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Toxicology and Applied Pharmacology

S S Ahmed, J Whritenour, M M Ahmed, L Bibby, L Darby, X N Wang, J Watson, A M Dickinson
The occurrence of drug hypersensitivity reactions (DHRs) following administration of low molecular weight (LMW) drugs is an important health concern. However, in vivo animal models which could be used as tools for the prediction of DHRs are lacking. As a result, research has focused on development of in vitro tools for predicting DHRs. In this study a novel human in vitro pre-clinical skin explant test was used to predict T cell-mediated hypersensitivity responses induced by LMW drugs. Responses in the skin explant test for 12 LMW drugs associated with T cell-mediated hypersensitivity in the clinic (abacavir, amoxicillin, carbamazepine, diclofenac, lamotrigine, lapatinib, lumiracoxib, nevirapine, ofloxacin, phenytoin, propranolol, sulfamethoxazole) were compared with responses for 5 drugs with few/no reports of T cell-mediated hypersensitivity reactions (acetaminophen, cimetidine, flecainide, metformin, verapamil)...
February 12, 2019: Toxicology and Applied Pharmacology
Chunyan Wang, Michael C Petriello, Beibei Zhu, Bernhard Hennig
Polychlorinated biphenyls (PCBs) are persistent organic pollutants that contribute to inflammatory diseases such as atherosclerosis, and macrophages play a key role in the overall inflammatory response. Depending on specific environmental stimuli, macrophages can be polarized either to pro-inflammatory (e.g., M1) or anti-inflammatory (e.g., M2) phenotypes. We hypothesize that dioxin-like PCBs can contribute to macrophage polarization associated with inflammation. To test this hypothesis, human monocytes (THP-1) were differentiated to macrophages and subsequently exposed to PCB 126...
February 12, 2019: Toxicology and Applied Pharmacology
Cristina da Costa Oliveira, Marina Gomes Miranda E Castor, Camila Gomes Miranda E Castor, Ághata de França Costa, Renata Cristina Mendes Ferreira, Josiane Fernandes da Silva, Juliana Maria Navia Pelaez, Luciano Dos Santos Aggum Capettini, Virginia Soares Lemos, Igor Dimitri Gama Duarte, Andrea de Castro Perez, Sérgio Henrique Sousa Santos, Thiago Roberto Lima Romero
Despite all the development of modern medicine, around 100 compounds derived from natural products were undergoing clinical trials only at the end of 2013. Among these natural substances in clinical trials, we found the resveratrol (RES), a pharmacological multi-target drug. RES analgesic properties have been demonstrated, although the bases of these mechanisms have not been fully elucidated. The aim of this study was to evaluate the involvement of opioid and cannabinoid systems in RES-induced peripheral antinociception...
February 11, 2019: Toxicology and Applied Pharmacology
Zhiyuan Liu, Yongyong Hou, Lu Li, Yang Yang, Jingkun Jia, Zhixuan Hong, Tingfeng Li, Yuanyuan Xu, Jingqi Fu, Yongxin Sun, Masayuki Yamamoto, Huihui Wang, Jingbo Pi
Arsenic exposure increases the risk of various bone disorders. For instance, chronic exposure to low level arsenic can cause bone resorption by promoting osteoclast differentiation. Osteoclast precursor cells produce hydrogen peroxide after low level arsenic exposure and then undergo differentiation, producing cells which break down bone matrix. Nuclear factor E2-related factor 2 (Nrf2) regulates receptor activator of nuclear factor-κB dependent osteoclastogenesis by modulating intracellular reactive oxygen species (ROS) signaling via expression of cytoprotective enzymes...
February 8, 2019: Toxicology and Applied Pharmacology
Wei Liu, Hui Qin, Yifan Pan, Fang Luo, Zhou Zhang
Humans are exposed to perfluorooctane sulfonate (PFOS) from sources of both continuing discharges and environmental legacies, and the health effects of low dose exposure remain unknown. We assessed the effects of PFOS at 0.2-200 nmol/L on osteogenic and adipogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). PFOS affected hBMSCs differentiation in a nonmonotonic dose-response relationship, where the effects peaked at 100 nmol/L. PFOS repressed calcium deposition on day 14 of osteogenic differentiation...
February 7, 2019: Toxicology and Applied Pharmacology
R Karahoda, M Ceckova, F Staud
In spite of remarkable reduction in the number of children born with HIV due to antiretroviral therapy, concerns remain on the short- and long-term effects of antiretroviral drugs at the feto-placental unit. Cardio- and skeletal myopathies have been reported in children exposed to antiretroviral drugs prenatally. These conditions have also been described in perturbed placental transfer of l-carnitine, an essential co-factor in fatty acid oxidation. Due to limited fetal and placental synthesis, carnitine supply is maintained through the placental carnitine uptake from maternal blood by the organic cation/carnitine transporters OCTN1 and OCTN2 (SLC22A4 and SLC22A5, respectively)...
February 5, 2019: Toxicology and Applied Pharmacology
Jingbo Pi, John D Hayes, Masayuki Yamamoto
No abstract text is available yet for this article.
