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Toxicology and Applied Pharmacology

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https://www.readbyqxmd.com/read/28641963/modulation-of-the-heart-s-electrical-properties-by-the-anticonvulsant-drug-retigabine
#1
Lena Rubi, Michael Kovar, Eva Zebedin-Brandl, Xaver Koenig, Manuel Dominguez-Rodriguez, Hannes Todt, Helmut Kubista, Stefan Boehm, Karlheinz Hilber
Retigabine, currently used as antiepileptic drug, has a wide range of potential medical uses. Administration of the drug in patients can lead to QT interval prolongation in the electrocardiogram and to cardiac arrhythmias in rare cases. This suggests that the drug may perturb the electrical properties of the heart, and the underlying mechanisms were investigated here. Effects of retigabine on currents through human cardiac ion channels, heterologously expressed in tsA-201 cells, were studied in whole-cell patch-clamp experiments...
June 19, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28625800/arsenic-alters-transcriptional-responses-to-pseudomonas-aeruginosa-infection-and-decreases-antimicrobial-defense-of-human-airway-epithelial-cells
#2
B C Goodale, E J Rayack, B A Stanton
Arsenic contamination of drinking water and food threatens the health of hundreds of millions of people worldwide by increasing the risk of numerous diseases. Arsenic exposure has been associated with infectious lung disease in epidemiological studies, but it is not yet understood how ingestion of low levels of arsenic increases susceptibility to bacterial infection. Accordingly, the goal of this study was to examine the effect of arsenic on gene expression in primary human bronchial epithelial (HBE) cells and to determine if arsenic altered epithelial cell responses to Pseudomonas aeruginosa, an opportunistic pathogen...
June 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28624444/distribution-lipid-bilayer-affinity-and-kinetics-of-the-metabolic-effects-of-dinoseb-in-the-liver
#3
Gabriela Bueno Franco Salla, Lívia Bracht, Anacharis Babeto de Sá-Nakanishi, Angela Valderrama Parizotto, Fabrício Bracht, Rosane Marina Peralta, Adelar Bracht
Dinoseb is a highly toxic pesticide of the dinitrophenol group. Its use has been restricted, but it can still be found in soils and waters in addition to being a component of related pesticides that, after ingestion by humans or animals, can originate the compound by enzymatic hydrolysis. As most dinitrophenols, dinoseb uncouples oxidative phosphorylation. In this study, distribution, lipid bilayer affinity and kinetics of the metabolic effects of dinoseb were investigated, using mainly the isolated perfused rat liver, but also isolated mitochondria and molecular dynamics simulations...
June 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28624443/inhibitory-effect-of-trans-caryophyllene-tc-on-leukocyte-endothelial-attachment
#4
Zhen Zhang, Chunfeng Yang, Xinlun Dai, Yu Ao, Yumei Li
trans-Caryophyllene (TC) is a major component found in the essential oils of many spices and foods/medicinal plants. It is a natural sesquiterpene and has been the subject of numerous studies. However, the effects of TC on vascular inflammation remain unknown. In this study, we reported that TC treatment in human umbilical vein endothelial cells (HUVECs) prevented attachment of monocytic leukemia cell line THP-1 cells to endothelial cells. In addition, in vivo results indicate that TC inhibited macrophage infiltration to the aortic surface and reduced total serum levels of cholesterol and triglycerides...
June 14, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28624442/loss-of-fructose-1-6-bisphosphatase-induces-glycolysis-and-promotes-apoptosis-resistance-of-cancer-stem-like-cells-an-important-role-in-hexavalent-chromium-induced-carcinogenesis
#5
Jin Dai, Yanli Ji, Wei Wang, Donghern Kim, Leonard Yenwong Fai, Lei Wang, Jia Luo, Zhuo Zhang
Hexavalent chromium (Cr(VI)) compounds are confirmed human carcinogens for lung cancer. Our previous studies has demonstrated that chronic exposure of human bronchial epithelial BEAS-2B cells to low dose of Cr(VI) causes malignant cell transformation. The acquisition of cancer stem cell-like properties is involved in the initiation of cancers. The present study has observed that a small population of cancer stem-like cells (BEAS-2B-Cr-CSC) exists in the Cr(VI)-transformed cells (BEAS-2B-Cr). Those BEAS-2B-Cr-CSC exhibit extremely reduced capability of generating reactive oxygen species (ROS) and apoptosis resistance...
