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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.429]   [H-I: 117]   [17 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [2970 journals]
  • Blood morphology and the levels of selected cytokines related to
           hematopoiesis in occupational short-term exposure to lead
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Michał Dobrakowski, Marta Boroń, Zenon P. Czuba, Ewa Birkner, Artur Chwalba, Edyta Hudziec, Sławomir Kasperczyk
      The aim of the study was to investigate the influence of a short-term exposure to lead on the blood morphology and the levels of selected cytokines related to hematopoiesis in occupationally exposed workers. The study population included 37 males occupationally exposed to lead for 36 to 44days. Their blood lead level raised from 10.7±7.67μg/dl at baseline to the level of 49.1±14.1μg/dl at the end of the study. The level of hemoglobin and values of MCH and MCHC were decreased due to a short-term exposure to lead by 2%, 2%, and 1%, respectively. The counts of WBC, LYM, and MXD increased significantly by 5%, 7%, and 35%. Similarly, the count of PLT increased by 7%, while PDW, MPV, and P-LCR decreased by 6%, 3%, and 9%, respectively. The levels of IL-7, G-CSF, HGF, PDGF AB/BB, SCF, and PECAM-1, decreased significantly by 30%, 33%, 8%, 30%, 25%, and 20%, respectively. A short-term occupational exposure to lead results in a decreased hemoglobin level and increased counts of WBC and PLT. Changes in counts and proportions of different types of leukocytes and decreased values of PLT indices, such as PDW, MPV, and P-LCR, due to the subacute lead-exposure may be associated with lead-induced decreased levels of cytokines related to hematopoiesis, including SCF, G-CSF, IL-7, and PDGF.


      PubDate: 2016-06-18T18:23:46Z
       
  • Nrf2 activation ameliorates cytotoxic effects of arsenic trioxide in acute
           promyelocytic leukemia cells through increased glutathione levels and
           arsenic efflux from cells
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Shoichi Nishimoto, Toshihiro Suzuki, Shin Koike, Bo Yuan, Norio Takagi, Yuki Ogasawara
      Carnosic acid (CA), a phenolic diterpene isolated from Rosmarinus officinalis, has been shown to activate nuclear transcription factor E2-related factor 2 (Nrf2), which plays a central role in cytoprotective responses to oxidative and electrophilic stress. Recently, the Nrf2-Kelch ECH associating protein 1 (Keap1) pathway has been associated with cancer drug resistance attributable to modulation of the expression and activation of antioxidant and detoxification enzymes. However, the exact mechanisms by which Nrf2 activation results in chemoresistance are insufficiently understood to date. This study investigated the mechanisms by which the cytotoxic effects of arsenic trioxide (ATO), an anticancer drug, were decreased in acute promyelocytic leukemia cells treated with CA, a typical activator of Nrf2 used to stimulate the Nrf2/Keap1 system. Our findings suggest that arsenic is non-enzymatically incorporated into NB4 cells and forms complexes that are dependent on intracellular glutathione (GSH) concentrations. In addition, the arsenic complexes are recognized as substrates by multidrug resistance proteins and subsequently excreted from the cells. Therefore, Nrf2-associated activation of the GSH biosynthetic pathway, followed by increased levels of intracellular GSH, are key mechanisms underlying accelerated arsenic efflux and attenuation of the cytotoxic effects of ATO.
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      PubDate: 2016-06-18T18:23:46Z
       
  • Kinin B1 receptor blockade and ACE inhibition attenuate cardiac
           postinfarction remodeling and heart failure in rats
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Xinchun Lin, Christian Bernloehr, Tobias Hildebrandt, Florian J. Stadler, Henri Doods, Dongmei Wu
      Introduction The aim of the present study was to evaluate the effects of the novel kinin B1 receptor antagonist BI113823 on postinfarction cardiac remodeling and heart failure, and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin 1 converting enzyme (ACE) inhibitor in rats. Methods and results Sprague Dawley rats were subjected to permanent occlusion of the left coronary artery. Cardiovascular function was determined at 6weeks postinfarction. Treatment with either B1 receptor antagonist (BI113823) or an ACE inhibitor (lisinopril) alone or in combination significantly reduced the heart weight-to-body weight and lung weight-to-body weight ratios, and improved postinfarction cardiac function as evidenced by greater cardiac output, the maximum rate of left ventricular pressure rise (±dP/dtmax), left ventricle ejection fraction, fractional shorting, better wall motion, and attenuation of elevated left ventricular end diastolic pressure (LVEDP). Furthermore, all three treatment groups exhibited significant reduction in cardiac interstitial fibrosis, collagen deposition, CD68 positive macrophages, neutrophils, and proinflammatory cytokine production (TNF-α and IL-1β), compared to vehicle controls. Conclusion The present study shows that treatment with the novel kinin B1 receptor antagonist, BI113823, reduces postinfarction cardiac remodeling and heart failure, and does not influence the cardiovascular effects of the ACE inhibitor.


      PubDate: 2016-06-18T18:23:46Z
       
  • Mobilization and removing of cadmium from kidney by GMDTC utilizing renal
           glucose reabsorption pathway
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Xiaojiang Tang, Jinqiu Zhu, Zhiyong Zhong, Minhui Luo, Guangxian Li, Zhihong Gong, Chenzi Zhang, Fan Fei, Xiaolin Ruan, Jinlin Zhou, Gaofeng Liu, Guoding Li, James Olson, Xuefeng Ren
      Chronic exposure to cadmium compounds (Cd2+) is one of the major public health problems facing humans in the 21st century. Cd2+ in the human body accumulates primarily in the kidneys which leads to renal dysfunction and other adverse health effects. Efforts to find a safe and effective drug for removing Cd2+ from the kidneys have largely failed. We developed and synthesized a new chemical, sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6 pentahydroxyhexyl)amino)-4-(methylthio) butanoate (GMDTC). Here we report that GMDTC has a very low toxicity with an acute lethal dose (LD50) of more than 10,000mg/kg or 5000mg/kg body weight, respectively, via oral or intraperitoneal injection in mice and rats. In in vivo settings, up to 94% of Cd2+ deposited in the kidneys of Cd2+-laden rabbits was removed and excreted via urine following a safe dose of GMDTC treatment for four weeks, and renal Cd2+ level was reduced from 12.9μg/g to 1.3μg/g kidney weight. We observed similar results in the mouse and rat studies. Further, we demonstrated both in in vitro and in animal studies that the mechanism of transporting GMDTC and GMDTC-Cd complex into and out of renal tubular cells is likely assisted by two glucose transporters, sodium glucose cotransporter 2 (SGLT2) and glucose transporter 2 (GLUT2). Collectively, our study reports that GMDTC is safe and highly efficient in removing deposited Cd2+ from kidneys assisted by renal glucose reabsorption system, suggesting that GMDTC may be the long-pursued agent used for preventive and therapeutic purposes for both acute and chronic Cd2+ exposure.


      PubDate: 2016-06-18T18:23:46Z
       
  • Dioscin protects against ANIT–induced cholestasis via regulating
           Oatps, Mrp2 and Bsep expression in rats
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Aijie zhang, Yongming Jia, Qinghan Xu, Changyuan Wang, Qi Liu, Qiang Meng, Jinyong Peng, Huijun Sun, Pengyuan Sun, Xiaokui Huo, Kexin Liu
      Alpha-naphthylisothiocyanate (ANIT) is a toxicant that is widely used in rodents to model human intrahepatic cholestasis. The aim of the study is to investigate whether effects of dioscin on ANIT-induced cholestasis are related to changes in expression of hepatic transporters in rats. Effects of dioscin on cholestasis were examined by histology and biochemical marker levels. The functional changes of hepatic transporters were determined by in vitro, in situ and in vivo. qRT-PCR and western blot were used to assess the expression of hepatic transporters in cholestatic rats. Dioscin administration could ameliorate cholestasis, as evidenced by reduced biochemical markers as well as improved liver pathology. The uptakes of organic anion transporting polypeptide (Oatp) substrates were altered in liver uptake index in vivo, perfused rat liver in situ and isolated rat hepatocytes in vitro in cholestasis rats. qRT-PCR and western blot analysis indicated co-treatment of ANIT with dioscin prevented the adaptive down-regulation of Oatp1a1, 1b2, and prompted the up-regulation of Oatp1a4, multidrug resistance-associated protein (Mrp) 2 and bile salt export pump (Bsep). In addition, concerted effects on Mrp2 and Bsep occurred through up-regulation of small heterodimer partner by activating farnesoid X receptor. Dioscin might prevent impairment of hepatic function by restoring hepatic transporter expression.
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      PubDate: 2016-06-18T18:23:46Z
       
  • Nrf2-dependent protection against acute sodium arsenite toxicity in
           zebrafish
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Yuji Fuse, Vu Thanh Nguyen, Makoto Kobayashi
      Transcription factor Nrf2 induces a number of detoxifying enzymes and antioxidant proteins to confer protection against the toxic effects of a diverse range of chemicals including inorganic arsenicals. Although a number of studies using cultured cells have demonstrated that Nrf2 has a cell-protective function against acute and high-dose arsenic toxicity, there is no clear in vivo evidence of this effect. In the present study, we genetically investigated the protective role of Nrf2 against acute sodium arsenite toxicity using the zebrafish Nrf2 mutant, nrf2a fh318 . After treatment with 1mM sodium arsenite, the survival of nrf2a fh318 larvae was significantly shorter than that of wild-type siblings, suggesting that Nrf2 protected the zebrafish larvae against high-dose arsenite exposure. To understand the molecular basis of the Nrf2-dependent protection, we analyzed the gene expression profiles after arsenite exposure, and found that the genes involved in the antioxidative function (prdx1 and gclc), arsenic metabolism (gstp1) and xenobiotic elimination (abcc2) were induced in an Nrf2-dependent manner. Furthermore, pre-treatment with sulforaphane, a well-known Nrf2 activator improved the survival of zebrafish larvae after arsenic exposure. Based on these results, we concluded that Nrf2 plays a fundamental and conserved role in protection against acute sodium arsenite toxicity.


