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Berlin Brandenburg

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  • 1
    Language: English
    In: Toxicology Letters, 2007, Vol.172, pp.S50-S50
    Keywords: Pharmacy, Therapeutics, & Pharmacology ; Public Health
    ISSN: 0378-4274
    E-ISSN: 1879-3169
    Source: ScienceDirect Journals (Elsevier)
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  • 2
    Language: English
    In: Bioorganic & Medicinal Chemistry, 01 February 2013, Vol.21(3), pp.814-823
    Description: The plant alkaloid lycobetaine has potent topoisomerase-targeting properties and shows anticancer activity. Based on these findings, several lycobetaine analogs were synthesized mainly differing in their substituents at 2, 8 and 9 position and their biological activities were evaluated. The topoisomerase-targeting properties and cytotoxicity of these structural analogs were assessed in the human gastric carcinoma cell line GXF251L. Performing a plasmid relaxation assay, an increased inhibition of topoisomerase I was found with -methylphenanthridinium chlorides bearing a 8,9-methylenedioxy moiety or a methoxy group in 2-position. Furthermore, quaternized phenanthridinium derivatives bearing either a 2-methoxy or a 8,9-methylenedioxy moiety in conjunction with a 2-hydroxy or 2-methoxy group display potent topoisomerase II inhibition as shown by decatenation of kinetoplast DNA. In general, the -methylphenanthridinium chlorides possess more potency in inhibiting topoisomerase I than topoisomerase II. All quaternized derivatives also exhibited potent inhibition of tumor cell growth in the low micromolar concentration range. Hence, -methylphenanthridinium compounds were found to represent a promising class of compounds, potently inhibiting both, topoisomerases I and II, and may be further developed into clinically useful topoisomerase inhibitors.
    Keywords: Lycobetaine ; Phenanthridines ; N-Methylphenanthridinium Chlorides ; DNA-Topoisomerase ; Structure–Activity ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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  • 3
    In: Nature, 2000, Vol.403(6766), p.196
    Description: Mutations in all four known KCNQ potassium channel alpha -subunit genes lead to human diseases. KCNQ1 (KvLQT1) interacts with the beta -subunit KCNE1 (IsK, minK) to form the slow, depolarization-activated potassium current I sub(Ks) that is affected in some forms of cardiac arrythmia. Here we show that the novel beta -subunit KCNE3 markedly changes KCNQ1 properties to yield currents that are nearly instantaneous and depend linearly on voltage. It also suppresses the currents of KCNQ4 and HERG potassium channels. In the intestine, KCNQ1 and KCNE3 messenger RNAs colocalized in crypt cells. This localization and the pharmacology, voltage-dependence and stimulation by cyclic AMP of KCNQ1/KCNE3 currents indicate that these proteins may assemble to form the potassium channel that is important for cyclic AMP-stimulated intestinal chloride secretion and that is involved in secretory diarrhoea and cystic fibrosis.
    Keywords: Potassium Channels ; Mutation ; Kcnq1 Gene ; Kcne3 Gene ; Proteins ; Man ; Kcne3 Gene ; Kcnq1 Gene ; Man;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 4
    Language: English
    In: Food and Chemical Toxicology, April 2014, Vol.66, pp.350-357
    Description: Piperine is responsible for the hot taste of black pepper. Publications on genotoxicity of piperine are reported: negative Ames Tests and one in vitro micronucleus test (MNT). In vivo tests were mainly negative. In the majority of the data the administered dose levels did not follow the dose selection requirements of regulatory guidelines of having dose levels up to the maximum tolerated dose (MTD). The only oral high dose studies were a positive in vivo MNT in mice in contrast to a negative in vivo chromosome aberration test in rats. Thus, conflicting results in genotoxicity testing are published. To investigate this further, we administered piperine to mice up to the MTD and determined micronuclei-frequency. Piperine reduces core body temperature and interferes with blood cells both being known to result in irrelevant positive in vivo MNTs. Therefore we added mechanistic endpoints: core body temperature, haematology, erythropoietin level, and organ weights. Additionally an in vitro MNT in Chinese hamster ovary cells was performed. Piperine was negative in the in vitro MNT. It caused significant reduction of core body temperature, decrease of white blood cells and spleen weights but no increase in the micronucleus-frequency. Thus, in our studies piperine was not genotoxic.
