http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2013 , Hindawi Publishing Corporation . All rights reserved. Sun, 12 May 2013 18:50:48 +0000 http://www.hindawi.com/journals/jt/2013/378168/ The present study was conducted in order to quantify to what extent cannabis consumers may be exposed to pesticide and other chemical residues through inhaled mainstream cannabis smoke. Three different smoking devices were evaluated in order to provide a generalized data set representative of pesticide exposures possible for medical cannabis users. Three different pesticides, bifenthrin, diazinon, and permethrin, along with the plant growth regulator paclobutrazol, which are readily available to cultivators in commercial products, were investigated in the experiment. Smoke generated from the smoking devices was condensed in tandem chilled gas traps and analyzed with gas chromatography-mass spectrometry (GC-MS). Recoveries of residues were as high as 69.5% depending on the device used and the component investigated, suggesting that the potential of pesticide and chemical residue exposures to cannabis users is substantial and may pose a significant toxicological threat in the absence of adequate regulatory frameworks. Nicholas Sullivan, Sytze Elzinga, and Jeffrey C. Raber Copyright © 2013 Nicholas Sullivan et al. All rights reserved. Thu, 09 May 2013 16:16:24 +0000 http://www.hindawi.com/journals/jt/2013/310904/ The historical approach to assessing health risks of environmental chemicals has been to evaluate them one at a time. In fact, we are exposed every day to a wide variety of chemicals and are increasingly aware of potential health implications. Although considerable progress has been made in the science underlying risk assessments for real-world exposures, implementation has lagged because many practitioners are unaware of methods and tools available to support these analyses. To address this issue, the US Environmental Protection Agency developed a toolbox of cumulative risk resources for contaminated sites, as part of a resource document that was published in 2007. This paper highlights information for nearly 80 resources from the toolbox and provides selected updates, with practical notes for cumulative risk applications. Resources are organized according to the main elements of the assessment process: (1) planning, scoping, and problem formulation; (2) environmental fate and transport; (3) exposure analysis extending to human factors; (4) toxicity analysis; and (5) risk and uncertainty characterization, including presentation of results. In addition to providing online access, plans for the toolbox include addressing nonchemical stressors and applications beyond contaminated sites and further strengthening resource accessibility to support evolving analyses for cumulative risk and sustainable communities. Margaret M. MacDonell, Lynne A. Haroun, Linda K. Teuschler, Glenn E. Rice, Richard C. Hertzberg, James P. Butler, Young-Soo Chang, Shanna L. Clark, Alan P. Johns, Camarie S. Perry, Shannon S. Garcia, John H. Jacobi, and Marcienne A. Scofield Copyright © 2013 Margaret M. MacDonell et al. All rights reserved. Wed, 20 Mar 2013 16:34:27 +0000 http://www.hindawi.com/journals/jt/2013/347312/ Paraquat (PQ), a cationic nonselective bipyridyl herbicide, has been used as neurotoxicant to modulate Parkinson’s disease in laboratory settings. Other compounds like rotenone (ROT), a pesticide, and 1-methyl-4-phenylpyridinium ion (MPP+) have been widely used as neurotoxicants. We compared the toxicity of these three neurotoxicants using differentiated dopaminergic SH-SY5Y human cells, aiming to elucidate their differential effects. PQ-induced neurotoxicity was shown to be concentration and time dependent, being mitochondrial dysfunction followed by neuronal death. On the other hand, cells exposure to MPP+ induced mitochondrial dysfunction, but not cellular lyses. Meanwhile, ROT promoted both mitochondrial dysfunction and neuronal death, revealing a biphasic pattern. To further elucidate PQ neurotoxic mechanism, several protective agents were used. SH-SY5Y cells pretreatment with tiron (TIR) and 2-hydroxybenzoic acid sodium salt (NaSAL), both antioxidants, and Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric oxide synthase inhibitor, partially protected against PQ-induced cell injury. Additionally, 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenyl-propyl)piperazine (GBR 12909), a dopamine transporter inhibitor, and cycloheximide (CHX), a protein synthesis inhibitor, also partially protected against PQ-induced cell injury. In conclusion, we demonstrated that PQ, MPP+, and ROT exerted differential toxic effects on dopaminergic cells. PQ neurotoxicity occurred through exacerbated oxidative stress, with involvement of uptake through the dopamine transporter and protein synthesis. João Barbosa Martins, Maria de Lourdes Bastos, Félix Carvalho, and João Paulo Capela Copyright © 2013 João Barbosa Martins et al. All rights reserved. Wed, 13 Mar 2013 09:15:56 +0000 http://www.hindawi.com/journals/jt/2013/956404/ Dog and rat hepatocytes were treated with phospholipogenics to identify the more sensitive species and to determine whether lysosomal or mitochondrial changes were the primary cause of cytotoxicity. Endpoints included cell death, lysosome membrane integrity, mitochondrial membrane polarization, and fluorescent phospholipid (NBD-PE). Dog cells exhibited lower survival IC50 values than did rat cells with all phospholipogenic treatments and exhibited a lower capacity to accumulate NBD-PE in 4 of 5 phospholipogenic test conditions. The lysosomal modulator Bafilomycin A1 (Baf) rescued dog cells from cytotoxicity caused by 3 phospholipogenic 5HT1b antagonists and hydroxychloroquine, but not fluoxetine, and rescued rat cells from hydroxychloroquine and NMTMB, a 5HT1b antagonist. Following NMTMB treatment, rat mitochondrial membrane hyperpolarization was observed at modestly cytotoxic concentrations and depolarization at the highest concentration. At the highest test concentration, lysosomal loss of acridine orange occurred by 30 min, mitochondrial polarity changes by 1 hr, and NBD-PE accumulation by 2 hr, respectively. Baf shifted mitochondrial polarity from a depolarized state to a hyperpolarized state. These data demonstrate that (a) dog hepatocytes were generally less capable of mounting an adaptive, protective phospholipidotic response than rat hepatocytes, (b) effects on mitochondria and survival were preventable by lysosomal protection, and (c) destabilizing changes in both organelles are involved causally in cytotoxicity. James K. Morelli and Paul J. Ciaccio Copyright © 2013 James K. Morelli and Paul J. Ciaccio. All rights reserved. Mon, 11 Mar 2013 17:26:10 +0000 http://www.hindawi.com/journals/jt/2013/870628/ Correlation between intensity of free radical processes estimated by biochemiluminesce parameters, content of lipoperoxidation products, and changes of glutathione peroxidase (GP, EC 1.11.1.9) and glutathione reductase (GR, EC 1.6.4.2) activities at rats liver injury, after 12, 36, 70, 96, 110, and 125 hours & tetrachloromethane administration have been investigated. The histological examination of the liver sections of rats showed that prominent hepatocytes with marked vacuolisation and inflammatory cells which were arranged around the necrotic tissue are more at 96 h after exposure to CCl4. Moreover maximum increase in GR and GP activities, 2.1 and 2.5 times, respectively, was observed at 96 h after exposure to CCl4, what coincided with the maximum of free radical oxidation processes. Using a combination of reverse transcription and real-time polymerase chain reaction, expression of the glutathione peroxidase and glutathione reductase genes (Gpx1 and Gsr) was analyzed by the determination of their respective mRNAs in the rat liver tissue under toxic hepatitis conditions. The analyses of Gpx1 and Gsr expression revealed that the transcript levels increased in 2.5- and 3.0-folds, respectively. Western blot analysis revealed that the amounts of hepatic Gpx1 and Gsr proteins increased considerably after CCl4 administration. It can be proposed that the overexpression of these enzymes could be a mechanism of enhancement of hepatocytes tolerance to oxidative stress. Igor Y. Iskusnykh, Tatyana N. Popova, Aleksander A. Agarkov, Miguel Â. A. Pinheiro de Carvalho, and Stanislav G. Rjevskiy Copyright © 2013 Igor Y. Iskusnykh et al. All rights reserved. Mon, 11 Mar 2013 09:07:31 +0000 http://www.hindawi.com/journals/jt/2013/802453/ Aloe vera, a common ingredient in cosmetics, is increasingly being consumed as a beverage supplement. Although consumer interest in aloe likely stems from its association with several health benefits, a concern has also been raised by a National Toxicology Program Report that a nondecolorized whole leaf aloe vera extract taken internally by rats was associated with intestinal mucosal hyperplasia and ultimately malignancy. We tested a decolorized whole leaf (DCWL) aloe vera, treated with activated charcoal to remove the latex portion of the plant, for genotoxicity in bacteria, acute/subacute toxicity in B6C3F1 mice, and subchronic toxicity in F344 rats. We found this DCWL aloe vera juice to be nongenotoxic in histidine reversion and DNA repair assays. Following acute administration, mice exhibited no adverse signs at 3- or 14-day evaluation periods. When fed to male and female F344 rats over 13 weeks, DCWL aloe led to no toxicity as assessed by behavior, stools, weight gain, feed consumption, organ weights, and hematologic or clinical chemistry profiles. These rats had intestinal mucosal morphologies—examined grossly and microscopically—that were similar to controls. Our studies show that oral administration of this DCWL aloe juice has a different toxicology profile than that of the untreated aloe juice at exposures up to 13 weeks. Inder Sehgal, Wallace D. Winters, Michael Scott, Andrew David, Glenn Gillis, Thaya Stoufflet, Anand Nair, and Konstantine Kousoulas Copyright © 2013 