      PubDate: 2016-06-18T18:23:46Z
       
  • Analysis of real-time mixture cytotoxicity data following repeated
           exposure using BK/TD models
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): S. Teng, C. Tebby, S. Barcellini-Couget, G. De Sousa, C. Brochot, R. Rahmani, A.R.R. Pery
      Cosmetic products generally consist of multiple ingredients. Thus, cosmetic risk assessment has to deal with mixture toxicity on a long-term scale which means it has to be assessed in the context of repeated exposure. Given that animal testing has been banned for cosmetics risk assessment, in vitro assays allowing long-term repeated exposure and adapted for in vitro – in vivo extrapolation need to be developed. However, most in vitro tests only assess short-term effects and consider static endpoints which hinder extrapolation to realistic human exposure scenarios where concentration in target organs is varies over time. Thanks to impedance metrics, real-time cell viability monitoring for repeated exposure has become possible. We recently constructed biokinetic/toxicodynamic models (BK/TD) to analyze such data (Teng et al., 2015) for three hepatotoxic cosmetic ingredients: coumarin, isoeugenol and benzophenone-2. In the present study, we aim to apply these models to analyze the dynamics of mixture impedance data using the concepts of concentration addition and independent action. Metabolic interactions between the mixture components were investigated, characterized and implemented in the models, as they impacted the actual cellular exposure. Indeed, cellular metabolism following mixture exposure induced a quick disappearance of the compounds from the exposure system. We showed that isoeugenol substantially decreased the metabolism of benzophenone-2, reducing the disappearance of this compound and enhancing its in vitro toxicity. Apart from this metabolic interaction, no mixtures showed any interaction, and all binary mixtures were successfully modeled by at least one model based on exposure to the individual compounds.


      PubDate: 2016-06-18T18:23:46Z
       
  • Combined effects of DNA methyltransferase 1 and 3A polymorphisms and
           urinary total arsenic levels on the risk for clear cell renal cell
           carcinoma
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Shu-Mei Yang, Chao-Yuan Huang, Horng-Sheng Shiue, Yeong-Shiau Pu, Yi-Hsun Hsieh, Wei-Jen Chen, Ying-Chin Lin, Yu-Mei Hsueh
      Our previous study showed that high urinary total arsenic levels were associated with higher odds ratio (OR) for renal cell carcinoma (RCC). Single nucleotide polymorphisms (SNPs) of DNA methyltransferases (DNMTs) might influence DNMT enzyme activity associated with tumorigenesis. In this study, we investigated the association of five SNPs from DNMT1 (rs8101626 and rs2228611), DNMT3A (rs34048824 and rs1550117), and DNMT3B (rs1569686) with the risk of clear cell renal cell carcinoma (ccRCC). We also examined the combined effects of DNMT genotypes and urinary arsenic levels on ccRCC risk. We conducted a hospital-based case-control study, which included 293 subjects with ccRCC and 293 age- and gender-matched controls. The urinary arsenic species were determined by a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Genotypes were investigated using polymerase chain reaction and restriction fragment length polymorphism analyses. We observed that the DNMT1 rs8101626 G/G genotype was significantly associated with reduced odds ratio (OR) of ccRCC [OR=0.38, 95% confidence interval (CI) 0.14–0.99]. Subjects with concurrent DNMT1 rs8101626 A/A+A/G and DNMT3A rs34048824 T/T+T/C genotypes had significantly higher OR for ccRCC [OR=2.88, 95% CI 1.44–5.77]. Participants with the high-risk genotype of DNMT1 rs8101626 and DNMT3A rs34048824 with concurrently high urinary total arsenic levels had even higher OR of ccRCC in a dose-response manner. This is the first study to evaluate variant DNMT1 rs8101626 and DNMT3A rs34048824 genotypes that modify the arsenic-related ccRCC risk in a geographic area without significant arsenic exposure in Taiwan.


      PubDate: 2016-06-18T18:23:46Z
       
  • Mitragynine and its potential blocking effects on specific cardiac
           potassium channels
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Yea Lu Tay, Yi Fan Teah, Yoong Min Chong, Mohd Fadzly Amar Jamil, Sina Kollert, Mohd Ilham Adenan, Habibah Abdul Wahab, Frank Döring, Erhard Wischmeyer, Mei Lan Tan
      Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac IKr current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, IK1, a Kir current mediated by Kir2.1 channel and IKACh, a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC50 value of 1.62μM and 1.15μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit IKACh current with an IC50 value of 3.32μM but has no significant effects on IK1. Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks.


      PubDate: 2016-06-15T19:57:29Z
       
  • Inhibition by ketamine and amphetamine analogs of the neurogenic nitrergic
           vasodilations in porcine basilar arteries
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Mei-Fang Chen, Su-Yu Lai, Po-Cheng Kung, Yo-Cheng Lin, Hui-I Yang, Po-Yi Chen, Ingrid Y. Liu, Ahai Chang Lua, Tony Jer-Fu Lee
      The abuse of ketamine and amphetamine analogs is associated with incidence of hypertension and strokes involving activation of sympathetic activities. Large cerebral arteries at the base of the brain from several species receive dense sympathetic innervation which upon activation causes parasympathetic-nitrergic vasodilation with increased regional blood flow via axo-axonal interaction mechanism, serving as a protective mechanism to meet O2 demand in an acutely stressful situation. The present study was designed to examine effects of ketamine and amphetamine analogs on axo-axonal interaction-mediated neurogenic nitrergic vasodilation in porcine basilar arteries using techniques of blood-vessel myography, patch clamp and two-electrode voltage clamp, and calcium imaging. In U46619-contracted basilar arterial rings, nicotine (100μM) and electrical depolarization of nitrergic nerves by transmural nerve stimulation (TNS, 8Hz) elicited neurogenic nitrergic vasodilations. Ketamine and amphetamine analogs concentration-dependently inhibited nicotine-induced parasympathetic-nitrergic vasodilation without affecting that induced by TNS, nitroprusside or isoproterenol. Ketamine and amphetamine analogs also concentration-dependently blocked nicotine-induced inward currents in Xenopus oocytes expressing α3β2-nicotinic acetylcholine receptors (nAChRs), and nicotine-induced inward currents as well as calcium influxes in rat superior cervical ganglion neurons. The potency in inhibiting both inward-currents and calcium influxes is ketamine>methamphetamine>hydroxyamphetamine. These results indicate that ketamine and amphetamine analogs, by blocking nAChRs located on cerebral perivascular sympathetic nerves, reduce nicotine-induced, axo-axonal interaction mechanism-mediated neurogenic dilation of the basilar arteries. Chronic abuse of these drugs, therefore, may interfere with normal sympathetic-parasympathetic interaction mechanism resulting in diminished neurogenic vasodilation and, possibly, normal blood flow in the brainstem.


      PubDate: 2016-06-15T19:57:29Z
       
  • TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular
           nucleus are involved in the effects of telmisartan in hypertension
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Hong-Bao Li, Xiang Li, Chan-Juan Huo, Qing Su, Jing Guo, Zu-Yi Yuan, Guo-Qing Zhu, Xiao-Lian Shi, Jin-Jun Liu, Yu-Ming Kang
      Previous findings from our laboratory and others indicate that the main therapeutic effect of angiotensin II type 1 receptor (AT1-R) antagonists is to decrease blood pressure and exert anti-inflammatory effects in the cardiovascular system. In this study, we determined whether AT1-R antagonist telmisartan within the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and hypothalamic inflammation via both the TLR4/MyD88/NF-κB signaling pathway and peroxisome proliferator-activated receptor-γ (PPAR-γ) in the PVN in hypertensive rats. Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated for 4weeks through bilateral PVN infusion with the AT1-R antagonist telmisartan (TEL, 10μg/h), or losartan (LOS, 20μg/h), or the PPAR-γ antagonist GW9662 (GW, 100μg/h), or vehicle via osmotic minipump. Mean arterial pressure (MAP) was recorded by a tail-cuff occlusion method. PVN tissue and blood were collected for the measurement of AT1-R, PPAR-γ, pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6), inducible nitric oxide synthase (iNOS), TLR4, MyD88, nuclear factor-kappa B (NF-κB) activity and plasma norepinephrine (NE), respectively. Hypertensive rats exhibited significantly higher level of AT1-R and lower level of PPAR-γ in the PVN. PVN treatment with TEL attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1β, IL-6, iNOS levels, and plasma NE in SHR but not in WKY rats. These results were associated with reduced TLR4, MyD88 and NF-κB levels and increased PPAR-γ level in the PVN of hypertensive rats. Our findings suggest that TLR4/MyD88/NF-κB signaling and PPAR-γ within the PVN are involved in the beneficial effects of telmisartan in hypertension.


