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news.gifArticles - - Toxicological Sciences

Toxicological Sciences Current Issue



(25/09/2017 @ 00:00)
(25/09/2017 @ 00:00)
Atrazine and Breast Cancer: A Framework Assessment of the Toxicological and Epidemiological Evidence  Voir?

In “Atrazine and Breast Cancer: A Framework Assessment of the Toxicological and Epidemiological Evidence” by James W. Simpkins, James A. Swenberg, Noel Weiss, David Brusick, J. Charles Eldridge, James T. Stevens, Robert J. Handa, Russell C. Hovey, Tony M. Plant, Timothy P. Pastoor, and Charles B. Breckenridge (Toxicological Sciences, 123, 441-459), the legends for Fig. 3 were incorrect, as this revised figure illustrates. The revised figure corrects the legend at the bottom of the figure, which does not correctly differentiate between persistent estrus and persistent diestrus, and this amendment provides additional clarification regarding the length of estrous cycles, as mapped within the figure.

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(22/08/2017 @ 00:00)
Chronic Low-Dose Cadmium Exposure Impairs Cutaneous Wound Healing With Defective Early Inflammatory Responses After Skin Injury  Voir?

Abstract
Impairment of the immune system is a developing concern in evaluating the toxicity of cadmium (Cd). In the present study, we investigated if Cd could impair cutaneous wound healing through interfering with inflammation after injury. We found that exposure of mice to CdCl2 through drinking water at doses of 10, 30, and 50 mg/l for 8 weeks significantly impaired cutaneous wound healing. Chronic 30 mg/l CdCl2 treatment elevated murine blood Cd level comparable to that of low dose Cd-exposed humans, had no effect on blood total and differential leukocyte counts, but reduced neutrophil infiltration, chemokines (CXCL1 and CXCL2), and proinflammatory cytokines (TNFα, IL-1β, and IL-6) expression in wounded tissue at early stage after injury. Wounded tissue homogenates from CdCl2-treated mice had lower chemotactic activity for neutrophils than those from untreated mice. Mechanistic studies showed that chronic Cd treatment suppressed ERK1/2 and NF-κB p65 phosphorylation in wounded tissue at early stage after injury. Compared with neutrophils isolated from untreated mice, neutrophils from CdCl2 treated mice and normal neutrophils treated with CdCl2 invitro both had lower chemotactic response, calcium mobilization and ERK1/2 phosphorylation upon chemoattractant stimulation. Collectively, our study indicate that chronic low-dose Cd exposure impaired cutaneous wound healing by reducing neutrophil infiltration through inhibiting chemokine expression and neutrophil chemotactic response, and suppressing proinflammatory cytokine expression. Cd may suppress chemokine and proinflammatory expression through inactivating ERK1/2 and NF-κB, and inhibit neutrophil chemotaxis by attenuating calcium mobilization and ERK1/2 phosphorylation in response to chemoattractants.

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(29/07/2017 @ 00:00)
Editor's Highlight: Pulmonary Vascular Thrombosis in Rats Exposed to Inhaled Sulfur Mustard  Voir?

Abstract
Sulfur mustard (SM) is a chemical warfare agent. When inhaled, SM causes significant injury to the respiratory tract. Although the mechanism involved in acute airway injury after SM inhalation has been well described previously, the mechanism of SM's contribution to distal lung vascular injury is not well understood. We hypothesized that acute inhalation of vaporized SM causes activated systemic coagulation with subsequent pulmonary vascular thrombi formation after SM inhalation exposure. Sprague Dawley rats inhaled SM ethanolic vapor (3.8 mg/kg). Barium/gelatin CT pulmonary angiograms were performed to assess for pulmonary vascular thrombi burden. Lung immunohistochemistry was performed for common procoagulant markers including fibrin(ogen), von Willebrand factor, and CD42d in control and SM-exposed lungs. Additionally, systemic levels of d-dimer and platelet aggregometry after adenosine diphosphate- and thrombin-stimulation were measured in plasma after SM exposure. In SM-exposed lungs, chest CT angiography demonstrated a significant decrease in the distal pulmonary vessel density assessed at 6 h postexposure. Immunohistochemistry also demonstrated increased intravascular fibrin(ogen), vascular von Willebrand factor, and platelet CD42d in the distal pulmonary vessels (<200 µm diameter). Circulating d-dimer levels were significantly increased (p < .001) at 6, 9, and 12 h after SM inhalation versus controls. Platelet aggregation was also increased in both adenosine diphosphate - (p < .01) and thrombin- (p < .001) stimulated platelet-rich plasma after SM inhalation. Significant pulmonary vascular thrombi formation was evident in distal pulmonary arterioles following SM inhalation in rats assessed by CT angiography and immunohistochemistry. Enhanced systemic platelet aggregation and activated systemic coagulation with subsequent thrombi formation likely contributed to pulmonary vessel occlusion.

