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Toxicological Sciences: An Official Journal of the Society of Toxicology

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https://www.readbyqxmd.com/read/27864544/investigative-nonclinical-cardiovascular-safety-and-toxicology-studies-with-bms-986094-an-ns5b-rna-dependent-rna-polymerase-inhibitor
#1
M Gill, K Horn, J Hennan, R White, D Bounous, S Clark, J R Megill, E Janovitz, M Davies, T Sanderson, M Graziano
BMS-986094, a 2'-C-methylguanosine prodrug that was in development for treatment of chronic hepatitis C infection was withdrawn from Phase 2 clinical trials because of unexpected cardiac and renal adverse events. Investigative nonclinical studies were conducted to extend the understanding of these findings using more comprehensive endpoints. BMS-986094 was given orally to female CD-1 mice (25 and 150 mg/kg/d) for 2 weeks (53/group) and to cynomolgus monkeys (15 and 30 mg/kg/d) for up to 6 weeks (2-3/sex/group for cardiovascular safety, and 5/sex/group for toxicology)...
November 17, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27864543/long-non-coding-rnas-a-novel-paradigm-for-toxicology
#2
REVIEW
Joseph L Dempsey, Julia Yue Cui
Long non-coding RNAs (lncRNAs) are over 200 nucleotides in length and are transcribed from the mammalian genome in a tissue-specific and developmentally regulated pattern. There is growing recognition that lncRNAs are novel biomarkers and/or key regulators of toxicological responses in humans and animal models. Lacking protein-coding capacity, the numerous types of lncRNAs possess a myriad of transcriptional regulatory functions that include cis and trans gene expression, transcription factor activity, chromatin remodeling, imprinting, and enhancer up-regulation...
November 17, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27837169/ccr2-regulates-inflammatory-cell-accumulation-in-the-lung-and-tissue-injury-following-ozone-exposure
#3
Mary Francis, Angela Groves, Richard Sun, Jessica A Cervelli, Hyejeong Choi, Jeffrey D Laskin, Debra L Laskin
Ozone-induced lung injury is associated with an accumulation of activated macrophages in the lung. Chemokine receptor CCR2 mediates the migration of inflammatory monocytes/macrophages to sites of tissue injury. It is also required for monocyte egress from the bone marrow. In the present studies, we analyzed the role of CCR2 in inflammatory cell trafficking to the lung in response to ozone. Treatment of mice with ozone (0.8 ppm, 3 h) resulted in increases in pro-inflammatory CCR2(+) macrophages in the lung at 24 h, as well as pro-inflammatory CD11b(+)Ly6C(Hi) and iNOS(+) macrophages at 24 h and 48 h...
November 11, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27837168/microbial-derived-1-4-dihydroxy-2-naphthoic-acid-and-related-compounds-as-aryl-hydrocarbon-receptor-agonists-antagonists-structure-activity-relationships-and-receptor-modeling
#4
Yating Cheng, Un-Ho Jin, Laurie A Davidson, Robert S Chapkin, Arul Jayaraman, Phanourios Tamamis, Asuka Orr, Clint Allred, Michael S Denison, Anatoly Soshilov, Evelyn Weaver, Stephen Safe
1,4-Dihydroxy-2-naphthoic acid (1,4-DHNA) is a bacterial-derived metabolite that binds the aryl hydrocarbon receptor (AhR) and exhibits anti-inflammatory activity in the gut. The structure-dependent AhR activity of hydroxyl/carboxy-substituted naphthoic acids was determined in young adult mouse colonic (YAMC) cells and human Caco2 colon cancer cells using CYP1A1/CYP1B1 mRNAs as Ah-responsive genes. Compounds used in this study include 1,4-, 3,5- and 3,7-DHNA, 1,4-dimethoxy-2-naphthoic acid (1,4-DMNA), 1- and 4-hydroxy-2-naphthoic acid (1-HNA, 4-HNA), 1- and 2-naphthoic acid (1-NA, 2-NA), and 1- and 2-naphthol (1-NOH, 2-NOH)...
