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Toxicology and Applied Pharmacology

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https://www.readbyqxmd.com/read/28927738/dmard-use-is-associated-with-a-higher-risk-of-dementia-in-patients-with-rheumatoid-arthritis-a-propensity-score-matched-case-control-study
#1
Ming-Hsien Chou, Jong-Yi Wang, Cheng-Li Lin, Wei-Sheng Chung
BACKGROUND: Patients with rheumatoid arthritis (RA) exhibit an increased risk of dementia. Disease-modifying antirheumatic drugs (DMARDs) are commonly used to slow RA progression, but studies investigating the relationship between DMARDs and dementia in patients with RA are lacking. We investigated the relationship between DMARDs and dementia in patients with RA. METHODS: Using the National Health Insurance Research Database, patients aged ≥20years, who were newly diagnosed with RA between 2000 and 2011 were identified...
September 16, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28923513/a-dioxin-like-compound-induces-hyperplasia-and-branching-morphogenesis-in-mouse-mammary-gland-through-alterations-in-tgf-%C3%AE-1-and-aryl-hydrocarbon-receptor-signaling
#2
Miret Noelia, Rico-Leo Eva, Pontillo Carolina, Zotta Elsa, Fernández-Salguero Pedro, Randi Andrea
Hexachlorobenzene (HCB) is a widespread environmental pollutant and a dioxin-like compound that binds weakly to the aryl hydrocarbon receptor (AhR). Because AhR and transforming growth factor β1 (TGF-β1) converge to regulate common signaling pathways, alterations in this crosstalk might contribute to developing preneoplastic lesions. The aim of this study was to evaluate HCB action on TGF-β1 and AhR signaling in mouse mammary gland, through AhR+/+ and AhR-/- models. Results showed a differential effect in mouse mammary epithelial cells (NMuMG), depending on the dose: 0...
September 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28919514/hz-6d-targeted-herc5-to-regulate-p53-isgylation-in-human-hepatocellular-carcinoma
#3
Yang Wang, Qi Ding, Tao Xu, Chang-Yao Li, Dan-Dan Zhou, Lei Zhang
Manipulating the posttranslational modulator of p53 is central in the regulation of its activity and function. ISGylated p53 can be degraded by the 20S proteasome. During this process, HERC5/Ceb1, an IFN-induced HECT-type E3 ligase, mediated p53 ISGylation. In this study, we indicated that HERC5 was over-expressed in both HCC tissue samples and cell lines. Knockdown of HERC5 significantly induced the expression of p53, p21 and Bax/Bcl-2 in HCC cells, resulting in apoptosis augment. Whereas, opposite results were obtained by using HERC5 over-expression...
September 14, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28916251/mk-801-but-not-naloxone-attenuates-high-dose-dextromethorphan-induced-convulsive-behavior-possible-involvement-of-the-glun2b-receptor
#4
Hai-Quyen Tran, Yoon Hee Chung, Eun-Joo Shin, The-Vinh Tran, Ji Hoon Jeong, Choon-Gon Jang, Seung-Yeol Nah, Kiyofumi Yamada, Toshitaka Nabeshima, Hyoung-Chun Kim
Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague-Dawley rats showed increased seizure occurrence and intensity...
September 13, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28911973/novel-oxolane-derivative-dmtd-mitigates-high-glucose-induced-erythrocyte-apoptosis-by-regulating-oxidative-stress
#5
Swamy Jagadish, Mahadevappa Hemshekhar, Somanathapura K NaveenKumar, Kothanahally S Sharath Kumar, Mahalingam S Sundaram, Basappa, Kesturu S Girish, Kanchugarakoppal S Rangappa
Chronic hyperglycemia is one of the characteristic conditions associated with Diabetes Mellitus (DM), which often exerts deleterious effects on erythrocyte morphology and hemodynamic properties leading to anemia and diabetes-associated vascular complications. High glucose-induced over production of reactive oxygen species (ROS) can alter the blood cell metabolism and biochemical functions subsequently causing eryptosis (red blood cell death), yet another complication of concern in DM. Therefore, blocking high glucose-induced oxidative damage and subsequent eryptosis is of high importance in the better management of DM and associated vascular complications...
