Special Issue "Advances in Molecular Toxicology"
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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".
Deadline for manuscript submissions: closed (15 September 2010)
Special Issue Editor
Guest Editor
Prof. Dr. Kenji Yamamoto
International Clinical Research Center, Research Institute of International Center Japan, 1-21-1, Toyama, Shinjyuku-ku Tokyo, Japan
E-Mail: backen@ri.imcj.go.jp
Special Issue Information
Dear Colleagues,
We define the toxic agents as the chemical substances which disturb homeostatic balance in the process of life. It can sometimes cause death. Some molecule, metal ion, cluster (nano meter sized crystal) and complex substance of them can be toxic. But we have to think about it much deep. For example, carcinogenic substance and toxic substance might be known as belonging to the different notions. Asbestos, however, causes methoterioma 30 years after the exposure, leading to death. Can it be called toxic agent? For another example, workers in saltpeter mine have a chance of Nitric Oxide (NO) poisoning. Because the blood concentration of NO is lowest on Monday morning, the number of angina cases is highest. Though the more we extend the definition, the more we have to deal with so many topics on the toxic agents, we urge researchers from variety of fields to submit for this issue.
Prof. Dr. Kenji Yamamoto
Guest Editor
Submission
Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.
Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed Open Access monthly journal published by MDPI.
Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs).
Keywords
- definition of poison
- slow poison
- new horizon of toxicology
- production process
- neutralization of poison
- natural poison and man maid poison
- industrial poison
- tolerable level of poison
Published Papers (13 papers)
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Received: 26 April 2010; in revised form: 19 May 2010 / Accepted: 1 June 2010 / Published: 7 June 2010
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Abstract: Titanium dioxide (titania) nanoparticle aggregation is an important factor in understanding cytotoxicity. However, the effect of the aggregate size of nanoparticles on cells is unclear. We prepared two sizes of titania aggregate particles and investigated their biological activity by analyzing biomarker expression based on mRNA expression analysis. The aggregate particle sizes of small and large aggregated titania were 166 nm (PDI = 0.291) and 596 nm (PDI = 0.417), respectively. These two size groups were separated by centrifugation from the same initial nanoparticle sample. We analyzed the gene expression of biomarkers focused on stress, inflammation, and cytotoxicity. Large titania aggregates show a larger effect on cell viability and gene expression when compared with the small aggregates. This suggests that particle aggregate size is related to cellular effects.
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Received: 26 May 2010; in revised form: 17 June 2010 / Accepted: 13 July 2010 / Published: 16 July 2010
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Abstract: The free radical nitric oxide (NO●) is known to play a dual role in human physiology and pathophysiology. At low levels, NO● can protect cells; however, at higher levels, NO● is a known cytotoxin, having been implicated in tumor angiogenesis and progression. While the majority of research devoted to understanding the role of NO● in cancer has to date been tissue-specific, we herein review underlying commonalities of NO● which may well exist among tumors arising from a variety of different sites. We also discuss the role of NO● in human physiology and pathophysiology, including the very important relationship between NO● and the glutathione-transferases, a class of protective enzymes involved in cellular protection. The emerging role of NO● in three main areas of epigenetics—DNA methylation, microRNAs, and histone modifications—is then discussed. Finally, we describe the recent development of a model cell line system in which human tumor cell lines were adapted to high NO● (HNO) levels. We anticipate that these HNO cell lines will serve as a useful tool in the ongoing efforts to better understand the role of NO● in cancer.
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Received: 7 July 2010; in revised form: 26 July 2010 / Accepted: 28 July 2010 / Published: 2 August 2010
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Abstract: In this study, we examined the cytotoxic effects of curcumin, the yellow pigment of Curcuma longa, on the blastocyst stage of mouse embryos, subsequent embryonic attachment, and outgrowth in vitro and in vivo implantation by embryo transfer. Mouse blastocysts were incubated in medium with or without curcumin (6, 12 or 24 μM) for 24 h. Cell proliferation and growth were investigated using dual differential staining, apoptosis was analyzed with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and implantation and post-implantation development of embryos were measured by in vitro development analysis and in vivo embryo transfer, respectively. Blastocysts treated with 24 μM curcumin displayed significantly increased apoptosis and decreased total cell number. Interestingly, we observed no marked differences in the implantation success rates between curcumin-pretreated and control blastocysts during in vitro embryonic development through implantation with a fibronectin-coated culture dish. However, in vitro treatment with 24 μM curcumin was associated with decreased implantation rate and increased resorption of postimplantation embryos in mouse uterus, as well as decreased fetal weight in the embryo transfer assay. Our results collectively indicate that in vitro exposure to curcumin triggers apoptosis and retards early postimplantation development after transfer to host mice. In addition, curcumin induces apoptotic injury effects on mouse blastocysts through ROS generation, and further promotes mitochondria-dependent apoptotic signaling processes to impair sequent embryonic development.