June 14, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28624441/hsp90-inhibitor-geldanamycin-attenuates-the-cytotoxicity-of-sunitinib-in-cardiomyocytes-via-inhibition-of-the-autophagy-pathway
#6
Takayuki Kimura, Mai Uesugi, Kazuma Takase, Norimasa Miyamoto, Kohei Sawada
Sunitinib malate (sunitinib) is an orally available, multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Although sunitinib is effective for the treatment of patients with gastrointestinal stromal tumor, advanced renal cell carcinoma, or pancreatic neuroendocrine tumor, adverse cardiac events associated with sunitinib administration have been reported. Here, we examined the effect of geldanamycin, an inhibitor of heat shock protein (Hsp) 90, on sunitinib-induced cytotoxicity in cardiomyocytes...
June 14, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28623180/behavioral-screening-of-the-lopac-1280-library-in-zebrafish-embryos
#7
Sara M Vliet, Trina C Ho, David C Volz
Spontaneous activity represents an early, primitive form of motor activity within zebrafish embryos, providing a potential readout for identification of neuroactive compounds. However, despite use as an endpoint in chemical screens around the world, the predictive power and limitations of assays relying on spontaneous activity remain unclear. Using an improved high-content screening assay that increased throughput from 384 to 3072 wells per week, we screened a well-characterized library of 1280 pharmacologically active compounds (LOPAC(1280)) - 612 of which target neurotransmission - to identify which targets are detected using spontaneous activity as a readout...
June 13, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28623179/modulation-of-tgf-%C3%AE-smad-and-erk-signaling-pathways-mediates-the-anti-fibrotic-effect-of-mirtazapine-in-mice
#8
Dalia M El-Tanbouly, Walaa Wadie, Rabab H Sayed
Serotonin (5-HT) has been implicated as a key driver of liver fibrosis, acting via 5-HT2 receptor activation in the hepatic stellate cells. The current study was conducted to investigate the effects of mirtazapine, a 5-HT2A antagonist, in a mouse model of liver fibrosis. Mice received thioacetamide (TAA, 150mg/kg/biweekly, ip) for nine successive weeks for induction of liver fibrosis. Administration of mirtazapine significantly improved the plasma aminotransferases, reduced hepatic 5-HT concentration and ameliorated TAA-induced liver fibrosis, as demonstrated by reduced portal blood pressure, liver procollagen I content and α alpha smooth muscle actin expression...
June 13, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28623178/adrenal-derived-stress-hormones-modulate-ozone-induced-lung-injury-and-inflammation
#9
Andres Henriquez, John House, Desinia B Miller, Samantha J Snow, Anna Fisher, Hongzu Ren, Mette C Schladweiler, Allen D Ledbetter, Fred Wright, Urmila P Kodavanti
Ozone-induced systemic effects are modulated through activation of the neuro-hormonal stress response pathway. Adrenal demedullation (DEMED) or bilateral total adrenalectomy (ADREX) inhibits systemic and pulmonary effects of acute ozone exposure. To understand the influence of adrenal-derived stress hormones in mediating ozone-induced lung injury/inflammation, we assessed global gene expression (mRNA sequencing) and selected proteins in lung tissues from male Wistar-Kyoto rats that underwent DEMED, ADREX, or sham surgery (SHAM) prior to their exposure to air or ozone (1ppm), 4h/day for 1 or 2days...
June 13, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28595984/cell-cycle-pathway-dysregulation-in-human-keratinocytes-during-chronic-exposure-to-low-arsenite
#10
Laila Al-Eryani, Sabine Waigel, Venkatakrishna Jala, Samantha F Jenkins, J Christopher States
BACKGROUND: Arsenic is naturally prevalent in the earth's crust and widely distributed in air and water. Chronic low arsenic exposure is associated with several cancers in vivo, including skin cancer, and with transformation in vitro of cell lines including immortalized human keratinocytes (HaCaT). Arsenic also is associated with cell cycle dysregulation at different exposure levels in multiple cell lines. In this work, we analyzed gene expression in HaCaT cells to gain an understanding of gene expression changes contributing to transformation at an early time point...
June 11, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28610995/zingerone-reduces-hmgb1-mediated-septic-responses-and-improves-survival-in-septic-mice
#11
Wonhwa Lee, Sae-Kwang Ku, Jong-Sup Bae
High mobility group box 1 (HMGB1) is considered a late mediator of sepsis and the inhibition of HMGB1-mediated severe inflammatory responses and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Zingerone (ZGR), a phenolic alkanone isolated from ginger, has been reported to possess various pharmacological activities. We examined the effects of ZGR on HMGB1-mediated septic responses and survival rate in a mouse model of sepsis. ZGR was administered after HMGB1 challenge...