      PubDate: 2016-06-15T19:57:29Z
       
  • Effects and mechanisms of cavidine protecting mice against LPS-induced
           endotoxic shock
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Weifeng Li, Hailin Zhang, Xiaofeng Niu, Xiumei Wang, Yu Wang, Zehong He, Huan Yao
      LPS sensitized mice are usually considered as an experimental model of endotoxin shock. The present study aims to evaluate effects of cavidine on LPS-induced endotoxin shock. Mice were intraperitoneally administrated with cavidine (1, 3 and 10mg/kg) or DEX (5mg/kg) at 1 and 12h before injecting LPS (30mg/kg) intraperitoneally. Blood samples, liver, lung and kidney tissues were harvested after LPS injection. The study demonstrated that pretreatment with cavidine reduced the mortality of mice during 72h after endotoxin injection. In addition, cavidine administration significantly attenuated histological pathophysiology features of LPS-induced injury in lung, liver and kidney. Furthermore, cavidine administration inhibited endotoxin-induced production of pro-inflammatory cytokines including TNF-α, IL-6 and HMGB1. Moreover, cavidine pretreatment attenuated the phosphorylation of mitogen-activated protein kinase primed by LPS. In summary, cavidine protects mice against LPS-induced endotoxic shock via inhibiting early pro-inflammatory cytokine TNF-α, IL-6 and late-phase cytokine HMGB1, and the modulation of HMGB1 may be related with MAPK signal pathway.
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      PubDate: 2016-06-15T19:57:29Z
       
  • Assessment of ABCG2-mediated transport of pesticides across the rabbit
           placenta barrier using a novel MDCKII in vitro model
    • Abstract: Publication date: Available online 8 June 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Sandra Halwachs, Ingo Schaefer, Carsten Kneuer, Peter Seibel, Walther Honscha
      In humans, the ATP-binding cassette efflux transporter ABCG2 contributes to the fetoprotective barrier function of the placenta, potentially limiting the toxicity of transporter substrates to the fetus. During testing of chemicals including pesticides, developmental toxicity studies are performed in rabbit. Despite its toxicological relevance, ABCG2-mediated transport of pesticides in rabbit placenta has not been yet elucidated. We therefore generated polarized MDCK II cells expressing the ABCG2 transporter from rabbit placenta (rbABCG2) and evaluated interaction of the efflux transporter with selected insecticides, fungicides, and herbicides. The Hoechst H33342 accumulation assay indicated that 13 widely used pesticidal active substances including azoxystrobin, carbendazim, chlorpyrifos, chlormequat, diflufenican, dimethoate, dimethomorph, dithianon, ioxynil, methiocarb, propamocarb, rimsulfuron and toclofos-methyl may be rbABCG2 inhibitors and/or substrates. No such evidence was obtained for chlorpyrifos-methyl, epoxiconazole, glyphosate, imazalil and thiacloprid. Moreover, chlorpyrifos (CPF), dimethomorph, tolclofos-methyl and rimsulfuron showed concentration-dependent inhibition of H33342 excretion in rbABCG2-transduced MDCKII cells. To further evaluate the role of rbABCG2 in pesticide transport across the placenta barrier, we generated polarized MDCKII-rbABCG2 monolayers. Confocal microscopy confirmed correct localization of rbABCG2 protein in the apical plasma membrane. In transepithelial flux studies, we showed the time-dependent preferential basolateral to apical (B>A) directed transport of [14C] CPF across polarized MDCKII-rbABCG2 monolayers which was significantly inhibited by the ABCG2 inhibitor fumitremorgin C (FTC). Using this novel in vitro cell culture model, we altogether showed functional secretory activity of the ABCG2 transporter from rabbit placenta and identified several pesticides like the insecticide CPF as potential rbABCG2 substrates.


      PubDate: 2016-06-10T00:33:52Z
       
  • Hypoxia-induced pulmonary arterial hypertension augments lung injury and
           airway reactivity caused by ozone exposure
    • Abstract: Publication date: Available online 7 June 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Katherine E. Zychowski, Selita N. Lucas, Bethany Sanchez, Guy Herbert, Matthew J. Campen
      Ozone (O3)-related cardiorespiratory effects are a growing public health concern. Ground level O3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O3-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O3 exacerbated HPH, male C57BL/6 mice were subject to either 3 wks continuous normoxia (20.9% O2) or hypoxia (10.0% O2), followed by a 4-h exposure to either 1ppm O3 or filtered air (FA). As an additional experimental intervention fasudil (20mg/kg) was administered intraperitoneally prior to and after O3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O3-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability.


      PubDate: 2016-06-10T00:33:52Z
       
  • Lysosomotropic cationic drugs induce cytostatic and cytotoxic effects:
           Role of liposolubility and autophagic flux and antagonism by cholesterol
           ablation
    • Abstract: Publication date: Available online 8 June 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Alexandre Parks, François Marceau
      Cation trapping in acidic cell compartments determines an antiproliferative effect that has a potential interest in oncology, as shown by clinical data and trials involving chloroquine and hydroxychloroquine. To further characterize the mechanism of this effect, we studied a series of 6 substituted triethylamine (s-Et3N) drugs that encompasses a wide range of liposolubility (amiodarone, quinacrine, chloroquine, hydroxychloroquine, lidocaine, and procainamide). Three tumor cell lines and primary human endothelial cells were exploited in proliferation assays (48h, cell counts). Accumulation of the autophagic effector LC3 II and the apoptotic marker cleaved PARP1 (immunoblots), cytotoxicity, cell cycle analysis and endocytic function were further tested in the p53-null histiocytic lymphoma U937 line. A profound and desynchronized antiproliferative effect was observed in response to all s-Et3Ns with essentially no cell type specificity. Predictors of s-Et3N potency were liposolubility and the acute accumulation of the autophagic effector LC3 II (6h-treatments). For each s-Et3N, there was an antiproliferative concentration range where cytotoxicity and apoptosis were not triggered in U937 cells (24–48h-treatments). Quinacrine was the most potent cytostatic drug (1–5μM). Co-treatment of cells with inhibitors of cholesterol, β-cyclodextrin or lovastatin, partially reversed the antiproliferative effect of each s-Et3N. The cytopathology induced by cationic drug accumulation includes a cytostatic effect. Its intensity is cell type- and p53-independent, but predicted by the inhibition of autophagic flux and by the liposolubility of individual drugs and alleviated by cholesterol ablation. The superiority of quinacrine, biomarker value of LC3 II and antagonism by a statin may be clinically relevant.
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      PubDate: 2016-06-10T00:33:52Z
       
  • Differences in toxicity of anionic and cationic PAMAM and PPI dendrimers
           in zebrafish embryos and cancer cell lines
    • Abstract: Publication date: Available online 8 June 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lambert Bodewein, Frank Schmelter, Stefano Di Fiore, Henner Hollert, Rainer Fischer, Martina Fenske
      Dendrimers are an emerging class of polymeric nanoparticles with beneficial biomedical applications like early diagnostics, in vitro gene transfection or controlled drug delivery. However, the potential toxic impact of exposure on human health or the environment is often inedequately defined. Thus, polyamidoamine (PAMAM) dendrimers of generations G3.0, 3.5, 4.0, 4.5 and 5.0 and polypropylenimine (PPI) dendrimers G3.0, 4.0 and 5.0 were tested in zebrafish embryos for 96h and human cancer cell lines for 24h, to assess and compare developmental in vivo toxicity with cytotoxicity. The zebrafish embryo toxicity of cationic PAMAM and PPI dendrimers increased over time, with EC50 values ranging from 0.16 to just below 1.7μM at 24 and 48 hpf. The predominant effects were mortality, plus reduced heartbeat and blood circulation for PPI dendrimers. Apoptosis in the embryos increased in line with the general toxicity concentration-dependently. Hatch and dechorionation of the embryos increased the toxicity, suggesting a protective role of the chorion. Lower generation dendrimers were more toxic in the embryos whereas the toxicity in the HepG2 and DU145 cell lines increased with increasing generation of cationic PAMAMs and PPI dendrimers. HepG2 were less sensitive than DU145 cells, with IC50 values ≥402μM (PAMAMs) and ≤240μM (PPIs) for HepG2 and ≤13.24μM (PAMAMs) and ≤12.84μM (PPIs) for DU145. Neither in fish embryos nor cells toxicity thresholds were determinable for anionic PAMAM G3.5 and G4.5. The study demonstrated that the cytotoxicity underestimated the in-vivo toxicity of the dendrimers in the fish embryos.


      PubDate: 2016-06-10T00:33:52Z
       
  • Several synthetic progestins disrupt the glial cell specific-brain
           aromatase expression in developing zebra fish
    • Abstract: Publication date: 15 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 305
      Author(s): Joel Cano-Nicolau, Clémentine Garoche, Nathalie Hinfray, Elisabeth Pellegrini, Noureddine Boujrad, Farzad Pakdel, Olivier Kah, François Brion
      The effects of some progestins on fish reproduction have been recently reported revealing the hazard of this class of steroidal pharmaceuticals. However, their effects at the central nervous system level have been poorly studied until now. Notwithstanding, progesterone, although still widely considered primarily a sex hormone, is an important agent affecting many central nervous system functions. Herein, we investigated the effects of a large set of synthetic ligands of the nuclear progesterone receptor on the glial-specific expression of the zebrafish brain aromatase (cyp19a1b) using zebrafish mechanism-based assays. Progesterone and 24 progestins were first screened on transgenic cyp19a1b-GFP zebrafish embryos. We showed that progesterone, dydrogesterone, drospirenone and all the progesterone-derived progestins had no effect on GFP expression. Conversely, all progestins derived from 19-nortesterone induced GFP in a concentration-dependent manner with EC50 ranging from the low nM range to hundreds nM. The 19-nortestosterone derived progestins levonorgestrel (LNG) and norethindrone (NET) were further tested in a radial glial cell context using U251-MG cells co-transfected with zebrafish ER subtypes (zfERα, zfERβ1 or zfERβ2) and cyp19a1b promoter linked to luciferase. Progesterone had no effect on luciferase activity while NET and LNG induced luciferase activity that was blocked by ICI 182,780. Zebrafish-ERs competition assays showed that NET and LNG were unable to bind to ERs, suggesting that the effects of these compounds on cyp19a1b require metabolic activation prior to elicit estrogenic activity. Overall, we demonstrate that 19-nortestosterone derived progestins elicit estrogenic activity by inducing cyp19a1b expression in radial glial cells. Given the crucial role of radial glial cells and neuro-estrogens in early development of brain, the consequences of exposure of fish to these compounds require further investigation.
      Graphical abstract image

      PubDate: 2016-06-10T00:33:52Z
       
  • The spleen as an extramedullary source of inflammatory cells responding to
           acetaminophen-induced liver injury
    • Abstract: Publication date: 1 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 304
      Author(s): Mili Mandal, Carol R. Gardner, Richard Sun, Hyejeong Choi, Sonali Lad, Vladimir Mishin, Jeffrey D. Laskin, Debra L. Laskin
      Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300mg/kg, i.p.) to control mice resulted in an increase in CD11b+ infiltrating Ly6G+ granulocytic and Ly6G− monocytic cells in the spleen and the liver. The majority of the Ly6G+ cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G− cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80+) and immature (F4/80−) pro-inflammatory Ly6Chi macrophages and mature anti-inflammatory (Ly6Clo) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3+ macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs.