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Received: 2 September 2010; in revised form: 8 September 2010 / Accepted: 8 September 2010 / Published: 17 September 2010
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Abstract: Cutaneous tissue is the first barrier against outdoor insults. The outer most layer of the skin, the stratum corneum (SC), is formed by corneocytes embedded in a lipid matrix (cholesterol, ceramide and fatty acids). Therefore, the regulation of lipids and, in particular, of cholesterol homeostasis in the skin is of great importance. ABCA1 is a membrane transporter responsible for cholesterol efflux and plays a key role in maintaining cellular cholesterol levels. Among the many factors that have been associated with skin diseases, the environmental stressor cigarette smoke has been recently studied. In the present study, we demonstrate that ABCA1 expression in human cells (HaCaT) was increased (both mRNA and protein levels) after CS exposure. This effect was mediated by the inhibition of NFkB (aldehydes adducts formation) that allows the translocation of liver X receptor (LXR). These findings suggest that passive smoking may play a role in skin cholesterol levels and thus affect cutaneous tissues functions.
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Received: 28 June 2010; in revised form: 3 August 2010 / Accepted: 9 September 2010 / Published: 20 September 2010
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Abstract: A systems-level understanding of molecular perturbations is crucial for evaluating chemical-induced toxicity risks appropriately, and for this purpose comprehensive gene expression analysis or toxicogenomics investigation is highly advantageous. The recent accumulation of toxicity-associated gene sets (toxicogenomic biomarkers), enrichment in public or commercial large-scale microarray database and availability of open-source software resources facilitate our utilization of the toxicogenomic data. However, toxicologists, who are usually not experts in computational sciences, tend to be overwhelmed by the gigantic amount of data. In this paper we present practical applications of toxicogenomics by utilizing biomarker gene sets and a simple scoring method by which overall gene set-level expression changes can be evaluated efficiently. Results from the gene set-level analysis are not only an easy interpretation of toxicological significance compared with individual gene-level profiling, but also are thought to be suitable for cross-platform or cross-institutional toxicogenomics data analysis. Enrichment in toxicogenomics databases, refinements of biomarker gene sets and scoring algorithms and the development of user-friendly integrative software will lead to better evaluation of toxicant-elicited biological perturbations.
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Received: 26 August 2010; in revised form: 9 September 2010 / Accepted: 16 September 2010 / Published: 29 September 2010
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Abstract: Aflatoxin B1 (AFB1) and deoxynivalenol (DON) are important food-borne mycotoxins that have been implicated in animal and human health. In this study, individual and combinative effects of AFB1 and DON were tested in primary hepatocytes of Cyprinus carpio. The results indicated that the combinative effects of AFB1 and DON (0.01 μg/mL AFB1 and 0.25 μg/mL DON; 0.02 μg/mL AFB1 and 0.25 μg/mL DON; 0.02 μg/mL AFB1 and 0.5 μg/mL DON) were higher than that of individual mycotoxin (P
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Received: 12 September 2010; in revised form: 22 October 2010 / Accepted: 15 November 2010 / Published: 18 November 2010
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Abstract: Idiosyncratic drug reactions (IDRs) are poorly understood, unpredictable, and not detected in preclinical studies. Although the cause of these reactions is likely multi-factorial, one hypothesis is that an underlying inflammatory state lowers the tolerance to a xenobiotic. Previously used in an inflammation IDR model, bacterial lipopolysaccharide (LPS) is heterogeneous in nature, making development of standardized testing protocols difficult. Here, the use of rat tumor necrosis factor-α (TNFα) to replace LPS as an inflammatory stimulus was investigated. Sprague-Dawley rats were treated with separate preparations of LPS or TNFα, and hepatic transcriptomic effects were compared. TNFα showed enhanced consistency at the transcriptomic level compared to LPS. TNFα and LPS regulated similar biochemical pathways, although LPS was associated with more robust inflammatory signaling than TNFα. Rats were then codosed with TNFα and trovafloxacin (TVX), an IDR-associated drug, and evaluated by liver histopathology, clinical chemistry, and gene expression analysis. TNFα/TVX induced unique gene expression changes that clustered separately from TNFα/levofloxacin, a drug not associated with IDRs. TNFα/TVX cotreatment led to autoinduction of TNFα resulting in potentiation of underlying gene expression stress signals. Comparison of TNFα/TVX and LPS/TVX gene expression profiles revealed similarities in the regulation of biochemical pathways. In conclusion, TNFα could be used in lieu of LPS as an inflammatory stimulus in this model of IDRs.
