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Toxicology and Applied Pharmacology

Jinning Suo, Xiangzhong Zhao, Xin Guo, Xiulan Zhao
Obesity and its related metabolic disorders including insulin resistance and fatty liver become major public health concerns in both developed and developing countries. Brown adipose tissue (BAT), a critical organ of energy expenditure due to thermogenesis, has been considered as an attractive target for prevention or treatment of obesity and obesity related diseases. Previous studies indicate Met-enkephalin (MetEnk) has the potential on adipocyte browning, however, whether MetEnk displays the impact on adipocyte browning in vivo to improve obesity associated morbidities is still unclear...
September 14, 2018: Toxicology and Applied Pharmacology
Riham M Mansour, Maha A E Ahmed, Ayman E El-Sahar, Nesrine S El Sayed
Montelukast (MK),a cysteinyl leukotriene (CysLT1) receptor antagonist, latterly exhibited a remarkable neuroprotective activity in various neurodegenerative disorders. This study aims to elucidate the neuroprotective effect of MK in rotenone-induced Parkinson's disease(PD) model in rats. Ninety six male rats were split into four groups: vehicle control (0.2 ml/kg/48 h, sc), MK (10 mg/kg/day, ip), rotenone (1.5 mg/kg/48 h, sc.) and rotenone pretreated with MK. Rotenone treatment led to significant reduction in motor functioning and elevation in oxidative stress markers...
September 14, 2018: Toxicology and Applied Pharmacology
John T Szilagyi, Karma C Fussell, Yun Wang, Yi-Hua Jan, Vladimir Mishin, Jason R Richardson, Diane E Heck, Shaojun Yang, Lauren M Aleksunes, Debra L Laskin, Jeffrey D Laskin
NADH cytochrome b5 reductase mediates electron transfer from NADH to cytochrome b5 utilizing flavin adenine dinucleotide as a redox cofactor. Reduced cytochrome b5 is an important cofactor in many metabolic reactions including cytochrome P450-mediated xenobiotic metabolism, steroid biosynthesis and fatty acid metabolism, hemoglobin reduction, and methionine and plasmalogen synthesis. Using recombinant human enzyme, we discovered that cytochrome b5 reductase mediates redox cycling of a variety of quinones generating superoxide anion, hydrogen peroxide, and, in the presence of transition metals, hydroxyl radicals...
September 14, 2018: Toxicology and Applied Pharmacology
Heloisa Aparecida Barbosa da Silva Pereira, Aline Salgado Dionizio, Tamara Teodoro Araujo, Mileni da Silva Fernandes, Flávia Godoy Iano, Marília Afonso Rabelo Buzalaf
Fluoride (F) can induce changes in the expression of several liver proteins.It is suggested that these changes are dose- and time-dependent. The objective of this study was to analyze the effect of different F concentrations and exposure times to this ion on the pattern of protein expression in the liver of rats. Thirt-six 21-day-old male Wistar rats were divided into 2 groups (n = 18) according to the treatment duration (20 or 60 days). Each of these groups was then divided into 3 subgroups (n = 6) according to the concentration of F administered in drinking water, as follows: 0 mg/L (control), 15 mg/L or 50 mg/L...
September 11, 2018: Toxicology and Applied Pharmacology
Ying-Jung Chen, Chia-Hui Huang, Yi-Jun Shi, Yuan-Chin Lee, Liang-Jun Wang, Long-Sen Chang
Arsenic trioxide (ATO) has been reported to inhibit the activity of Ten-eleven translocation methylcytosine dioxygenase (TET). TET modulates FOXP3 expression, while dysregulation of FOXP3 expression promotes the malignant progression of leukemia cells. We examined the role of TET-FOXP3 axis in the cytotoxic effects of ATO on the human acute myeloid leukemia cell line, U937. ATO-induced apoptosis in U937 cells was characterized by activation of caspase-3/-9, mitochondrial depolarization, and MCL1 downregulation...
