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Case Reports 2014; 35(5): 411-416 PubMed PMID: 25275259 Citation  Keywords:  ATP-Binding Cassette Transporters:genetics, Adolescent, Adrenal Insufficiency:diagnosis, Adrenoleukodystrophy:diagnosis, Amino Acid Sequence, Base Sequence, Brain:pathology, Cognition Disorders:diagnosis, Humans, Magnetic Resonance Imaging, Male, Middle A.   

OBJECTIVES: X-linked adrenoleukodystrophy is a genetically determined disorder that causes varying degrees of malfunction of the adrenal cortex and central nervous system. Our aim was to investigate the occurrence of known, or new, mutations in the ABCD1 gene in two unrelated patients with clinical suspicion of the adrenoleukodystrophy.

METHODS: Two unrelated patients - the first with behavioral changes, the second with progressive cognitive deficit - underwent a clinical and genetic examination in order to establish a diagnosis and discover a possible mutation.

RESULTS: In the first patient, a 47 year old man, the clinical examination showed dementia of the frontal type and spastic quadriparesis. The patient also suffered from adrenal insufficiency for 6 years. An MRI showed confluent hyperintensive lesions in FLAIR images in the frontal lobe of both hemispheres. The second patient, a 16 year old boy, suffered also from Addison's disease since the age of 9, and developed cognitive deficit in the course of one year. The MRI showed posterior atrophy and hyperintensive lesions in parietal and occipital lobes in T2WI. In both cases, genetic analyses showed a missense mutation at the codon 887 (A>G) in exon 1 of the ABCD1 gene, predicting the substitution Y296C in the ALD protein.

CONCLUSION: We detected the same mutation of the ABCD1 gene in two unrelated patients with ALD. In the first case there was frontal lobe involvement, in the second case parieto-occipital involvement. Both pathologic involvement and clinical presentation differed in two cases of the same mutation....

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Case Reports 2014; 35(2): 89-94 PubMed PMID: 24878972 Citation  Keywords:  Adaptor Proteins, Signal Transducing:genetics, Adult, Colorectal Neoplasms, Hereditary Nonpolyposis:complications, DNA Mismatch Repair:genetics, Fatal Outcome, Female, Humans, MutL Protein Homolog 1, Neuroendocrine Tumors:etiology, Nuclear Proteins:geneti.   

: Neuroendocrine tumors rarely occur in the cervix or other components of the reproductive system. These tumors have been associated with microsatellite instability, are very aggressive and often associated with poor outcome. Lynch syndrome is an inherited cancer syndrome that has also been associated with microsatellite instability. Here we report a 34-year-old female with Lynch syndrome and a family history of loss of DNA mismatch of the hereditary non-polyposis colorectal cancer repair gene expression who presented with a neuroendocrine tumor of her cervix as the first manifestation of Lynch syndrome. This is the first case reported of a neuroendocrine tumor of the cervix in a patient with Lynch syndrome. We also review the relationship between Lynch Syndrome and neuroendocrine tumors....

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Journal Article 2014; 35(1): 13-19 PubMed PMID: 24625911 Citation  Keywords:  Actins:chemistry, Animals, Brain-Derived Neurotrophic Factor:physiology, Female, Hippocampus:cytology, Interleukin-1beta:physiology, NF-kappa B:antagonists & inhibitors, Neurons:cytology, Rats, Rats, Wistar, Signal Transduction:physiology,.   

OBJECTIVES: To examine the effect of BDNF on F-actin during the stimulation of IL-1β in hippocampal neurons.

MATERIALS & METHODS: We cultured hippocampal neurons from rat embryos. Cell stimulation was induced by IL-1β. Cell culture success was evaluated by an activity analysis of CCK-8, staining of gliocyte by immunohistochemistry. Changes in F-actin, BDNF and NF-ĸB were examined using molecular analyses.

RESULTS: Our results demonstrate that a high concentration of IL-1β exaggerates the stimulation-induced degradation of F-actin by BDNF, whereas a low concentration of IL-1β protects F-actin against this degradation. These beneficial effects might be associated with the inhibition or exaggeration of the NF-ĸB signaling cascade.

CONCLUSIONS: Taken together, our findings indicate that BDNF acts as an F-actin-protective regulator during stimulation by IL-1β and that this function largely occurs via the regulation of NF- ĸB signaling. These results suggest that interventions targeting the BDNF signaling system may be of therapeutic value against major depressive disorder (MDD)....

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Journal Article 2013; 34(7): 675-680 PubMed PMID: 24464006 Citation  Keywords:  Adult, Aged, Cadherins:genetics, Carcinogenesis:genetics, DNA Methylation:genetics, Endometrial Neoplasms:epidemiology, Endometrium:physiology, Female, Gene Expression Regulation, Neoplastic, Glutathione S-Transferase pi:genetics, Humans, Hyperplasia:epid.   