Inder Sehgal et al. All rights reserved. Thu, 07 Mar 2013 17:55:36 +0000 http://www.hindawi.com/journals/jt/2013/967029/ Phenanthrene (Phe), a polycyclic aromatic hydrocarbon (PAH), is a major constituent of urban air pollution. There have been conflicting results regarding the role of other AhR ligands 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and 6-formylindolo [3,2-b]carbazole (FICZ) in modifying regulatory T cell populations (Treg) or T helper (Th)17 differentiation, and the effects of Phe have been understudied. We hypothesized that different chemical entities of PAH induce Treg to become either Th2 or Th17 effector T cells through epigenetic modification of FOXP3. To determine specific effects on T cell populations by phenanthrene, primary human Treg were treated with Phe, TCDD, or FICZ and assessed for function, gene expression, and phenotype. Methylation of CpG sites within the FOXP3 locus reduced FOXP3 expression, leading to impaired Treg function and conversion of Treg into a CD4+CD25lo Th2 phenotype in Phe-treated cells. Conversely, TCDD treatment led to epigenetic modification of IL-17A and conversion of Treg to Th17 T cells. These findings present a mechanism by which exposure to AhR-ligands mediates human T cell responses and begins to elucidate the relationship between environmental exposures, immune modulation, and initiation of human disease. Jing Liu, Luhua Zhang, Lisa C. Winterroth, Marco Garcia, Shannon Weiman, Jillian W. Wong, John B. Sunwoo, and Kari C. Nadeau Copyright © 2013 Jing Liu et al. All rights reserved. Tue, 26 Feb 2013 11:31:10 +0000 http://www.hindawi.com/journals/jt/2013/371610/ Chlorophenoxy compounds, particularly 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxy)acetic acid (MCPA), are amongst the most widely used herbicides in the United States for both agricultural and residential applications. Epidemiologic studies suggest that exposure to 2,4-D and MCPA may be associated with increased risk non-Hodgkins lymphoma (NHL), Hodgkin’s disease (HD), leukemia, and soft-tissue sarcoma (STS). Toxicological studies in rodents show no evidence of carcinogenicity, and regulatory agencies worldwide consider chlorophenoxies as not likely to be carcinogenic or unclassifiable as to carcinogenicity. This systematic review assembles the available data to evaluate epidemiologic, toxicological, pharmacokinetic, exposure, and biomonitoring studies with respect to key cellular events noted in disease etiology and how those relate to hypothesized modes of action for these constituents to determine the plausibility of an association between exposure to environmentally relevant concentrations of 2,4-D and MCPA and lymphohematopoietic cancers. The combined evidence does not support a genotoxic mode of action. Although plausible hypotheses for other carcinogenic modes of action exist, a comparison of biomonitoring data to oral equivalent doses calculated from bioassay data shows that environmental exposures are not sufficient to support a causal relationship. Genetic polymorphisms exist that are known to increase the risk of developing NHL. The potential interaction between these polymorphisms and exposures to chlorophenoxy compounds, particularly in occupational settings, is largely unknown. Katherine von Stackelberg Copyright © 2013 Katherine von Stackelberg. All rights reserved. Mon, 04 Feb 2013 11:24:38 +0000 http://www.hindawi.com/journals/jt/2013/463595/ Objectives. The purpose of this trial was to evaluate the safety of long-term pterostilbene administration in humans. Methodology. The trial was a prospective, randomized, double-blind placebo-controlled intervention trial enrolling patients with hypercholesterolemia (defined as a baseline total cholesterol ≥200 mg/dL and/or baseline low-density lipoprotein cholesterol ≥100 mg/dL). Eighty subjects were divided equally into one of four groups: (1) pterostilbene 125 mg twice daily, (2) pterostilbene 50 mg twice daily, (3) pterostilbene 50 mg + grape extract (GE) 100 mg twice daily, and (4) matching placebo twice daily for 6–8 weeks. Safety markers included biochemical and subjective measures. Linear mixed models were used to estimate primary safety measure treatment effects. Results. The majority of patients completed the trial (91.3%). The average age was 54 years. The majority of patients were females (71%) and Caucasians (70%). There were no adverse drug reactions (ADRs) on hepatic, renal, or glucose markers based on biochemical analysis. There were no statistically significant self-reported or major ADRs. Conclusion. Pterostilbene is generally safe for use in humans up to 250 mg/day. Daniel M. Riche, Corey L. McEwen, Krista D. Riche, Justin J. Sherman, Marion R. Wofford, David Deschamp, and Michael Griswold Copyright © 2013 Daniel M. Riche et al. All rights reserved. Tue, 29 Jan 2013 08:18:50 +0000 http://www.hindawi.com/journals/jt/2013/545802/ Like other persistent organochlorine pesticides, endosulfan residues have been detected in foods including