September 10, 2018: Toxicology and Applied Pharmacology
Daniela Edith Igartúa, Pamela Liliana Azcona, Carolina Soledad Martinez, Silvia Del Valle Alonso, Verónica Leticia Lassalle, María Jimena Prieto
Doxorubicin (DOXO) is a chemotherapeutic agent widely used for the treatment of solid tumors and hematologic malignancies in both adults and children. However, DOXO causes short- and long-term cardiotoxicity and others undesirable side effects, such as nephrotoxicity and neurotoxicity. Magnetic nanoparticles (MNPs) allow the delivery of drugs specifically to target place, employing an external magnet. Moreover, they may act as contrast agents in MRI providing information on the diagnostic of diverse pathologies...
September 8, 2018: Toxicology and Applied Pharmacology
Xinjian Cui, Xionghua Sun, Fanqing Lu, Xiaogang Jiang
Fibroblast-to-myofibroblast differentiation is a highly important pathological characteristic of pulmonary fibrosis. In this study, we aimed to investigate the effects and mechanisms of baicalein on the differentiation of human lung fibroblasts. Baicalein reduced the levels of α-smooth muscle actin (α-SMA) mRNA and protein expression in TGF-β1-treated human lung fibroblasts. It also decreased the contents of collagen type I and fibronectin in time- and dose-dependent manners, and retarded TGF-β1-stimulated α-SMA filament formation...
September 7, 2018: Toxicology and Applied Pharmacology
Jiayu Zhu, Huihui Wang, Feng Chen, Hang Lv, Zijin Xu, Jingqi Fu, Yongyong Hou, Yuanyuan Xu, Jingbo Pi
Non-small cell lung cancer (NSCLC) has a high mortality rate worldwide. Various treatments strategies have been used against NSCLC including individualized chemotherapies, but innate or acquired cancer cell drug resistance remains a major obstacle. Recent studies revealed that the Kelch-like ECH associated protein 1/Nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) pathway is intimately involved in cancer progression and chemoresistance. Thus, antagonizing Nrf2 would seem to be a viable strategy in cancer therapy...
September 6, 2018: Toxicology and Applied Pharmacology
Iwona Sidorkiewicz, Jan Czerniecki, Katarzyna Jarząbek, Monika Zbucka-Krętowska, Sławomir Wołczyński
Environmental factors, particularly xenoestrogens adversely affect reproductive health and their main mechanism is based on steroid-signaling pathway alterations. The presence of bisphenol A (BPA) in the environment has been confirmed and it is about to be replaced by analogues such as bisphenol F (BPF) and bisphenol S (BPS). Whether the BPF and BPS exert similar adverse effects to BPA has become the subject of intense scientific scrutiny. The aim of the present study was to evaluate and compare the cellular, transcriptomic and methylome effects of exposure to BPA, BPF, BPS individually and in combination on GC-2 spermatocyte cell line...
September 6, 2018: Toxicology and Applied Pharmacology
Huiyao Li, Daochuan Li, Zhini He, Junling Fan, Qingye Li, Xiaoling Liu, Ping Guo, Haiyan Zhang, Shen Chen, Qiong Li, Rui Zhang, Xiumei Xing, Xiaowen Zeng, Aihua Zhang, Huanwen Tang, Guanghui Dong, Qing Wang, Yongmei Xiao, Liping Chen, Wen Chen
Previous studies have demonstrated that oxidative stress is implicated in benzene-induced hematotoxicity. However, the low dose-response effects and the mechanism underlying perturbation of hematopoiesis remain to be defined. This study aims to address the role of Nrf2 pathway in mediating benzene-induced hematotoxicity. Nrf2+/+ (wildtype, Nrf2-WT) and Nrf2-/- (knockout, Nrf2-KO) mice were administrated with benzene at doses of 0.1, 1.0, 10.0, 100.0 mg/kg by oral gavage for a consecutive 4 weeks (6 times/week)...
