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Toxicology and Applied Pharmacology

John J Guardiola, Juliane I Beier, K Cameron Falkner, Benjamin Wheeler, Craig James McClain, Matt Cave
BACKGROUND: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. METHODS: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS(2) analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed...
October 17, 2016: Toxicology and Applied Pharmacology
Maciej Woźny, Bogdan Lewczuk, Natalia Ziółkowska, Piotr Gomułka, Stefan Dobosz, Alicja Łakomiak, Maciej Florczyk, Paweł Brzuzan
To date, there has been no systematic approach comprehensively describing the sequence of pathological changes in fish during prolonged exposure to microcystin-LR (MC-LR). Towards this aim, juvenile whitefish individuals received an intraperitoneal injection with pure MC-LR, and the injection was repeated every week to maintain continuous exposure for 28days. During the exposure period, growth and condition of the fish were assessed based on biometric measurements. Additionally, selected biochemical markers were analysed in the fishes' blood, and their livers were carefully examined for morphological, ultrastructural, and molecular changes...
October 17, 2016: Toxicology and Applied Pharmacology
Esther Peters, Bülent Ergin, Asli Kandil, Ebru Gurel-Gurevin, Andrea van Elsas, Rosalinde Masereeuw, Peter Pickkers, Can Ince
Two small clinical trials indicated that administration of bovine intestinal alkaline phosphatase (AP) improves renal function in critically ill patients with sepsis-associated acute kidney injury (AKI), for which the mechanism of action is not completely understood. Here, we investigated the effects of a newly developed human recombinant AP (recAP) on renal oxygenation and hemodynamics and prevention of kidney damage and inflammation in two in vivo AKI models. To induce AKI, male Wistar rats (n=18) were subjected to renal ischemia (30min) and reperfusion (I/R), or sham-operated...
October 16, 2016: Toxicology and Applied Pharmacology
Wenwen Wang, Yanqin Yang, Zhewen Xiong, Jiamin Kong, Xinlu Fu, Feihai Shen, Zhiying Huang
Triptolide (TP), a diterpene triepoxide, is a major active component of Tripterygium wilfordii extracts, which are prepared as tablets and has been used clinically for the treatment of inflammation and autoimmune disorders. However, TP's therapeutic potential is limited by severe adverse effects. In a previous study, we reported that TP induced mitochondria dependent apoptosis in cardiomyocytes. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase that plays important roles in the necrosis and apoptosis of cardiomyocytes...
October 14, 2016: Toxicology and Applied Pharmacology
Andrea Villar-Lorenzo, Alejandro E Ardiles, Ana I Arroba, Enrique Hernández-Jiménez, Virginia Pardo, Eduardo López-Collazo, Ignacio A Jiménez, Isabel L Bazzochi, Águeda González-Rodríguez, Ángela M Valverde
A series of 31 pentacyclic triterpenoids isolated from the root barks of Celastrus vulcanicola and Maytenus jelskii were tested for cytotoxicity and inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 18 (C18) and 25 (C25) exhibited significant inhibition of LPS-induced NO release at 50 and 25μM concentrations, respectively, and decreased mRNAs of pro-inflammatory cytokines. At the molecular level, C18 neither inhibited LPS-mediated phosphorylation of mitogen activated protein kinases (MAPKs) nor nuclear translocation of nuclear factor kappa beta (NFκB)...
October 14, 2016: Toxicology and Applied Pharmacology
Nicole Kurhanewicz, Rachel McIntosh-Kastrinsky, Haiyan Tong, Allen Ledbetter, Leon Walsh, Aimen Farraj, Mehdi Hazari
Short-term exposure to ambient air pollution is linked with adverse cardiovascular effects. While previous research focused primarily on particulate matter-induced responses, gaseous air pollutants also contribute to cause short-term cardiovascular effects. Mechanisms underlying such effects have not been adequately described, however the immediate nature of the response suggests involvement of irritant neural activation and downstream autonomic dysfunction. Thus, this study examines the role of TRPA1, an irritant sensory receptor found in the airways, in the cardiac response of mice to acrolein and ozone...
October 13, 2016: Toxicology and Applied Pharmacology
Mohamed Balaha, Samah Kandeel, Waleed Barakat
Carvedilol is an anti-oxidant non-selective β-blocker used for reduction of portal blood pressure, prophylaxis of esophageal varices development and bleeding in chronic liver diseases. Recently, it exhibited potent anti-inflammatory, anti-fibrotic, anti-proliferative and anti-carcinogenic effects. In the present study, we evaluated the possible suppressive effect of carvedilol on circulating and hepatic IL-6 levels responsible for hepatocarcinogenesis in a rat model of hepatic cirrhosis. Besides, its effect on hepatic STAT-3 levels, function tests, oxidative stress markers, and hydroxyproline content, hepatic tissue histopathological changes and immunohistochemical expression of E & N-cadherin...