fruit, vegetables, and fish. The aim of our study was to assess the impact of a dietary exposure to low doses of endosulfan from foetal development until adult age on metabolic homeostasis in mice and to identify biomarkers of exposure using an 1H-NMR-based metabonomic approach in various tissues and biofluids. We report in both genders an increase in plasma glucose as well as changes in levels of factors involved in the regulation of liver oxidative stress, confirming the prooxidant activities of this compound. Some metabolic changes were distinct in males and females. For example in plasma, a decrease in lipid LDL and choline content was only observed in female. Lactate levels in males were significantly increased. In conclusion, our results show that metabolic changes in liver could be linked to the onset of pathologies like diabetes and insulin resistance. Moreover from our results it appears that the NMR-based metabonomic approach could be useful for the characterization in plasma of a dietary exposure to low dose of pesticide in human. Cécile Canlet, Marie Tremblay-Franco, Roselyne Gautier, Jérôme Molina, Benjamin Métais, Florence Blas-Y Estrada, and Laurence Gamet-Payrastre Copyright © 2013 Cécile Canlet et al. All rights reserved. Wed, 28 Nov 2012 17:14:47 +0000 http://www.hindawi.com/journals/jt/2012/758182/ Jane C. Caldwell, Kannan Krishnan, and Marina V. Evans Copyright © 2012 Jane C. Caldwell et al. All rights reserved. Thu, 01 Nov 2012 13:24:45 +0000 http://www.hindawi.com/journals/jt/2012/204830/ Background. Rabbit skin model was used to test skin irritation of the most commonly used cosmetic products in Jimma town, southwestern Ethiopia. The most commonly used cosmetics were Dove, Glysolid, College, Top Society, Fair and Lovely, Nivea, Lux, Magic fruit world, Solea, Body talk, Kris, Holly, Victoria, and Sweet Heart. Methods. Intact and abraded rabbit skins were tested for erythema and edema under shade and under sun exposure. Draize Primary Irritation Index (PII) was used to calculate skin irritation of each cosmetic. Cosmetic ingredients were analyzed from the labels. Results and Discussion. Only Dove cream caused no skin irritation except for an abraded skin under sun exposure for five consecutive days. It has been identified that application of cosmetics on abraded skin under sunny condition worsens the irritation. Cosmetic labels revealed that most ingredients used in all products were those restricted chemicals due to their adverse health effects. Conclusion. This study has concluded that use of cosmetics under sunshine and also on abraded skin increases skin irritation. Hence, those users who have abraded skin are advised not to apply those cosmetics on continuous basis specifically under sun exposure. Wayessa Amasa, Dante Santiago, Seblework Mekonen, and Argaw Ambelu Copyright © 2012 Wayessa Amasa et al. All rights reserved. Thu, 18 Oct 2012 11:45:04 +0000 http://www.hindawi.com/journals/jt/2012/678963/ Martha L. Hale, Shuowei Cai, and S. Ashraf Ahmed Copyright © 2012 Martha L. Hale et al. All rights reserved. Thu, 18 Oct 2012 09:47:38 +0000 http://www.hindawi.com/journals/jt/2012/589520/ The safety of Zigbir®, a polyherbal formulation intended for use as food supplement, was evaluated in Sprague-Dawley rats treated orally at the dose of 2000 mg/kg in acute and at 250, 500, and 1000 mg/kg for 90 days in subchronic toxicity study. The median lethal dose of Zigbir® was found to be more than 2000 mg/kg, and fourteen-day repeated dose toxicity study revealed it to be safe up to 1000 mg/kg. The subchronic study did not show any mortality or treatment-related adverse clinical signs. The treated animals exhibited normal feed intake and comparable body weight gain except for a decrease in females of 500 and 1000 mg/kg groups. Ocular examination revealed no abnormalities. Further, Zigbir® administration in rats did not induce any major changes in urinalysis, hematological, and biochemical evaluations except for minor alterations in few parameters at different dose levels. Gross and histopathological findings did not show any lesions attributable to Zigbir® administration. The no observed effect level of Zigbir® was found to be 500 and 250 mg/kg in male and female Sprague-Dawley rats. Joseph Joshua Allan, Ranjit Madhukar Bhide, and Amit Agarwal Copyright © 2012 Joseph Joshua Allan et al. All rights reserved. Thu, 06 Sep 2012 14:57:09 +0000 http://www.hindawi.com/journals/jt/2012/501438/ Yonghua Ji and Maria Elena De Lima Copyright © 2012 Yonghua Ji and Maria Elena De Lima. All rights reserved. Sun, 05 Aug 2012 10:38:14 +0000 http://www.hindawi.com/journals/jt/2012/645460/ Reactive oxygen species (ROS) are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity. Damian G. Deavall, Elizabeth A. Martin, Judith M. Horner, and Ruth Roberts Copyright © 2012 Damian G. Deavall et al. All rights reserved. Tue, 31 Jul 2012 09:53:25 +0000 http://www.hindawi.com/journals/jt/2012/546915/ Oxidative stress is a toxic state caused by an imbalance between the production