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(29/07/2017 @ 00:00)
Editor's Highlight: The Altered DNA Methylome of Chronic Doxorubicin Exposure in Sprague Dawley Rats  Voir?

Abstract
Doxorubicin (DOX) is a widely used treatment for human cancers, but increases the risk of life-threatening congestive heart failure (CHF). DOX-induced mitochondrial damage is cumulative and persistent, similar to that observed clinically for risk of CHF. Recent evidence suggests the persistent nature of this injury is caused by altered regulation of genes important to normal cardiac functioning. We hypothesize that chronic DOX therapy is associated with epigenetic modifications of DNA methylation status, particularly in critical regulators of mitochondrial function and capacity. Cardiac tissue from Sprague Dawley rats receiving injections of DOX (2 mg/kg, s.c.) or saline once a week for 6 weeks, followed by 5 weeks of drug-free holiday was used for Reduced Representation Bisulfite Sequencing to map specific sites of DNA methylation. Comparison of these methylomes indicated DOX exposure alters DNA methylation landscapes, and identified 14 genes with highly altered methylation status. Preliminary functional effects of DNA methylation changes were characterized by quantifying mRNA expression of selected targets (Rbm20, Nmnat2, Klhl29, Cacna1c, Scn5a.) Gene expression of Rbm20, Klhl29, and Nmnat2 were significantly altered in DOX treated animals; Klhl29 and Nmnat2 demonstrated significant decreases in protein expression corresponding to gene expression. Through an epigenotype-to-phenotype approach, this study identifies potential markers and molecular regulators of irreversible DOX-induced cardiovascular toxicity associated with clinically limiting CHF. However, none of the most prevalent genes identified directly relate to mitochondrial structure or function. Thus, the investigation fails to demonstrate a direct association between this altered methylome and persistent mitochondrionopathy associated with chronic doxorubicin cardiac toxicity.

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(28/07/2017 @ 00:00)
Hepatic Amiodarone Lipotoxicity Is Ameliorated by Genetic and Pharmacological Inhibition of Endoplasmatic Reticulum Stress  Voir?

Abstract
Amiodarone is a commonly used antiarrhythmic drug and can cause liver steatosis. We investigated the role of endoplasmic reticulum (ER) stress/unfolded protein response in the pathogenesis of amiodarone-induced steatosis. Amiodarone-induced liver injury was obtained by 1 intraperitoneal injection to wild-type (WT) or C/EBP homologous protein knock-out mice (Ddit3−/−). Amiodarone directly reduced intracellular ATP and Ca2+ in hepatocytes invitro, inducing ER stress and lipid accumulation. In vivo, amiodarone-driven liver damage and lipid accumulation was accompanied by activation of ER stress/unfolded protein response, as demonstrated by up-regulation of genes encoding key ER stress mediators and by phosphorylation of eIF2α. In contrast to WT mice, Ddit3−/− mice were protected from amiodarone-induced ER stress and lipid accumulation. Importantly, amiodarone-induced lipid accumulation was not mediated by de novo hepatic lipogenesis, increased adipose tissue lipolysis or increased hepatic uptake of triglycerides or free fatty acids. Rather, amiodarone strongly increased hepatic mRNA expression of lipid droplet proteins, particularly Cidea and Cidec, in WT, but less so in Ddit3−/− mice, suggesting a link between ER stress and increased triglyceride storage. Moreover, while insulin attenuated amiodarone-induced phosphorylation of hormone sensitive lipase (HSL) in WT, it did not affect pHSL in Ddit3−/−, indicating increased lipolysis and therefore reduced lipid accumulation in these mice. Finally, ER stress attenuation using 2 different pharmacological chaperones reduced lipid accumulation, accompanied by reduced mRNA expression of Cidec. In conclusion, amiodarone-induced ER stress drives liver steatosis and may be considered for therapeutic targeting.

