothesized that the associations of urinary Cd with blood pressure and cardiovascular disease (CVD) mortality may be modified by renal function. Methods We tested these hypotheses using data from the National Health and Nutrition Examination Survey (NHANES, 1999–2010). Results Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were positively associated with blood Cd. DBP was positively related to urinary Cd whereas SBP was inversely associated with urinary Cd. In the stratified analyses by level of eGFR, the associations between SBP and urinary Cd were not statistically significant among those with normal renal function and those with mildly reduced renal function whereas SBP significantly positively associated with urinary Cd among those with moderately or severely decreased renal function (p for trend, 0.0004). Renal function appeared to be a modifying factor of the association between urinary Cd and mortality. CVD mortality risks (p for trend, 0.04) were significantly increased with increasing urinary Cd with hazard ratios (HRs) (95% CIs) of 2.18 (0.68–7.01) for the highest quartile of urinary Cd compared to the lowest. The association between urinary Cd and CVD mortality became stronger in the stratified analyses by renal function and these associations became more consistent in those who never smoked. Conclusions The inverse association between urinary Cd and blood pressure observed in previous studies may be due to lack of consideration of renal function as an effect modifier. The strength of the association between urinary Cd and CVD mortality may be underestimated without considering renal function.

      PubDate: 2018-06-18T16:04:06Z
       
  • The tamoxifen derivative ridaifen-B is a high affinity selective CB2
           receptor inverse agonist exhibiting anti-inflammatory and
           anti-osteoclastogenic effects
    • Abstract: Publication date: 15 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 353
      Author(s): Lirit N. Franks, Benjamin M. Ford, Toshifumi Fujiwara, Haibo Zhao, Paul L. Prather
      Selective estrogen receptor modulators (SERMs) target estrogen receptors (ERs) to treat breast cancer and osteoporosis. Several SERMs exhibit anti-cancer activity not related to ERs. To discover novel anti-cancer drugs acting via ER-independent mechanisms, derivatives of the SERM tamoxifen, known as the “ridaifen” compounds, have been developed that exhibit reduced or no ER affinity, while maintaining cytotoxicity. Tamoxifen and other SERMs bind to cannabinoid receptors with moderate affinity. Therefore, ER-independent effects of SERMs might be mediated via cannabinoid receptors. This study determined whether RID-B, a first generation ridaifen compound, exhibits affinity and/or activity at CB1 and/or CB2 cannabinoid receptors. RID-B binds with high affinity (Ki = 43.7 nM) and 17-fold selectivity to CB2 over CB1 receptors. RID-B acts as an inverse agonist at CB2 receptors, modulating G-protein and adenylyl cyclase activity with potency values predicted by CB2 affinity. Characteristic of an antagonist, RID-B co-incubation produces a parallel-rightward shift in the concentration-effect curve of CB2 agonist WIN-55,212-2 to inhibit adenylyl cyclase activity. CB2 inverse agonists are reported to exhibit anti-inflammatory and anti-ostoeclastogenic effects. In LPS-activated macrophages, RID-B exhibits anti-inflammatory effects by reducing levels of nitric oxide (NO), IL-6 and IL-1α, but not TNFα. Only reduction of NO concentration by RID-B is mediated by cannabinoid receptors. RID-B also exhibits pronounced anti-osteoclastogenic effects, reducing the number of osteoclasts differentiating from primary bone marrow macrophages in a cannabinoid receptor-dependent manner. In summary, the tamoxifen derivative RID-B, developed with reduced affinity for ERs, is a high affinity selective CB2 inverse agonist with anti-inflammatory and anti-osteoclastogenic properties.