OBJECTIVES: Endometrial cancer is one of the most common malignancies in women. The prevention has failed so far to develop an effective screening program and its incidence is rising in proportion to the incidence of cervical cancer. In recent years the investigation of malignancy genomics (genetic and epigenetic changes) has become the main focus of scientists because of its high sensitivity and specificity.

MATERIAL AND METHODS: We conducted a prospective longitudinal study at the Dpt. of Gynaecology and Obstetrics of the Jessenius Faculty of Medicine in Martin from 2010 to 2012, in collaboration with the Institute of Pathology of the University Hospital in Martin. We analysed paraffin blocks of endometrial tissue from 123 women with endometrial cancer, hyperplasia and normal endometrial findings. By the use of bisulphidic modification technique and nested methylation-specific PCR (MSP), we analysed the methylation patterns of three genes: GSTP1, E-cad, RASSF1.

RESULTS: We found a statistically significant increase of methylation of the RASSF1 gene in endometrial cancer compared to simplex hyperplasia and intact endometrial tissue (p<0.001). GSTP1 and E-cad did not show any relevant methylation pattern in various endometrial lesions.

CONCLUSION: According to the results of our study, RASSF1 gene methylation could serve as a prognostic factor of endometrial carcinogenesis and could help to predict the behaviour of endometrial hyperplasia....

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Journal Article 2013; 34(Suppl 2): 116-122 PubMed PMID: 24362103 Citation  Keywords:  Animals, Antioxidants:metabolism, Aspirin:toxicity, Behavior, Animal:drug effects, Environmental Exposure, Fishes:metabolism, Glutathione Transferase:metabolism, Lipid Peroxidation:drug effects, Oxidative Stress:drug effects, Thiobarbituric Acid Reactive .   

OBJECTIVES: The aim of this study was to investigate the effects of subchronic exposure of juvenile development stages of zebrafish (Danio rerio) to acetylsalicylic acid using selected oxidative stress biomarkers.

DESIGN: Toxicity test with acetylsalicylic acid was performed according to the OECD Guideline No. 215, fish D. rerio aged 30 days were used. The tested concentrations were 0.004, 0.4, 40, 120 and 250 mg.L-1, duration of the test was 28 days. Products of lipid peroxidation and antioxidant enzymes were determined as the markers of oxidative stress.

RESULTS: Significantly increased glutathione S-transferase activity was found in fish exposed to acetylsalicylic acid concentrations 40, 120 and 250 mg.L-1. The highest values of glutathione reductase activity were found in the groups exposed to acetylsalicylic acid concentrations 0.4, 40 and 120 mg.L-1. In the group exposed to acetylsalicylic acid concentrations 40 mg.L-1, catalase activity was significantly higher compared to the control group. Significantly higher glutathione peroxidase activity was found in the groups exposed to acetylsalicylic acid concentrations 0.004 and 120 mg.L-1. The concentrations of TBARS were lower in fish exposed to acetylsalicylic acid at all tested concentrations compared to control.

CONCLUSION: The subchronic exposure of zebrafish to acetylsalicylic acid causes an increase in activity of antioxidant and biotransformation enzymes and a decrease in lipid peroxidation....

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Journal Article 2013; 34(Suppl 2): 109-115 PubMed PMID: 24362102 Citation  Keywords:  Animals, Biomarkers:analysis, Brain:drug effects, Cytochrome P-450 CYP1A1:metabolism, Cytochrome P-450 Enzyme System:metabolism, Czech Republic, Environmental Monitoring:methods, Fishes:blood, Gills:chemistry, Glutathione Transferase:metabolism, Kidney:ch.   

OBJECTIVES: The objective of the presented study was to investigate levels of the most important biochemical markers in fish which were caught upstream and downstream from sites near waste water treatment plants situated at 3 selected small streams of the Czech Republic. Organic pollutants and mercury were determined in muscle tissue of fish for complex assessment.

DESIGN: Levels of biochemical markers (cytochrome P450 (CYP450), ethoxyresorufin-O-deethylase (EROD), glutathione S-transferase (GST), vitellogenin (VTG)) were measured in selected tissues (liver, plasma, brain, gill and kidney) samples of brown trout. The concentrations of persistent organic pollutants (POPs) and mercury were determined in muscle samples.

RESULTS: Significantly higher levels of biochemical markers (EROD, GST, VTG) were measured downstream from waste water treatment plant (WWTP) in Vlachovo Březí (the small Libotýňský brook). Values of biochemical markers at the other localities Černý brook and Moravice River were measured downstream from WWTP consistently or slightly lower with values of upstream. The values of POPs and mercury were in all monitored sites higher upstream compared with downstream from WWTP. The highest values of POPs and mercury were found on Černý brook in Bruntál (more industrial and agricultural activity).