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Received: 11 October 2010; in revised form: 8 November 2010 / Accepted: 15 November 2010 / Published: 23 November 2010
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Abstract: The present study was designed to evaluate the inhibitory effect of nutmeg (Myristica fragrans Houtt.) seed essential oil on the locomotor activity of mice in a wheel cage. Active compounds in the essential oil were identified by off-line solid phase extraction (SPE-C18) and GC/MS analysis. The essential oil was administered by inhalation at doses of 0.1, 0.3, and 0.5 mL/cage. The results showed that inhalation of nutmeg seed essential oil at a dose of 0.5 mL/cage decreased locomotion by 68.62%; and inhalation of 0.1 and 0.3 mL/cage inhibited locomotion by 62.81% and 65.33%, respectively. Generally, larger doses and longer administrations of nutmeg seed essential oil exhibited greater locomotor inhibition. Subsequently, the plasma concentrations of essential oil compounds were measured. The most concentrated compound in the plasma was myristicin. Half an hour after the addition of 1 mL/cage of nutmeg seed oil, the plasma concentration of myristicin was 3.7 mg/mL; one and two hours after the addition, the blood levels of myristicin were 5.2 mg/mL and 7.1 mg/mL, respectively. Other essential oil compounds identified in plasma were safrole (two-hour inhalation: 1.28 mg/mL), 4‑terpineol (half-hour inhalation: 1.49 mg/mL, one-hour inhalation: 2.95 mg/mL, two-hour inhalation: 6.28 mg/mL) and fatty esters. The concentrations of the essential oil compounds in the blood plasma were relatively low (mg/mL or ppm). In conclusion, the volatile compounds of nutmeg seed essential oil identified in the blood plasma may correlate with the locomotor-inhibiting properties of the oil when administered by inhalation.
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Received: 29 September 2010; in revised form: 22 November 2010 / Accepted: 22 November 2010 / Published: 24 November 2010
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Abstract: Traditional toxicity testing using animal models is slow, low capacity, expensive and assesses a limited number of endpoints. Such approaches are inadequate to deal with the increasingly large number of compounds found in the environment for which there are no toxicity data. Mechanism-centered high-throughput testing represents an alternative approach to meet this pressing need but is limited by our current understanding of toxicity pathways. Functional toxicogenomics, the global study of the biological function of genes on the modulation of the toxic effect of a compound, can play an important role in identifying the essential cellular components and pathways involved in toxicity response. The combination of the identification of fundamental toxicity pathways and mechanism-centered targeted assays represents an integrated approach to advance molecular toxicology to meet the challenges of toxicity testing in the 21st century.
