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Toxicology and Applied Pharmacology

Laëtitia Chézeau, Sylvie Sébillaud, Ramia Safar, Carole Seidel, Doulaye Dembélé, Mylène Lorcin, Cristina Langlais, Stéphane Grossmann, Hervé Nunge, Sylvie Michaux, Hélène Dubois Pot Schneider, Bertrand Rihn, Olivier Joubert, Stéphane Binet, Frédéric Cosnier, Laurent Gaté
The number of workers potentially exposed to nanoparticles (NPs) during industrial processes is increasing, although the toxicological properties of these compounds still need to be fully characterized. As NPs may be aerosolized during industrial processes, inhalation represents their main route of occupational exposure. Here, the short- and long-term pulmonary toxicological properties of titanium dioxide were studied, using conventional and molecular toxicological approaches. Fischer 344 rats were exposed to 10 mg/m3 of a TiO2 nanostructured aerosol (NSA) by nose-only inhalation for 6 h/day, 5 days/week over 4 weeks...
July 13, 2018: Toxicology and Applied Pharmacology
Xiao Jiang, Li Yin, Ning Zhang, Fei Han, Wen-Bin Liu, Xi Zhang, Hong-Qiang Chen, Jia Cao, Jin-Yi Liu
Bisphenol A (BPA) impairs male fertility by acting as an endocrine disruptor. However, the mechanisms by which BPA cause reproductive toxicity are not fully elucidated. Here, we explored the role of XAF1, a novel pro-apoptosis molecule, in BPA-induced abnormal spermatogenesis and the transcriptional regulation mechanism of BPA-induced XAF1. BPA exposure detrimentally impacted spermatogenesis by inducing excessive germ cell apoptosis. XAF1 was upregulated in germ cells after BPA exposure, which was involved in the apoptosis pathway...
July 12, 2018: Toxicology and Applied Pharmacology
Yue Xi, Wenwen Wang, Li Wang, Ji Pan, Yisen Cheng, Feihai Shen, Zhiying Huang
Triptolide (TP), a major active component of Tripterygium wilfordii Hook f., is widely used in the treatment of inflammation and autoimmune disorders. Its clinical application is limited by severe adverse effects, especially cardiotoxicity. Accumulative evidences indicate that TP induces DNA damage by inhibiting RNA polymerase. Considering the relationship among DNA damage, p53, and the role of p53 in mitochondria-dependent apoptosis, we speculate that TP-induced cardiotoxicity results from p53 activation. In this study, the role of p53 in TP-induced cardiotoxicity was investigated in H9c2 cells, primary cardiomyocytes, and C57BL/6 genetic background p53-/- mice...
July 12, 2018: Toxicology and Applied Pharmacology
Neetika Lal, Vishal Nemaysh, Pratibha Mehta Luthra
Recently, we have reported that Demethoxycurcumin induced Reactive oxygen species generation via inhibition of Mitochondrial Superoxide Dismutase is an initial event to trigger apoptosis through caspase-8 and 9 activation and to inhibit Akt/NF-κB survival signaling in human glioma U87 MG cells (R. Kumar, Lal, Nemaysh, & Luthra, 2018). Although cell-cycle disruption had been suggested to be the possible mechanism for DMC inhibitory effect on human glioma U87 MG cells, comprehensive mechanisms of cell-cycle arrest caused by DMC are not fully understood...
July 12, 2018: Toxicology and Applied Pharmacology
Yashika Bansal, Raghunath Singh, Priyanka Saroj, Rupinder Kaur Sodhi, Anurag Kuhad
Oxido-inflammatory aberrations play a substantial role in the pathophysiology of depression. Oxido-inflammatory stress increases catabolism of tryptophan into kynurenine which leads to imbalance in kynurenine and serotonin levels in the brain. Naringenin a flavonoid, has been reported to possess antidepressant property by restoring serotonin and noradrenaline levels in the brain. Its effects on oxido-inflammatory aberrations in depression has not been investigated. With this background, the present study was designed to investigate the antidepressant-like potential of naringenin in olfactory bulbectomy (OBX)-induced neuroinflammation, oxidative stress, altered kynurenine pathway, and behavioural deficits in BALB/C mice...
July 11, 2018: Toxicology and Applied Pharmacology
Yuko Watanabe, Emi Makino, Risako Tajiki-Nishino, Aya Koyama, Hitoshi Tajima, Makoto Ishimota, Tomoki Fukuyama
It has been reported that endogenous or exogenous estrogens can affect the immune system, resulting in immune disorders; however, their direct involvement in such conditions remains to be demonstrated. The purpose of this study was to investigate whether estrogen receptors (ER) are directly implicated in pro-pruritic and pro-inflammatory reactions in cutaneous allergy. Initially, enhancement of the pro-inflammatory response by several ER agonists [methoxychlor (MXC), β-estradiol (E2), propylpyrazoletriol (PPT; an ERα agonist), and diarylpropionitrile (DPN; an ERβ agonist)] was examined in vivo using a male BALB/c mouse model of allergic dermatitis induced by toluene-2,4-diisocyanate administration...