November 11, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27837167/nrf2-activation-is-required-for-ligustrazine-to-inhibit-hepatic-steatosis-in-alcohol-preferring-mice-and-hepatocytes
#5
Chunfeng Lu, Wenxuan Xu, Jiangjuan Shao, Feng Zhang, Anping Chen, Shizhong Zheng
Hepatic steatosis is the most distinctive feature of alcoholic liver disease (ALD). Our previous in vivo study showed that ligustrazine, a major active alkaloid isolated from Ligusticum chuanxiong Hort, attenuated alcohol-induced hepatic steatosis and in vitro study revealed that nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation might be a prerequisite. This study was aimed to explore the in vivo function of Nrf2 in the protective effect of ligustrazine and illustrate downstream mechanisms. Nrf2 shRNA lentivirus was introduced to establish Nrf2-knockdown mice...
November 11, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27815493/net-reclassification-index-nri-and-integrated-discrimination-index-idi-are-not-appropriate-for-testing-whether-a-biomarker-improves-predictive-performance
#6
Peter M Burch, Warren E Glaab, Daniel J Holder, Jonathan A Phillips, John-Michael Sauer, Elizabeth G Walker
One of the goals of the Critical Path Institute's Predictive Safety Testing Consortium (PSTC) is to promote best practices for evaluating novel markers of drug induced injury. This includes the use of sound statistical methods. For rat studies, these practices have centered around comparing the area under the receiver-operator characteristic (ROC) curve for each novel injury biomarker to those for the standard markers. In addition, the PSTC has previously used the net reclassification index (NRI) and integrated discrimination index (IDI) to assess the increased certainty provided by each novel injury biomarker when added to the information already provided by the standard markers...
November 4, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27815492/preclinical-biodistribution-and-safety-evaluation-of-a-pbi-shrna-stmn1-lipoplex-after-subcutaneous-delivery
#7
Zhaohui Wang, Christopher M Jay, Courtney Evans, Padmasini Kumar, Connor Phalon, Donald D Rao, Neil Senzer, John Neumantis
Stathmin-1 (STMN1) is a microtubule-destabilizing protein which is overexpressed in cancer. Its overexpression is associated with poor prognosis and also serves as a predictive marker to taxane therapy. We have developed a proprietary bi-functional shRNA (bi-shRNA) platform to execute RNA interference (RNAi)-mediated gene silencing and a liposome-carrier complex to systemically deliver the pbi-shRNA plasmids. In vitro and in vivo testing demonstrated efficacy and specificity of pbi-shRNA plasmid in targeting STMN1 (Phadke et al...
November 4, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27815491/vulnerability-of-c6-astrocytoma-cells-after-single-compound-and-joint-exposure-to-type-i-and-type-ii-pyrethroid-insecticides
#8
D M Romero, B G Berardino, M J Wolansky, M L Kotler
A primary mode of action of all pyrethroid insecticides (PYRs) is the disruption of the voltage-gated sodium channel electrophysiology in neurons of target pests and nontarget species. The neurological actions of PYRs on non-neuronal cells of the nervous system remain poorly investigated. In the present work, we used C6 astrocytoma cells to study PYR actions (0.1-50 μM) under the hypothesis that glial cells may be targeted by and vulnerable to PYRs. To this end, we characterized the effects of bifenthrin (BF), tefluthrin (TF), α-cypermethrin (α-CYP), and deltamethrin (DM) on the integrity of nuclear, mitochondrial and lysosomal compartments...
November 4, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27803388/viral-vectors-the-road-to-reducing-genotoxicity
#9
Rhiannon M David, Ann T Doherty
Viral vector use in gene therapy has highlighted several safety concerns, including genotoxic events. Generally, vector-mediated genotoxicity results from upregulation of cellular proto-oncogenes via promoter insertion, promoter activation, or gene transcript truncation, with enhancer-mediated activation of nearby genes the primary mechanism reported in gene therapy trials. Vector-mediated genotoxicity can be influenced by virus type, integration target site, and target cell type; different vectors have distinct integration profiles which are cell-specific...