September 11, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28911972/sex-specific-effects-of-developmental-lead-exposure-on-the-immune-neuroendocrine-network
#6
REVIEW
Jane Kasten-Jolly, David A Lawrence
The environmental toxicant lead (Pb) has long been known to induce neurological deficits. The 1st century Greek physician Pedanius Dioscorides noted that "lead makes the mind give way". Current studies are suggesting the effects of Pb on behaviors may involve the immune system and conversely some immunomodulatory changes may be due to Pb effects in the central nervous system. Although Pb-induced disorders do not appear to discriminate among females and males, this report discusses the differences observed in human and animal studies regarding differential gender effects on gene expression after Pb exposure...
September 11, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28899750/downregulation-of-ube2e2-in-rat-liver-cells-after-hepatocarcinogen-treatment-facilitates-cell-proliferation-and-slowing-down-of-dna-damage-response-in-gst-p-expressing-preneoplastic-lesions
#7
Sayaka Mizukami, Yousuke Watanabe, Yukie Saegusa, Kota Nakajima, Yuko Ito, Yasunori Masubuchi, Toshinori Yoshida, Makoto Shibutani
We previously found downregulation of ubiquitin-conjugating enzyme E2E 2 (UBE2E2) in GST-P-expressing ((+)) proliferative lesions produced by tumor promotion from early hepatocarcinogenesis stages in rats. Here we investigated the role of UBE2E2 downregulation in preneoplastic lesions of the liver and other target organs produced by tumor promotion in rats. Increased number of UBE2E2-related ubiquitination target proteins, phosphorylated c-MYC, KDM4A and KMT5A, was found in the UBE2E2-downregulated GST-P-positive foci, compared with GST-P(+) foci expressing UBE2E2...
September 9, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28899749/cyp4a-cyp2c-modulation-of-the-interaction-of-calcium-channel-blockers-with-cyclosporine-on-edhf-mediated-renal-vasodilations-in-rats
#8
Safaa H Hammoud, Amal G Omar, Assaad A Eid, Mahmoud M El-Mas
The endothelium-derived hyperpolarizing factor (EDHF) serves as a back-up mechanism that compensates for reduced nitric oxide (NO)/prostanoids bioavailability. Here we investigated whether (i) under conditions of vascular endothelium dysfunction, the immunosuppressant drug cyclosporine (CSA) upregulates EDHF-dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combinations for 7days...
September 9, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28893587/current-nonclinical-testing-paradigm-enables-safe-entry-to-first-in-human-clinical-trials-the-iq-consortium-nonclinical-to-clinical-translational-database
#9
Thomas M Monticello, Thomas W Jones, Donna M Dambach, David M Potter, Michael W Bolt, Maggie Liu, Douglas A Keller, Timothy K Hart, Vivek J Kadambi
The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2×2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis...
September 8, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28893586/effects-of-diisononyl-phthalate-on-osteopenia-in-intact-mice
#10
Yun-Ho Hwang, Young-Jin Son, Man-Jeong Paik, Sung-Tae Yee
Osteopenia is characterized by bone loss and deterioration of trabecular bone, which leads to osteoporotic fractures. This disease is highly prevalent in industrialized areas and is associated with exposure to endocrine disrupting chemicals (EDCs). Diisononyl phthalate (DINP) is one of these EDCs and is mainly used as a plasticizer in flexible polyvinyl chloride (PVC) products. Although it is well known that exposure to DINP is harmful to humans, no studies have been reported concerning its contribution to osteopenia...
September 8, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28870655/comparative-health-effects-in-mice-of-libby-amphibole-asbestos-and-a-fibrous-amphibole-from-arizona
#11
Jean C Pfau, Brenda Buck, Rodney V Metcalf, Zoie Kaupish, Caleb Stair, Maria Rodriguez, Deborah E Keil
This project developed from studies demonstrating that Libby Amphibole Asbestos (LAA) causes a non-typical set of health outcomes not generally reported for asbestos, including systemic autoimmunity and an unusual and devastating lamellar pleural thickening that progresses to severe pulmonary dysfunction and death. Further, mineral fiber mixtures with some similarities to LAA have recently been discovered in southern Nevada and northwestern Arizona, where the material exists in extensive recreational areas and is present in yards, roads, parking lots and school yards...