      PubDate: 2016-06-10T00:33:52Z
       
  • Editorial Board
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303




      PubDate: 2016-06-05T01:48:50Z
       
  • Corrigendum to “Use of a combined effect model approach for
           discriminating between ABCB1- and ABCC1-type efflux activities in native
           
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303
      Author(s): Melissa Faria, Vasiliy Pavlichenko, Kathleen Burkhardt-Medicke, Amadeu M.V.M. Soares, Rolf Altenburger, Carlos Barata, Till Luckenbach



      PubDate: 2016-06-05T01:48:50Z
       
  • Contents
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303




      PubDate: 2016-06-05T01:48:50Z
       
  • The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid-
           and perfluorooctanesulfonic acid-induced hepatocellular dysfunction
    • Abstract: Publication date: 1 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 304
      Author(s): Kevin M. Beggs, Steven R. McGreal, Alex McCarthy, Sumedha Gunewardena, Jed N. Lampe, Christoper Lau, Udayan Apte
      Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), chemicals present in a multitude of consumer products, are persistent organic pollutants. Both compounds induce hepatotoxic effects in rodents, including steatosis, hepatomegaly and liver cancer. The mechanisms of PFOA- and PFOS-induced hepatic dysfunction are not completely understood. We present evidence that PFOA and PFOS induce their hepatic effects via targeting hepatocyte nuclear factor 4-alpha (HNF4α). Human hepatocytes treated with PFOA and PFOS at a concentration relevant to occupational exposure caused a decrease in HNF4α protein without affecting HNF4α mRNA or causing cell death. RNA sequencing analysis combined with Ingenuity Pathway Analysis of global gene expression changes in human hepatocytes treated with PFOA or PFOS indicated alterations in the expression of genes involved in lipid metabolism and tumorigenesis, several of which are regulated by HNF4α. Further investigation of specific HNF4α target gene expression revealed that PFOA and PFOS could promote cellular dedifferentiation and increase cell proliferation by down regulating positive targets (differentiation genes such as CYP7A1) and inducing negative targets of HNF4α (pro-mitogenic genes such as CCND1). Furthermore, in silico docking simulations indicated that PFOA and PFOS could directly interact with HNF4α in a similar manner to endogenous fatty acids. Collectively, these results highlight HNF4α degradation as novel mechanism of PFOA and PFOS-mediated steatosis and tumorigenesis in human livers.


      PubDate: 2016-05-31T01:30:42Z
       
  • The antitripanocide benznidazole promotes adaptive response to oxidative
           injury: Involvement of the nuclear factor-erythroid 2-related factor-2
           (Nrf2) and multidrug resistance associated protein 2 (MRP2)
    • Abstract: Publication date: 1 August 2016
      Source:Toxicology and Applied Pharmacology, Volume 304
      Author(s): Juan Pablo Rigalli, Virginia Gabriela Perdomo, Nadia Ciriaci, Daniel Eleazar Antonio Francés, María Teresa Ronco, Amy Michele Bataille, Carolina Inés Ghanem, María Laura Ruiz, José Enrique Manautou, Viviana Alicia Catania
      Oxidative stress is a frequent cause underlying drug-induced hepatotoxicity. Benznidazole (BZL) is the only antitripanocide agent available for treatment of Chagas disease in endemic areas. Its use is associated with side effects, including increases in biomarkers of hepatotoxicity. However, BZL potential to cause oxidative stress has been poorly investigated. Here, we evaluated the effect of a pharmacologically relevant BZL concentration (200μM) at different time points on redox status and the counteracting mechanisms in the human hepatic cell line HepG2. BZL increased reactive oxygen species (ROS) after 1 and 3h of exposure, returning to normality at 24h. Additionally, BZL increased glutathione peroxidase activity at 12h and the oxidized glutathione/total glutathione (GSSG/GSSG+GSH) ratio that reached a peak at 24h. Thus, an enhanced detoxification of peroxide and GSSG formation could account for ROS normalization. GSSG/GSSG+GSH returned to control values at 48h. Expression of the multidrug resistance-associated protein 2 (MRP2) and GSSG efflux via MRP2 were induced by BZL at 24 and 48h, explaining normalization of GSSG/GSSG+GSH. BZL activated the nuclear erythroid 2-related factor 2 (Nrf2), already shown to modulate MRP2 expression in response to oxidative stress. Nrf2 participation was confirmed using Nrf2-knockout mice in which MRP2 mRNA expression was not affected by BZL. In summary, we demonstrated a ROS increase by BZL in HepG2 cells and a glutathione peroxidase- and MRP2 driven counteracting mechanism, being Nrf2 a key modulator of this response. Our results could explain hepatic alterations associated with BZL therapy.


      PubDate: 2016-05-31T01:30:42Z
       
  • Arsenic silences hepatic PDK4 expression through activation of histone
           H3K9 methylatransferase G9a
    • Abstract: Publication date: Available online 20 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Xi Zhang, Jianguo Wu, Jonathan Choiniere, Zhihong Yang, Yi Huang, Jason Bennett, Li Wang
      It is well established that increased liver cancer incidence is strongly associated with epigenetic silencing of tumor suppressor genes; the latter is contributed by the environmental exposure to arsenic. Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial protein that regulates the TCA cycle. However, the epigenetic mechanisms mediated by arsenic to control PDK4 expression remain elusive. In the present study, we showed that histone methyltrasferase G9a- and Suv39H-mediated histone H3 lysine 9 (H3K9) methylations contributed to PDK4 silencing in hepatic cells. The PDK4 expression was induced by G9a inhibitor BRD4770 (BRD) and Suv39H inhibitor Chaetocin (CHA). In contrast, arsenic exposure decreased PDK4 expression by inducing G9a and increasing H3K9 di- and tri-methylations levels (H3K9me2/3). In addition, arsenic exposure antagonizes the effect of BRD by enhancing the enrichment of H3K9me2/3 in the PKD4 promoter. Moreover, knockdown of G9a using siRNA induced PDK4 expression in HCC cells. Furthermore, arsenic decreased hepatic PDK4 expression as well as diminished the induction of PDK4 by BRD in mouse liver and hepatocytes. Overall, the results suggest that arsenic causes aberrant repressive histone modification to silence PDK4 in both HCC cells and in mouse liver.
      Graphical abstract image

      PubDate: 2016-05-26T01:10:40Z
       
  • Arsenic trioxide mediates HAPI microglia inflammatory response and
           subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303
      Author(s): Jiamin Mao, Jianbing Yang, Yan Zhang, Ting Li, Cheng Wang, Lingfei Xu, Qiaoyun Hu, Xiaoke Wang, Shengyang Jiang, Xiaoke Nie, Gang Chen
      Arsenic is a widely distributed toxic metalloid all over the world. Inorganic arsenic species are supposed to affect astrocytic functions and to cause neuron apoptosis in CNS. Microglias are the key cell type involved in innate immune responses in CNS, and microglia activation has been linked to inflammation and neurotoxicity. In this study, using ELISA, we showed that Arsenic trioxide up-regulated the expression and secretion of IL-1β in a dose-dependent manner and a time-dependent manner in cultured HAPI microglia cells. The secretion of IL-1β caused the apoptosis of SH-SY5Y. These pro-inflammatory responses were inhibited by the STAT3 blocker, AG490 and P38/JNK MAPK blockers SB202190, SP600125. Further, Arsenic trioxide exposure could induce phosphorylation and activation of STAT3, and the translocation of STAT3 from the cytosol to the nucleus in this HAPI microglia cell line. Thus, the STAT3 signaling pathway can be activated after Arsenic trioxide treatment. However, P38/JNK MAPK blockers SB202190, SP600125 also obviously attenuated STAT3 activation and transnuclear transport induced by Arsenic trioxide. In concert with these results, we highlighted that the secretion of IL-1β and STAT3 activation induced by Arsenic trioxide can be mediated by elevation of P38/JNK MAPK in HAPI microglia cells and then induced the toxicity of neurons.


      PubDate: 2016-05-26T01:10:40Z
       
  • Health effects following subacute exposure to geogenic dusts from
           arsenic-rich sediment at the Nellis Dunes Recreation Area, Las Vegas, NV
    • Abstract: Publication date: Available online 21 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Jamie DeWitt, Brenda Buck, Dirk Goossens, Qing Hu, Rebecca Chow, Winnie David, Sharon Young, Yuanxin Teng, Mallory Leetham-Spencer, Lacey Murphy, James Pollard, Brett McLaurin, Russell Gerads, Deborah Keil
      Geogenic dust from arid environments is a possible inhalation hazard for humans, especially when using off-road vehicles that generate significant dust. This study focused on immunotoxicological and neurotoxicological effects following subacute exposure to geogenic dust generated from sediments in the Nellis Dunes Recreation Area near Las Vegas, Nevada that are particularly high in arsenic; the naturally-occurring arsenic concentrations in these surficial sediments ranged from 4.8 to 346μg/g. Dust samples from sediments used in this study had a median diameter of 4.5μm and also were a complex mixture of naturally-occurring metals, including aluminum, vanadium, chromium, manganese, iron, cobalt, copper, zinc, strontium, cesium, lead, uranium, and arsenic. Adult female B6C3F1 mice exposed via oropharyngeal aspiration to 0.01 to 100mg dust/kg body weight, four times, a week apart, for 28-days, were evaluated 24h after the last exposure. Peripheral eosinophils were increased at all concentrations, serum creatinine was dose responsively increased beginning at 1.0mg/kg/day, and blood urea nitrogen was decreased at 10 and 100mg/kg/day. Antigen-specific IgM responses and natural killer cell activity were dose-responsively suppressed at 0.1, mg/kg/day and above. Splenic CD4+CD25+ T cells were decreased at 0.01, 0.1, 10, and 100mg/kg/day. Antibodies against MBP, NF-68, and GFAP were selectively reduced. A no observed adverse effect level of 0.01mg/kg/day and a lowest observed adverse effect level of 0.1mg/kg/day were determined from IgM responses and natural killer cell activity, indicating that exposure to this dust, under conditions similar to our design, could affect these responses.