July 11, 2018: Toxicology and Applied Pharmacology
Michal W Luczak, Anatoly Zhitkovich
DNA double-strand breaks (DSBs) are a highly toxic form of DNA damage produced by a number of carcinogens, drugs, and metabolic abnormalities. Involvement of DSBs in many pathologies has led to frequent measurements of these lesions, primarily via biodosimetry of S139-phosphorylated histone H2AX (γ-H2AX). However, γ-H2AX is also induced by some non-DSB conditions and abundantly formed in apoptosis, raising concerns about the overestimation of potential genotoxic agents and accuracy of DSB assessments. DSB-triggered γ-H2AX undergoes RNF168-mediated K13/K15 monoubiquitination, which is rarely analyzed in DSB/genotoxicity studies...
July 10, 2018: Toxicology and Applied Pharmacology
Iris Q Kim, Yusuke Marikawa
Developmental toxicity of compounds, which women of reproductive age are exposed to, should be assessed to minimize the incidence of miscarriage and birth defects. The present study examined the potential developmental toxicity of resveratrol, a dietary supplement widely marketed with various health claims, using the P19C5 embryoid body (EB) morphogenesis assay, which evaluates adverse effects of chemical exposures on tissue growth and axial elongation. Resveratrol (trans isoform) impaired morphogenesis at 4 μM and higher, creating smaller and rounder EBs, whereas cis isoform, and glucuronated and sulfonated metabolites did not...
July 7, 2018: Toxicology and Applied Pharmacology
Xueying Zhao, Guiwu Qu, Chenguang Song, Rongrong Li, Weili Liu, Changjun Lv, Xiaodong Song, Jinjin Zhang, Minge Li
Pulmonary fibrosis is a progressive disorder with poor prognosis and limited treatment options. Therefore, novel therapeutic drugs should be developed in preclinical studies. In this study, we designed and synthesized a novel compound named formononetin-7-sal ester (FS). We also investigated its anti-pulmonary fibrosis ability on transforming growth factor beta 1 (TGF-β1)-stimulated pulmonary epithelial cells and fibroblasts in vitro and on bleomycin (BLM)-induced pulmonary fibrosis in vivo. FS strongly blocked cell proliferation and migration, which were activated by TGF-β1, thereby reducing the expression of lung fibrosis markers, such as vimentin, alpha-smooth muscle actin (α-SMA), Snail, and collagen I and III, and increasing the expression of the epithelial cell marker E-cadherin...
July 7, 2018: Toxicology and Applied Pharmacology
C Behr, S Sperber, X Jiang, V Strauss, H Kamp, T Walk, M Herold, K Beekmann, I M C M Rietjens, B van Ravenzwaay
The metabolic functionality of the gut microbiota contributes to the metabolism and well-being of its host, although detailed insight in the microbiota's metabolism is lacking. Omics technologies could facilitate unraveling metabolism by the gut microbiota. In this study, we performed metabolite profiling of different matrices of the gut, after antibiotic treatment of rats in order to evaluate metabolite changes observed at different dose levels and in different sexes, and to identify the best tissue matrix for further investigations regarding an assessment of metabolic effects of new compounds with antibiotic activity...
July 6, 2018: Toxicology and Applied Pharmacology
Kristy Zera, Jason Zastre
Vitamin B1, or thiamine is a critical enzyme cofactor required for metabolic function and energy production. Thiamine deficiency (TD) is common in various diseases, and results in severe neurological complications due to diminished mitochondrial function, oxidative stress, excitotoxicity and inflammation. These pathological sequelae result in apoptotic cell death in both neurons and astrocytes in distinct regions, in particular the thalamus and mammillary bodies. Comparable histological injuries in patients with hypoxia/ischemia (H/I) have also been described, suggesting a congruency between the cellular responses to these stresses...
July 6, 2018: Toxicology and Applied Pharmacology
Theerut Luangmonkong, Su Suriguga, Adhyatmika Adhyatmika, Amirah Adlia, Dorenda Oosterhuis, Chuthamanee Suthisisang, Koert P de Jong, Henricus A M Mutsaers, Peter Olinga
Fibrosis is a pathophysiological state characterized by the excessive formation/deposition of fibrous extracellular matrix. Transforming growth factor-beta (TGF-β) is a central profibrotic mediator, and targeting TGF-β is a promising strategy in the development of drugs for the treatment of fibrosis. Therefore, the effect of LY2109761, a small molecule inhibitor against TGF-β with targets beyond TGF-β signaling, on fibrogenesis was elucidated in vitro (HepG2 cells and LX-2 cells) and ex vivo (human and rat precision-cut liver slices)...
July 3, 2018: Toxicology and Applied Pharmacology
Myrto Dimopoulou, Aart Verhoef, Jeroen Pennings, Bennard van Ravenzwaay, Ivonne M C M Rietjens, Aldert H Piersma
No abstract text is available yet for this article.