February 4, 2019: Toxicology and Applied Pharmacology
Alaeddin B Abukabda, Elizabeth C Bowdridge, Carroll R McBride, Thomas P Batchelor, William T Goldsmith, Krista L Garner, Sherri Friend, Timothy R Nurkiewicz
The fetal consequences of gestational engineered nanomaterial (ENM) exposure are unclear. The placenta is a barrier protecting the fetus and allowing transfer of substances from the maternal circulation. The purpose of this study was to determine the effects of maternal pulmonary titanium dioxide nanoparticle (nano-TiO2 ) exposure on the placenta and umbilical vascular reactivity. We hypothesized that pulmonary nano-TiO2 inhalation exposure increases placental vascular resistance and impairs umbilical vascular responsiveness...
January 31, 2019: Toxicology and Applied Pharmacology
Deepti Singh, Rebecca Mendonsa, Mrunesh Koli, Mahesh Subramanian, Sandip Kumar Nayak
Structure-activity relationship (SAR) studies have led to significant improvement in desirable biological activity in different classes of molecules. A general consensus about the substitutions that improve the activity remains elusive in stilbene class of molecules especially in regard to antibacterial activity. Lack of this knowledge remains a major hurdle in developing stilbene based antibacterial molecules. A panel of gram positive and gram negative bacteria were employed for screening the comparative efficacy of the stilbenes...
January 31, 2019: Toxicology and Applied Pharmacology
D Medina-Buelvas, E Estrada-Muñiz, M Flores-Valadez, L Vega
Diethyldithiophosphate (DEDTP) is a metabolite produced by the degradation of organophosphorus pesticides and a dialkylphosphate that is chemically synthesized with widespread commercial use. DEDTP is a stable compound, and most studies considered it harmless. However, some studies found adverse effects in vitro, including toxicity in different human cell types. However, there are no in vivo studies characterizing the toxicological effects of DEDTP. Therefore, we investigated the genotoxicity and immunotoxicity of DEDTP in a murine model...
January 28, 2019: Toxicology and Applied Pharmacology
Zheng Deng, Fei Shi, Zheng Zhou, Feng Sun, Meng-Hao Sun, Qian Sun, Lei Chen, Deng Li, Chen-Yi Jiang, Rui-Zhe Zhao, Di Cui, Xing-Jie Wang, Yi-Feng Jing, Shu-Jie Xia, Bang-Min Han
Thulium laser resection of the prostate (TmLRP), a major treatment for benign prostatic hyperplasia (BPH), has several postoperative complications that affect the patients' quality of life. The aim of this study was to investigate the effect of the M1 macrophage-secreted reactive oxygen species (ROS) on prostatic wound healing, and the role of MAPK signaling in this process. A co-culture model in vitro was established using macrophages and prostate epithelial or stromal cells. Cell proliferation, migration, apoptosis, MAPK pathway-related gene expression levels were evaluated by standard assays...
January 25, 2019: Toxicology and Applied Pharmacology
Lindsay Reed, Radek Indra, Iveta Mrizova, Michaela Moserova, Heinz H Schmeiser, C Roland Wolf, Colin J Henderson, Marie Stiborova, David H Phillips, Volker M Arlt
The anticancer drug ellipticine exerts its genotoxic effects after metabolic activation by cytochrome P450 (CYP) enzymes. The present study has examined the role of cytochrome P450 oxidoreductase (POR) and cytochrome b5 (Cyb5), electron donors to P450 enzymes, in the CYP-mediated metabolism and disposition of ellipticine in vivo. We used Hepatic Reductase Null (HRN) and Hepatic Cytochrome b5 /P450 Reductase Null (HBRN) mice. HRN mice have POR deleted specifically in hepatocytes; HBRN mice also have Cyb5 deleted in the liver...
January 24, 2019: Toxicology and Applied Pharmacology
Zhenxian Lin, Xiaona Zhang, Fei Zhao, Shaoguo Ru
Bisphenol S (BPS), exhibiting estrogenic activity, has been reported to promote cell proliferation in MCF-7 breast cancer cells; however, the underlying mechanism remains unclear. In this study, BPS (1-100 μM) significantly promoted cell proliferation in ERα positive MCF-7 cells, but not in ERα negative MDA-MB-231 or SK-BR-3 cells, confirming the important role of ERα in BPS-induced cell proliferation. Results of the flow cytometry analysis indicated that 10 μM BPS promoted MCF-7 proliferation by accelerating G1 to S phase transition of the cell cycle...
January 23, 2019: Toxicology and Applied Pharmacology
Delu Che, Yajing Hou, Yingnan Zeng, Chaomei Li, Yongjing Zhang, Di Wei, Shiling Hu, Rui Liu, Hongli An, Yajun Wang, Tao Zhang
The classical mast cells degranulation pathway is mediated by FcεRI aggregation and varies in strength among subjects. Dehydroandrographolide (DA) is one of principal components of Andrographis paniculata (Burm.f.) Nees (family: Acanthaceae) and considered the main contributors of its therapeutic properties, such as anti-tumor. In this study, inhibition of IgE-mediated anaphylactic reactions and anti-inflammatory potential of DA were investigated. The anti-anaphylactic activity of DA was investigated using skin swelling and extravasation assays in vivo and mast cell degranulation assay in vitro...