June 10, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28610994/manganese-induced-sex-specific-gut-microbiome-perturbations-in-c57bl-6-mice
#12
Liang Chi, Bei Gao, Xiaoming Bian, Pengcheng Tu, Hongyu Ru, Kun Lu
Overexposure to manganese (Mn) leads to toxic effects, such as promoting the development of Parkinson's-like neurological disorders. The gut microbiome is deeply involved in immune development, host metabolism, and xenobiotics biotransformation, and significantly influences central nervous system (CNS) via the gut-brain axis, i.e. the biochemical signaling between the gastrointestinal tract and the CNS. However, it remains unclear whether Mn can affect the gut microbiome and its metabolic functions, particularly those linked to neurotoxicity...
June 10, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28610993/effects-of-a-co-micronized-composite-containing-palmitoylethanolamide-and-polydatin-in-an-experimental-model-of-benign-prostatic-hyperplasia
#13
Marika Cordaro, Daniela Impellizzeri, Rosalba Siracusa, Enrico Gugliandolo, Roberta Fusco, Antonino Inferrera, Emanuela Esposito, Rosanna Di Paola, Salvatore Cuzzocrea
Palmitoylethanolamide (PEA), a fatty acid amide-signaling molecule has well-known anti-inflammatory and neuroprotective effects. Nevertheless, PEA does not possess the ability to prevent free radicals formation. Polydatin (PLD), a biological precursor of resveratrol, has antioxidant activity. A combination of PEA and PLD could, conceivably, have beneficial effects on oxidative stress produced by inflammatory processes. In the present study we investigated the effects of a co-micronized composite containing PEA and PLD (m(PEA/PLD)) in a model of testosterone-induced benign hyperplasia (BPH)...
June 10, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28610992/anti-liver-cancer-activity-in-vitro-and-in-vivo-induced-by-2-pyridyl-2-3-thiazole-derivatives
#14
Thiago David Dos Santos Silva, Larissa Mendes Bomfim, Ana Carolina Borges da Cruz Rodrigues, Rosane Borges Dias, Caroline Brandi Schlaepfer Sales, Clarissa Araújo Gurgel Rocha, Milena Botelho Pereira Soares, Daniel Pereira Bezerra, Marcos Veríssimo de Oliveira Cardoso, Ana Cristina Lima Leite, Gardenia Carmen Gadelha Militão
A total of 24 hybrid compounds containing pyridyl and 1,3-thiazole moieties were screened against HL-60 (leukemia), MCF-7 (breast adenocarcinoma), HepG2 (hepatocellular carcinoma), NCI-H292 (lung carcinoma) human tumor cell lines and non-tumor cells (PBMC, human peripheral blood mononuclear cells). Most of them were highly potent in at least one cell line tested (IC50≤3μM), being HL-60 the most sensitive and HepG2 the most resistant cell line. Among them, TAP-07 and TP-07 presented cytotoxic activity in all tumor cell lines, including HepG2 (IC50 2...
June 10, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28610991/antitumor-effectiveness-of-a-combined-therapy-with-a-new-cucurbitacin-b-derivative-and-paclitaxel-on-a-human-lung-cancer-xenograft-model
#15
REVIEW
Lucas Lourenço Marostica, André Luís Branco de Barros, Juliana Oliveira, Breno Souza Salgado, Geovanni Dantas Cassali, Elaine Amaral Leite, Valbert Nascimento Cardoso, Karen Luise Lang, Miguel Soriano Balparda Caro, Fernando Javier Durán, Eloir Paulo Schenkel, Mônica Cristina de Oliveira, Cláudia Maria Oliveira Simões
Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, with a high mortality rate due to the elevated risk of resistance. Natural cucurbitacins and their derivatives are recognized as promising antitumor compounds for several types of cancer, including NSCLC. In a recent study published by our research group, DACE (2-deoxy-2-amine-cucurbitacin E), which is a semisynthetic derivative of cucurbitacin B, showed potential in vitro synergistic antiproliferative effects combined with paclitaxel (PTX) in A549 cells...