      PubDate: 2018-06-18T16:04:06Z
       
  • Protective roles of fenofibrate against cisplatin-induced ototoxicity by
           the rescue of peroxisomal and mitochondrial dysfunction
    • Abstract: Publication date: 15 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 353
      Author(s): Se-Jin Kim, Channy Park, Joon No Lee, Raekil Park
      Cisplatin is an alkylating agent that interferes with DNA replication and kills proliferating carcinogenic cells. Several studies have been conducted to attenuate the side effects of cisplatin; one such side effect in cancer patients undergoing cisplatin chemotherapy is ototoxicity. However, owing to a lack of understanding of the precise mechanism underlying cisplatin-induced side effects, management of cisplatin-induced ototoxicity remains unsolved. We investigated the protective effects of fenofibrate, a PPAR-α activator, on cisplatin-induced ototoxicity. Fenofibrate prevented cisplatin-induced loss of hair cells and improved cell viability; moreover, fenofibrate significantly attenuated the threshold of auditory brainstem responses (ABR) in cisplatin-injected mice. Fenofibrate significantly increased PPAR-α, PPAR-γ, and PGC-1α expression, which consequently resulted in increased number and functional enzyme levels of peroxisomes and mitochondria, and markedly decreased phospho-p53 (S15), activated caspase-3, cleaved-PARP, and NF-κB p65 nuclear translocation, which reduced NADPH oxidase isoform (NOX3 and NOX4) expression, thereby decreasing reactive oxygen species (ROS) production in cisplatin-treated tissues ex vivo. Taken together, these results indicate that fenofibrate rescues cisplatin-induced ototoxicity by maintaining peroxisome and mitochondria number and function, reducing inflammation, and decreasing ROS levels. Our findings suggest that fenofibrate administration might serve as an effective therapeutic agent against cisplatin-induced ototoxicity.
      Graphical abstract image

      PubDate: 2018-06-18T16:04:06Z
       
  • Antinociceptive effect of tadalafil in various pain models: Involvement of
           opioid receptors and nitric oxide cyclic GMP pathway
    • Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Mohammed M. Mehanna, Souraya Domiati, Hania Nakkash Chmaisse, Ahmed El Mallah
      Nitric oxide has been proven to play an important role in nociception, accordingly, its promoters, phosphodiesterase inhibitors have been investigated as pain response modulators. Aiming to evaluate the central antinociceptive effect of tadalafil, a phosphodiesterase 5 inhibitor, and to determine its EC50, tail flick and hot plate tests were employed. On the other hand, tadalafil antinociceptive peripheral effect was assessed through acetic acid-induced writhing model. Formalin test was used to appraise both non-inflammatory and inflammatory pain responses. In order to elaborate the involvement of opioid receptors and nitric oxide/cyclic guanosine monophosphate/potassium-ATP pathway in tadalafil-induced analgesia, mice were pretreated with naloxone, l-nitro-arginine-methyl-ester (l-NAME), methylene blue, and glibenclamide. The results illustrated that tadalafil had a significant antinociceptive effect in the tail flick, hot plate, acetic acid-induced writhing and formalin tests indicating the involvement of peripheral and central analgesic mechanisms. Moreover, tadalafil mechanism of action involved several receptors and mediators, specifically NO/cGMP pathway and opioid receptors. In the formalin test, naloxone significantly blocked the effect of tadalafil in the first phase and partially in the second phase which is an inflammatory pain-dependent aspect. l-NAME, methylene blue and glibenclamide partially blocked the effect of tadalafil in the first phase and enhanced its effect in the second phase which is related to nitric oxide role in the inflammatory process. As a conclusion, tadalafil possesses a potential analgesic effect via the involvement of opioid and nitric oxide pathways.