      PubDate: 2016-05-26T01:10:40Z
       
  • TCDD modulation of gut microbiome correlated with liver and immune
           toxicity in streptozotocin (STZ)-induced hyperglycemic mice
    • Abstract: Publication date: Available online 21 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Daniel E. Lefever, Joella Xu, Yingjia Chen, Guannan Huang, Nagy Tamas, Tai L. Guo
      An increasing body of evidence has shown the important role of the gut microbiome in mediating toxicity following environmental contaminant exposure. The goal of this study was to determine if the adverse metabolic effects of chronic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure would be sufficient to exacerbate hyperglycemia, and to further determine if these outcomes were attributable to the gut microbiota alteration. Adult male CD-1 mice were exposed to TCDD (6μg/kg body weight biweekly) by gavage and injected (i.p.) with STZ (4×50mg/kg body weight) to induced hyperglycemia. 16S rRNA sequencing was used to characterize the changes in the microbiome community composition. Glucose monitoring, flow cytometry, histopathology, and organ characterization were performed to determine the deleterious phenotypic changes of TCDD exposure. Chronic TCDD treatment did not appear to exacerbate STZ-induced hyperglycemia as blood glucose levels were slightly reduced in the TCDD treated mice; however, polydipsia and polyphagia were observed. Importantly, TCDD exposure caused a dramatic change in microbiota structure, as characterized at the phylum level by increasing Firmicutes and decreasing Bacteroidetes while at the family level most notably by increasing Lactobacillaceae and Desulfovibrionaceae, and decreasing Prevotellaceae and ACK M1. The changes in microbiota were further found to be broadly associated with phenotypic changes seen from chronic TCDD treatment. In particular, the phylum level Bacteroidetes to Firmicutes ratio negatively correlated with both liver weight and liver pathology, and positively associated with %CD3+ NK+ T cells, a key mediator of host-microbial interactions. Collectively, these findings suggest that the dysregulated gut microbiome may contribute to the deleterious effects (e.g., liver toxicity) seen with TCDD exposure.


      PubDate: 2016-05-26T01:10:40Z
       
  • Global gene expression and morphological alterations in the mammary gland
           after gestational exposure to bisphenol A, genistein and indole-3-carbinol
           in female Sprague-Dawley offspring
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303
      Author(s): Tony F. Grassi, Glenda N. da Silva, Lucas T. Bidinotto, Bruna F. Rossi, Marília M. Quinalha, Laura Kass, Mónica Muñoz-de-Toro, Luís F. Barbisan



      PubDate: 2016-05-26T01:10:40Z
       
  • Honokiol induces autophagic cell death in malignant glioma through
           reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR
           signaling pathway
    • Abstract: Publication date: Available online 25 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Chien-Ju Lin, Ta-Liang Chen, Yuan-Yun Tseng, Gong-Jhe Wu, Ming-Hui Hsieh, Yung-Wei Lin, Ruei-Ming Chen
      Honokiol, an active constituent extracted from the bark of Magnolia officinalis, possesses anticancer effects. Apoptosis is classified as type I programmed cell death, while autophagy is type II programmed cell death. We previously proved that honokiol induces cell cycle arrest and apoptosis of U87 MG glioma cells. Subsequently in this study, we evaluated the effect of honokiol on autophagy of glioma cells and examined the molecular mechanisms. Administration of honokiol to mice with an intracranial glioma increased expressions of cleaved caspase 3 and light chain 3 (LC3)-II. Exposure of U87 MG cells to honokiol also induced autophagy in concentration- and time-dependent manners. Results from the addition of 3-methyladenine, an autophagy inhibitor, and rapamycin, an autophagy inducer confirmed that honokiol-induced autophagy contributed to cell death. Honokiol decreased protein levels of PI3K, phosphorylated (p)-Akt, and p-mammalian target of rapamycin (mTOR) in vitro and in vivo. Pretreatment with a p53 inhibitor or transfection with p53 small interfering (si)RNA suppressed honokiol-induced autophagy by reversing downregulation of p-Akt and p-mTOR expressions. In addition, honokiol caused generation of reactive oxygen species (ROS), which was suppressed by the antioxidant, vitamin C. Vitamin C also inhibited honokiol-induced autophagic and apoptotic cell death. Concurrently, honokiol-induced alterations in levels of p-p53, p53, p-Akt, and p-mTOR were attenuated following vitamin C administration. Taken together, our data indicated that honokiol induced ROS-mediated autophagic cell death through regulating the p53/PI3K/Akt/mTOR signaling pathway.
      Graphical abstract image

      PubDate: 2016-05-26T01:10:40Z
       
  • Activation of the Constitutive Androstane Receptor induces hepatic
           
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303
      Author(s): Alice Marmugi, Céline Lukowicz, Frederic Lasserre, Alexandra Montagner, Arnaud Polizzi, Simon Ducheix, Adeline Goron, Laurence Gamet-Payrastre, Sabine Gerbal-Chaloin, Jean Marc Pascussi, Marthe Moldes, Thierry Pineau, Hervé Guillou, Laila Mselli-Lakhal
      The Constitutive Androstane Receptor (CAR, NR1I3) has been newly described as a regulator of energy metabolism. A relevant number of studies using animal models of obesity suggest that CAR activation could be beneficial on the metabolic balance. However, this remains controversial and the underlying mechanisms are still unknown. This work aimed to investigate the effect of CAR activation on hepatic energy metabolism during physiological conditions, i.e. in mouse models not subjected to metabolic/nutritional stress. Gene expression profiling in the liver of CAR knockout and control mice on chow diet and treated with a CAR agonist highlighted CAR-mediated up-regulations of lipogenic genes, concomitant with neutral lipid accumulation. A strong CAR-mediated up-regulation of the patatin-like phospholipase domain-containing protein 3 (Pnpla3) was demonstrated. Pnpla3 is a gene whose polymorphism is associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD) development. This observation was confirmed in human hepatocytes treated with the antiepileptic drug and CAR activator, phenobarbital and in immortalized human hepatocytes treated with CITCO. Studying the molecular mechanisms controlling Pnpla3 gene expression, we demonstrated that CAR does not act by a direct regulation of Pnpla3 transcription or via the Liver X Receptor but may rather involve the transcription factor Carbohydrate Responsive Element-binding protein. These data provide new insights into the regulation by CAR of glycolytic and lipogenic genes and on pathogenesis of steatosis. This also raises the question concerning the impact of drugs and environmental contaminants in lipid-associated metabolic diseases.


      PubDate: 2016-05-26T01:10:40Z
       
  • Resveratrol protects the ovary against chromium-toxicity by enhancing
           endogenous antioxidant enzymes and inhibiting metabolic clearance of
           estradiol
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303
      Author(s): Sakhila K. Banu, Jone A. Stanley, Kirthiram K. Sivakumar, Joe A. Arosh, Robert C. Burghardt
      Resveratrol (RVT), a polyphenolic component in grapes and red wine, has been known for its cytoprotective actions against several diseases. However, beneficial effects of RVT against early exposure to endocrine disrupting chemicals (EDCs) have not been understood. EDCs are linked to several ovarian diseases such as premature ovarian failure, polycystic ovary syndrome, early menopause and infertility in women. Hexavalent chromium (CrVI) is a heavy metal EDC, and widely used in >50 industries. Environmental contamination with CrVI in the US is rapidly increasing, predisposing the human to several illnesses including cancers and still birth. Our lab has been involved in determining the molecular mechanism of CrVI-induced female infertility and intervention strategies to mitigate CrVI effects. Lactating mother rats were exposed to CrVI (50ppm potassium dichromate) from postpartum days 1–21 through drinking water with or without RVT (10mg/kg body wt., through oral gavage daily). During this time, F1 females received respective treatments through mother's milk. On postnatal day (PND) 25, blood and the ovary, kidney and liver were collected from the F1 females for analyses. CrVI increased atresia of follicles by increasing cytochrome C and cleaved caspase-3; decreasing antiapoptotic proteins; decreasing estradiol (E2) biosynthesis and enhancing metabolic clearance of E2, increasing oxidative stress and decreasing endogenous antioxidants. RVT mitigated the effects of CrVI by upregulating cell survival proteins and AOXs; and restored E2 levels by inhibiting hydroxylation, glucuronidation and sulphation of E2. This is the first study to report the protective effects of RVT against any toxicant in the ovary.


      PubDate: 2016-05-21T00:25:53Z
       
  • Epigenetic silencing of miR-218 by the lncRNA CCAT1, acting via BMI1,
           promotes an altered cell cycle transition in the malignant transformation
           of HBE cells induced by cigarette smoke extract
    • Abstract: Publication date: Available online 19 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lu Lu, Hui Xu, Fei Luo, Xinlu Liu, Xiaolin Lu, Qianlei Yang, Junchao Xue, Chao Chen, Le Shi, Qizhan Liu
      Cigarette smoking is the strongest risk factor for the development of lung cancer, the leading cause of cancer-related deaths. However, the molecular mechanisms leading to lung cancer are largely unknown. A long-noncoding RNA (lncRNA), CCAT1, regarded as cancer-associated, has been investigated extensively. Moreover, the molecular mechanisms of lncRNAs in regulation of microRNAs (miRNAs) induced by cigarette smoke remain unclear. In the present investigation, cigarette smoke extract (CSE) caused an altered cell cycle and increased CCAT1 levels and decreased miR-218 levels in human bronchial epithelial (HBE) cells. Depletion of CCAT1 attenuated the CSE-induced decreases of miR-218 levels, suggesting that miR-218 is negatively regulated by CCAT1 in HBE cells exposed to CSE. The CSE-induced increases of BMI1 levels and blocked by CCAT1 siRNA were attenuated by an miR-218 inhibitor. Moreover, in CSE-transformed HBE cells, the CSE-induced cell cycle changes and elevated neoplastic capacity were reversed by CCAT1 siRNA or BMI1 siRNA. This epigenetic silencing of miR-218 by CCAT1 induces an altered cell cycle transition through BMI1 and provides a new mechanism for CSE-induced lung carcinogenesis.