June 10, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28595985/curcumin-inhibits-adipogenesis-induced-by-benzyl-butyl-phthalate-in-3t3-l1-cells
#16
Satoru Sakuma, Maki Sumida, Yukiko Endoh, Ayaka Kurita, Ayana Yamaguchi, Tomoki Watanabe, Tetsuya Kohda, Yui Tsukiyama, Yohko Fujimoto
Phthalates are a group of endocrine disrupting chemicals and may have contributed to the recent global obesity health crisis. Increased adipogenesis via the peroxisome proliferator-activated receptor γ (PPARγ)-CCAAT-enhancer binding protein α (C/EBPα) pathway could be one critical mechanism responsible for phthalate-induced weight gain. On the other hand, curcumin has been shown to inhibit adipogenesis in cells and animal models. The present study was undertaken to evaluate, for the first time, whether curcumin could reduce adipogenesis induced by benzyl butyl phthalate (BBP) via downregulation of the PPARγ-C/EBPα pathway...
June 10, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28602947/radiation-exposure-from-depleted-uranium-the-radiation-bystander-effect
#17
Alexandra C Miller, Rafael Rivas, Leonard Tesoro, Gregor Kovalenko, Nikola Kovaric, Peter Pavlovic, David Brenner
Depleted uranium (DU) is a radioactive heavy metal used primarily in military applications. Published data from our laboratory have demonstrated that DU exposure in vitro to immortalized human osteoblast cells (HOS) is both neoplastically transforming and genotoxic. In vivo studies have also demonstrated that DU is leukemogenic and genotoxic. DU possesses both a radiological (alpha particle) and chemical (metal) component but is generally considered a chemical biohazard. Studies have shown that alpha particle radiation does play a role in DU's toxic effects...
June 8, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28601433/characterization-of-xenobiotic-metabolizing-enzymes-of-a-reconstructed-human-epidermal-model-from-adult-hair-follicles
#18
Daniel Bacqueville, Carine Jacques, Laure Duprat, Emilien L Jamin, Beatrice Guiraud, Elisabeth Perdu, Sandrine Bessou-Touya, Daniel Zalko, Hélène Duplan
In this study, a comprehensive characterization of xenobiotic metabolizing enzymes (XMEs) based on gene expression and enzyme functionality was made in a reconstructed skin epidermal model derived from the outer root sheath (ORS) of hair follicles (ORS-RHE). The ORS-RHE model XME gene profile was consistent with native human skin. Cytochromes P450 (CYPs) consistently reported to be detected in native human skin were also present at the gene level in the ORS-RHE model. The highest Phase I XME gene expression levels were observed for alcohol/aldehyde dehydrogenases and (carboxyl) esterases...
June 7, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28587817/human-renal-tubular-cells-contain-cd24-cd133-progenitor-cell-populations-implications-for-tubular-regeneration-after-toxicant-induced-damage-using-cadmium-as-a-model
#19
Swojani Shrestha, Seema Somji, Donald A Sens, Andrea Slusser-Nore, Divyen H Patel, Evan Savage, Scott H Garrett
The proximal tubules of the kidney are target sites of injury by various toxicants. Cadmium (Cd(+2)), an environmental nephrotoxicant can cause adverse effects and overt renal damage. To decipher the mechanisms involved in nephrotoxicity, an in vitro model system is required. Mortal cultures of human proximal tubule (HPT) cells have served, as models but are difficult to acquire and do not lend themselves to stable transfection. The immortalized human proximal tubule cell line HK-2, has served as a model but it lacks vectorial active transport and shows signs of lost epithelial features...
June 3, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28583304/transgenerational-inheritance-of-neurobehavioral-and-physiological-deficits-from-developmental-exposure-to-benzo-a-pyrene-in-zebrafish
#20
Andrea L Knecht, Lisa Truong, Skylar W Marvel, David M Reif, Abraham Garcia, Catherine Lu, Michael T Simonich, Justin G Teeguarden, Robert L Tanguay
Benzo[a]pyrene (B[a]P) is a well-known genotoxic polycylic aromatic compound whose toxicity is dependent on signaling via the aryl hydrocarbon receptor (AHR). It is unclear to what extent detrimental effects of B[a]P exposures might impact future generations and whether transgenerational effects might be AHR-dependent. This study examined the effects of developmental B[a]P exposure on 3 generations of zebrafish. Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to 5 and 10μM B[a]P and raised in chemical-free water until adulthood (F0)...
June 3, 2017: Toxicology and Applied Pharmacology
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