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(25/07/2017 @ 00:00)
From the Cover: Manganese and Rotenone-Induced Oxidative Stress Signatures Differ in iPSC-Derived Human Dopamine Neurons  Voir?

Abstract
Parkinson's disease (PD) is the result of complex interactions between genetic and environmental factors. Two chemically distinct environmental stressors relevant to PD are the metal manganese and the pesticide rotenone. Both are thought to exert neurotoxicity at least in part via oxidative stress resulting from impaired mitochondrial activity. Identifying shared mechanism of action may reveal clues towards an understanding of the mechanisms underlying PD pathogenesis. Here we compare the effects of manganese and rotenone in human-induced pluripotent stem cells-derived postmitotic mesencephalic dopamine neurons by assessing several different oxidative stress endpoints. Manganese, but not rotenone caused a concentration and time-dependent increase in intracellular reactive oxygen/nitrogen species measured by quantifying the fluorescence of oxidized chloromethyl 2′,7′-dichlorodihydrofluorescein diacetate (DCF) assay. In contrast, rotenone but not manganese caused an increase in cellular isoprostane levels, an indicator of lipid peroxidation. Manganese and rotenone both caused an initial decrease in cellular reduced glutathione; however, glutathione levels remained low in neurons treated with rotenone for 24 h but recovered in manganese-exposed cells. Neurite length, a sensitive indicator of overall neuronal health was adversely affected by rotenone, but not manganese. Thus, our observations suggest that the cellular oxidative stress evoked by these 2 agents is distinct yielding unique oxidative stress signatures across outcome measures. The protective effect of rasagiline, a compound used in the clinic for PD, had negligible impact on any of oxidative stress outcome measures except a subtle significant decrease in manganese-dependent production of reactive oxygen/nitrogen species detected by the DCF assay.

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(24/07/2017 @ 00:00)
Cardiac and Metabolic Effects of Dietary Selenomethionine Exposure in Adult Zebrafish  Voir?

Abstract
Selenium (Se) is an essential micronutrient involved in important metabolic functions for all vertebrate species. As Se is reported to have a narrow margin between essentiality and toxicity, there is growing concern surrounding the adverse effects of elevated Se exposure caused by anthropogenic activities. Recent studies have reported that elevated dietary exposure of fish to selenomethionine (Se-Met) can alter aerobic metabolic capacity, energetics and swimming performance. This study aims to further investigate mechanisms of sublethal Se-Met toxicity, particularly potential underlying cardiovascular implications of chronic exposure to environmentally relevant concentrations of dietary Se-Met in adult zebrafish (Danio rerio). Adult zebrafish were fed either control food (1.1 μg Se/g dry mass [d.m.]) or Se-Met spiked food (10.3 or 28.8 μg Se/g d.m.) for 90 d at 5% body weight per day. Following exposure, ultrahigh resolution B-mode and Doppler ultrasound was used to characterize cardiac function. Chronic dietary exposure to elevated Se-Met significantly reduced ventricular contractile rate, stroke volume, and cardiac output. Exposure to Se-Met significantly decreased mRNA expression of methionine adenosyltransferase 1 alpha and glutathione-S-transferase pi class in liver, and a key cardiac remodelling enzyme, matrix metalloproteinase 2, in adult zebrafish heart. Se-Met significantly increased echodensity at the junction between atrium and ventricle, and these results combined with increased matrix metalloproteinase 2 expression are consistent with cardiac remodelling and fibrosis. The results of this study suggest that chronic exposure to dietary Se-Met can negatively impact cardiac function, and such physiological consequences could reduce the aerobic capacity and survivability of fish.

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(21/07/2017 @ 00:00)
Metabolic Disruption Early in Life is Associated With Latent Carcinogenic Activity of Dichloroacetic Acid in Mice  Voir?