    Keywords: Black Pepper ; Piperine ; Micronucleus ; Genotoxicity ; Chemistry ; Public Health ; Economics
    ISSN: 0278-6915
    E-ISSN: 1873-6351
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  • 5
    Language: English
    In: Mycotoxin Research, 2010, Vol.26(4), pp.247-256
    Description: Alternariol (AOH) was reported recently to act as a topoisomerase poison. To underline the relevance of topoisomerase targeting for the genotoxic properties of AOH, we addressed the question whether human tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme vital to the repair of covalent DNA-topoisomerase adducts, affects AOH-mediated genotoxicity. The relevance of TDP1 activity on AOH-induced genotoxicity was investigated by the comet assay in human cells overexpressing GFP chimera of TDP1 or the inactive mutant TDP1 H263A as well as in cells subjected to siRNA-mediated knock-down of endogenous TDP1. Cells overexpressing TDP1 exhibited significantly less DNA damage after treatment with AOH in comparison to cells expressing the inactive mutant TDP1 H263A . In accordance with these results, levels of AOH inducing DNA strand breaks were increased in TDP1-suppressed cells in comparison to cells transfected with control siRNA. The specific topoisomerase poisons camptothecin and etoposide caused comparable effects, underlining that TDP1 plays an important role in the repair of topoisomerase-mediated DNA damage. In summary, the repair enzyme TDP1 was identified as a factor for the modulation of AOH-mediated DNA damage in human cells.
    Keywords: Genotoxicity ; Topoisomerase ; Comet assay ; ICE assay
    ISSN: 0178-7888
    E-ISSN: 1867-1632
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  • 6
    Language: English
    In: Toxicology Letters, 10 January 2013, Vol.216(1), pp.23-30
    Description: ► AOH and AME affect the redox status of HT29 cells. ► Activate the Nrf2/ARE pathway. ► But do not affect the level of fpg-sensitive sites in the DNA. ► Indicating that oxidative stress is not substantially contributing to the genotoxic properties. The mycotoxin alternariol (AOH) has been reported to possess genotoxic properties, inducing enhanced levels of DNA damage after only 1 h of incubation. In the present study we addressed the question whether the induction of oxidative stress might contribute to the genotoxic effects of AOH or its naturally occurring monomethylether (AME). In the dichlorofluorescein (DCF) assay, treatment of HT29 cells for 1 h enhanced the formation of dichlorofluorescein, indicative for ROS formation. The total glutathione (tGSH) was transiently decreased. In accordance with the results of the DCF assay, AOH and AME enhanced the proportion of the transcription factor Nrf2 in the nucleus. Concomitantly, the Nrf2/ARE-dependent genes γ-glutamylcysteine ligase (γ-GCL) and glutathione-S-transferase (GSTA1/2) showed enhanced transcript levels. After 24 h of incubation this effect was also reflected on the protein level by an increase of GST activity. However, in spite of the positive DCF assay and the activation of the redox-sensitive Nrf2/ARE-pathway, the level of oxidative DNA damage, measured in the comet assay by the addition of formamidopyrimidine-DNA-glycosylase (fpg) remained unaffected. Of note, after 3 h of incubation no significant DNA damaging potential of AOH and AME was detectable, indicating either inactivation of the compounds or enhanced DNA repair. In summary, the mycotoxins AOH and AME were found to modulate the redox balance of HT29 cells but without apparent negative effect on DNA integrity.
    Keywords: Oxidative Stress ; Mycotoxin ; Alternaria Alternata ; Nrf2-Translocation ; Glutathione ; Pharmacy, Therapeutics, & Pharmacology ; Public Health
    ISSN: 0378-4274
    E-ISSN: 1879-3169
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  • 7
    Language: English
    In: The Journal of cell biology, 16 February 2004, Vol.164(4), pp.501-7
    Description: During the past years, yeast has been successfully established as a model to study mechanisms of apoptotic regulation. However, the beneficial effects of such a cell suicide program for a unicellular organism remained obscure. Here, we demonstrate that chronologically aged yeast cultures die exhibiting typical markers of apoptosis, accumulate oxygen radicals, and show caspase activation. Age-induced cell death is strongly delayed by overexpressing YAP1, a key transcriptional regulator in oxygen stress response. Disruption of apoptosis through deletion of yeast caspase YCA1 initially results in better survival of aged cultures. However, surviving cells lose the ability of regrowth, indicating that predamaged cells accumulate in the absence of apoptotic cell removal. Moreover, wild-type cells outlast yca1 disruptants in direct competition assays during long-term aging. We suggest that apoptosis in yeast confers a selective advantage for this unicellular organism, and demonstrate that old yeast cells release substances into the medium that stimulate survival of the clone.