October 13, 2016: Toxicology and Applied Pharmacology
K Dziendzikowska, A Krawczyńska, M Oczkowski, T Królikowski, K Brzóska, A Lankoff, M Dziendzikowski, T Stępkowski, M Kruszewski, J Gromadzka-Ostrowska
The growing use of silver nanoparticles (AgNPs) in various applications, including consumer, agriculture and medicine products, has raised many concerns about the potential risks of nanoparticles (NPs) to human health and the environment. An increasing body of evidence suggests that AgNPs may have adverse effects of humans, thus the aim of this study was to investigate the effects of AgNPs on the male reproductive system. Silver particles (20nm AgNPs (groups Ag I and Ag II) and 200nm Ag sub-micron particles (SPs) (group Ag III)) were administered intravenously to male Wistar rats at a dose of 5 (groups Ag I and Ag III) or 10 (group Ag II) mg/kg of body weight...
October 13, 2016: Toxicology and Applied Pharmacology
Oliver G Weingart, Martin J Loessner
Botulinum neurotoxins (BoNT) are the most toxic substances known, and their neurotoxic properties and paralysing effects are exploited for medical treatment of a wide spectrum of disorders. To accurately quantify the potency of a pharmaceutical BoNT preparation, its physiological key activities (binding to membrane receptor, translocation, and proteolytic degradation of SNARE proteins) need to be determined. To date, this was only possible using animal models, or, to a limited extent, cell-based assays. We here report a novel in vitro system for BoNT/B analysis, based on nerve-cell mimicking liposomes presenting motoneuronal membrane receptors required for BoNT binding...
October 12, 2016: Toxicology and Applied Pharmacology
Xiaojiaoyang Li, Zihang Yuan, Runping Liu, Hozeifa M Hassan, Hang Yang, Rong Sun, Luyong Zhang, Zhenzhou Jiang
Estrogen-induced cholestasis, known as intrahepatic cholestasis of pregnancy (ICP), is an estrogen-related liver disease that is widely recognized as female or pregnancy-specific. Our previous findings showed that the synthetic estrogen, 17α-ethinylestradiol (EE), induced cholestatic injury through ERK1/2-LKB1-AMP-activated protein kinase (AMPK) signaling pathway and its mediated suppression of farnesoid X receptor (FXR). To investigate the role played by bile acids in EE-induced cholestasis, we evaluated the effects of chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) on sandwich cultured rat primary hepatocytes (SCRHs) and an in vivo rat model...
October 12, 2016: Toxicology and Applied Pharmacology
Guojun Zhang, Mingkai Xu, Huiwen Zhang, Yubo Song, Jian Wang, Chenggang Zhang
Staphylococcal enterotoxin C2 (SEC2), a member of bacterial superantigen, is one of the most potent known activators of T lymphocytes. With this property, SEC2 has already been used in clinic as a tumor immunotherapy agent in China. To increase the antitumor activity, a SEC2 mutant named ST-4 (GKVTG102-106WWH) with amino acid substitutions in T cell receptor (TCR)-binding domain was generated by site-directed mutagenesis, and the molecular mechanism of the enhanced antitumor activity was investigated. Results showed that ST-4 could activate much more Vβ 8...
October 11, 2016: Toxicology and Applied Pharmacology
Gabriel A Knudsen, Michael F Hughes, J Michael Sanders, Samantha M Hall, Linda S Birnbaum
: 2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl)tetrabromophthalate (BEH-TEBP) are novel brominated flame retardants used in consumer products. A parallelogram approach was used to predict human dermal absorption and flux for EH-TBB and BEH-TEBP. [(14)C]-EH-TBB or [(14)C]-BEH-TEBP was applied to human or rat skin at 100nmol/cm(2) using a flow-through system. Intact rats received analogous dermal doses. Treated skin was washed and tape-stripped to remove "unabsorbed" [(14)C]-radioactivity after continuous exposure (24h)...
October 11, 2016: Toxicology and Applied Pharmacology
Ananddeep Patel, Shaojie Zhang, Amrit Kumar Shrestha, Paramahamsa Maturu, Bhagavatula Moorthy, Binoy Shivanna
Omeprazole (OM) is an aryl hydrocarbon receptor (AhR) agonist and a proton pump inhibitor that is used to treat humans with gastric acid related disorders. Recently, we showed that OM induces NAD (P) H quinone oxidoreductase-1 (NQO1) via nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent mechanism. Heme oxygenase-1 (HO-1) is another cytoprotective and antioxidant enzyme that is regulated by Nrf2. Whether OM induces HO-1 in fetal human pulmonary microvascular endothelial cells (HPMEC) is unknown. Therefore, we tested the hypothesis that OM will induce HO-1 expression via Nrf2 in HPMEC...