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Received: 13 October 2010; in revised form: 4 November 2010 / Accepted: 8 November 2010 / Published: 26 November 2010
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Abstract: 3,4-Methylenedioxymethamphetamine (MDMA) is an illicit psychoactive drug with cardiovascular effects that have not been fully described. In the current study, we observed the effects of acute MDMA on rabbit left ventricular function. We also observed the effects of MDMA on nuclear factor-kappa B (NF-kB) activity in cultured rat ventricular myocytes (H9c2). In the rabbit, MDMA (2 mg/kg) alone caused a significant increase in heart rate and a significant decrease in the duration of the cardiac cycle. Inhibition of nitric oxide synthase (NOS) by pretreatment with L-NAME (10 mg/kg) alone caused significant dysfunction in heart rate, systolic pressure, diastolic pressure, duration of relaxation, duration of cardiac cycle, and mean left ventricular pressure. Pretreatment with L-NAME followed by treatment with MDMA caused significant dysfunction in additional parameters that were not abnormal upon exposure to either compound in isolation: duration of contraction, inotropy, and pulse pressure. Exposure to 1.0 mM MDMA for 6 h or 2.0 mM MDMA for 12 h caused increased nuclear localization of NF-kB in cultured H9c2 cells. The current results suggest that MDMA is acutely detrimental to heart function and that an intact cardiovascular NOS system is important to help mitigate early sequelae in some functional parameters. The delayed timing of NF-kB activation suggests that this factor may be relevant to MDMA induced cardiomyopathy of later onset.
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Received: 5 February 2011; in revised form: 12 March 2011 / Accepted: 28 March 2011 / Published: 4 April 2011
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Abstract: To understand and characterize the pathogenic mechanisms of inflammatory bowel disease, dextran sulfate sodium (DSS) has been used to induce acute and chronic colitis in animal models by causing intestinal epithelium damage. The mechanism of action of DSS in producing this outcome is not well understood. In an effort to understand how DSS might impact epithelial cell metabolism, we studied the intestinal epithelial cell line Caco-2 incubated with 1% DSS over 56 hours using 1H NMR spectroscopy. We observed no difference in cell viability as compared to control cultures, and an approximately 1.5-fold increase in IL-6 production upon incubation with 1% DSS. The effect on Caco-2 cell metabolism as measured through changes in the concentration of metabolites in the cell supernatant included a three-fold decrease in the concentration of alanine. Given that the concentrations of other amino acids in the cell culture supernatant were not different between treated and control cultures over 56 hours suggest that DSS inhibits alanine synthesis, specifically alanine aminotransferase, without affecting other key metabolic pathways. The importance of alanine aminotransferase in inflammatory bowel disease is discussed.
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Received: 21 February 2011; in revised form: 14 April 2011 / Accepted: 18 April 2011 / Published: 28 April 2011
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Abstract: Past research has demonstrated that oestrogenic compounds produce strand breaks in the DNA of sperm and lymphocytes via reactive oxygen species (ROS). In the current investigation, sperm and lymphocytes were treated in vitro with oestrogenic compounds (diethylstilboestrol, progesterone, 17β-oestradiol, noradrenaline and triiodotyronine) and several aspects of DNA damage were investigated. Firstly, mediation of DNA damage by lipid peroxidation was investigated in the presence of BHA (a lipid peroxidation blocker). BHA reduced the DNA damage generated by 17β-oestradiol and diethylstilboestrol in a statistically significant manner. No effects were observed for sperm. Secondly, the presence of oxidized bases employing FPG and EndoIII were detected for lymphocytes and sperm in the negative control and after 24 h recovery in lymphocytes but not immediately after treatment for both cell types. The successful detection of oxidized bases in the negative control (untreated) of sperm provides an opportunity for its application in biomonitoring studies. DNA repair at 24 h after exposure was also studied. A nearly complete recovery to negative control levels was shown in lymphocytes 24 h recovery after oestrogenic exposure and this was statistically significant in all cases. Rapid rejoining of DNA, in a matter of hours, is a characteristic of DNA damaged by ROS.
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Received: 8 January 2012 / Published: 9 February 2012
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Abstract: It has been brought to our attention by the corresponding author that the results presented this article [1] are in error due to the fact that the media supplement glutaMAX was used in place of L-glutamine for culture of the control cells, while L-glutamine was used for culture of the treated cells. All authors have confirmed that the reported result could not be reproduced using the correct culture conditions. We would like to thank the authors for pointing out this error thereby upholding the ethics of scientific publication. The Editorial Team and Publisher have agreed with the authors that this manuscript should be retracted. We apologize for any inconvenience this may have caused.
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Last update: 12 January 2011
