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Benyu Su, Qiangdong Guan, Miaomiao Wang, Ning Liu, Xiaomin Wei, Shue Wang, Xiwei Yang, Wenchong Jiang, Mengmeng Xu, Sufang Yu
The aim of this study is to explore the potent neuroprotective effect of calpeptin (CP) on neuron damage induced by acrylamide (ACR) and its mechanism. Behavioural indicators such as hind limb splay, rota-rod performance, and gait analysis were assessed weekly to evaluate neurobehavioural changes after ACR and/or CP administration. The histopathological alterations and the changes of μ-calpain, m-calpain, microtubule-associated protein 2 (MAP2), and α-tubulin and β-tubulin protein levels in spinal cord were determined...
March 7, 2018: Toxicology
Theodore A Slotkin, Samantha Skavicus, Frederic J Seidler
Terbutaline and dexamethasone are used in the management of preterm labor, often for durations of treatment exceeding those recommended, and both have been implicated in increased risk of neurodevelopmental disorders. We used a variety of cell models to establish the critical stages at which neurodifferentiation is vulnerable to these agents and to determine whether combined exposures produce a worsened outcome. Terbutaline selectively promoted the initial emergence of glia from embryonic neural stem cells (NSCs)...
March 7, 2018: Toxicology
Meiyuan Yang, Yaobin Li, Lei Hu, Dan Luo, Yi Zhang, Xue Xiao, Guilin Li, Lixia Zhang, Gaochun Zhu
Lead (Pb) exposure has been shown to affect presynaptic neurotransmitter release in the animal and cell models. The mechanism by which Pb exposure impairs neurotransmitter release remains unknown. In this study, we aimed to investigate the effect of Pb exposure on synaptic vesicle protein 2C (SV2C) and its molecular mechanism. SV2C promoter region contains a neuron-restrictive silencer element (NRSE) binding motif. Neuron-restrictive silencer factor (NRSF) is a transcription repressor that regulates gene expression by binding to NRSE...
March 2, 2018: Toxicology
Shugo Suzuki, Samuel M Cohen, Lora L Arnold, Hiroyuki Kato, Satoshi Fuji, Karen L Pennington, Yuko Nagayasu, Aya Naiki-Ito, Yoriko Yamashita, Satoru Takahashi
Tobacco smoking is a major risk factor for human cancers including urinary bladder carcinoma. Cigarette smoke inhalation in mice and orally administered nicotine in rats and mice increased urothelial cell proliferation. Nicotine, a major component of smoke, induced cell proliferation in multiple cell types in vitro. In the present study, the enhancing effects of nicotine on F344 rat bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were examined. Nicotine administered in drinking water for 32 weeks following 4 weeks of BBN treatment significantly increased the incidence and number of urothelial carcinomas dose-dependently...
February 28, 2018: Toxicology
Gagandeep Kaur, Prathyusha Bagam, Rakeysha Pinkston, Dhirendra P Singh, Sanjay Batra
Chronic obstructive pulmonary disease (COPD) is a progressive, life-threatening disease that causes irreversible lung damage. Cigarette smoking is the chief etiologic factor for the commencement of this condition. Despite constant efforts to develop therapeutic interventions and to ascertain the molecular mechanism leading to the pathophysiology of this disease, much remains unknown. However, pattern recognition receptor (PRRs), i.e., Toll-like-receptors (TLRs) and NOD-like receptors (NLRs) are believed to play important roles in this disease and could serve as effective therapeutic targets...
February 28, 2018: Toxicology
Patricia Rosales-Cruz, Mayra Domínguez-Pérez, Elizabeth Reyes-Zárate, Oscar Bello-Monroy, Cristina Enríquez-Cortina, Roxana Miranda-Labra, Leticia Bucio, Luis Enrique Gómez-Quiroz, Emilio Rojas-Del Castillo, María Concepción Gutiérrez-Ruíz, Verónica Souza-Arroyo
Metabolic factors are the major risk of non-alcoholic fatty liver disease, although other factors may contribute steatosis. Cadmium exposure produces histopathological and molecular changes in liver, which are consistent with steatosis. In the present study, we describe the effect of low cadmium acute treatment on hepatocytes obtained from mice fed with a high cholesterol diet. Our data suggest that hepatocytes with cholesterol overload promote an adaptive response against cadmium-induced acute toxicity by up-regulating anti-apoptotic proteins, managing ROS overproduction, increasing GSH synthesis and MT-II content to avoid protein oxidation...
February 24, 2018: Toxicology
Alexandra J Willis, Radek Indra, Laura E Wohak, Osman Sozeri, Kerstin Feser, Iveta Mrizova, David H Phillips, Marie Stiborova, Volker M Arlt
Polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP) can induce cytochrome P450 1A1 (CYP1A1) via a p53-dependent mechanism. The effect of different p53-activating chemotherapeutic drugs on CYP1A1 expression, and the resultant effect on BaP metabolism, was investigated in a panel of isogenic human colorectal HCT116 cells with differing TP53 status. Cells that were TP53(+/+), TP53(+/-) or TP53(-/-) were treated for up to 48 hr with 60 μM cisplatin, 50 μM etoposide or 5 μM ellipticine, each of which caused high p53 induction at moderate cytotoxicity (60-80% cell viability)...