Abstract
Early-life environmental factors can influence later-life susceptibility to cancer. Recent evidence suggests that metabolic pathways may mediate this type of latency effect. Previously, we reported that short-term exposure to dichloroacetic acid (DCA) increased liver cancer in mice 84 weeks after exposure was stopped. Here, we evaluated time course dynamics for key events related to this effect. This study followed a stop-exposure design in which 28-day-old male B6C3F1 mice were given the following treatments in drinking water for up to 93 weeks: deionized water (dH2O, control); 3.5 g/l DCA continuously; or 3.5 g/l DCA for 4–52 weeks followed by dH2O. Effects were evaluated at eight interim time points. A short-term biomarker study was used to evaluate DCA effects at 6, 15, and 30 days. Liver tumor incidence was higher in all DCA treatment groups, including carcinomas in 82% of mice previously treated with DCA for only 4 weeks. Direct effects of DCA in the short-term study included decreased liver cell proliferation and marked mRNA changes related to mitochondrial dysfunction and altered cell metabolism. However, all observed short-term effects of DCA were ultimately reversible, and prior DCA treatment did not affect liver cell proliferation, apoptosis, necrosis, or DNA sequence variants with age. Key intermediate events resulting from transient DCA exposure do not fit classical cytotoxic, mitogenic, or genotoxic modes of action for carcinogenesis, suggesting a distinct mechanism associated with early-life metabolic disruption.

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(20/07/2017 @ 00:00)
Characterization of Triptolide-Induced Hepatotoxicity by Imaging and Transcriptomics in a Novel Zebrafish Model  Voir?

Abstract
Triptolide is a vine extract used in traditional Chinese medicines and associated with hepatotoxicity. In vitro data suggest that inhibition of RNA synthesis may be the mechanism of toxicity. For studying drug-induced liver injury the zebrafish has experimental, practical and financial advantages compared with rodents. The aim of this study was to explore the mechanism of triptolide toxicity using zebrafish as the model system. The effect of triptolide exposure on zebrafish larvae was determined with regard to mortality, histology, expression of liver specific microRNA-122 and liver volume. Fluorescent microscopy was used to track toxicity in the Tg(-2.8lfabp:GFP)as3 zebrafish line. Informed by microscopy, RNA-sequencing was used to explore the mechanism of toxicity. Triptolide exposure resulted in dose-dependent mortality, a reduction in the number of copies of microRNA-122 per larva, hepatocyte vacuolation, disarray and oncotic necrosis, and a reduction in liver volume. These findings were consistent across replicate experiments. Time-lapse imaging indicated the onset of injury was 6 h after the start of exposure, at which point, RNA-sequencing revealed that 88% of genes were down-regulated. Immune response associated genes were up-regulated in the triptolide-treated larvae including nitric oxide synthase. Inhibition of nitric oxide synthase increased mortality. Triptolide induces hepatotoxicity in zebrafish larvae. This represents a new model of drug-induced liver injury that complements rodents. RNA sequencing, guided by time-lapse microscopy, revealed early down-regulation of genes consistent with previous invitro studies, and facilitated the discovery of mechanistic inflammatory pathways.

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(20/07/2017 @ 00:00)
From the Cover: Metabolism Modulation in Different Organs by Silver Nanoparticles: An NMR Metabolomics Study of a Mouse Model  Voir?

Abstract
Although silver nanoparticles (AgNPs) are widely disseminated and show great potential in the biomedical field, there is a recognized need to better understand their action at the metabolic and functional levels. In this work, we have used NMR metabolomics, together with conventional clinical chemistry and histological examination, to characterize multi-organ and systemic metabolic responses to AgNPs intravenously administered to mice at 8 mg/kg body weight (a dose not eliciting overt toxicity). The major target organs of AgNPs accumulation, liver and spleen, showed the greatest metabolic changes, in a clear 2-stage response. In particular, the liver of dosed mice was found to switch from glycogenolysis and lipid storage, at 6 h postinjection, to glycogenesis and lipolysis, at subsequent times up to 48 h. Moreover, metabolites related to antioxidative defense, immunoregulation and detoxification seemed to play a crucial role in avoiding major hepatic damage. The spleen showed several early changes, including depletion of several amino acids, possibly reflecting impairment of hemoglobin recycling, while only a few differences remained at 48 h postinjection. In the heart, the metabolic shift towards TCA cycle intensification and increased ATP production possibly reflected a beneficial adaptation to the presence of AgNPs. On the other hand, the TCA cycle appeared to be down regulated in the lungs of injected mice, which showed signs of inflammation. Thekidneys showed the mildest metabolic response to AgNPs. Overall, this study has shown that NMR metabolomics is a powerful tool to monitor invivo metabolic responses to nanoparticles, revealing unforeseen effects.