      PubDate: 2016-05-21T00:25:53Z
       
  • Mustard Vesicant-induced Lung Injury: Advances in Therapy
    • Abstract: Publication date: Available online 19 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Barry Weinberger, Rama Malaviya, Vasanthi Sunil, Alessandro Venosa, Diane E. Heck, Jeffrey D. Laskin, Debra L. Laskin
      Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant.


      PubDate: 2016-05-21T00:25:53Z
       
  • Sinomenine attenuates renal fibrosis through Nrf2-mediated inhibition of
           oxidative stress and TGFβ signaling
    • Abstract: Publication date: Available online 17 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Tian Qin, Shasha Yin, Jun Yang, Qin Zhang, Yangyang Liu, Fengjie Huang, Wangsen Cao
      Renal fibrosis is the common feature of chronic kidney disease and mainly mediated by TGFβ-associated pro-fibrogenic signaling, which causes excessive extracellular matrix accumulation and successive loss of kidney functions. Sinomenine (SIN), an alkaloid derived from medicinal herb extensively used in treatment of rheumatoid arthritis and various inflammatory disorders, displays renal protective properties in experimental animals; however its pharmacological potency against renal fibrosis is not explored. In this study we report that SIN possesses strong anti-renal fibrosis functions in kidney cell and in mouse fibrotic kidney. SIN beneficially modulated the pro-fibrogenic protein expression in TGFβ-treated kidney cells and attenuated the renal fibrotic pathogenesis incurred by unilateral ureteral obstruction (UUO), which correlated with its activation of Nrf2 signaling - the key defender against oxidative stress with anti-fibrotic potentials. Further investigation on its regulation of Nrf2 downstream events revealed that SIN significantly balanced oxidative stress via improving the expression and activity of anti-oxidant and detoxifying enzymes, and interrupted the pro-fibrogenic signaling of TGFβ/Smad and Wnt/β-catenin. Even more impressively SIN achieved its anti-fibrotic activities in an Nrf2-dependent manner, suggesting that SIN regulation of Nrf2-associated anti-fibrotic activities constitutes a critical component of SIN's renoprotective functions. Collectively our studies have demonstrated a novel anti-fibrotic property of SIN and its upstream events and provided a molecular basis for SIN's potential applications in treatment of renal fibrosis-associated kidney disorders.
      Graphical abstract image

      PubDate: 2016-05-21T00:25:53Z
       
  • Development of HSPA1A promoter-driven luciferase reporter gene assays in
           human cells for assessing the oxidative damage induced by silver
           nanoparticles
    • Abstract: Publication date: Available online 17 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lili Xin, Jianshu Wang, Leshuai W. Zhang, Bizhong Che, Guangzhu Dong, Guoqiang Fan, Kaiming Cheng
      The exponential increase in the total number of engineered nanoparticles in consumer products requires novel tools for rapid and cost-effective toxicology screening. In order to assess the oxidative damage induced by nanoparticles, toxicity test systems based on a human HSPA1A promoter-driven luciferase reporter in HepG2, LO2, A549, and HBE cells were established. After treated with heat shock and a group of silver nanoparticles (AgNPs) with different primary particle sizes, the cell viability, oxidative damage, and luciferase activity were determined. The time-dependent Ag+ ions release from AgNPs in cell medium was also evaluated. Our results showed that heat shock produced a strong time-dependent induction of relative luciferase activity in the four luciferase reporter cells. Surprisingly, at 4h of recovery, the relative luciferase activity was >98× the control level in HepG2-luciferase cells. Exposure to different sizes of AgNPs resulted in activation of the HSPA1A promoter in a dose-dependent manner, even at low cytotoxic or non-cytotoxic doses. The smaller (5nm) AgNPs were more potent in luciferase induction than the larger (50 and 75nm) AgNPs. These results were generally in accordance with the oxidative damage indicated by malondialdehyde concentration, reactive oxygen species induction and glutathione depletion, and Ag+ ions release in cell medium. Compared with the other three luciferase reporter cells, the luciferase signal in HepG2-luciferase cells is obviously more sensitive and stable. We conclude that the luciferase reporter cells, especially the HepG2-luciferase cells, could provide a valuable tool for rapid screening of the oxidative damage induced by AgNPs.


      PubDate: 2016-05-21T00:25:53Z
       
  • Modulation of expression and activity of intestinal multidrug
           resistance-associated protein 2 by xenobiotics
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303
      Author(s): Guillermo Nicolás Tocchetti, Juan Pablo Rigalli, Maite Rocío Arana, Silvina Stella Maris Villanueva, Aldo Domingo Mottino
      The multidrug resistance-associated protein 2 (MRP2/ABCC2) is a transporter that belongs to the ATP-binding cassette (ABC) superfamily. In the intestine, it is localized to the apical membrane of the enterocyte and plays a key role in limiting the absorption of xenobiotics incorporated orally. MRP2 may also play a role in systemic clearance of xenobiotics available from the serosal side of the intestine. MRP2 transports a wide range of substrates, mainly organic anions conjugated with glucuronic acid, glutathione and sulfate and its expression can be modulated by xenobiotics at transcriptional- and post-transcriptional levels. Transcriptional regulation is usually mediated by a group of nuclear receptors. The pregnane X receptor (PXR) is a major member of this group. Relevant drugs described to up-regulate intestinal MRP2 via PXR are rifampicin, spironolactone and carbamazepine, among others. The constitutive androstane receptor (CAR, NR1I3) was also reported to modulate MRP2 expression, phenobarbital being a typical activator. Dietary compounds, including micronutrients and other natural products, are also capable of regulating intestinal MRP2 expression transcriptionally. We have given them particular attention since the composition of the food ingested daily is not necessarily supervised and may result in interactions with therapeutic drugs. Post-transcriptional regulation of MRP2 activity by xenobiotics, e.g. as a consequence of inhibitory actions, is also described in this review. Unfortunately, only few studies report on drug-drug or nutrient-drug interactions as a consequence of modulation of intestinal MRP2 activity by xenobiotics. Future clinical studies are expected to identify additional interactions resulting in changes in efficacy or safety of therapeutic drugs.
      Graphical abstract image

      PubDate: 2016-05-21T00:25:53Z
       
  • Curcumin rescues high fat diet-induced obesity and insulin sensitivity in
           mice through regulating SREBP pathway
    • Abstract: Publication date: Available online 18 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lili Ding, Jinmei Li, Baoliang Song, Xu Xiao, Binfeng Zhang, Meng Qi, Wendong Huang, Li Yang, Zhengtao Wang
      Obesity and its major co-morbidity, type 2 diabetes, have reached an alarming epidemic prevalence without an effective treatment available. It has been demonstrated that inhibition of SREBP pathway may be a useful strategy to treat obesity with type 2 diabetes. Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. In current study, we identified a small molecule, curcumin, inhibited the SREBP expression in vitro. The inhibition of SREBP by curcumin decreased the biosynthesis of cholesterol and fatty acid. In vivo, curcumin ameliorated HFD-induced body weight gain and fat accumulation in liver or adipose tissues, and improved serum lipid levels and insulin sensitivity in HFD-induced obese mice. Consistently, curcumin regulates SREBPs target genes and metabolism associated genes in liver or adipose tissues, which may directly contribute to the lower lipid level and improvement of insulin resistance. Take together, curcumin, a major active component of Curcuma longa could be a potential leading compound for development of drugs for the prevention of obesity and insulin resistance.


      PubDate: 2016-05-21T00:25:53Z
       
  • The effects of MEK1/2 inhibition on cigarette smoke exposure-induced ET
           receptor upregulation in rat cerebral arteries
    • Abstract: Publication date: Available online 19 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lei Cao, Na-Na Ping, Yong-Xiao Cao, Wei Li, Yan Cai, Karin Warfvinge, Lars Edvinsson
      Cigarette smoking, a major stroke risk factor, upregulates endothelin receptors in cerebral arteries. The present study examined the effects of MEK1/2 pathway inhibition on cigarette smoke exposure-induced ET receptor upregulation. Rats were exposed to the secondhand smoke (SHS) for 8weeks followed by intraperitoneal injection of MEK1/2 inhibitor, U0126 for another 4weeks. The urine cotinine levels were assessed with high-performance liquid chromatography. Contractile responses of isolated cerebral arteries were recorded by a sensitive wire myograph. The mRNA and. Protein expression levels of receptor and MEK/ERK1/2 pathway molecules were examined by real-time PCR and Western blotting, respectively. Cerebral artery receptor localization was determined with immunohistochemistry. The results showed the urine cotinine levels from SHS exposure group were significantly higher than those from the fresh group. In addition, the MEK1/2 inhibitor, U0126 significantly reduced SHS exposure-increased ETA receptor mRNA and protein levels as well as contractile responses mediated by ETA receptors. The immunoreactivity of increased ETA receptor expression was primarily cytoplasmic in smooth muscle cells. In contrast, ETB receptor was noted in endothelial cells. However, the SHS-induced decrease in endothelium-dependent relaxation was unchanged after treatment. Furthermore, SHS increased the phosphorylation of MEK1/2 and ERK1/2 protein in cerebral arteries. By using U0126 could inhibit the phosphorylated ERK1/2 protein but not MEK1/2. Taken together, our data show that treatment with MEK1/2 pathway inhibitor offsets SHS exposure-induced ETA receptor upregulation in rat cerebral arteries.