and elimination of reactive oxygen species (ROS). ROS cause oxidative damage to cellular components such as proteins, lipids, and nucleic acids. While the role of ROS in cellular damage is frequently all that is noted, ROS are also important in redox signalling. The “Redox Hypothesis" has been proposed to emphasize a dual role of ROS. This hypothesis suggests that the primary effect of changes to the redox state is modified cellular signalling rather than simply oxidative damage. In extreme cases, alteration of redox signalling can contribute to the toxicity of ROS, as well as to ageing and age-related diseases. The nematode species Caenorhabditis elegans provides an excellent model for the study of oxidative stress and redox signalling in animals. We use protein sequences from central redox systems in Homo sapiens, Drosophila melanogaster, and Saccharomyces cerevisiae to query Genbank for homologous proteins in C. elegans. We then use maximum likelihood phylogenetic analysis to compare protein families between C. elegans and the other organisms to facilitate future research into the genetics of redox biology. Andrew D. Johnston and Paul R. Ebert Copyright © 2012 Andrew D. Johnston and Paul R. Ebert. All rights reserved. Mon, 30 Jul 2012 14:09:03 +0000 http://www.hindawi.com/journals/jt/2012/852384/ Physiologically based Pharmacokinetic (PBPK) models are used for predictions of internal or target dose from environmental and pharmacologic chemical exposures. Their use in human risk assessment is dependent on the nature of databases (animal or human) used to develop and test them, and includes extrapolations across species, experimental paradigms, and determination of variability of response within human populations. Integration of state-of-the science PBPK modeling with emerging computational toxicology models is critical for extrapolation between in vitro exposures, in vivo physiologic exposure, whole organism responses, and long-term health outcomes. This special issue contains papers that can provide the basis for future modeling efforts and provide bridges to emerging toxicology paradigms. In this overview paper, we present an overview of the field and introduction for these papers that includes discussions of model development, best practices, risk-assessment applications of PBPK models, and limitations and bridges of modeling approaches for future applications. Specifically, issues addressed include: (a) increased understanding of human variability of pharmacokinetics and pharmacodynamics in the population, (b) exploration of mode of action hypotheses (MOA), (c) application of biological modeling in the risk assessment of individual chemicals and chemical mixtures, and (d) identification and discussion of uncertainties in the modeling process. Jane C. Caldwell, Marina V. Evans, and Kannan Krishnan Copyright © 2012 Jane C. Caldwell et al. All rights reserved. Thu, 19 Jul 2012 14:19:01 +0000 http://www.hindawi.com/journals/jt/2012/413279/ Considering the wide, positive reporting of the role of reactive oxygen species in ischemic brain injury, searching for antioxidant drugs within herbal remedies is logical. In this study, the protective effects of Scutellaria litwinowii Bornm. & Sint. on cell viability and reactive oxygen species production in cultured PC12 cells were investigated under serum/glucose-deprivation-induced cell death. After cells were seeded overnight, they were then deprived of serum/glucose for 24 h. Cells were treated with different concentrations of S. litwinowii extract (7.75–250 μg/mL). Cell viability was quantitated by MTT assay, and intracellular reactive oxygen species production was measured by flow cytometry. Serum/glucose-deprivation induced significant cell death after 24 h (𝑃 < 0.001). Treatment with S. litwinowii (7.75–250 μg/mL) reduced serum/glucose deprivation-induced cytotoxicity in PC12 cells after 24 h. A significant increase in intracellular reactive oxygen species production was seen following serum/glucose deprivation (𝑃 < 0.001). S. litwinowii (62 and 125 μg/mL, 𝑃 < 0.01) treatment reversed the increased reactive oxygen species production following ischemic insult. This demonstrates that S. litwinowii extract protects PC12 cells against serum/glucose-deprivation-induced cell death by antioxidant mechanisms, which indicates the potential therapeutic application of S. litwinowii in managing cerebral ischemic and neurodegenerative disorders. Maryam Afsharzadeh, Zahra Tayarani-Najaran, Aryo Zare, and Seyed Hadi Mousavi Copyright © 2012 Maryam Afsharzadeh et al. All rights reserved. Sun, 08 Jul 2012 11:23:07 +0000 http://www.hindawi.com/journals/jt/2012/843787/ Voltage-gated sodium channels (VGSCs) are important membrane protein carrying on the molecular basis for action potentials (AP) in neuronal firings. Even though the structure-function studies were the most pursued spots, the posttranslation modification processes, such as glycosylation, phosphorylation, and alternative splicing associating with channel