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Toxicology and Applied Pharmacology

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https://www.readbyqxmd.com/read/29155087/capsaicin-reduces-genotoxicity-colonic-cell-proliferation-and-preneoplastic-lesions-induced-by-1-2-dimethylhydrazine-in-rats
#1
Brunno Felipe Ramos Caetano, Mariana Baptista Tablas, Natália Elias Ferreira Pereira, Nelci Antunes de Moura, Robson Francisco Carvalho, Maria Aparecida Marchesan Rodrigues, Luis Fernando Barbisan
Capsaicin (8-Methyl-N-vanillyl-(trans)-6-nonenamide) is the major pungent ingredient found in chili peppers consumed worldwide. Most reports on capsaicin potential carcinogenicity have yielded inconsistent findings. Some studies have shown that capsaicin exerts anti-proliferative and pro-apoptotic effects on different cancer cell lines, while others have reported an association between capsaicin at high doses with mutagenicity and carcinogenicity. Thus, this study aimed at assessing the effects of capsaicin administration on 1,2-dimethyl-hydrazine (DMH)-induced colon carcinogenesis in male Wistar rats...
November 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29155086/systemic-exposure-of-vinpocetine-in-pregnant-sprague-dawley-rats-following-repeated-oral-exposure-an-investigation-of-fetal-transfer
#2
Suramya Waidyanatha, Heather Troy, Natalie South, Seth Gibbs, Esra Mutlu, Brian Burback, Barry S McIntyre, Natasha Catlin
Vinpocetine is being used worldwide by people of all ages, including pregnant women, for its purported multiple health benefits. However, limited data is available addressing the safety/toxicity of vinpocetine. The National Toxicology Program conducted studies to examine potential effects of vinpocetine on the developing rat. Disposition data is helpful to put the fetal findings into context and provide information on the potential risk for humans. The current study reports the systemic exposure and toxicokinetic (TK) parameters of vinpocetine and metabolite, apovincaminic acid (AVA), in pregnant Harlan Sprague Dawley rats, fetuses and amniotic fluid following oral gavage exposure of dams to 5 and 20mg/kg vinpocetine from gestational day 6 to 18...
November 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29146463/age-dependent-in-vitro-metabolism-of-bifenthrin-in-rat-and-human-hepatic-microsomes
#3
Gopinath C Nallani, Appavu Chandrasekaran, Kelem Kassahun, Li Shen, Shaaban F ElNaggar, Zhiwei Liu
Bifenthrin, a pyrethroid insecticide, undergoes oxidative metabolism leading to the formation of 4'-hydroxy-bifenthrin (4'-OH-BIF) and hydrolysis leading to the formation of TFP acid in rat and human hepatic microsomes. In this study, age-dependent metabolism of bifenthrin in rats and humans were determined via the rates of formation of 4'-OH-BIF and TFP acid following incubation of bifenthrin in juvenile and adult rat (PND 15 and PND 90) and human (<5years and >18years) liver microsomes. Furthermore, in vitro hepatic intrinsic clearance (CLint) of bifenthrin was determined by substrate consumption method in a separate experiment...
November 13, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29146462/individual-serum-bile-acid-profiling-in-rats-aids-in-human-risk-assessment-of-drug-induced-liver-injury-due-to-bsep-inhibition
#4
Steven Cepa, David Potter, Lisa Wong, Leah Schutt, Jacqueline Tarrant, Jodie Pang, Xiaolin Zhang, Roxanne Andaya, Laurent Salphati, Yingqing Ran, Le An, Ryan Morgan, Jonathan Maher
Drug-induced liver injury (DILI) has been the most frequent cause of post-marketing drug withdrawals in the last 50years. The multifactorial nature of events that precede severe liver injury in human patients is difficult to model in rodents due to a variety of confounding or contributing factors that include disease state, concurrent medications, and translational species differences. In retrospective analyses, a consistent risk factor for DILI has been the inhibition of the Bile Salt Export Pump (BSEP). One compound known for potent BSEP inhibition and severe DILI is troglitazone...
November 13, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29146461/resveratrol-supports-and-alpha-naphthoflavone-disrupts-growth-of-human-ovarian-follicles-in-an-in-vitro-tissue-culture-model
#5
Jie Hao, Astrud R Tuck, Marcus O D Sjödin, Johan Lindberg, Anna Sand, Boel Niklasson, Maria Argyraki, Outi Hovatta, Pauliina Damdimopoulou
Infertility is a global health problem with an estimated incidence of 15%. Exposure to chemicals is a potential causal factor, and there is a lack of studies examining the effects on female germ cells. Here, we have studied the impact of different aryl hydrocarbon receptor (AHR) modulators on human ovarian follicles using a human ovarian tissue culture model. Expression of AHR was analyzed in tissue samples, and effects of the selected ligands resveratrol (RSVL), 6-formylindolo(3,2-b)carbazole (FICZ), and alpha-naphthoflavone (aNF) on AHR transactivation studied in a granulosa cell tumor line...