October 8, 2016: Toxicology and Applied Pharmacology
Craig Steinmaus, Catterina Ferreccio, Johanna Acevedo, John R Balmes, Jane Liaw, Patricia Troncoso, David C Dauphiné, Anthony Nardone, Allan H Smith
BACKGROUND: Arsenic in drinking water has been associated with increases in lung disease, but information on the long-term impacts of early-life exposure or moderate exposure levels are limited. METHODS: We investigated pulmonary disease and lung function in 795 subjects from three socio-demographically similar areas in northern Chile: Antofagasta, which had a well-described period of high arsenic water concentrations (860μg/L) from 1958 to 1970; Iquique, which had long-term arsenic water concentrations near 60μg/L; and Arica, with long-term water concentrations ≤10μg/L...
October 7, 2016: Toxicology and Applied Pharmacology
Octavio Caba, Antonio Irigoyen, Cristina Jimenez-Luna, Manuel Benavides, Francisco M Ortuño, Javier Gallego, Ignacio Rojas, Carmen Guillen-Ponce, Carolina Torres, Enrique Aranda, Jose Prados
Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that showed activity against pancreatic ductal adenocarcinoma (PDAC). The drug's most frequently reported side effect as a result of EGFR inhibition is skin rash (SR), a symptom which has been associated with a better therapeutic response to the drug. Gene expression profiling can be used as a tool to predict which patients will develop this important cutaneous manifestation. The aim of the present study was to identify which genes may influence the appearance of SR in PDAC patients...
October 6, 2016: Toxicology and Applied Pharmacology
Karen E Weis, Lori T Raetzman
The plant flavonoid isoliquiritigenin (ISL) is a botanical estrogen widely taken as an herbal supplement to ease the symptoms of menopause. ISL has been also shown to have anti-tumor properties in a number of cancer cell backgrounds. However, the effects of ISL on normal cells are less well known and virtually unstudied in the context of the pituitary gland. We have established a pituitary explant culture model to screen chemical agents for gene expression changes within the pituitary gland during a period of active proliferation and differentiation...
October 1, 2016: Toxicology and Applied Pharmacology
Lisanne C Anders, Heegook Yeo, Brenna R Kaelin, Anna L Lang, Adrienne M Bushau, Amanda N Douglas, Matt Cave, Gavin E Arteel, Craig J McClain, Juliane I Beier
BACKGROUND: Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied...
September 28, 2016: Toxicology and Applied Pharmacology
Cheri L Lamb, Giovan N Cholico, Xinzhu Pu, Gerald D Hagler, Kenneth A Cornell, Kristen A Mitchell
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant and high-affinity ligand for the aryl hydrocarbon receptor (AhR). Increasing evidence indicates that AhR signaling contributes to wound healing, which involves the coordinated deposition and remodeling of the extracellular matrix. In the liver, wound healing is attributed to the activation of hepatic stellate cells (HSCs), which mediate fibrogenesis through the production of soluble mediators and collagen type I. We recently reported that TCDD treatment increases the activation of human HSCs in vitro...
September 28, 2016: Toxicology and Applied Pharmacology
Rabab H Sayed, Muhammed A Saad, Ayman E El-Sahar
Serotonin level plays a role in suppressing the pathological findings of benign prostatic hyperplasia (BPH). Thus a new selective serotonin reuptake inhibitor, dapoxetine was used to test its ability to ameliorate the pathological changes in the rat prostate. A dose response curve was constructed between the dose of dapoxetine and prostate weight as well as relative prostate weight, then a 5mg/kg dose was used as a representative dose for dapoxetine administration. Rats were divided into four groups; the control group that received the vehicle; the BPH-induced group received daily s...
September 27, 2016: Toxicology and Applied Pharmacology
Ala Abdelali, Maie Al-Bader, Narayana Kilarkaje
Diabetes induces oxidative stress, DNA damage and alters several intracellular signaling pathways in organ systems. This study investigated modulatory effects of Trans-Resveratrol on type 1 diabetes mellitus (T1DM)-induced abnormal spermatogenesis, DNA damage and alterations in poly (ADP-ribose) polymerase (PARP) signaling in rat testis. Trans-Resveratrol administration (5mg/kg/day, ip) to Streptozotocin-induced T1DM adult male Wistar rats from day 22-42 resulted in recovery of induced oxidative stress, abnormal spermatogenesis and inhibited DNA synthesis, and led to mitigation of 8-hydroxy-2'-deoxyguanosine formation in the testis and spermatozoa, and DNA double-strand breaks in the testis...
September 27, 2016: Toxicology and Applied Pharmacology
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