functions captured less eyesights. The accumulative research suggested an interaction between the sialic acids chains and ion-permeable pores, giving rise to subtle but significant impacts on channel gating. Sodium channel-specific neurotoxic toxins, a family of long-chain polypeptides originated from venomous animals, are found to potentially share the binding sites adjacent to glycosylated region on VGSCs. Thus, an interaction between toxin and glycosylated VGSC might hopefully join the campaign to approach the role of glycosylation in modulating VGSCs-involved neuronal network activity. This paper will cover the state-of-the-art advances of researches on glycosylation-mediated VGSCs function and the possible underlying mechanisms of interactions between toxin and glycosylated VGSCs, which may therefore, fulfill the knowledge in identifying the pharmacological targets and therapeutic values of VGSCs. Zhirui Liu, Jie Tao, Pin Ye, and Yonghua Ji Copyright © 2012 Zhirui Liu et al. All rights reserved. Thu, 05 Jul 2012 09:44:22 +0000 http://www.hindawi.com/journals/jt/2012/207594/ Alcoholic liver disease (ALD) is a primary cause of morbidity and mortality in the United States and constitutes a significant socioeconomic burden. Previous work has implicated oxidative stress and endoplasmic reticulum (ER) stress in the etiology of ALD; however, the complex and interrelated nature of these cellular responses presently confounds our understanding of ethanol-induced hepatopathy. In this paper, we assessed the pathological contribution of oxidative stress and ER stress in a time-course mouse model of early-stage ALD. Ethanol-treated mice exhibited significant hepatic panlobular steatosis and elevated plasma ALT values compared to isocaloric controls. Oxidative stress was observed in the ethanol-treated animals through a significant increase in hepatic TBARS and immunohistochemical staining of 4-HNE-modified proteins. Hepatic glutathione (GSH) levels were significantly decreased as a consequence of decreased CBS activity, increased GSH utilization, and increased protein glutathionylation. At the same time, immunoblot analysis of the PERK, IRE1α, ATF6, and SREBP pathways reveals no significant role for these UPR pathways in the etiology of hepatic steatosis associated with early-stage ALD. Collectively, our results indicate a primary pathogenic role for oxidative stress in the early initiating stages of ALD that precedes the involvement of the ER stress response. James J. Galligan, Rebecca L. Smathers, Colin T. Shearn, Kristofer S. Fritz, Donald S. Backos, Hua Jiang, Christopher C. Franklin, David J. Orlicky, Kenneth N. MacLean, and Dennis R. Petersen Copyright © 2012 James J. Galligan et al. All rights reserved. Thu, 28 Jun 2012 14:27:26 +0000 http://www.hindawi.com/journals/jt/2012/373678/ Thimerosal generates ethylmercury in aqueous solution and is widely used as preservative. We have investigated the toxicology of Thimerosal in normal human astrocytes, paying particular attention to mitochondrial function and the generation of specific oxidants. We find that ethylmercury not only inhibits mitochondrial respiration leading to a drop in the steady state membrane potential, but also concurrent with these phenomena increases the formation of superoxide, hydrogen peroxide, and Fenton/Haber-Weiss generated hydroxyl radical. These oxidants increase the levels of cellular aldehyde/ketones. Additionally, we find a five-fold increase in the levels of oxidant damaged mitochondrial DNA bases and increases in the levels of mtDNA nicks and blunt-ended breaks. Highly damaged mitochondria are characterized by having very low membrane potentials, increased superoxide/hydrogen peroxide production, and extensively damaged mtDNA and proteins. These mitochondria appear to have undergone a permeability transition, an observation supported by the five-fold increase in Caspase-3 activity observed after Thimerosal treatment. Martyn A. Sharpe, Andrew D. Livingston, and David S. Baskin Copyright © 2012 Martyn A. Sharpe et al. All rights reserved. Sun, 17 Jun 2012 10:31:59 +0000 http://www.hindawi.com/journals/jt/2012/973134/ Aims. 3,5,4′-Trihydroxy-trans-stilbene, a natural polyphenolic compound present in wine and grapes and better known as resveratrol, has free radical scavenging properties and is a potent protector against oxidative stress induced by alcohol metabolism. Today, the mechanism by which ethanol exerts its toxicity is still not well understood, but it is generally considered that free radical generation plays an important role in the appearance of structural and functional alterations in cells. The aim of this study was to evaluate the protective action of resveratrol against ethanol-induced brain cell injury. Methods. Primary cultures of rat astrocytes were exposed to ethanol, with or without a pretreatment with resveratrol. We examined the dose-dependent effects of this resveratrol pretreatment on cytotoxicity and genotoxicity induced by ethanol. Cytotoxicity was assessed