September 7, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28888487/impaired-autophagic-flux-and-p62-mediated-emt-are-involved-in-arsenite-induced-transformation-of-l-02-cells
#12
Xinlu Liu, Min Ling, Chao Chen, Fei Luo, Ping Yang, Dapeng Wang, Xiong Chen, Hui Xu, Junchao Xue, Qianlei Yang, Lu Lu, Jiachun Lu, Qian Bian, Aihua Zhang, Qizhan Liu
Autophagy is a catabolic process essential for preserving cellular homeostasis, and the epithelial-to-mesenchymal transition (EMT) is involved during tissue development and cancer progression. In arsenite-treated human hepatic epithelial (L-02) cells, arsenite reduced the autophagic flux, which caused accumulation of p62, an adaptor and receptor of autophagy. Further, in arsenite-transformed L-02 cells, the levels of E-cadherin were attenuated, but the levels of vimentin, which is expressed in mesenchymal cells, and Snail, a transcription regulator of the EMT, were up-regulated...
September 6, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28887131/prostacyclin-mimetics-afford-protection-against-lipopolysaccharide-d-galactosamine-induced-acute-liver-injury-in-mice
#13
Hiroki Misawa, Wakana Ohashi, Kengo Tomita, Kohshi Hattori, Yutaka Shimada, Yuichi Hattori
Prostacyclin (PGI2) serves as a protective, anti-inflammatory mediator and PGI2 mimetics may be useful as a hepatoprotective agent. We examined whether two PGI2 mimetics, ONO-1301 and beraprost, are beneficial in acute liver injury and attempted to delineate the possible mechanism underlying the hepatoprotective effect. Acute liver injury was induced by lipopolysaccharide/d-galactosamine (LPS/GalN) in mice. Mice were given an intraperitoneal injection of PGI2 mimetics 1h before LPS/GalN challenge. Both ONO-1301 and beraprost significantly declined the LPS/GalN-induced increase in serum aminotransferase activity...
September 5, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28887130/gender-specific-impairment-of-in-vitro-sinoatrial-node-chronotropic-responses-and-of-myocardial-ischemia-tolerance-in-rats-exposed-prenatally-to-betamethasone
#14
L R A Kiguti, C S Borges, A Mueller, K P Silva, C M Polo, J L Rosa, P V Silva, G Missassi, L Valencise, W G Kempinas, A S Pupo
Excessive fetal glucocorticoid exposure has been linked to increased susceptibility to hypertension and cardiac diseases in the adult life, a process called fetal programming. The cardiac contribution to the hypertensive phenotype of glucocorticoid-programmed progeny is less known, therefore, we investigated in vitro cardiac functional parameters from rats exposed in utero to betamethasone. Pregnant Wistar rats received vehicle (VEH) or betamethasone (BET, 0.1mg/kg, i.m.) at gestational days 12, 13, 18 and 19...
September 5, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28882485/zinc-chloride-rapidly-stimulates-efflux-transporters-in-renal-proximal-tubules-of-killifish-fundulus-heteroclitus
#15
Alexander Zaremba, David S Miller, Gert Fricker
Multidrug resistance-related protein 2 (Mrp2) is an ATP-driven efflux pump at the luminal membrane in renal proximal tubules. It acts as detoxification mechanism by transporting xenobiotics and metabolic products into urine. The trace element zinc is essential for cellular growth, differentiation and survival. It modulates immune response and is used as dietary supplement. Here, we found that 0.1-10μM ZnCl2 rapidly stimulated transport of the Mrp2 probe substrate Texas Red (TR) in isolated killifish renal proximal tubules, which provide an established model system to measure efflux transporter activity by using fluorescent probe substrates, confocal microscopy and image analysis...
September 4, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28870656/a-two-step-model-of-tio2-nanoparticle-toxicity-in-human-liver-tissue
#16
T Laomettachit, I K Puri, M Liangruksa
We examine the toxicity of titanium dioxide (TiO2) nanoparticles on human liver through a two-step approach, including a physiologically-based pharmacokinetic (PBPK) model and a cell-response model. The PBPK model predicts the bio-distribution of nanoparticles that remain in the human body after exposure, with special attention to their accumulation in liver tissue. The cell-response model predicts liver cell death as a consequence of the accumulated TiO2 nanoparticles by considering cell fate dynamics through the interplay between cellular uptake of the nanoparticles and their dilution due to cell division...