      PubDate: 2018-06-18T16:04:06Z
       
  • Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its
           prevention by sulforaphane
    • Authors: Yuting Wang; Ardhendu Kumar Mandal; Young-OK Son; Poyil Pratheeshkumar; James T.F. Wise; Lei Wang; Zhuo Zhang; Xianglin Shi; Zhimin Chen
      Abstract: Publication date: Available online 6 June 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Yuting Wang, Ardhendu Kumar Mandal, Young-OK Son, Poyil Pratheeshkumar, James T.F. Wise, Lei Wang, Zhuo Zhang, Xianglin Shi, Zhimin Chen
      Environmental and occupational exposures to cadmium increase the risk of various cancers, including lung cancer. The carcinogenic mechanism of cadmium, including its prevention remains to be investigated. Using fluorescence and electron spin resonance spin trapping, the present study shows that in immortalized lung cells (BEAS-2BR cells), exposure cadmium generated reactive oxygen species (ROS). Through ROS generation, cadmium increased the protein level of TNF-α, which activated NF-κB and its target protein COX-2, creating an inflammatory microenvironment. As measured by anchorage-independent colony formation assay, cadmium induced malignant cell transformation. Inhibition of ROS by antioxidants inhibited transformation, showing that ROS were important in the mechanism of this process. The inflammatory microenvironment created by cadmium may also contribute to the mechanism of the transformation. Using tandem fluorescence protein mCherry-GFP-LC3 construct, the present study shows that cadmium-transformed cells had a property of autophagy deficiency, resulting in accumulation of autophagosomes and increased p62. This protein upregulated Nrf2, which also upregulated p62 through positive feed-back mechanism. Constitutive Nrf2 activation increased its downstream anti-apoptotic proteins, Bcl-2 and Bcl-xl, resulting in apoptosis resistance. In untransformed BEAS-2BR cells, sulforaphane, a natural compound, increased autophagy, activated Nrf2, and decreased ROS. In cadmium-transformed BEAS-2BR cells, sulforaphane restored autophagy, decreased Nrf2, and decreased apoptosis resistance. In untransformed cells, this sulforaphane induced inducible Nrf2 to decrease ROS and possibly malignant cell transformation. In cadmium-transformed cells, it decreased constitutive Nrf2 and reduced apoptosis resistance. The dual roles of sulforaphane make this natural compound a valuable agent for prevention against cadmium-induced carcinogenesis.

      PubDate: 2018-06-08T15:48:39Z
      DOI: 10.1016/j.taap.2018.06.003
       
  • Glutathione deficiency sensitizes cultured embryonic mouse ovaries to
           benzo[a]pyrene-induced germ cell apoptosis
    • Authors: Jinhwan Lim; Ulrike Luderer
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Jinhwan Lim, Ulrike Luderer
      Mice lacking the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in glutathione (GSH) synthesis, have decreased tissue GSH. We previously showed that Gclm−/− embryos have increased sensitivity to the prenatal in vivo ovarian toxicity of the polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP) compared with Gclm+/+ littermates. We also showed that BaP-induced germ cell death in cultured wild type embryonic ovaries is caspase-dependent. Here, we hypothesized that GSH deficiency increases sensitivity of cultured embryonic ovaries to BaP-induced germ cell death. 13.5 days post coitum (dpc) embryonic ovaries of all Gclm genotypes were fixed immediately or cultured for 24 h in media supplemented with DMSO vehicle or 500 ng/ml BaP. The percentage of activated caspase-3 positive germ cells varied significantly among groups. Within each genotype, DMSO and BaP-treated groups had increased germ cell caspase-3 activation compared to uncultured. Gclm+/− ovaries had significantly increased caspase-3 activation with BaP treatment compared to DMSO, and caspase-3 activation increased non-significantly in Gclm−/− ovaries treated with BaP compared to DMSO. There was no statistically significant effect of BaP treatment on germ cell numbers at 24 h, consistent with our prior observations in wild type ovaries, but Gclm−/− ovaries in both cultured groups had lower germ cell numbers than Gclm+/+ ovaries. There were no statistically significant BaP-treatment or genotype-related differences among groups in lipid peroxidation and germ cell proliferation. These data indicate that Gclm heterozygous or homozygous deletion sensitizes embryonic ovaries to BaP- and tissue culture-induced germ cell apoptosis.