using the MTT reduction test. Genotoxicity was evidenced using single cell gel electrophoresis. In addition, DNA staining with fluorescent dyes allowed visualization of nuclear damage using confocal microscopy. Results. Cell pretreatment with low concentrations of trans-resveratrol (0.1–10 μM) slowed down cell death and DNA damage induced by ethanol exposure, while higher concentrations (50–100 μM) enhanced these same effects. No protection by cis-resveratrol was observed. Conclusion. Protection offered by trans-resveratrol against ethanol-induced neurotoxicity was only effective for low concentrations of this polyphenol. Brigitte Gonthier, Nathalie Allibe, Cécile Cottet-Rousselle, Frédéric Lamarche, Laurence Nuiry, and Luc Barret Copyright © 2012 Brigitte Gonthier et al. All rights reserved. Thu, 14 Jun 2012 10:11:49 +0000 http://www.hindawi.com/journals/jt/2012/648384/ Type A neurotoxin (NTX) of Clostridium botulinum was purified by a simple procedure using a lactose gel column. The toxicity of this purified toxin preparation was retained for at least 1 year at −30°C by supplementation with either 0.1% albumin or 0.05% albumin plus 1% trehalose. When purified NTX was used to treat 49 patients with urinary incontinence caused by either refractory idiopathic or neurogenic detrusor overactivity, 36 patients showed significant improvement in symptoms. These beneficial effects were also observed in cases of prostatic hyperplasia. The results obtained with NTX were similar to that of Botox. The effects of NTX on trigeminal neuralgia induced by infraorbital nerve constriction (IoNC) in rats were also studied. Trigeminal ganglion neurons from ipsilateral to IoNC exhibited significantly faster onset of FM4-64 release than sham-operated contralateral neurons. Intradermal injection of NTX in the area of IoNC alleviated IoNC-induced pain behavior and reduced the exaggerated FM4-64 release in trigeminal ganglion neurons. Yoshizo Matsuka, Teruhiko Yokoyama, Yumiko Yamamoto, Tomonori Suzuki, Ni Nengah Dwi Fatmawati, Atsushi Nishikawa, Tohru Ohyama, Toshihiro Watanabe, Takuo Kuboki, Atsushi Nagai, and Keiji Oguma Copyright © 2012 Yoshizo Matsuka et al. All rights reserved. Thu, 14 Jun 2012 09:33:37 +0000 http://www.hindawi.com/journals/jt/2012/308594/ While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo toxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validated in silico and in vitro models. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics. Linda R. Barone, Scott Boyer, James R. Damewood Jr., James Fikes, and Paul J. Ciaccio Copyright © 2012 Linda R. Barone et al. All rights reserved. Mon, 11 Jun 2012 08:28:47 +0000 http://www.hindawi.com/journals/jt/2012/325250/ Lipocalin family members have been implicated in development, regeneration, and pathological processes, but their roles are unclear. Interestingly, these proteins are found abundant in the venom of the Lonomia obliqua caterpillar. Lipocalins are β-barrel proteins, which have three conserved motifs in their amino acid sequence. One of these motifs was shown to be a sequence signature involved in cell modulation. The aim of this study is to investigate the effects of a synthetic peptide comprising the lipocalin sequence motif in fibroblasts. This peptide suppressed caspase 3 activity and upregulated Bcl-2 and Ki-67, but did not interfere with GPCR calcium mobilization. Fibroblast responses also involved increased expression of proinflammatory mediators. Increase of extracellular matrix proteins, such as collagen, fibronectin, and tenascin, was observed. Increase in collagen content was also observed in vivo. Results indicate that modulation effects displayed by lipocalins through this sequence motif involve cell survival, extracellular matrix remodeling, and cytokine signaling. Such effects can be related to the lipocalin roles in disease, development, and tissue repair. Linda Christian Carrijo-Carvalho, Durvanei A. Maria, Janaina S. Ventura, Kátia L. P. Morais, Robson L. Melo, Consuelo Junqueira Rodrigues, and Ana Marisa Chudzinski-Tavassi Copyright © 2012 Linda Christian Carrijo-Carvalho et al. All rights reserved. Mon, 11 Jun 2012 08:04:07 +0000 http://www.hindawi.com/journals/jt/2012/629781/ Bromochloromethane (BCM) is a volatile compound and a by-product of disinfection of water by chlorination. Physiologically based pharmacokinetic (PBPK) models are used in risk assessment applications. An updated PBPK model for BCM is generated and applied to hypotheses testing calibrated using vapor uptake data. The two different metabolic hypotheses examined are (1) a two-pathway model using both CYP2E1 and glutathione transferase enzymes and (2) a two-binding site model where metabolism can occur on one enzyme, CYP2E1. Our computer simulations show that both hypotheses describe the experimental data in a similar manner. The two pathway results were comparable to previously reported values (𝑉max=3.8 mg/hour, 𝐾𝑚=0.35 mg/liter, and 𝑘GST=4.7 /hour). The two binding site results were 𝑉max1=3.7 