Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism

Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/β-Catenin/IGFR-IR Signaling Axis

Biglycan, a small leucine rich proteoglycan (SLRP), is an important participant in bone homeostasis and development as well as in bone pathology. In the present study biglycan was identified as a positive regulator of MG63 osteosarcoma cell growth (p ≤ 0.001). IGF-I was shown to increase biglycan expression (p ≤ 0.01), whereas biglycan-deficiency attenuated significantly both basal and IGF-I induced cell proliferation of MG63 cells (p ≤ 0.001; p ≤ 0.01, respectively). These effects were executed through the IGF-IR receptor whose activation was strongly attenuated (p ≤ 0.01) in biglycan-deficient MG63 cells. Biglycan, previously shown to regulate Wnt/β-catenin pathway, was demonstrated to induce a significant increase in β-catenin protein expression evident at cytoplasmic (p ≤ 0.01), membrane (p ≤ 0.01), and nucleus fractions in MG63 cells (p ≤ 0.05). As demonstrated by immunofluorescence, increase in β-catenin expression is attributed to co-localization of biglycan with the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) resulting in attenuated β-catenin degradation. Furthermore, applying anti-β-catenin and anti-pIGF-IR antibodies to MG-63 cells demonstrated a cytoplasmic and to the membrane interaction between these molecules that increased upon exogenous biglycan treatment. In parallel, the downregulation of biglycan significantly inhibited both basal and IGF-I-dependent ERK1/2 activation, (p ≤ 0.001). In summary, we report a novel mechanism where biglycan through a LRP6/β-catenin/IGF-IR signaling axis enhances osteosarcoma cell growth

The concentration of three anti-seizure medications in hair: the effects of hair color, controlling for dose and age

BACKGROUND: This paper assess the relationship between the quantity of three anti-seizure medications in hair and the color of the analyzed hair, while controlling for the effects of dose, dose duration, and patient age for 140 clinical patients undergoing anti-seizure therapy. Three drugs are assessed: carbamazepine (40 patients), valproic acid (40 patients), and phenytoin (60 patients). The relationship between hair assay results, hair color, dose, dose duration, and age is modeled using an analysis of covariance. The covariance model posits the hair assay results as the dependent variable, the hair color as the qualitative categorical independent variable, and dose, dose duration, and age as covariates. The null hypothesis assessed is that there is a no relationship between hair color and the quantity of analyte determined by hair assay such that darker colored hair will demonstrate higher concentrations of analyte than lighter colored hair. RESULTS: The analysis reveals that there is a significant relationship between dose and concentration for all hair color categories independent of the other covariates or the categorical independent variable. CONCLUSION: There does not appear to be any relationship between carbamazepine concentration and hair color. There is a weak relationship between hair color and valproic acid concentration, which the data suggest may be mediated by age. There is a significant, moderate relationship between phenytoin concentration and hair color such that darker colored hair has greater concentration values than lighter colored hair

Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development

Toxic metals are extensively found in the environment, households, and workplaces and contaminate food and drinking water. The crosstalk between environmental exposure to toxic metals and human diseases has been frequently described. The toxic mechanism of action was classically viewed as the ability to dysregulate the redox status, production of inflammatory mediators and alteration of mitochondrial function. Recently, growing evidence showed that heavy metals might exert their toxicity through microRNAs (miRNA)-short, single-stranded, noncoding molecules that function as positive/negative regulators of gene expression. Aberrant alteration of the endogenous miRNA has been directly implicated in various pathophysiological conditions and signaling pathways, consequently leading to different types of cancer and human diseases. Additionally, the gene-regulatory capacity of miRNAs is particularly valuable in the brain-a complex organ with neurons demonstrating a significant ability to adapt following environmental stimuli. Accordingly, dysregulated miRNAs identified in patients suffering from neurological diseases might serve as biomarkers for the earlier diagnosis and monitoring of disease progression. This review will greatly emphasize the effect of the toxic metals on human miRNA activities and how this contributes to progression of diseases such as cancer and neurodegenerative disorders (NDDs)

Impact on environment, ecosystem, diversity and health from culturing and using GMOs as feed and food

Modern agriculture provides the potential for sustainable feeding of the world's increasing population. Up to the present moment, genetically modified (GM) products have enabled increased yields and reduced pesticide usage. Nevertheless, GM products are controversial amongst policy makers, scientists and the consumers, regarding their possible environmental, ecological, and health risks. Scientific-and-political debates can even influence legislation and prospective risk assessment procedure. Currently, the scientifically-assessed direct hazardous impacts of GM food and feed on fauna and flora are conflicting; indeed, a review of literature available data provides some evidence of GM environmental and health risks. Although the consequences of gene flow and risks to biodiversity are debatable. Risks to the environment and ecosystems can exist, such as the evolution of weed herbicide resistance during GM cultivation. A matter of high importance is to provide precise knowledge and adequate current information to regulatory agencies, governments, policy makers, researchers, and commercial GMO-releasing companies to enable them to thoroughly investigate the possible risks

The European Registered Toxicologist (ERT) : Current status and prospects for advancement

Acknowledgements We would like to thank the participants of the five workshops in which the issues presented in this paper were discussed and the revised guidelines prepared, as well as the EUROTOX Executive Committee and the societies of toxicology of Sweden, the Netherlands, Switzerland, Austria and France for their support which allowed the workshops to take place.Peer reviewedPostprin