September 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28867438/neuromuscular-paralysis-by-the-basic-phospholipase-a2-subunit-of-crotoxin-from-crotalus-durissus-terrificus-snake-venom-needs-its-acid-chaperone-to-concurrently-inhibit-acetylcholine-release-and-produce-muscle-blockage
#17
Walter L G Cavalcante, José B Noronha-Matos, Maria A Timóteo, Marcos R M Fontes, Márcia Gallacci, Paulo Correia-de-Sá
BACKGROUND AND PURPOSE: Crotoxin (CTX), a heterodimeric phospholipase A2 (PLA2) neurotoxin from Crotalus durissus terrificus snake venom, promotes irreversible blockade of neuromuscular transmission. Indirect electrophysiological evidence suggests that CTX exerts a primary inhibitory action on transmitter exocytosis, yet contribution of a postsynaptic action of the toxin resulting from nicotinic receptor desensitization cannot be excluded. Here, we examined the blocking effect of CTX on nerve-evoked transmitter release measured directly using radioisotope neurochemistry and video microscopy with the FM4-64 fluorescent dye...
September 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28867437/quinacrine-induces-the-apoptosis-of-human-leukemia-u937-cells-through-foxp3-mir-183-%C3%AE-trcp-sp1-axis-mediated-bax-upregulation
#18
Chia-Hui Huang, Yuan-Chin Lee, Ying-Jung Chen, Liang-Jun Wang, Yi-Jun Shi, Long-Sen Chang
Quinacrine, which is clinically used as an antimalarial drug, has anti-cancer activity. However, mechanism underlying its cytotoxic effect remains to be completely elucidated. In the present study, we investigated the cytotoxic effect of quinacrine on human leukemia U937 cells. Quinacrine-induced apoptosis of U937 cells was accompanied with ROS generation, mitochondrial depolarization, and BAX upregulation. Quinacrine-treated U937 cells showed ROS-mediated p38 MAPK activation and ERK inactivation, which in turn upregulated FOXP3 transcription...
September 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28867436/effects-of-diosmetin-on-nine-cytochrome-p450-isoforms-ugts-and-three-drug-transporters-in-vitro
#19
Jun-Jun Chen, Jing-Xian Zhang, Xiang-Qi Zhang, Mei-Juan Qi, Mei-Zhi Shi, Jiao Yang, Ke-Zhi Zhang, Cheng Guo, Yong-Long Han
Diosmetin (3', 5, 7-trihydroxy-4'-methoxyflavone), a natural flavonoid from traditional Chinese herbs, has been used in various medicinal products because of its anticancer, antimicrobial, antioxidant, estrogenic and anti-inflammatory activity. However, flavonoids could affect the metabolic enzymes and cause drug-drug interactions (DDI), reducing the efficacy of co-administered drugs and potentially resulting in serious adverse reactions. To evaluate its potential to interact with co-administered drugs, the IC50 value of phase I cytochrome P450 enzymes (CYPs), phase II UDP-glucuronyltransferases (UGTs) and hepatic uptake transporters (organic cation transporters (OCTs), organic anion transporter polypeptides (OATPs) and Na(+)-taurocholate cotransporting polypeptides (NTCPs)) were examined in vitro by LC-MS/MS...
September 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28865757/a-cell-impedance-based-real-time-in-vitro-assay-to-assess-the-toxicity-of-amphotericin-b-formulations
#20
Jean Menotti, Alexandre Alanio, Aude Sturny-Leclère, Sandrine Vitry, Félix Sauvage, Gillian Barratt, Stéphane Bretagne
Aerosolized liposomal amphotericin B (L-AmB) has been investigated as prophylaxis against invasive aspergillosis. However, the clinical results are controversial and some trials suggest that toxicity could be a limitation for wider use. Our aim was to assess the dynamics of cell toxicity induced in a human alveolar epithelial cell line (A549) after exposure to L-AmB (50 to 400μg/ml) or amphotericin B deoxycholate (D-AmB; 50 to 200μg/ml) by monitoring real-time A549 cell viability using an impedance-based technology...
September 1, 2017: Toxicology and Applied Pharmacology
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