mg/hour, 𝐾𝑚1=0.3 mg/hour, CL2 = 0.047 liter/hour. In addition, we explore the sensitivity of different parameters for each model using our obtained optimized values. W. S. Cuello, T. A. T. Janes, J. M. Jessee, M. A. Venecek, M. E. Sawyer, C. R. Eklund, and M. V. Evans Copyright © 2012 W. S. Cuello et al. All rights reserved. Thu, 07 Jun 2012 10:23:40 +0000 http://www.hindawi.com/journals/jt/2012/862764/ Solid tumour accounts for 90% of all cancers. The current treatment approach for most solid tumours is surgery, however it is limited to early stage tumours. Other treatment options such as chemotherapy and radiotherapy are non-selective, thus causing damage to both healthy and cancerous tissue. Past research has focused on understanding tumour cells themselves, and conventional wisdom has aimed at targeting these cells directly. Recent research has shifted towards understanding the tumour microenvironment and it’s differences from that of healthy cells/tissues in the body and then to exploit these differences for treatmeat of the tumour. One such approach is utilizing anaerobic bacteria. Several strains of bacteria have been shown to selectively colonize in solid tumours, making them valuable tools for selective tumour targeting and destruction. Amongst them, the anaerobic Clostridium has shown great potential in penetration and colonization of the hypoxic and necrotic areas of the tumour microenvironment, causing significant oncolysis as well as enabling the delivery of therapeutics directly to the tumour in situ. Various strategies utilizing Clostridium are currently being investigated, and represent a novel area of emerging cancer therapy. This review provides an update review of tumour microenvironment as well as summary of the progresses and current status of Clostridial spore-based cancer therapies. Brittany Umer, David Good, Jozef Anné, Wei Duan, and Ming Q. Wei Copyright © 2012 Brittany Umer et al. All rights reserved. Mon, 04 Jun 2012 10:29:01 +0000 http://www.hindawi.com/journals/jt/2012/756358/ Potassium channels are the most heterogeneous and widely distributed group of ion channels and play important functions in all cells, in both normal and pathological mechanisms, including learning and memory processes. Being fundamental for many diverse physiological processes, K+-channels are recognized as potential therapeutic targets in the treatment of several Central Nervous System (CNS) diseases, such as multiple sclerosis, Parkinson's and Alzheimer's diseases, schizophrenia, HIV-1-associated dementia, and epilepsy. Blockers of these channels are therefore potential candidates for the symptomatic treatment of these neuropathies, through their neurological effects. Venomous animals have evolved a wide set of toxins for prey capture and defense. These compounds, mainly peptides, act on various pharmacological targets, making them an innumerable source of ligands for answering experimental paradigms, as well as for therapeutic application. This paper provides an overview of CNS K+-channels involved in memory acquisition and storage and aims at evaluating the use of highly selective K+-channel blockers derived from arthropod venoms as potential therapeutic agents for CNS diseases involving learning and memory mechanisms. Christiano D. C. Gati, Márcia R. Mortari, and Elisabeth F. Schwartz Copyright © 2012 Christiano D. C. Gati et al. All rights reserved. Tue, 22 May 2012 09:38:25 +0000 http://www.hindawi.com/journals/jt/2012/286079/ The objectives of this study were (i) to develop a screening-level Quantitative property-property relationship (QPPR) for intrinsic clearance (CLint) obtained from in vivo animal studies and (ii) to incorporate it with human physiology in a PBPK model for predicting the inhalation pharmacokinetics of VOCs. CLint, calculated as the ratio of the in vivo 𝑉max (μmol/h/kg bw rat) to the 𝐾𝑚 (μM), was obtained for 26 VOCs from the literature. The QPPR model resulting from stepwise linear regression analysis passed the validation step (𝑅2=0.8; leave-one-out cross-validation 𝑄2=0.75) for CLint normalized to the phospholipid (PL) affinity of the VOCs. The QPPR facilitated the calculation of CLint (L PL/h/kg bw rat) from the input data on log 𝑃ow, log blood: water PC and ionization potential. The predictions of the QPPR as lower and upper bounds of the 95% mean confidence intervals (LMCI and UMCI, resp.) were then integrated within a human PBPK model. The ratio of the maximum (using LMCI for CLint) to minimum (using UMCI for CLint) AUC predicted by the QPPR-PBPK model was 1.36±0.4 and ranged from 1.06 (1,1-dichloroethylene) to 2.8 (isoprene). Overall, the integrated QPPR-PBPK modeling method developed in this study is a pragmatic way of characterizing the impact of the lack of knowledge of CLint in predicting human pharmacokinetics of VOCs, as well as the impact of prediction uncertainty of CLint on human pharmacokinetics of VOCs. Thomas Peyret and Kannan Krishnan Copyright © 2012 Thomas Peyret and Kannan Krishnan. All rights reserved.