      PubDate: 2016-05-21T00:25:53Z
       
  • Mustard vesicants alter expression of the endocannabinoid system in mouse
           skin
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303
      Author(s): Irene M. Wohlman, Gabriella M. Composto, Diane E. Heck, Ned D. Heindel, C. Jeffrey Lacey, Christophe D. Guillon, Robert P. Casillas, Claire R. Croutch, Donald R. Gerecke, Debra L. Laskin, Laurie B. Joseph, Jeffrey D. Laskin
      Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants.
      Graphical abstract image

      PubDate: 2016-05-21T00:25:53Z
       
  • Editorial Board
    • Abstract: Publication date: 1 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 302




      PubDate: 2016-05-16T00:12:21Z
       
  • Obaculactone protects against bleomycin-induced pulmonary fibrosis in mice
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303
      Author(s): Xingqi Wang, Zijun Ouyang, Qian You, Shuai He, Qianqian Meng, Chunhui Hu, Xudong Wu, Yan Shen, Yang Sun, Xuefeng Wu, Qiang Xu
      Idiopathic pulmonary fibrosis is a progressive, degenerative and almost irreversible disease. There is hardly an effective cure for lung damage due to pulmonary fibrosis. The purpose of this study was to evaluate the role of obaculactone in an already-assessed model of idiopathic pulmonary fibrosis induced by bleomycin administration. Mice were subjected to intratracheal instillation of bleomycin, and obaculactone was given orally after bleomycin instillation daily for 23days. Treatment with obaculactone ameliorated body weight loss, lung histopathology abnormalities and pulmonary collagen deposition, with a decrease of the inflammatory cell number and the cytokine level in bronchoalveolar lavage fluid. Moreover, obaculactone inhibited the expression of icam1, vcam1, inos and cox2, and attenuated oxidative stress in bleomycin-treated lungs. Importantly, the production of collagen I and α-SMA in lung tissues as well as the levels of TGF-β1, ALK5, p-Smad2 and p-Smad3 in lung homogenates was also reduced after obaculactone treatment. Finally, the TGF-β1-induced epithelial-mesenchymal transition via Smad-dependent and Smad-independent pathways was reversed by obaculactone. Collectively, these data suggest that obaculactone may be a promising drug candidate for the treatment of idiopathic pulmonary fibrosis.


      PubDate: 2016-05-16T00:12:21Z
       
  • Bronchopulmonary C-fibers' IL1RI contributes to the prolonged apneic
           response to intra-atrial injection of capsaicin by prenatal nicotinic
           exposure in rat pups
    • Abstract: Publication date: Available online 12 May 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lei Zhao, Jianguo Zhuang, Fadi Xu
      Prenatal nicotinic exposure (PNE) as a SIDS model reportedly sensitizes bronchopulmonary C-fibers (PCFs), contributing to the prolonged PCF-mediated apnea in rat pups, but the relevant mechanisms are not fully understood. Pulmonary IL-1β upregulated by cigarette smoke is known to stimulate or sensitize PCFs acting via IL-1 type I receptor (IL1RI) and inhibit inspiration frequency. Because of its upregulation observed in SIDS victims, we hypothesized that PNE increased pulmonary IL-1β release and IL1RI expression in pulmonary C-neurons via action on α7 nicotinic acetylcholine receptors (α7nAChR) to induce the prolonged PCF-mediated apnea. IL-1β in BALF and IL1RI in the nodose/jugular (N/J) ganglion and vagal pulmonary C-neurons retrogradely-traced were compared between Ctrl (saline) and PNE pups and among the vehicle-treated Ctrl and PNE and methyllycaconitine (a selective α7nAChR antagonist)-treated PNE pups. The effect of IL-1RI blockade (IL-1Ra) on the PCF-mediated apnea was also compared between Ctrl and PNE pups. PNE significantly elevated IL-1β in BALF and upregulated IL1RI gene and protein expression in N/J ganglia and gene in vagal pulmonary C-neurons. All of these responses were eliminated by pretreatment with blockade of α7nAChR. In addition, the prolonged PCF-mediated apnea in PNE pups was significantly shortened by right atrial bolus injection of IL-1Ra. We conclude that PNE enhances pulmonary IL-1β release and PCF IL1RI expression acting via α7nAChR in contributing to sensitization of PCFs and prolongation of the PCF-mediated apneic response.


      PubDate: 2016-05-16T00:12:21Z
       
  • ABC transporters affect the elimination and toxicity of CdTe quantum dots
           in liver and kidney cells
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303
      Author(s): Mingli Chen, Huancai Yin, Pengli Bai, Peng Miao, Xudong Deng, Yingxue Xu, Jun Hu, Jian Yin
      This paper aimed to investigate the role of adenosine triphosphate-binding cassette (ABC) transporters on the efflux and the toxicity of nanoparticles in liver and kidney cells. In this study, we synthesized CdTe quantum dots (QDs) that were monodispersed and emitted green fluorescence (maximum peak at 530nm). Such QDs tended to accumulate in human hepatocellular carcinoma cells (HepG2), human kidney cells 2 (HK-2), and Madin-Darby canine kidney (MDCK) cells, and cause significant toxicity in all the three cell lines. Using specific inhibitors and inducers of P-glycoprotein (Pgp) and multidrug resistance associated proteins (Mrps), the cellular accumulation and subsequent toxicity of QDs in HepG2 and HK-2 cells were significantly affected, while only slight changes appeared in MDCK cells, corresponding well with the functional expressions of ABC transporters in cells. Moreover, treatment of QDs caused concentration- and time- dependent induction of ABC transporters in HepG2 and HK-2 cells, but such phenomenon was barely found in MDCK cells. Furthermore, the effects of CdTe QDs on ABC transporters were found to be greater than those of CdCl2 at equivalent concentrations of cadmium, indicating that the effects of QDs should be a combination of free Cd2+ and specific properties of QDs. Overall, these results indicated a strong dependence between the functional expressions of ABC transporters and the efflux of QDs, which could be an important reason for the modulation of QDs toxicity by ABC transporters.


      PubDate: 2016-05-10T20:19:43Z
       
  • Evaluation of novel biomarkers of nephrotoxicity in Cynomolgus monkeys
           treated with gentamicin
    • Abstract: Publication date: 15 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 303
      Author(s): Jean-Charles Gautier, Xiaobing Zhou, Yi Yang, Thierry Gury, Zhe Qu, Xavier Palazzi, Jean-François Léonard, Mohamed Slaoui, Yaligara Veeranagouda, Isabelle Guizon, Eric Boitier, Aziz Filali-Ansary, Bart H.J. van den Berg, Oliver Poetz, Thomas Joos, Tianyi Zhang, Jufeng Wang, Philippe Detilleux, Bo Li
      Most studies to evaluate kidney safety biomarkers have been performed in rats. This study was conducted in Cynomolgus monkeys in order to evaluate the potential usefulness of novel biomarkers of nephrotoxicity in this species. Groups of 3 males were given daily intramuscular injections of gentamicin, a nephrotoxic agent known to produce lesions in proximal tubules, at dose-levels of 10, 25, or 50mg/kg/day for 10days. Blood and 16-h urine samples were collected on Days −7, −3, 2, 4, 7, and at the end of the dosing period. Several novel kidney safety biomarkers were evaluated, with single- and multiplex immunoassays and in immunoprecipitation-LC/MS assays, in parallel to histopathology and conventional clinical pathology parameters. Treatment with gentamicin induced a dose-dependent increase in kidney tubular cell degeneration/necrosis, ranging from minimal to mild severity at 10mg/kg/day, moderate at 25mg/kg/day, and to severe at 50mg/kg/day. The results showed that the novel urinary biomarkers, microalbumin, α1-microglobulin, clusterin, and osteopontin, together with the more traditional clinical pathology parameters, urinary total protein and N-acetyl-β-D-glucosaminidase (NAG), were more sensitive than blood urea nitrogen (BUN) and serum creatinine (sCr) to detect kidney injury in the monkeys given 10mg/kg/day gentamicin for 10days, a dose leading to an exposure which is slightly higher than the desired therapeutic exposure in clinics. Therefore, these urinary biomarkers represent non-invasive biomarkers of proximal tubule injury in Cynomolgus monkeys which may be potentially useful in humans.


      PubDate: 2016-05-06T22:03:23Z
       
  • Specific histone modification responds to arsenic-induced oxidative stress
    • Abstract: Publication date: 1 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 302
      Author(s): Lu Ma, Jun Li, Zhengbao Zhan, Liping Chen, Daochuan Li, Qing Bai, Chen Gao, Jie Li, Xiaowen Zeng, Zhini He, Shan Wang, Yongmei Xiao, Wen Chen, Aihua Zhang
      To explore whether specific histone modifications are associated with arsenic-induced oxidative damage, we recruited 138 arsenic-exposed and arsenicosis subjects from Jiaole Village, Xinren County of Guizhou province, China where the residents were exposed to arsenic from indoor coal burning. 77 villagers from Shang Batian Village that were not exposed to high arsenic coal served as the control group. The concentrations of urine and hair arsenic in the arsenic-exposure group were 2.4-fold and 2.1-fold (all P <0.001) higher, respectively, than those of the control group. Global histone modifications in human peripheral lymphocytes (PBLCs) were examined by ELISA. The results showed that altered global levels of H3K18ac, H3K9me2, and H3K36me3 correlated with both urinary and hair-arsenic levels of the subjects. Notably, H3K36me3 and H3K18ac modifications were associated with urinary 8-OHdG (H3K36me3: β=0.16; P =0.042, H3K18ac: β=−0.24; P =0.001). We also found that the modifications of H3K18ac and H3K36me3 were enriched in the promoters of oxidative stress response (OSR) genes in human embryonic kidney (HEK) cells and HaCaT cells, providing evidence that H3K18ac and H3K36me3 modifications mediate transcriptional regulation of OSR genes in response to NaAsO2 treatment. Particularly, we found that reduced H3K18ac modification correlated with suppressed expression of OSR genes in HEK cells with long term arsenic treatment and in PBLCs of all the subjects. Taken together, we reveal a critical role for specific histone modification in response to arsenic-induced oxidative damage.