      PubDate: 2018-05-28T15:37:07Z
       
  • Isoalantolactone induces apoptosis through reactive oxygen
           species-dependent upregulation of death receptor 5 in human esophageal
           cancer cells
    • Authors: Zhengyang Guangxin; Zhang Yifan Zhang Peiyan Hua Meidan Fang Meiliang
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Zhengyang Lu, Guangxin Zhang, Yifan Zhang, Peiyan Hua, Meidan Fang, Meiliang Wu, Tongjun Liu
      Esophageal cancer is the eighth most prevalent cancer and has high mortality in our society. Isoalantolactone, extracted from Inula helenium L, has shown potent anticancer effects on a variety of cancers. However, its effect on human esophageal cancer, and the underlying molecular mechanism, remain to be investigated. In the present study, we demonstrated that isoalantolactone induced apoptosis in esophageal cancer cells. Treatment with isoalantolactone activated caspases-3, -7, and -10, and upregulated death receptor (DR)5. Furthermore, DR5 knockdown partially reversed the effect of isoalantolactone. These results indicated the extrinsic apoptosis was induced by isoalantolactone. In addition, intracellular reactive oxygen species (ROS) were significantly elevated after treatment with isoalantolactone. N-Acetylcysteine, an ROS scavenger, blocked both the apoptosis and decreased cell viability caused by isoalantolactone. In vivo, significant suppression of tumor growth by isoalantolactone was observed in an ECA109 cell xenograft mouse model. Isoalantolactone showed no obvious adverse effects on mouse weight and histology of heart, liver, spleen, lung, and kidney. In conclusion, our results revealed that isoalantolactone induced apoptosis through the extrinsic pathway via upregulation of DR5 and elevation of ROS in human esophageal cancer cells. Isoalantolactone, therefore, could be a potential candidate in developing anticancer agents for esophageal cancer patients.

      PubDate: 2018-05-28T15:37:07Z
       
  • The roles of bone morphogenetic protein 2 in perfluorooctanoic acid
           induced developmental cardiotoxicity and l-carnitine mediated protection
    • Authors: Meng Zhao; Yantao Han Lianhua Cui Weizhen Zhong Chunbo Wang
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Na Lv, Meng Zhao, Yantao Han, Lianhua Cui, Weizhen Zhong, Chunbo Wang, Qixiao Jiang
      Perfluorooctanoic acid (PFOA), a wide spread environmental pollutant, was associated with developmental cardiotoxicity in chicken embryo, while the underlying molecular mechanism had not been fully elucidated. In the current study, 2 mg/kg (egg weight) PFOA and/or 100 mg/kg (egg weight) l-carnitine were exposed to embryonic day zero (ED0) chicken embryo via air cell injection, and then bone morphogenic protein 2 (BMP2) silencing lentivirus or BMP2 recombinant protein were introduced into ED2 embryo. Electrocardiography and histological methods were utilized to assess the cardiac function and morphology in hatchling chickens, respectively. Consistent with previous results, 2 mg/kg PFOA exposure at ED0 significantly elevated heart rate and thinned right ventricular wall in hatchling chickens, while l-carnitine co-treatment reverted such changes. BMP2 silencing induced very similar changes in hatchling chicken hearts as PFOA exposure, while co-exposure of recombinant BMP2 protein alleviated PFOA-induced changes. l-carnitine exposure alleviated the BMP2-silencing induced changes as well. Western blotting revealed that PFOA exposure enhanced BMP2 expression and suppressed pSMAD1 expression in ED15 chicken embryo hearts, while both changes were reverted by l-carnitine co-exposure. Furthermore, silencing of BMP2 significantly increased the expression level of PPAR alpha in ED15 chicken embryo hearts, while silencing of PPAR alpha did not have significant impact on BMP2 expression. In conclusion, BMP2/pSMAD1 signaling participates in the PFOA-induced developmental cardiotoxicity in chicken embryo, which is likely located upstream of PPAR alpha for this particular endpoint. Protection of BMP2 signaling might contribute to l-carnitine mediated protection against PFOA-induced developmental cardiotoxicity.