September 5, 2018: Toxicology and Applied Pharmacology
Xuanxuan Dai, Guilong Guo, Changtian Yin, Yi Zhang, Chenguang Zhao, Jianchang Qian, Ouchen Wang, Xiaohua Zhang, Guang Liang
Triple negative breast cancer (TNBC) is an aggressive subgroup of human breast cancer. In this study, we have examined the potential of Schisandrin B (Sch B), a bioactive chemical compound found in Schisandra chinensis, against TNBC. We used MDA-MB-231, BT-549, and MDA-MB-468 TNBC cells and immunodeficient mice to study the effect of Sch B. Our results show that Sch B inhibits TNBC growth by inducing cell cycle arrest and by triggering apoptotic death. Sch B also inhibited the migration and colony formation of tumor cells, and prevented the growth of TNBC cells in mice...
September 5, 2018: Toxicology and Applied Pharmacology
Gwan Ui Hong, Jin Whan Cho, Soo Youl Kim, Joo Ho Shin, Jai Youl Ro
This study aimed to investigate the role of transglutaminase 2 (TG2) expressed in mast cells in substantia nigra (SN) in Parkinson's disease (PD) model or human PD patients. C57BL/6 mice received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by ip injection to induce PD. Bone marrow-derived mast cells (BMMCs) were adoptively transferred to TG2 knockout (KO or TG2-/- ) mice by iv injection 1 day before MPTP injection or stimulated by 1 methyl-4-phenylpyridinium (MMP+ ). KO-MPTP mice showed reduced expression of tyrosine hydroxylase (TH) and dopamine (DA) transporter (DAT) and loss of TH+ DA neurons, and expression of markers (c-kit, tryptase, FcεRI), mediators' release (histamine, leukotrienes, cytokines), and TG2 related to mast cells, and co-localization of DA neuronal cells and mast cells in SN tissues or release of mediators and TG2 activity in SN tissues and sera versus those in WT (wild type)-MPTP or BM + KO-MPTP mice...
September 5, 2018: Toxicology and Applied Pharmacology
Yea-Hwey Wang, Kuo-Tong Liou, Keng-Chang Tsai, Hui-Kang Liu, Li-Ming Yang, Chang-Ming Chern, Yuh-Chiang Shen
An aminopropyl carbazole compound, P7C3, has been shown to be a potent neurogenesis promoting agent; however, its fundamental signaling action has yet to be elucidated. A cerebral ischemic/reperfusional (CI/R) injury model in mice was implemented to elucidate the neuronal protective mechanism(s) of P7C3. Treating CI/R mice using P7C3 (50-100 μg/kg, i.v.) significantly improved tracking distance and walking behavior, and reduced brain damage. Specifically, P7C3 promoted the expression of neurogenesis-associated proteins, including doublecortin, beta tubulin III (β-tub3), adam11 and adamts20, near the peri-infarct cortex, accompanied by glycogen synthase kinase 3 (GSK-3) inhibition and β-catenin upregulation...
September 4, 2018: Toxicology and Applied Pharmacology
Sadiatu Musah, Jing Chen, Connie Schlueter, David M Humphrey, Kendall Stocke, Mona I Hoyle, Gary W Hoyle
Chlorine is a chemical threat agent that can be harmful to humans. Acute inhalation of high levels of chlorine results in the death of airway epithelial cells and can lead to persistent adverse effects on respiratory health, including airway remodeling and hyperreactivity. We previously developed a mouse chlorine exposure model in which animals developed inflammation and fibrosis in large airways. In the present study, examination by laser capture microdissection of developing fibroproliferative lesions in FVB/NJ mice exposed to 240 ppm-h chlorine revealed upregulation of genes related to macrophage function...
September 3, 2018: Toxicology and Applied Pharmacology
Richard C Pleus, Lisa M Corey
Perchlorate pharmacology and toxicology studies date back at least 65 years in the peer-reviewed literature. Repeated studies in animals and humans have demonstrated perchlorate's mechanism of action, dose-response, and adverse effects over a range of doses. The first measurable effect of perchlorate is inhibition of iodine uptake to the thyroid gland. Adequate levels of thyroid hormones are critical for the development of the fetal nervous system. With sufficient dose and exposure duration, perchlorate can reduce thyroid hormones in the pregnant or non-pregnant woman via this mechanism...