January 23, 2019: Toxicology and Applied Pharmacology
Qian Wu, Shelly Odwin-Dacosta, Shuyuan Cao, James D Yager, Wan-Yee Tang
Catechol-O-methyltransferase (COMT) acts as a 'gate-keeper' to prevent DNA damage during estrogen metabolism. Both experimental and epidemiological studies suggest the role of COMT in pathogenesis of human breast cancer (BCa). It was previously reported that inhibition of COMT enzyme activity in estradiol-treated human breast epithelial carcinoma-derived MCF-7 cells caused increased oxidative DNA damage and formation of mutagenic depurinating adducts. To improve our understanding of factors influencing estrogen metabolism in BCa, it requires a mechanistic study illustrating the regulation of this 'gate-keeper'...
January 23, 2019: Toxicology and Applied Pharmacology
Kai-Che Wei, Rui-Fang Chen, Yu-Fu Chen, Chia-Ho Lin
Metastasis is the major cause of treatment failure in patients with cancer. Hinokitiol, a metal chelator derived from natural plants, has anti-inflammatory and antioxidant activities as well as anticancer effects. We investigated the potential anticancer effects of hinokitiol in metastatic melanoma cell line B16-F10. Exposure of the melanoma B16-F10 cells to hinokitiol significantly inhibited colony formation and cell viability in a time and concentration-dependent manner. The hinokitiol-treated cells exhibited apoptotic features in morphological assay...
January 23, 2019: Toxicology and Applied Pharmacology
Döníz Degovics, Petra Hartmann, István Balázs Németh, Noémi Árva-Nagy, Enikő Kaszonyi, Edit Szél, Gerda Strifler, Balázs Bende, László Krenács, Lajos Kemény, Gábor Erős
Ryanodine receptors have an important role in the regulation of intracellular calcium levels in the nervous system and muscle. It has been described that ryanodine receptors influence keratinocyte differentiation and barrier homeostasis. Our goal was to examine the role of ryanodine receptors in the healing of full-thickness dermal wounds by means of in vitro and in vivo methods. The effect of ryanodine receptors on wound healing, microcirculation and inflammation was assessed in an in vivo mouse wound healing model, using skin fold chambers in the dorsal region, and in HaCaT cell scratch wound assay in vitro...
January 23, 2019: Toxicology and Applied Pharmacology
David K Scoville, James D Nolin, H Luke Ogden, Dowon An, Zahra Afsharinejad, Brian W Johnson, Theo K Bammler, Xiaohu Gao, Charles W Frevert, William A Altemeier, Teal S Hallstrand, Terrance J Kavanagh
Quantum dot nanoparticles (QDs) are engineered nanomaterials (ENMs) that have utility in many industries due to unique optical properties not available in small molecules or bulk materials. QD-induced acute lung inflammation and toxicity in rodent models raise concerns about potential human health risks. Recent studies have also shown that some ENMs can exacerbate allergic airway disease (AAD). In this study, C57BL/6J and A/J mice were exposed to saline, house dust mite (HDM), or a combination of HDM and QDs on day 1 of the sensitization protocol...
January 22, 2019: Toxicology and Applied Pharmacology
Hao Zhang, Yongchun Chen, Zhipeng Pei, Huanhuan Gao, Wenwen Shi, Mingxue Sun, Qingqiang Xu, Jie Zhao, Wenqi Meng, Kai Xiao
Sulfur mustard (SM) is a chemical warfare agent that was applied in a series of military conflicts and still poses a severe threat to civilians and military personnel. Although the cellular and molecular mechanisms of SM toxicity are still not fully understood, oxidative stress has been considered as the initial vital process for damage. Polydatin, the product of resveratrol and glucose, is a promising candidate for the treatment of oxidative stress-related diseases. However, its effects on SM-induced hepatic injury remain unknown...
January 21, 2019: Toxicology and Applied Pharmacology
Xue Gao, Yuming Zhou, Hongliu Sun, Desheng Liu, Jing Zhang, Junru Zhang, Weizhong Liu, Xiaohong Pan
Peniciketal A (Pe-A), a spiroketal compound, is isolated from the saline soil-derived fungus Penicillium raistrickii. However, the underlying molecular mechanistic basis for the effects of Pe-A on leukemia is poorly understood. Here, we investigated that Pe-A reduced cell proliferation in three leukemia cell lines (THP-1, K562 and HL60). Importantly, Pe-A showed little cytotoxicity in primary mouse embryonic fibroblast (MEF) cells in a long-duration treatment. For the mechanistic research, we identified 3449 differentially expressed Pe-A-induced proteins through liquid chromatography-tandem mass spectrometry (LC-MS/MS) with TMT label in THP-1 cells...
January 17, 2019: Toxicology and Applied Pharmacology
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