CONCLUSION: The highest occurrence of selected POPs and mercury was generally upstream suggesting that small WWTP are able to partially remove these substances in those locations. But finding higher values of biochemical markers in downstream shows that there are many other substances endocrine disrupting chemicals (EDCs) that WWTP are unable to remove....

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Journal Article 2013; 34(Suppl 2): 102-108 PubMed PMID: 24362101 Citation  Keywords:  Animals, Anti-Inflammatory Agents, Non-Steroidal:toxicity, Biomarkers:metabolism, Catalase:metabolism, Dose-Response Relationship, Drug, Glutathione Peroxidase:metabolism, Glutathione Reductase:metabolism, Glutathione Transferase:metabolism, Ibuprofen:tox.   

OBJECTIVES: The aim of the study was to investigate the effects of subchronic exposure of zebrafish to ibuprofen, using selected oxidative stress parameters as a target.

DESIGN: Toxicity tests were performed on Danio rerio according to OECD No. 203 and No. 215. In the growth test, fish were exposed to subletal concentrations of ibuprofen (0.0001, 0.05, 1, 8, and 25 mg.L-1) for 28 days. For the assessment of free radical defense in fish, the catalytic activities of glutathione reductase (GR), glutathione S-transferase (GST), glutathione peroxidase (GPx), and catalase (CAT), as well as the concentration of malondialdehyde (MDA) were measured.

RESULTS: Ibuprofen did not affect the activity of glutathione reductase and catalase. A significant (p<0.01) increase in the activity of glutathione peroxidase was found, which was proved dose-dependent (10.58 nmol NADPH per min per mg protein in the control and 20.53, 26.36, 26.89, and 45.87 nmol NADPH per min per mg protein in the ibuprofen concentrations of 0.5, 1, 8, and 25 mg.L-1. An increased (p<0.05) activity of glutathione S-transferase in the highest concentration was found compared to control. Malondialdehyde levels were found significantly (p<0.01) decreased from control in the concentrations of 0.0001 and 8 mg.L-1, but no dose-dependence was found.

CONCLUSION: The results suggest that ibuprofen causes the increase in the activity of some antioxidative and biotransformation enzymes in zebrafish (GPx and GST). We also found a significant decrease in lipid peroxidation in the concentrations of 0.0001 and 8 mg.L-1 compared to control....

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Journal Article 2013; 34(Suppl 2): 43-54 PubMed PMID: 24362092 Citation  Keywords:  Animals, Antineoplastic Agents:pharmacokinetics, Benzo(a)pyrene:pharmacology, Biotransformation:drug effects, Cytochrome P-450 CYP1A1:metabolism, Cytochrome P-450 CYP1A2:metabolism, Cytochrome P-450 Enzyme System:metabolism, Drug Evaluation, Preclinical, .   

OBJECTIVES: The aim of this study was to investigate a role of cytochrome P450 (CYP) and peroxidase in ellipticine oxidative activation in two mouse strains differing in expression of NADPH:CYP reductase (POR) [the HRN (Hepatic Cytochrome P450 Reductase Null) mice, in which POR is deleted in hepatocytes and its wild-type (WT) counterpart], and in levels of CYP1A1/2 and cytochrome b5 that were modulated by treatment of these mouse models with a CYP1A inducer, benzo[a]pyrene (BaP).

METHODS: Ellipticine-DNA adducts were detected by 32P-postlabeling. HPLC was employed for the separation and characterization of ellipticine metabolites.

RESULTS: Hepatic microsomes of HRN and WT mice activate ellipticine to form ellipticine-derived DNA adducts. A 2.2- and 10.4-fold increase in amounts of ellipticine-derived DNA adducts formed by liver microsomes was caused by exposure of HRN and WT mice to BaP, respectively. The results found and utilization of NADPH and arachidonic acid, cofactors of CYP- and cyclooxygenase (COX)-dependent enzyme systems, respectively, as well as inhibitors of CYP1A1/2 and 3A, demonstrate that the CYP1A and 3A enzymes play a major role in ellipticine activation in liver microsomes. In addition, the COX enzyme is important in ellipticine activation in liver of HRN mice.

CONCLUSION: The CYP1A and 3A enzymes activate ellipticine mainly in liver of WT mice, whereas peroxidase COX plays this role in liver of HRN mice. Treatment of mice with BaP increases an impact of CYP1A on ellipticine activation. A pattern of expression levels of these enzymes plays a crucial role in their impact on this process....

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