      PubDate: 2018-05-28T15:37:07Z
       
  • cAMP/PKA/EGR1 signaling mediates the molecular mechanism of
           ethanol-induced inhibition of placental 11β-HSD2 expression
    • Authors: Luting Jin; Zhou Guohui Zhang Wen Huang Linguo Pei Feng
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Luting Yu, Jin Zhou, Guohui Zhang, Wen Huang, Linguo Pei, Feng Lv, Yuanzhen Zhang, Wei Zhang, Hui Wang
      It is known that inhibiting 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression in the placenta can cause fetal over-exposure to maternal glucocorticoids and induce intrauterine growth restriction (IUGR); these effects ultimately increase the risk of adult chronic diseases. This study aimed to investigate the molecular mechanism of the prenatal ethanol exposure (PEE)-induced inhibition of placental 11β-HSD2 expression. Pregnant Wistar rats were intragastrically administered ethanol (4 g/kg/d) from gestational days 9 to 20. The levels of maternal and fetal serum corticosterone and placental 11β-HSD2-related gene expression were analyzed. Furthermore, we investigated the mechanism of reduced placental 11β-HSD2 expression induced by ethanol treatment (15–60 mM) in HTR-8/SVneo cells. In vivo, PEE decreased fetal body weights and increased maternal and fetal serum corticosterone and early growth response factor 1 (EGR1) expression levels. Moreover, histone modification changes (decreased acetylation and increased di-methylation of H3K9) to the HSD11B2 promoter and lower 11β-HSD2 expression levels were observed. In vitro, ethanol decreased cAMP/PKA signaling and 11β-HSD2 expression and increased EGR1 expression in a concentration-dependent manner. A cAMP agonist and EGR1 siRNA reversed the ethanol-induced inhibition of 11β-HSD2 expression. Together, PEE reduced placental 11β-HSD2 expression, and the underlying mechanism is associated with ethanol-induced histone modification changes to the HSD11B2 promoter through the cAMP/PKA/EGR1 pathway.

      PubDate: 2018-05-28T15:37:07Z
       
  • Caffeic acid prevents UVB radiation induced photocarcinogenesis through
           regulation of PTEN signaling in human dermal fibroblasts and mouse skin
    • Authors: Agilan Balupillai; Rajendra Prasad Nagarajan Karthikeyan Ramasamy Kanimozhi Govindasamy Ganesan
      Abstract: Publication date: 1 August 2018
      Source:Toxicology and Applied Pharmacology, Volume 352
      Author(s): Agilan Balupillai, Rajendra Prasad Nagarajan, Karthikeyan Ramasamy, Kanimozhi Govindasamy, Ganesan Muthusamy
      Previously, we proved that caffeic acid (CA), a major dietary phenolic acid, prevents skin carcinogenesis by modulating inflammatory signaling in mouse skin. However, the actual mechanisms of CA against UVB (280–320 nm) induced photocarcinogenesis remains unclear. The present results confirms that CA significantly inhibits single UVB-induced CPDs formation, oxidative DNA damage, ROS generation and frequency of apoptotic cell death in human dermal fibroblasts (HDFa). Furthermore, CA prevents UVB-induced expression of PI3K and AKT kinases through activation of PTEN which subsequently promotes XPC dependant NER proteins such as XPC, XPE, TFIIH (p44) and ERCC1 in HDFa cells and mouse skin tissue. Further, CA directly activates PTEN through hydrogen bond and hydrophobic interactions. Taken together, these findings suggest that CA prevents UVB-induced photodamage through the activation of PTEN expression in human dermal fibroblasts and mouse skin.