    Keywords: Aging -- Physiology ; Apoptosis -- Physiology ; Saccharomyces Cerevisiae -- Physiology
    ISSN: 0021-9525
    E-ISSN: 15408140
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  • 8
    In: Nature, 2005, Vol.435(7042), p.673
    Description: Trust pervades human societies. Trust is indispensable in friendship, love, families and organizations, and plays a key role in economic exchange and politics. In the absence of trust among trading partners, market transactions break down. In the absence of trust in a country's institutions and leaders, political legitimacy breaks down. Much recent evidence indicates that trust contributes to economic, political and social success. Little is known, however, about the biological basis of trust among humans. Here we show that intranasal administration of oxytocin, a neuropeptide that plays a key role in social attachment and affiliation in non-human mammals, causes a substantial increase in trust among humans, thereby greatly increasing the benefits from social interactions. We also show that the effect of oxytocin on trust is not due to a general increase in the readiness to bear risks. On the contrary, oxytocin specifically affects an individual's willingness to accept social risks arising through interpersonal interactions. These results concur with animal research suggesting an essential role for oxytocin as a biological basis of prosocial approach behaviour. [PUBLICATION ]
    Keywords: Human ; Economics ; Breaking Down ; Risk ; Biological ; Politics ; Mammals ; Copyrights ; Bears ; Attachment ; Marketing ; Documents ; Organizations ; Animals ; General and Nonclassified (MD) ; General and Nonclassified (EC) ; General and Nonclassified (Ed) ; General and Nonclassified (Ep) ; Surveying, Theory, and Analysis (CE) ; Design Principles, Theory, and Analysis (Mt) ; Computing Milieux (General) (Ci) ; Electronics and Communications Milieux (General) (Ea) ; Solid State Milieux (General) (So) ; Article;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 9
    Language: English
    In: Toxicology in Vitro, April 2016, Vol.32, pp.278-286
    Description: Several non-animal methods are now available to address the key events leading to skin sensitization as defined by the adverse outcome pathway. The KeratinoSens™ assay addresses the cellular event of keratinocyte activation and is a method accepted under OECD TG 442D. In this study, the results of an inter-laboratory evaluation of the “me-too” LuSens assay, a bioassay that uses a human keratinocyte cell line harboring a reporter gene construct composed of the rat antioxidant response element (ARE) of the NADPH:quinone oxidoreductase 1 gene and the luciferase gene, are described. Earlier in-house validation with 74 substances showed an accuracy of 82% in comparison to human data. When used in a battery of non-animal methods, even higher predictivity is achieved. To meet European validation criteria, a multicenter study was conducted in 5 laboratories. The study was divided into two phases, to assess 1) transferability of the method, and 2) reproducibility and accuracy. Phase I was performed by testing 8 non-coded test substances; the results showed a good transferability to naïve laboratories even without on-site training. Phase II was performed with 20 coded test substances (performance standards recommended by OECD, 2015). In this phase, the intra- and inter-laboratory reproducibility as well as accuracy of the method was evaluated. The data demonstrate a remarkable reproducibility of 100% and an accuracy of over 80% in identifying skin sensitizers, indicating a good concordance with in vivo data. These results demonstrate good transferability, reliability and accuracy of the method thereby achieving the standards necessary for use in a regulatory setting to detect skin sensitizers.
    Keywords: Pharmacy, Therapeutics, & Pharmacology ; Chemistry ; Public Health
    ISSN: 0887-2333
    E-ISSN: 1879-3177
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  • 10
    Language: English
    In: Molecular Nutrition & Food Research, April 2009, Vol.53(4), pp.441-451
    Description: Alternariol (AOH), a mycotoxin formed by, has been reported to possess genotoxic properties. However, the underlying mechanism of action is unclear. Here, we tested the hypothesis that interactions with DNA–topoisomerases play a role in the DNA‐damaging properties of AOH. First we compared DNA‐damaging properties of AOH with other mycotoxins such as AOH monomethyl ether (AME), altenuene and isoaltenuene. AOH and AME significantly increased the rate of DNA strand breaks in human carcinoma cells (HT29, A431) at micromolar concentrations, whereas altenuene and isoaltenuene did not affect DNA integrity up to 100 μM. Next, we selected AOH as the most DNA‐damaging metabolite for further studies of interactions with DNA topoisomerases. In cell‐free assays, AOH potently inhibited DNA relaxation and stimulated DNA cleavage activities of topoisomerase I, IIα and IIβ. Stabilisation of covalent topoisomerase II–DNA intermediates by AOH was also detectable in cell culture, and here, the IIα isoform was preferentially targeted. AOH is thus characterised as a poison of topoisomerase I and II with a certain selectivity for the IIα isoform. Since topoisomerase poisoning and DNA strand breakage occurred within the same concentration range, poisoning of topoisomerase I and II might at least contribute to the genotoxic properties of AOH.
    Keywords: Alternariol ; Dna‐Topoisomerase ; Mycotoxin
    ISSN: 1613-4125
    E-ISSN: 1613-4133
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