November 13, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29132816/deferiprone-inhibits-iron-overload-induced-tissue-factor-bearing-endothelial-microparticle-generation-by-inhibition-oxidative-stress-induced-mitochondrial-injury-and-apoptosis
#6
Shing Chan, Qizhou Lian, Mei-Pian Chen, Dan Jiang, Jolie T K Ho, Yiu-Fai Cheung, Godfrey C F Chan
Iron overload-induced cardiovascular toxicity is one of the most common causes of morbidity and mortality in beta-thalassemia major patients. We have previously shown that iron overload-induced systemic arterial changes characterized by endothelial dysfunction are associated with increased endothelial microparticle (EMP) release. In this study, we further demonstrate how EMP release is associated with iron-induced mitochondrial injury and apoptosis of endothelial cells. Iron increased the production of reactive oxygen species (ROS) and calcium influx into mitochondria [Ca(2+)]m...
November 10, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29129777/trichloroethylene-metabolite-s-1-2-dichlorovinyl-l-cysteine-induces-lipid-peroxidation-associated-apoptosis-via-the-intrinsic-and-extrinsic-apoptosis-pathways-in-a-first-trimester-placental-cell-line
#7
Elana R Elkin, Sean M Harris, Rita Loch-Caruso
Trichloroethylene (TCE), a prevalent environmental contaminant, is a potent renal and hepatic toxicant through metabolites such as S-(1, 2-dichlorovinyl)-l-cysteine (DCVC). However, effects of TCE on other target organs such as the placenta have been minimally explored. Because elevated apoptosis and lipid peroxidation in placenta have been observed in pregnancy morbidities involving poor placentation, we evaluated the effects of DCVC exposure on apoptosis and lipid peroxidation in a human extravillous trophoblast cell line, HTR-8/SVneo...
November 10, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29128402/an-anti-inflammatory-chalcone-derivative-prevents-heart-and-kidney-from-hyperlipidemia-induced-injuries-by-attenuating-inflammation
#8
Xiong Chen, Weihui Yu, Weixin Li, Hailing Zhang, Weijian Huang, Jingying Wang, Weiwei Zhu, Qilu Fang, Chao Chen, Xiaokun Li, Guang Liang
Obesity is a growing pandemic in both developed and developing countries. Lipid overload in obesity generates a chronic, low-grade inflammation state. Increased inflammation in heart and renal tissues has been shown to promote the progression of heart and renal damage in obesity. Previously, we found that a novel chalcone derivative, L6H21, inhibited lipopolysaccharide-induced inflammatory response. In the present study, we investigated the effects of L6H21 on inflammatory responses in culture and in animal models of lipid overload...
November 8, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29128401/h2s-protects-lipopolysaccharide-induced-inflammation-by-blocking-nf%C3%AE%C2%BAb-transactivation-in-endothelial-cells
#9
Caitlyn Bourque, Yanjie Zhang, Ming Fu, Mélanie Racine, Adam Greasley, Yanxi Pei, Lingyun Wu, Rui Wang, Guangdong Yang
Hydrogen sulfide (H2S) is a novel gasotransmitter and acts as a multifunctional regulator in various cellular functions. Past studies have demonstrated a significant role of H2S and its generating enzyme cystathionine gamma-lyase (CSE) in the cardiovascular system. Lipopolysaccharide (LPS), a major pathogenic factor, is known to initiate the inflammatory immune response. The cross talk between LPS-induced inflammation and the CSE/H2S system in vascular cells has not yet been elucidated in detail. Here we showed that LPS decreased CSE mRNA and protein expression in human endothelial cells and blocked H2S production in mouse aorta tissues...
November 8, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29122671/temporal-cytokine-and-lymphoid-responses-to-an-inhaled-tlr7-antedrug-agonist-in-the-cynomolgus-monkey-demonstrates-potential-safety-and-tolerability-of-this-approach
#10
John Bell, Mike Dymond, Mark Biffen, Stephen Delaney, David Keeling, Hui Zhang, Ian Robinson
AZD8848 is a TLR7 agonist antedrug developed for administration by inhalation dosing for the treatment of allergic diseases, such as asthma. Allergic asthma is associated with increased levels of Th2 cytokines which are suppressed for extended periods by TLR7 agonists in a number of preclinical models of allergic airway inflammation. However, TLRs form a central part of innate immunity and their activation often results in proinflammatory responses. Whilst AZD8848's antedrug mechanism is designed to restrict its pharmacological action beyond the lung, the effect of chronic, supramaximal dosing to the target tissue has yet to be defined...