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(14/07/2017 @ 00:00)
Editor's Highlight: PPARβ/δ and PPARγ Inhibit Melanoma Tumorigenicity by Modulating Inflammation and Apoptosis  Voir?

Abstract
Skin tumorigenesis results from DNA damage, increased inflammation, and evasion of apoptosis. The peroxisome proliferator-activated receptors (PPARs) can modulate these mechanisms in non-melanoma skin cancer. However, limited data exists regarding the role of PPARs in melanoma. This study examined the effect of proliferator-activated receptor-β/δ (PPARβ/δ) and PPARγ on cell proliferation, anchorage-dependent clonogenicity, and ectopic xenografts in the UACC903 human melanoma cell line. Stable overexpression of either PPARβ/δ or PPARγ enhanced ligand-induced expression of a PPARβ/δ/PPARγ target gene in UACC903 cell lines as compared with controls. The induction of target gene expression by ligand activation of PPARγ was not altered by overexpression of PPARβ/δ, or vice versa. Stable overexpression of either PPARβ/δ or PPARγ reduced the percentage of cells in the G1 and S phase of the cell cycle, and increased the percentage of cells in the G2/M phase of the cell cycle in UACC903 cell lines as compared with controls. Ligand activation of PPARβ/δ did not further alter the distribution of cells within each phase of the cell cycle. By contrast, ligand activation of PPARγ enhanced these changes in stable UACC903 cells overexpressing PPARγ compared with controls. Stable overexpression of either PPARβ/δ or PPARγ and/or ligand activation of either PPARβ/δ or PPARγ inhibited cell proliferation, and anchorage-dependent clonogenicity of UACC903 cell lines as compared with controls. Further, overexpression of either PPARβ/δ or PPARγ and/or ligand activation of either PPARβ/δ or PPARγ inhibited ectopic xenograft tumorigenicity derived from UACC903 melanoma cells as compared with controls, and this was likely due in part to induction of apoptosis. Results from these studies demonstrate the antitumorigenic effects of both PPARβ/δ and PPARγ and suggest that targeting these receptors may be useful for primary or secondary melanoma chemoprevention.

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(14/07/2017 @ 00:00)
Editor's Highlight: Complete Attenuation of Mouse Lung Cell Proliferation and Tumorigenicity in CYP2F2 Knockout and CYP2F1 Humanized Mice Exposed to Inhaled Styrene for up to 2 Years Supports a Lack of Human Relevance  Voir?

Abstract
Styrene is a mouse-specific lung carcinogen, and short-term mode of action studies have demonstrated that cytotoxicity and/or cell proliferation, and genomic changes are dependent on CYP2F2 metabolism. The current study examined histopathology, cell proliferation, and genomic changes in CD-1, C57BL/6 (WT), CYP2F2(−/−) (KO), and CYP2F2(−/−) (CYP2F1, 2B6, 2A13-transgene) (TG; humanized) mice following exposure for up to 104 weeks to 0- or 120-ppm styrene vapor. Five mice per treatment group were sacrificed at 1, 26, 52, and 78 weeks. Additional 50 mice per treatment group were followed until death or 104 weeks of exposure. Cytotoxicity was present in the terminal bronchioles of some CD-1 and WT mice exposed to styrene, but not in KO or TG mice. Hyperplasia in the terminal bronchioles was present in CD-1 and WT mice exposed to styrene, but not in KO or TG mice. Increased cell proliferation, measured by KI-67 staining, occurred in CD-1 and WT mice exposed to styrene for 1 week, but not after 26, 52, or 78 weeks, nor in KO or TG mice. Styrene increased the incidence of bronchioloalveolar adenomas and carcinomas in CD-1 mice. No increase in lung tumors was found in WT despite clear evidence of lung toxicity, or, KO or TG mice. The absence of preneoplastic lesions and tumorigenicity in KO and TG mice indicates that mouse-specific CYP2F2 metabolism is responsible for both the short-term and chronic toxicity and tumorigenicity of styrene, and activation of styrene by CYP2F2 is a rodent MOA that is neither quantitatively or qualitatively relevant to humans.