September 2, 2018: Toxicology and Applied Pharmacology
Ju Yeon Kim, Jeong Hyun Cho, Jong-Ryoo Choi, Hyun-Jin Shin, Jie-Young Song, Sang-Gu Hwang, Hong-Duck Um, Young Do Yoo, Joon Kim, Jong Kuk Park
We previously reported that podophyllotoxin acetate (PA) inhibits the growth and proliferation of non-small cell lung cancer (NSCLC) cells and also makes them more sensitive to radiation and chemotherapeutic agents. In an attempt to enhance PA activity, we synthesized 34 derivatives based on podophyllotoxin (PPT). Screening of the derivative compounds for anti-cancer activity against NSCLC led to the identification of β-apopicropodophyllin (APP) as a strong anti-cancer agent. In addition to its role as an immunosuppressive regulator of the T-cell mediated immune response, the compound additionally showed anti-cancer activity against A549, NCI-H1299 and NCI-460 cell lines with IC50 values of 16...
August 29, 2018: Toxicology and Applied Pharmacology
Jing Sun, Jingqi Fu, Lu Li, Chengjie Chen, Huihui Wang, Yongyong Hou, Yuanyuan Xu, Jingbo Pi
Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality of liver disorders and a major health issue globally. ALD refers to a spectrum of liver pathologies ranging from steatosis, steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Various mechanisms, including oxidative stress, protein and DNA modification, inflammation and impaired lipid metabolism, have been implicated in the pathogenesis of ALD. Further, reactive oxygen species (ROS) in particular, have been identified as a key component in the initiation and progression of ALD...
August 27, 2018: Toxicology and Applied Pharmacology
Clotilde Maurice, Jason M O'Brien, Carole L Yauk, Francesco Marchetti
The Organisation for Economic Co-operation and Development (OECD) endorses test guidelines (TG) for identifying chemicals that are genotoxic, such as the transgenic rodent gene mutation assay (TG 488). Current OECD TG do not include assays for sperm DNA damage resulting in a critical testing gap. We evaluated the performance of the Sperm Chromatin Structure Assay (SCSA) and the Terminal Deoxynucleotidyl Transferase-Mediated Deoxyuridine Triphosphate Nick end Labeling (TUNEL) assay to detect sperm DNA damage within the recommended TG 488 protocol...
August 27, 2018: Toxicology and Applied Pharmacology
Jessica De Loma, Helena Skröder, Rubhana Raqib, Marie Vahter, Karin Broberg
BACKGROUND: Arsenic methylation efficiency, a susceptibility factor for arsenic toxicity, is in adults partly explained by variation in arsenite methyltransferase (AS3MT) gene. Little is known about the role of AS3MT for children's arsenic methylation. OBJECTIVES: Evaluating associations between AS3MT polymorphisms and children's arsenic methylation efficiency. METHODS: Bangladeshi children's arsenic exposure (9-years; n = 424) was assessed as sum urinary concentration of inorganic arsenic (iAs) and its metabolites (monomethylarsonic acid [MMA] and dimethylarsinic acid [DMA]) using HPLC-HG-ICPMS...
August 25, 2018: Toxicology and Applied Pharmacology
Sante E I Carone, Danilo L Menaldo, Marco A Sartim, Carolina P Bernardes, Renato C Caetano, Ronivaldo R da Silva, Hamilton Cabral, Benedito Barraviera, Rui S Ferreira Junior, Suely V Sampaio
Snake venom serine proteases (SVSPs) are commonly described as capable of affecting hemostasis by interacting with several coagulation system components. In this study, we describe the isolation and characterization of BjSP from Bothrops jararaca snake venom, a serine protease with distinctive properties. This enzyme was isolated by three consecutive chromatographic steps and showed acidic character (pI 4.4), molecular mass of 28 kDa and N-carbohydrate content around 10%. Its partial amino acid sequence presented 100% identity to a serine protease cDNA clone previously identified from B...
August 24, 2018: Toxicology and Applied Pharmacology
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