      PubDate: 2018-05-28T15:37:07Z
       
  • Expression and function of TLR4- induced B1R bradykinin receptor on
           cardiac fibroblasts
    • Authors: Claudia Samuel; Miguel Osorio Francisco Olivares Renatto Anfossi Samir Bolivar
      Abstract: Publication date: 15 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 351
      Author(s): Claudia Muñoz-Rodríguez, Samuel Fernández, José Miguel Osorio, Francisco Olivares, Renatto Anfossi, Samir Bolivar, Claudio Humeres, Pía Boza, Raúl Vivar, Viviana Pardo-Jimenez, Karen E. Hemmings, Neil A. Turner, Guillermo Díaz-Araya
      Cardiac fibroblasts (CF) are key cells for maintaining extracellular matrix (ECM) protein homeostasis in the heart, and for cardiac repair through CF-to-cardiac myofibroblast (CMF) differentiation. Additionally, CF play an important role in the inflammatory process after cardiac injury, and they express Toll like receptor 4 (TLR4), B1 and B2 bradykinin receptors (B1R and B2R) which are important in the inflammatory response. B1R and B2R are induced by proinflammatory cytokines and their activation by bradykinin (BK: B2R agonist) or des-arg-kallidin (DAKD: B1R agonist), induces NO and PGI2 production which is key for reducing collagen I levels. However, whether TLR4 activation regulates bradykinin receptor expression remains unknown. CF were isolated from human, neonatal rat and adult mouse heart. B1R mRNA expression was evaluated by qRT-PCR, whereas B1R, collagen, COX-2 and iNOS protein levels were evaluated by Western Blot. NO and PGI2 were evaluated by commercial kits. We report here that in CF, TLR4 activation increased B1R mRNA and protein levels, as well as COX-2 and iNOS levels. B1R mRNA levels were also induced by interleukin-1α via its cognate receptor IL-1R1. In LPS-pretreated CF the DAKD treatment induced higher responses with respect to those observed in non LPS-pretreated CF, increasing PGI2 secretion and NO production; and reducing collagen I protein levels in CF. In conclusion, no significant response to DAKD was observed (due to very low expression of B1R in CF) – but pre-activation of TLR4 in CF, conditions that significantly enhanced B1R expression, led to an additional response of DAKD.

      PubDate: 2018-05-28T15:37:07Z
       
  • Adiponectin gene polymorphisms and obesity increase the susceptibility to
           arsenic-related renal cell carcinoma
    • Authors: Yu-Mei Hsueh; Wei-Jen Chen Ying-Chin Lin Chao-Yuan Huang Horng-Sheng Shiue
      Abstract: Publication date: 1 July 2018
      Source:Toxicology and Applied Pharmacology, Volume 350
      Author(s): Yu-Mei Hsueh, Wei-Jen Chen, Ying-Chin Lin, Chao-Yuan Huang, Horng-Sheng Shiue, Shu-Mei Yang, Pui-Lam Ao, Yeong-Shiau Pu, Chien-Tien Su
      Our recent study found that high urinary total arsenic levels were associated with renal cell carcinoma (RCC). Recent studies demonstrated that low circulating adiponectin was related to RCC. The aim of the present study was to explore the relationship between adiponectin gene (ADIPOQ) polymorphisms and RCC and investigate whether individuals with an ADIPOQ risk genotype, obesity, and high urinary total arsenic levels have a modified odds ratio (OR) of RCC. A total of 389 RCC patients and 389 age- and sex-matched controls were recruited between November 2006 and December 2012 in Taiwan. Image-guided biopsy or surgical resection of renal tumors was performed to pathologically verify RCC. Genomic DNA was used to examine the genotypes of the ADIPOQ rs182052, ADIPOQ rs2241766, ADIPOQ rs1501299, and ADIPOQ rs1063539 SNPs by PCR-RFLP. HPLC-HG-AAS was used to measure the concentrations of urinary arsenic species. Participants with the ADIPOQ rs182052 G/A+A/A genotype had a significantly higher OR of RCC compared with those with the ADIPOQ rs182052 G/G genotype. The OR (95% confidence interval [CI]) was 1.70 (1.23–2.36). The OR of RCC for the combined effect of high urinary total arsenic levels and obesity, which was dose-dependent, in individuals with the ADIPOQ rs182052 G/A+A/A genotype was 9.33 (3.85–22.62). The present study found significant combined effects of obesity and the ADIPOQ rs182052 G/A+A/A genotype on the arsenic-related risk of RCC in a population with low arsenic exposure. Arsenic exposure, obesity, and the ADIPOQ rs182052 polymorphism could be predictors of a higher OR of RCC.

      PubDate: 2018-05-28T15:37:07Z
       
 
 
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