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(13/07/2017 @ 00:00)
From the Cover: An Animal-Free In Vitro Three-Dimensional Testicular Cell Coculture Model for Evaluating Male Reproductive Toxicants  Voir?

Abstract
Primary testicular cell coculture model has been used to evaluate testicular abnormalities during development, and was able to identify the testicular toxicity of phthalates. However, the primary testicular cell coculture model has disadvantages in employing animals for the isolation of testicular cells, and the complicated isolation procedure leads to inconsistent results. We developed an invitro testicular coculture model from rodent testicular cell lines, including spermatogonial cells, Sertoli cells, and Leydig cells with specified cell density and extracellular matrix (ECM) composition. Using comparative high-content analysis of F-actin cytoskeletal structure between the coculture and single cell culture models, we demonstrated a 3D structure of the coculture, which created an invivo-like niche, and maintained and supported germ cells within a 3D environment. We validated this model by discriminating between reproductive toxicants and nontoxicants among 32 compounds in comparison to the single cell culture models. Furthermore, we conducted a comparison between the invitro (IC50) and invivo reproductive toxicity testing (lowest observed adverse effect level on reproductive system). We found the invitro coculture model could classify the tested compounds into 4 clusters, and identify the most toxic reproductive substances, with high concordance, sensitivity, and specificity of 84%, 86.21%, and 100%, respectively. We observed a strong correlation of IC50 between the invitro coculture model and the invivo testing results. Our results suggest that this novel invitro coculture model may be useful for screening testicular toxicants and prioritize chemicals for further assessment in the future.

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(11/07/2017 @ 00:00)
From the Cover: Alcohol Inhibition of the Enzymatic Activity of Glyceraldehyde 3-Phosphate Dehydrogenase Impairs Cardiac Glucose Utilization, Contributing to Alcoholic Cardiomyopathy  Voir?

Abstract
Heavy consumption of alcohol induces cardiomyopathy and is associated with metabolic changes in the heart. The role of altered metabolism in the development of alcoholic cardiomyopathy remains largely unknown but is examined in the present study. The effect of chronic alcohol consumption on cardiac damage was examined in mice fed an alcohol or isocaloric control diet for 2 months. Signaling pathways of alcohol-induced metabolic alteration and pathologic changes were examined in both animal hearts and H9c2 cell cultures. Compared with controls, the hearts from the alcohol-fed mice exhibited cardiac oxidative stress, cell death, a fibrotic response, hypertrophic remodeling, and the eventual development of cardiac dysfunction. All these detrimental effects could be ameliorated by superoxide dismutase mimic Mn (111) tetrakis 1-methyl 4-pyridylporphyrin pentachloride (MnTMPyP) therapy. A mechanistic study showed that chronic alcohol exposure enhanced the expression of proteins regulating fatty acid uptake but impaired the expression of proteins involved in mitochondrial fatty acid oxidation, which compensatively geared the heart to the suboptimal energy source, glucose. However, chronic alcohol exposure also impaired the glycolytic energy production step regulated by glyceraldehyde-3-phosphate dehydrogenase, which further feeds back to enhance glucose uptake signaling and the accumulation of glycolytic intermediate product fructose, resulting in aggravation of alcohol-induced cardiac oxidative stress, cell death, and remodeling. All these dysmetabolic alterations could be normalized by MnTMPyP treatment, along with significant improvement in cardiac cell death and remodeling. These results demonstrate that alcohol-induced oxidative stress and altered glucose metabolism are causal factors for the development of alcoholic cardiomyopathy.

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(11/07/2017 @ 00:00)
Permitted Daily Exposure of the Androgen Receptor Antagonist Flutamide  Voir?