November 1, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27803387/neurorespiratory-effects-of-buprenorphine-and-ethanol-in-combination-a-mechanistic-study-of-drug-drug-interactions-in-the-rat
#10
Camille Cohier, Lucie Chevillard, Sophie Salle, Patricia Risède, Olivier Roussel, Bruno Mégarbane
Respiratory depression and fatalities have been attributed to ethanol/buprenorphine combination in drug addicts maintained with buprenorphine/naloxone or buprenorphine alone. The exact mechanisms of the ethanol/buprenorphine interaction and the contribution to the toxicity of norbuprenorphine, the main buprenorphine metabolite with respiratory depressant properties are unknown. We investigated the sedative and plethsymographic effects resulting from the co-administration of intragastric ethanol (3g/kg) and intravenous buprenorphine (30mg/kg) in Sprague-Dawley rats...
November 1, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27803386/characterization-of-isoniazid-specific-t-cell-clones-in-patients-with-anti-tuberculosis-drug-related-liver-and-skin-injury
#11
Toru Usui, Xiaoli Meng, Katy Saide, John Farrell, Paul Thomson, Paul Whitaker, John Watson, Neil S French, B Kevin Park, Dean J Naisbitt
Isoniazid, rifampicin, pyrazinamide and ethambutol are commonly used for the treatment of tuberculosis. Drug exposure is occasionally associated with liver and/or skin injury. The aim of this study was to determine whether drug-specific T-cells are detectable in patients with adverse reactions and if so characterize the nature of the T-cell response. PBMC from 6 patients with anti-tuberculosis drug-related adverse reactions (4 liver, 2 skin) were used to detect drug-responsive T-lymphocytes. Positive lymphocyte transformation test and/or ELIspot results were observed with all 6 patients...
November 1, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27803385/oxidative-signalling-response-to-cadmium-exposure
#12
Saïd Nemmiche
Changes in the intracellular thiol-disulfide balance are considered major determinants in the redox status/signalling of the cell. Cellular signalling is very sensitive to both exogenous and intracellular redox status and respond to many exogenous pro-oxidative or oxidative stresses. Redox status has dual effects on upstream signalling systems and downstream transcription factors. Redox signalling pathways use ROS to transfer signals from different sources to the nucleus to regulate such functions as growth, differentiation, proliferation and apoptosis...
November 1, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27803384/exposure-of-pregnant-mice-to-perfluorobutanesulfonate-causes-hypothyroxinemia-and-developmental-abnormalities-in-female-offspring
#13
Xuejiao Feng, Xinyuan Cao, Shasha Zhao, Xiaoli Wang, Xu Hua, Lin Chen, Ling Chen
Perfluorobutanesulfonate (PFBS) is widely used in many industrial products. We evaluated the influence of prenatal PFBS exposure on perinatal growth and development, pubertal onset, and reproductive and thyroid endocrine system in female mice. Here, we show that when PFBS (200 and 500 mg/kg/day) was orally administered to pregnant mice (PFBS-dams) on days 1-20 of gestation, their female offspring (PFBS-offspring) exhibited decreased perinatal body weight and delayed eye opening compared to control offspring...
November 1, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27803383/role-of-mitochondrial-toxicity-in-bms-986094-induced-toxicity
#14
LETTER
Joy Y Feng, Chin H Tay, Adrian S Ray
No abstract text is available yet for this article.
November 1, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27780885/futuretox-iii-bridges-for-translation
#15
Daland R Juberg, Thomas B Knudsen, Miriam Sander, Nancy B Beck, Elaine M Faustman, Donna L Mendrick, John R Fowle, Thomas Hartung, Raymond R Tice, Emmanuel Lemazurier, Richard A Becker, Suzanne Compton Fitzpatrick, George P Daston, Alison Harrill, Ronald N Hines, Douglas A Keller, John C Lipscomb, David Watson, Tina Bahadori, Kevin M Crofton
Future Tox III, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2015. Building upon Future Tox I and II, Future Tox III was focused on developing the high throughput risk assessment paradigm and taking the science of in vitro data and in silico models forward to explore the question-what progress is being made to address challenges in implementing the emerging big-data toolbox for risk assessment and regulatory decision-making. This article reports on the outcome of the workshop including 2 examples of where advancements in predictive toxicology approaches are being applied within Federal agencies, where opportunities remain within the exposome and AOP domains, and how collectively the toxicology community across multiple sectors can continue to bridge the translation from historical approaches to Tox21 implementation relative to risk assessment and regulatory decision-making...