      PubDate: 2016-05-02T21:50:30Z
       
  • A semisynthetic diterpenoid lactone inhibits NF-κB signalling to
           ameliorate inflammation and airway hyperresponsiveness in a mouse asthma
           model
    • Abstract: Publication date: 1 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 302
      Author(s): J.C.-W. Lim, F.-Y. Goh, S.-R. Sagineedu, A.C.-H. Yong, S.M. Sidik, N.H. Lajis, W.S.F. Wong, J. Stanslas
      Andrographolide (AGP) and 14-deoxy-11,12-didehydroandrographolide (DDAG), two main diterpenoid constituents of Andrographis paniculata were previously shown to ameliorate asthmatic symptoms in a mouse model. However, due to inadequacies of both compounds in terms of drug-likeness, DDAG analogues were semisynthesised for assessment of their anti-asthma activity. A selected analogue, 3,19-diacetyl-14-deoxy-11,12-didehydroandrographolide (SRS27), was tested for inhibitory activity of NF-κB activation in TNF-α-induced A549 cells and was subsequently evaluated in a mouse model of ovalbumin (OVA)-induced asthma. Female BALB/c mice, 6–8weeks old were sensitized on days 0 and 14, and challenged on days 22, 23 and 24 with OVA. Compound or vehicle (3% dimethyl sulfoxide) was administered intraperitoneally 1h before and 11h after each OVA aerosol challenge. On day 25, pulmonary eosinophilia, airway hyperresponsiveness, mucus hypersecretion, inflammatory cytokines such as IL-4, -5 and -13 in BAL fluid, gene expression of inflammatory mediators such as 5-LOX, E-selectin, VCAM-1, CCL5, TNF-α, AMCase, Ym2, YKL-40, Muc5ac, CCL2 and iNOS in animal lung tissues, and serum IgE were determined. SRS27 at 30μM was found to suppress NF-κB nuclear translocation in A549 cells. In the ovalbumin-induced mouse asthma model, SRS27 at 3mg/kg displayed a substantial decrease in pulmonary eosinophilia, BAL fluid inflammatory cytokines level, serum IgE production, mucus hypersecretion and gene expression of inflammatory mediators in lung tissues. SRS27 is the first known DDAG analogue effective in ameliorating inflammation and airway hyperresponsiveness in the ovalbumin-induced mouse asthma model.
      Graphical abstract image

      PubDate: 2016-04-27T21:29:31Z
       
  • An extensive cocktail approach for rapid risk assessment of in vitro
           CYP450 direct reversible inhibition by xenobiotic exposure
    • Abstract: Publication date: Available online 20 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Dany Spaggiari, Youssef Daali, Serge Rudaz
      Acute exposure to environmental factors strongly affects the metabolic activity of P450. As a consequence, the risk of interaction could be increased, modifying the clinical outcomes of a medication. Because toxic agents cannot be administered to humans for ethical reasons, in vitro approaches are therefore essential to evaluate their impact on P450 activities. In this work, an extensive cocktail mixture was developed and validated for in vitro P450 inhibition studies using human liver microsomes (HLM). The cocktail comprised eleven P450-specific probe substrates to simultaneously assess the activities of the following isoforms: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2 and subfamily 3A. The high selectivity and sensitivity of the developed UHPLC-MS/MS method were critical for the success of this methodology, whose main advantages are: (i) the use of eleven probe substrates with minimized interactions, (ii) a low HLM concentration, (iii) fast incubation (5min) and (iv) the use of metabolic ratios as microsomal P450 activities markers. This cocktail approach was successfully validated by comparing the obtained IC50 values for model inhibitors with those generated with the conventional single probe methods. Accordingly, reliable inhibition values could be generated 10-fold faster using a 10-fold smaller amount of HLM compared to individual assays. This approach was applied to assess the P450 inhibition potential of widespread insecticides, namely, chlorpyrifos, fenitrothion, methylparathion and profenofos. In all cases, P450 2B6 was the most affected with IC50 values in the nanomolar range. For the first time, mixtures of these four insecticides incubated at low concentrations showed a cumulative inhibitory in vitro effect on P450 2B6.
      Graphical abstract image

      PubDate: 2016-04-23T21:01:14Z
       
  • Mitochondrial nucleoid clusters protect newly synthesized mtDNA during
           Doxorubicin- and Ethidium Bromide-induced mitochondrial stress
    • Abstract: Publication date: Available online 19 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lukáš Alán, Tomáš Špaček, David Pajuelo Reguera, Martin Jabůrek, Petr Ježek
      Mitochondrial DNA (mtDNA) is compacted in ribonucleoprotein complexes called nucleoids, which can divide or move within the mitochondrial network. Mitochondrial nucleoids are able to aggregate into clusters upon reaction with intercalators such as the mtDNA depletion agent Ethidium Bromide (EB) or anticancer drug Doxorobicin (DXR). However, the exact mechanism of nucleoid clusters formation remains unknown. Resolving these processes may help to elucidate the mechanisms of DXR-induced cardiotoxicity. Therefore, we addressed the role of two key nucleoid proteins; mitochondrial transcription factor A (TFAM) and mitochondrial single-stranded binding protein (mtSSB); in the formation of mitochondrial nucleoid clusters during the action of intercalators. We found that both intercalators cause numerous aberrations due to perturbing their native status. By blocking mtDNA replication, both agents also prevented mtDNA association with TFAM, consequently causing nucleoid aggregation into large nucleoid clusters enriched with TFAM, co-existing with the normal nucleoid population. In the later stages of intercalation (>48h), TFAM levels were reduced to 25%. In contrast, mtSSB was released from mtDNA and freely distributed within the mitochondrial network. Nucleoid clusters mostly contained nucleoids with newly replicated mtDNA, however the nucleoid population which was not in replication mode remained outside the clusters. Moreover, the nucleoid clusters were enriched with p53, an anti-oncogenic gatekeeper. We suggest that mitochondrial nucleoid clustering is a mechanism for protecting nucleoids with newly replicated DNA against intercalators mediating genotoxic stress. These results provide new insight into the common mitochondrial response to mtDNA stress and can be implied also on DXR-induced mitochondrial cytotoxicity.


      PubDate: 2016-04-19T20:48:53Z
       
  • Assessment of mitochondrial dysfunction-related, drug-induced
           hepatotoxicity in primary rat hepatocytes
    • Abstract: Publication date: Available online 16 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Cong Liu, Shuichi Sekine, Kousei Ito
      Evidence that mitochondrial dysfunction plays a central role in drug-induced liver injury is rapidly accumulating. In contrast to physiological conditions, in which almost all adenosine triphosphate (ATP) in hepatocytes is generated in mitochondria via aerobic respiration, the high glucose content and limited oxygen supply of conventional culture systems force primary hepatocytes to generate most ATP via cytosolic glycolysis. Thus, such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, and are not suitable to identify drugs with mitochondrial liabilities. In this study, primary rat hepatocytes were cultured in galactose-based medium, instead of the conventional glucose-based medium, and in hyperoxia to improve the reliance of energy generation on aerobic respiration. Activation of mitochondria was verified by diminished cellular lactate release and increased oxygen consumption. These conditions improved sensitivity to the mitochondrial complex I inhibitor rotenone. Since oxidative stress is also a general cause of mitochondrial impairment, cells were exposed to test compounds in the presence of transferrin to increase the generation of reactive oxygen species via increased uptake of iron. Finally, 14 compounds with reported mitochondrial liabilities were tested to validate this new drug-induced mitochondrial toxicity assay. Overall, the culture of primary rat hepatocytes in galactose, hyperoxia and transferrin is a useful model for the identification of mitochondrial dysfunction-related drug-induced hepatotoxicity.


      PubDate: 2016-04-19T20:48:53Z
       
  • Advantageous use of HepaRG cells for the screening and mechanistic study
           of drug-induced steatosis
    • Abstract: Publication date: Available online 16 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Laia Tolosa, M. José Gómez-Lechón, Nuria Jiménez, David Hervás, Ramiro Jover, M. Teresa Donato
      Only a few in vitro assays have been proposed to evaluate the steatotic potential of new drugs. The present study examines the utility of HepaRG cells as a cell-based assay system for screening drug-induced liver steatosis. A high-content screening assay was run to evaluate multiple toxicity-related cell parameters in HepaRG cells exposed to 28 compounds, including drugs reported to cause steatosis through different mechanisms and non-steatotic compounds. Lipid content was the most sensitive parameter for all the steatotic drugs, whereas no effects on lipid levels were produced by non-steatotic compounds. Apart from fat accumulation, increased ROS production and altered mitochondrial membrane potential were also found in the cells exposed to steatotic drugs, which indicates that all these cellular events contributed to drug-induced hepatotoxicity. These findings are of clinical relevance as most effects were observed at drug concentrations under 100-fold of the therapeutic peak plasmatic concentration. HepaRG cells showed increased lipid overaccumulation vs. HepG2 cells, which suggests greater sensitivity to drug-induced steatosis. An altered expression profile of transcription factors and the genes that code key proteins in lipid metabolism was also found in the cells exposed to drugs capable of inducing liver steatosis. Our results generally indicate the value of HepaRG cells for assessing the risk of liver damage associated with steatogenic compounds and for investigating the molecular mechanisms involved in drug-induced steatosis.
      Graphical abstract image

      PubDate: 2016-04-19T20:48:53Z
       
 
 
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