Abstract
This report aims to determine the permitted daily exposure (PDE) of flutamide, an androgen receptor blocker, as directed by guideline EMA/CHMP/CVPM/SWP/169430/2012 that came into effect on June 2015. A literature review was conducted to identify toxicity studies of flutamide. Hazards and sensitive endpoints were determined. Based on the no adverse effect levels (NOAELs) and lowest observed adverse effect levels (LOAELs) reported from both reproductive, developmental, and 28-day toxicity studies the PDE was calculated. Most of the toxicity studies converge toward a NOAEL of 1 mg/kg/d that translates to a PDE of 0.1 mg/d. However, taking into consideration the worst case scenarios for additional safety a PDE of 0.025 mg/d (25 μg/d) was calculated based on a reported NOAEL of 0.25 mg/kg/d. A PDE of 0.05 mg/d (50 μg/d) was also calculated from reproductive/developmental toxicity studies, which is in close agreement with the PDE from the 28-day toxicity studies. Considering the lowest PDE of 0.025 mg/d, residual flutamide at this dose is unlikely to pose any risk to humans. Nonmonotonic dose response (NMDR) effects of flutamide were not supported by literature. Oral route of administration was considered.

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(28/06/2017 @ 00:00)
A Mechanistic Model for Predicting Lung Inflammogenicity of Oxide Nanoparticles  Voir?

Abstract
This study presents a mechanistic model for identifying oxide nanoparticles that induce a high level of neutrophils in the bronchoalveolar lavage fluid, an important marker for lung inflammogenicity. The model is based on 4 nanoparticles' physicochemical properties, ie, the reactivity, surface charge, wettability, and dissolution. First, I calculate these properties and show that theoretical values reproduce acceptably the experimental measurements. Then, I combine these properties with mechanistic knowledge to build a classification model for the prediction of acute invivo lung inflammogenicity, measured as the total number of polymorphonuclear neutrophils. The model uses reactivity and dissolution properties of nanoparticles as toxicological initiating events, whereas surface charge and wettability are characteristics involved in the interactions between the nanoparticles and the lung surfactant, eventually leading to increased cellular uptake and bioaccumulation. The model is validated on a set of 43 oxide nanoparticles tested invivo to confirm that acute lung inflammation can be described using this mechanistic framework. In addition, I also develop a linear regression model for insoluble nanoparticles to quantitatively predict the polymorphonuclear neutrophil count as a function of reactivity and surface charge. The proposed models are based on mechanistic knowledge and can support the development of adverse outcome pathways, risk assessment frameworks and safe design strategies at early stages of material's R&D.

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(28/06/2017 @ 00:00)
Insulin Resistance Disrupts the Interaction Between AKT and the NMDA Receptor and the Inactivation of the CaMKIV/CREB Pathway in Minimal Hepatic Encephalopathy  Voir?

Abstract
Hepatic cirrhosis-induced Minimal hepatic encephalopathy (MHE) has been characterized for cognitive dysfunction and central nervous system (CNS) insulin resistance (IR) has been acknowledged to be closely correlated with cognitive impairment while hepatic cirrhosis has been recognized to induce IR. Thus, this study aimed to investigate whether CNS IR occurred in MHE and induced MHE, as well as the underlying mechanism. We found IR in the MHE rats, an especially decreased level of the insulin receptor (InsR), and an increased serine phosphorylation of IRS1 in CNS. PI3K/AKT pathway signaling to the phosphorylation of N-Methyl-d-Aspartate receptors (NMDA receptors, NRs, NR1/NR2B) and downstream activation of the CaMKIV/CREB pathway and final production of neurotrophic factors were triggered by insulin, but impaired in the MHE rats. Additionally, CNS IR, memory impairment, the desensitization of the PI3K/AKT/NMDA receptor (NR)/CaMKIV/CREB pathway and decreased production of BDNF/NT3 in MHE rats were improved by rosiglitazone (RSG). These results suggested that IR, which induces the deficits in the insulin-mediated PI3K/AKT/NR/CaMKIV/CREB/neurotrophin pathway and subsequent memory decline, contributes to the pathogenesis of MHE.

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(15/05/2017 @ 00:00)

Dernière mise à jour : 19/10/2017 @ 12:47

 
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