February 19, 2018: Toxicology
Alexandre F Cunha, Igor S A Felippe, Nilson C Ferreira-Junior, Leonardo B M Resstel, Daniela A M Guimarães, Vanessa Beijamini, Julian F R Paton, Karla N Sampaio
Although it is well-established that severe poisoning by organophosphorus (OP) compounds strongly affects the cardiorespiratory system, the effects of sub-lethal exposure to these compounds on the neural control of cardiovascular function are poorly explored. The aim of this study was to evaluate the effects of acute sub-lethal exposure to chlorpyrifos (CPF), a commonly used OP insecticide, on three basic reflex mechanisms involved in blood pressure regulation, the peripheral chemoreflex, the baroreflex and the Bezold-Jarisch reflex...
February 19, 2018: Toxicology
Jinpeng Li, Anthony Bach, Robert B Crawford, Ashwini S Phadnis-Moghe, Weimin Chen, Shawna D'Ingillo, Natalia Kovalova, Jose E Suarez-Martinez, Jiajun Zhou, Barbara L F Kaplan, Norbert E Kaminski
Bisphenol A (BPA) is extensively used in manufacturing of a broad range of consumer products worldwide. Due to its widespread use, human exposure to BPA is virtually ubiquitous. Broad human exposure coupled with a large scientific literature describing estrogenic activity of BPA in animals has raised public health concerns. To comprehensively evaluate the health effects of BPA exposure, a chronic toxicity study using a wide-range of BPA doses (2.5-25000 μg/kg bw/day) was conducted jointly by the NTP, thirteen NIEHS-supported grantees, and the FDA, which is called the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA)...
February 8, 2018: Toxicology
Jinpeng Li, Anthony Bach, Robert B Crawford, Ashwini S Phadnis-Moghe, Weimin Chen, Shawna D'Ingillo, Natalia Kovalova, Jose E Suarez-Martinez, Jiajun Zhou, Barbara L F Kaplan, Norbert E Kaminski
Bisphenol A (BPA) is commonly used in the manufacturing of a wide range of consumer products, including polycarbonate plastics, epoxy resin that lines beverage and food cans, and some dental sealants. Consumption of food and beverages containing BPA represents the primary route of human BPA exposure, which is virtually ubiquitous. An increasing number of studies have evaluated the effects of BPA on immune responses in laboratory animals that have reported a variety of effects some of which have been contradictory...
February 7, 2018: Toxicology
Jiekun Xuan, Zhen Ren, Tao Qing, Letha Couch, Leming Shi, William H Tolleson, Lei Guo
Leflunomide, an anti-inflammatory drug used for the treatment of rheumatoid arthritis, has been marked with a black box warning regarding an increased risk of liver injury. The active metabolite of leflunomide, A771726, which also carries a boxed warning about potential hepatotoxicity, has been marketed as teriflunomide for the treatment of relapsing multiple sclerosis. Thus far, however, the mechanism of liver injury associated with the two drugs has remained elusive. In this study, cytotoxicity assays showed that ATP depletion and subsequent LDH release were induced in a time- and concentration-dependent manner by leflunomide in HepG2 cells, and to a lesser extent, by A77 1726...
February 7, 2018: Toxicology
Stephanie Carvalho Borges, Paulo Emílio Botura Ferreira, Luisa Mota da Silva, Maria Fernanda de Paula Werner, Juan Manuel Irache, Osvaldo Albuquerque Cavalcanti, Nilza Cristina Buttow
The gastrointestinal tract is extremely sensitive to ischemia and reperfusion (I/R). Studies have reported that resveratrol (RSV) is able to combat damage caused by intestinal I/R. Because of its effectiveness in increasing the permanence and bioavailability of resveratrol in the intestinal epithelium, we investigated whether the effect of resveratrol-loaded in poly(anhydride) nanoparticles reduce oxidative stress and promote myenteric neuroprotection in the ileum of rats subjected to I/R. Physicochemical evaluations were performed on nanoparticles...
February 7, 2018: Toxicology
Corinne Haines, Barbara M Elcombe, Lynsey R Chatham, Audrey Vardy, Larry G Higgins, Clifford R Elcombe, Brian G Lake
Phenobarbital (PB), a constitutive androstane receptor (CAR) activator, produces liver tumours in rodents by a mitogenic mode of action involving CAR activation. In this study, the hepatic effects of sodium phenobarbital (NaPB) were compared in male C57BL/6J wild type (WT) mice and in humanized mice, where both the mouse CAR and pregnane X receptor (PXR) have been replaced by their human counterparts (hCAR/hPXR mice). Investigations were also performed in cultured male C57BL/6J and CD-1 mouse, male Sprague-Dawley rat and male and female human hepatocytes...