November 6, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29111148/effects-of-opioid-and-nonopioid-analgesics-on-canine-wheal-formation-and-cultured-human-mast-cell-degranulation
#11
Eric Schmidt-Rondon, Zhenping Wang, Shelle A Malkmus, Anna Di Nardo, Keith Hildebrand, Linda Page, Tony L Yaksh
Mast cell (MC) degranulation has been implicated in the side effect profile of a variety of clinically useful agents. Thus, after intrathecal delivery, formation of space-occupying, meningeally-derived masses may be related to local MC degranulation. We systematically characterized degranulating effects of opioid and nonopioid analgesics on cutaneous flares in the dog and in primary human MC (hMC) cultures. METHODS: Dogs were anesthetized with IV propofol and received intradermal (ID) injections (50μL)...
October 27, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29066182/tetramethylpyrazine-suppresses-angiotensin-ii-induced-soluble-epoxide-hydrolase-expression-in-coronary-endothelium-via-anti-er-stress-mechanism
#12
Shiu-Kwong Mak, Cheuk-Man Yu, Wen-Tao Sun, Guo-Wei He, Xiao-Cheng Liu, Qin Yang
Activation of soluble epoxide hydrolase (sEH) is associated with endothelial dysfunction in hypertension, though the underlying mechanisms are inadequately understood and the role of endoplasmic reticulum (ER) stress is yet to be studied in detail. Tetramethylpyrazine (TMP), a major bioactive ingredient of Chinese herb Chuanxiong, is well-known for its cardiovascular benefits. Nevertheless, whether TMP may protect vascular endothelium from ER stress and whether regulation of sEH is involved remain unknown. This study aimed at investigating the role of ER stress in angiotensin-II (Ang-II)-induced sEH dysregulation and elucidating the significance of ER stress regulation in the vasoprotective effect of TMP...
October 21, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29054683/the-anthelminthic-drug-praziquantel-is-a-selective-agonist-of-the-sensory-transient-receptor-potential-melastatin-type-8-channel
#13
Ramona-Madalina Babes, Tudor Selescu, Dan Domocos, Alexandru Babes
Praziquantel is the most effective anthelminthic drug for the treatment of schistosomiasis, an infectious disease caused by the platyhelminth Schistosoma mansoni. While praziquantel is known to trigger calcium influx into schisostomes, followed by spastic paralysis of the worms and tegumental disruption, the mechanism of action of the drug is not completely understood. Although relatively well tolerated, praziquantel has been reported to cause mild adverse effects, including nausea, abdominal pain and headaches...
October 18, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29054681/role-of-histone-acetylation-in-activation-of-nuclear-factor-erythroid-2-related-factor-2-heme-oxygenase-1-pathway-by-manganese-chloride
#14
Zhipeng Zhang, Zhenkun Guo, Yanting Zhan, Huangyuan Li, Siying Wu
Manganese neurotoxicity is characterized by Parkinson-like symptoms with degeneration of dopaminergic neurons in the basal ganglia as the principal pathological feature. Manganese neurotoxicity studies may contribute to a good understanding of the mechanism of Parkinson's disease (PD). In this study, we first confirmed that MnCl2 can promote the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) protein in the nucleus or cytoplasm while increasing the binding activity of Nrf2 and antioxidant response elements, further promoting the expression of downstream target gene heme oxygenase 1 (HO-1) and leading to increase levels of reactive oxygen species (ROS) and reduce the levels of reduced glutathione (GSH)...
October 17, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29054680/phosphorylation-of-protein-phosphatase-2a-facilitated-an-early-stage-of-chemical-carcinogenesis
#15
Yuji Ishii, Ken Kuroda, Kohei Matsushita, Yuh Yokoo, Shinji Takasu, Aki Kijima, Takehiko Nohmi, Kumiko Ogawa, Takashi Umemura
Protein phosphatase 2A (PP2A) is a serine-threonine phosphatase that regulates cell signaling pathways. Its inactivation is correlated with tumor malignancy, possibly due to the effects on cell differentiation and malignant cell transformation. Therefore, it has been noted that PP2A could be a promising target for cancer therapy. In our previous study of the hepatocarcinogen estragole (ES), cell proliferation may be required to convert ES-specific DNA adducts to mutations. To explore the trigger for cell proliferation, gpt delta rats were administered ES by gavage at doses of 3, 30 and 300mg/kg/day for 4weeks...