October 25, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27742870/response-to-the-letter-to-the-editor-metallothionein-mt2a-a-5g-polymorphism-and-the-risk-for-chronic-kidney-disease-and-diabetes
#16
Yuta Hattori, Mariko Naito, Masahiko Satoh, Masahiro Nakatochi, Hisao Naito, Masashi Kato, Sahoko Takagi, Takashi Matsunaga, Toshio Seiki, Tae Sasakabe, Shino Suma, Sayo Kawai, Rieko Okada, Asahi Hishida, Nobuyuki Hamajima, Kenji Wakai
No abstract text is available yet for this article.
October 13, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27742869/metallothionein-mt2a-a-5g-polymorphism-and-the-risk-for-chronic-kidney-disease-and-diabetes
#17
Tomoyuki Kawada
No abstract text is available yet for this article.
October 13, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27742868/comparative-renal-safety-assessment-of-the-hepatitis-b-drugs-adefovir-tenofovir-telbivudine-and-entecavir-in-rats
#18
Marianne Uteng, Andreas Mahl, Nicolau Beckmann, Alessandro Piaia, David Ledieu, Valerie Dubost, Elaine Tritto, Armin Wolf, Pierre Moulin, Li Li, Salah-Dine Chibout, Francois Pognan
The aim of this study was to determine the relative safety of four antiviral drugs (telbivudine, tenofovir, adefovir, entecavir) against hepatitis B virus with respect to kidney function and toxicity in male Spraque-Dawley rats. The antiviral drugs were administered once daily for four weeks by oral gavage at about 10 and 25-40 times the human equivalent dose. Main assessments included markers of renal toxicity in urine, magnetic resonance imaging (MRI) of kidney function, histopathology and electron microscopic examination...
October 13, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27742867/functional-analysis-reveals-glutamate-gated-chloride-and-%C3%AE-amino-butyric-acid-channels-as-targets-of-avermectins-in-the-carmine-spider-mite
#19
Zhifeng Xu, Qiong Wu, Qiang Xu, Lin He
The carmine spider mite, Tetranychus cinnabarinus (Boisduval), is one of the most important pests in the agricultural industry. Avermectins, as efficient acaricides, have been extensively used in the mite control. The targets for avermectins in mammals, nematodes and insects had already been identified as γ-amino butyric acid and glutamate chloride channels. However, the targets for avermectins in mites are still not clear. Here we report the cloning of five full-length glutamate chloride channel genes (TcGluCls) and three γ-amino butyric acid chloride channel genes (TcGABACls) and their expression levels in different developmental stages in T...
October 13, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27708194/effects-of-the-janus-kinase-inhibitor-tofacitinib-on-testicular-leydig-cell-hyperplasia-and-adenoma-in-rats-and-on-prolactin-signaling-in-cultured-primary-rat-leydig-cells
#20
Robert E Chapin, Douglas J Ball, Zaher A Radi, Steven W Kumpf, Petra H Koza-Taylor, David M Potter, W Mark Vogel
Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis. Tofacitinib preferentially inhibits receptor signaling through JAK3 and JAK1, relative to JAK2. In the 2-year rat carcinogenicity study, there were tofacitinib, dose-related increases in the incidences of testicular Leydig cell hyperplasia and benign adenomas in male rats, and decreased incidences of mammary tumors and duct dilatation/galactocele in female rats. Such findings in rats are typical of agents, such as dopamine agonists, which decrease prolactin (PRL) activity...
October 5, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
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