February 6, 2018: Toxicology
Hongyu Yan, Zhenlin Huang, Qingyun Bai, Yuchen Sheng, Zhanxia Hao, Zhengtao Wang, Lili Ji
As a well-known analgesic drug, acetaminophen (APAP) is commonly used to relieve pain for patients with chronic painful diseases. Our previous study has shown that long-term ingestion of APAP caused liver fibrosis in mice. This study further investigated the critical role of nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating APAP-induced liver fibrosis in mice and the anti-fibrotic effect of natural compound andrographolide (Andro). Our results showed that hepatic collagen deposition and hepatic stellate cells (HSCs) activation induced by APAP were more serious in Nrf2 knock-out mice than in normal wild-type mice...
January 18, 2018: Toxicology
Sanki Asakawa, Ryo Onodera, Koji Kasai, Yu Kishimoto, Taiki Sato, Ryosuke Segawa, Natsumi Mizuno, Kouetsu Ogasawara, Takahiro Moriya, Masahiro Hiratsuka, Noriyasu Hirasawa
Nickel ions (Ni2+) eluted from biomedical devices cause inflammation and Ni allergy. Although Ni2+ and Co2+ elicit common effects, Ni2+ induces a generally stronger inflammatory reaction. However, the molecular mechanism by which Ni2+ and Co2+ induce such different responses remains to be elucidated. In the present study, we compared the effects of Ni2+ and Co2+ on the expression of interleukin (IL)-8 in human monocyte THP-1 cells. We report that NiCl2 but not CoCl2 induced the expression of IL-8; in contrast, CoCl2 elicited a higher expression of hypoxia-inducible factor-1α (HIF-1α)...
January 16, 2018: Toxicology
Franziska Paech, Cécile Mingard, David Grünig, Vanessa F Abegg, Jamal Bouitbir, Stephan Krähenbühl
Previous studies have shown that certain kinase inhibitors are mitochondrial toxicants. In the current investigation, we determined the mechanisms of mitochondrial impairment by the kinase inhibitors ponatinib, regorafenib, and sorafenib in more detail. In HepG2 cells cultured in galactose and exposed for 24 hours, all three kinase inhibitors investigated depleted the cellular ATP pools at lower concentrations than cytotoxicity occurred, compatible with mitochondrial toxicity. The kinase inhibitors impaired the activity of different complexes of the respiratory chain in HepG2 cells exposed to the toxicants for 24 hours and in isolated mouse liver mitochondria exposed acutely...
January 13, 2018: Toxicology
Guoxin Hu, Junwei Li, Yuanyuan Shan, Xiaoheng Li, Qiqi Zhu, Huitao Li, Yiyan Wang, Xiaofang Chen, Qingquan Lian, Ren-Shan Ge
Phthalate diesters, including di-(2-ethylhexyl) phthalate (DEHP) and diethyl phthalate (DEP), are chemicals to which humans are ubiquitously exposed. Humans are exposed simultaneously to multiple environmental chemicals, including DEHP and DEP. There is little information available about how each chemical may interact to each other if they were exposed at same time. The present study investigated effects of the combinational exposure of rats to DEP and DEHP on fetal Leydig cell development. The results showed that the gestational (GD12-20) exposure of DEP + DEHP resulted in synergistic and/or dose-additive effects on the development of fetal Leydig cell...
January 8, 2018: Toxicology
Yun-Fang An, Xiao-Rui Geng, Li-Hua Mo, Jiang-Qi Liu, Li-Teng Yang, Xiao-Wen Zhang, Zhi-Gang Liu, Chang-Qing Zhao, Ping-Chang Yang
BACKGROUND AND AIMS: It is recognized that the air pollution is associated with the pathogenesis of airway diseases. This study aims to elucidate the role of the 3-methyl-4-nitrophenol (PNMC), one of the components of diesel-exhaust particles, in compromising the airway epithelial barrier integrity. METHODS: A549 cells, an airway epithelial cell line, were cultured to monolayers to be used as an in vitro epithelial barrier model. BALB/c mice were treated with nasal drops containing PNMC to test the effects of PNMC on alternating the airway epithelial barrier functions...
January 4, 2018: Toxicology
Michael Aagaard Andersen, Karen Malene Wegener, Steen Larsen, Lassina Badolo, Garrick Paul Smith, Ross Jeggo, Poul Henning Jensen, Florence Sotty, Kenneth Vielsted Christensen, Annemette Thougaard
Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no existing therapeutic approach to delay or stop progression. Genetic, biochemical and pre-clinical studies have provided evidence that leucine-rich-repeat-kinase-2 (LRRK2) kinase is involved in the pathogenesis of PD, and small molecule LRRK2 inhibitors represent a novel potential therapeutic approach. However, potentially adverse target-related effects have been discovered in the lung and kidneys of LRRK2 knock-out (ko) mice and rats...
January 4, 2018: Toxicology
Peter Dornbos, John J LaPres
Humans respond to chemical exposures differently due to many factors, such as previous and concurrent stressors, age, sex, and genetic background. The vast majority of laboratory-based toxicology studies, however, have not considered the impact of population-level variability within dose-response relationships. The lack of data dealing with the influence of genetic diversity on the response to chemical exposure provides a difficult challenge for risk assessment as individuals within the population will display a wide-range of responses following toxicant challenge...
December 21, 2017: Toxicology
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