October 17, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29051111/perspectives-on-using-a-multiplex-human-kidney-safety-biomarker-panel-to-detect-cisplatin-induced-tubular-toxicity-in-male-and-female-cynomolgus-monkeys
#16
Yafei Chen, J Dale Thurman, Lewis B Kinter, Russell Bialecki, J Eric McDuffie
Multiplex biomarker panel assays would enable early de-risking of discovery compound related kidney safety liabilities. The objective of this study was to evaluate the usefulness of the Myriad RBM Human KidneyMAP (Multi-Analyte Profile)® v.1.0 panel to detect experimental nephrotoxicity in Cynomolgus monkeys following a single intravenous administration of cisplatin (2.5mg/kg). Urine samples were collected at baseline on day -2; at approximately 4hr post-dose on day 1; and on days 4, 9, 15 and/or 20. Blood samples were collected at predose on day -2; at 4hr post-dose on day 1; and on days 2, 5, 10 and/or 21...
October 16, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29042214/synthetic-cannabinoid-am2201-induces-seizures-involvement-of-cannabinoid-cb1-receptors-and-glutamatergic-transmission
#17
Masahiko Funada, Mika Takebayashi-Ohsawa
Abuse of synthetic cannabinoids is a serious social problem worldwide. Intentional ingestion of synthetic cannabinoids can cause severe toxicity, including seizures. Here we investigated the effects of acute administration of synthetic cannabinoids on the induction of epileptic seizures by monitoring electroencephalographic activity in freely moving mice. The synthetic cannabinoid, AM2201, induced abnormal, high-amplitude (>2-fold baseline amplitude), sharp-wave activity. The abnormal spike-wave discharges were accompanied by epileptiform behavior: rigid posture, tail extension, rearing with forepaws extended, jumping, and intermittent tonic-clonic jerking movements...
October 16, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29032082/effects-of-triclosan-on-hormones-and-reproductive-axis-in-female-yellow-river-carp-cyprinus-carpio-potential-mechanisms-underlying-estrogen-effect
#18
Fan Wang, Xiangmeng Guo, Wanguang Chen, Yaowen Sun, Chaojie Fan
Triclosan (TCS), a member of the class of compounds called pharmaceutical and personal care products (PPCPs), is a broad antibacterial and antifungal agent found in a lot of consumer products. However, TCS hormone effect mechanism in teleost female fish is not clear. Female Yellow River carp (Cyprinus carpio) were exposed to 1/20, 1/10 and 1/5 LC50 TCS (96h LC50 of TCS to carp) under semi-static conditions for 42days. Vitellogenin (Vtg), 17β-estradiol (E2), testosterone(T), estrogen receptor (Er), gonadotropin (GtH), and gonadotropin-releasing hormone (GnRH) levels were measured by enzyme-linked immunosorbent assay (ELISA)...
October 13, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29031523/6-hydroxy-3-o-methyl-kaempferol-6-o-glucopyranoside-potentiates-the-anti-proliferative-effect-of-interferon-%C3%AE-%C3%AE-by-promoting-activation-of-the-jak-stat-signaling-by-inhibiting-socs3-in-hepatocellular-carcinoma-cells
#19
Orawan Wonganan, Yu-Jiao He, Xiao-Fei Shen, Kanjana Wongkrajang, Apichart Suksamrarn, Guo-Lin Zhang, Fei Wang
Suppressor of cytokine signaling 3 (SOCS3) is a key negative regulator of type I interferon (IFN α/β) signaling. Inhibition of SOCS3 by small molecules may be a new strategy to enhance the efficacy of type I IFN and reduce its side effects. We established a cell-based screening assay using human hepatoma HepG2 cells stably transfected with a plasmid wherein the luciferase reporter activity was propelled by interferon α-stimulated response element (ISRE), which is a motif specifically recognized by type I IFN-induced activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway...
October 12, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28987381/altered-gene-expression-profiles-in-the-lungs-of-benzo-a-pyrene-exposed-mice-in-the-presence-of-lipopolysaccharide-induced-pulmonary-inflammation
#20
Q Shi, R R Fijten, D Spina, Y Riffo Vasquez, V M Arlt, R W Godschalk, F J Van Schooten
Patients with inflammatory lung diseases are often additionally exposed to polycyclic aromatic hydrocarbons like B[a]P and B[a]P-induced alterations in gene expression in these patients may contribute to the development of lung cancer. Mice were intra-nasally treated with lipopolysaccharide (LPS, 20μg/mouse) to induce pulmonary inflammation and subsequently exposed to B[a]P (0.5mg/mouse) by intratracheal instillation. Gene expression changes were analyzed in mouse lungs by RNA microarrays. Analysis of genes that are known to be involved in the cellular response to B[a]P indicated that LPS significantly inhibited gene expression of various enzymes linked to B[a]P metabolism, which was confirmed by phenotypic analyses of enzyme activity...
October 5, 2017: Toxicology and Applied Pharmacology
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