July 3, 2018: Toxicology and Applied Pharmacology
Nicholas Buss, Jean-Martin Lapointe, Lolke de Haan, Sally Price, Andrea Ahnmark, Lorraine Irving, Andrew Buchanan, Feenagh Keyes, Pia Davidsson, Rakesh Dixit, Daniel Lindén
Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) have been proposed as potential drug targets for the treatment of obesity. The aim of this study was to assess the potential toxicity in rats of three anti-FGFR1c mAbs with differential binding activity prior to clinical development. Groups of male rats received weekly injections of either one of two FGFR1c-specific mAbs or an FGFR1c/FGFR4-specific mAb at 10 mg/kg for up to 4 weeks. All three mAbs caused significant reductions in food intake and weight loss leading to some animals being euthanized early for welfare reasons...
July 2, 2018: Toxicology and Applied Pharmacology
Bei Yang, Hao Cheng, Linlin Wang, Jingqi Fu, Guohua Zhang, Dawei Guan, Ruiqun Qi, Xinghua Gao, Rui Zhao
Hypoxia is a key pathological process involved in many cutaneous diseases. Nuclear factor E2-related factor 2 (NRF2) is a central regulator of antioxidant response element (ARE)-dependent transcription and plays a pivotal role in the cellular adaptive response to oxidative stress. Kelch-like ECH-associated protein 1 (KEAP1) is a cullin-3-adapter protein that represses the activity of NRF2 by mediating its ubiquitination and degradation. In the present study, we examined the role of NRF2 signaling pathway in the cytotoxicity induced by cobalt chloride(CoCl2 ), a hypoxia-mimicking agent, in human keratinocyte HaCaT cells with stable knockdown of NRF2 (NRF2-KD) and KEAP1 (KEAP1-KD)...
June 29, 2018: Toxicology and Applied Pharmacology
Jenelle Govender, Ben Loos, Erna Marais, A-M Engelbrecht
Mitochondrial dysfunction is a central element in the development of doxorubicin (DXR)-induced cardiotoxicity. In this context, melatonin is known to influence mitochondrial homeostasis and function. This study aimed to investigate the effects of melatonin on cardiac function, tumor growth, mitochondrial fission and fusion, PGC1-α and sirtuin activity in an acute model of DXR-induced cardiotoxicity. During the in vitro study, H9c2 rat cardiomyoblasts were pre-treated with melatonin (10 μM, 24 h) followed by DXR exposure (3 μM, 24 h)...
June 29, 2018: Toxicology and Applied Pharmacology
Yichen Ge, Jinqiu Zhu, Xue Wang, Nina Zheng, Chengjian Tu, Jun Qu, Xuefeng Ren
Arsenic is a known potent risk factor for bladder cancer. Increasing evidence suggests that epigenetic alterations, e.g., DNA methylation and histones posttranslational modifications (PTMs), contribute to arsenic carcinogenesis. Our previous studies have demonstrated that exposure of human urothelial cells (UROtsa cells) to monomethylarsonous acid (MMAIII ), one of arsenic active metabolites, changes the histone acetylation marks across the genome that are correlated with MMAIII -induced UROtsa cell malignant transformation...
June 29, 2018: Toxicology and Applied Pharmacology
K Cizkova
CYP epoxygenases metabolize arachidonic acid into four regioisomers of epoxyeicosatrienoic acids (EETs) which are hydrolysed into their corresponding diols by soluble epoxide hydrolase (sEH). EETs are very biologically active molecules. They promote proliferation and inhibit apoptosis as well as numerous other functions within organisms. Peroxisome proliferator-activated receptor α (PPARα) play role in regulation of CYP epoxygenases and sEH. PPARα is the ligand-dependent transcriptional factor which is activated by various compounds, including fibrates...
June 27, 2018: Toxicology and Applied Pharmacology
Hyun Lim, Dong Suk Min, Haeil Park, Hyun Pyo Kim
NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome is a component of innate immunity, and is responsible for producing mature IL-1β and -18. Several flavonoids were found to affect inflammasome pathway, but the mechanism of action is still obscure. To elucidate the effects on NLRP3 inflammasome pathway and to determine the structure-activity relationships, NLRP3 inflammasome in differentiated THP-1 cells was activated via treatment with monosodium urate (MSU) crystals. Levels of mature IL-1β, NLRP3 inflammasome components and apoptosis-associated speck-like protein containing a CARD (caspase recruitment domain) (ASC) oligomerization were investigated and the mechanisms of action were also elucidated...
June 27, 2018: Toxicology and Applied Pharmacology
Agnes B Kane, Robert H Hurt, Huajian Gao
Nanotechnology is an emerging industry based on commercialization of materials with one or more dimensions of 100 nm or less. Engineered nanomaterials are currently incorporated into thin films, porous materials, liquid suspensions, or filler/matrix nanocomposites with future applications predicted in energy and catalysis, microelectronics, environmental sensing and remediation, and nanomedicine. Carbon nanotubes are one-dimensional fibrous nanomaterials that physically resemble asbestos fibers. Toxicologic studies in rodents demonstrated that some types of carbon nanotubes can induce mesothelioma, and the World Health Organization evaluated long, rigid multiwall carbon nanotubes as possibly carcinogenic for humans in 2014...
June 27, 2018: Toxicology and Applied Pharmacology
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