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In vitro and in vivo studies on oxygen free radical and DNA adduct formation in rat lung and liver during benzo[a]pyrene metabolism 总被引:2,自引:0,他引:2
Briedé JJ Godschalk RW Emans MT De Kok TM Van Agen E Van Maanen J Van Schooten FJ Kleinjans JC 《Free radical research》2004,38(9):995-1002
Reactive oxygen species (ROS), possibly produced during the metabolic conversion of benzo(a)pyrene (B[a]P), could be involved in B[a]P-induced genotoxicity and, eventually, carcinogenicity. Therefore, ROS formation by rat lung and liver microsomes was studied in vitro by electron spin resonance (ESR/EPR) spectrometry. B[a]P-mediated generation of ROS was detected in incubations with rat lung, but not with liver microsomes. Inhibition of cytochrome P450 (CYP450) by the non isoform-specific inhibitor SKF-525A resulted in a complete inhibition of B[a]P-dependent ROS formation, whereas ROS formation was not affected by inhibition of prostaglandin H synthase by indomethacin. Subsequently, bulky DNA adduct formation and 8-oxo-dG levels after a single oral dose of B[a]P were examined in vivo in rat lung and liver, in combination with urinary excretion of 8-oxodG. B[a]P exposure resulted in increased urinary 8-oxo-dG levels. On the contrary, 8-oxo-dG levels decreased in liver and lung after B[a]P exposure. Bulky DNA adducts reached higher levels and were more persistent in rat lung than in liver. These results indicate that ROS are generated during the CYP450 dependent metabolism of B[a]P, particularly in the rat lung, but this does not necessarily result in increased levels of oxidative DNA damage in vivo, possibly by induction of DNA repair mechanisms. 相似文献
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Background
Automated identification of cell cycle phases of individual live cells in a large population captured via automated fluorescence microscopy technique is important for cancer drug discovery and cell cycle studies. Time-lapse fluorescence microscopy images provide an important method to study the cell cycle process under different conditions of perturbation. Existing methods are limited in dealing with such time-lapse data sets while manual analysis is not feasible. This paper presents statistical data analysis and statistical pattern recognition to perform this task. 相似文献34.
Langie SA Knaapen AM Ramaekers CH Theys J Brun J Godschalk RW van Schooten FJ Lambin P Gray DA Wouters BG Chiu RK 《DNA Repair》2007,6(6):852-862
Benzo[a]pyrene exerts its mutagenic effects via induction of benzo[a]pyrene-diol-epoxide (BPDE)-DNA adducts. Such helix-distorting adducts are not always successfully repaired prior to DNA replication, which may result in a blocked replication fork. To alleviate this stall, cells utilize DNA damage tolerance systems involving either error-free damage avoidance or error-prone translesion synthesis. Studies in yeast suggest the modification of PCNA by lysine 63-linked poly-ubiquitin (K63-polyUb) chains as a key mediator of the error-free damage avoidance pathway. Recently, we extended this observation to human cells, showing the occurrence of poly-ubiquitination of PCNA in UV-irradiated human cells. In the present study, we hypothesized that disrupting the formation of K63-polyUb chains inhibits damage avoidance and favors error-prone repair involving low-fidelity polymerases (e.g. POLeta), causing increased BPDE-induced mutagenicity. To test this hypothesis, we generated A549 cells expressing either a mutant ubiquitin (K63R-Ub) which blocks further ubiquitination through K63, or the wild type ubiquitin (WT-Ub). We show that PCNA is poly-ubiquitinated in these cells upon BPDE-exposure and that disruption of K63-polyUb chain formation has no effect on BPDE-induced toxicity. In contrast, significantly higher frequencies of BPDE-induced HPRT mutations were observed in K63R-Ub expressing cells, of which the majority (74%) was G-->T transversion. BPDE treatment caused an enhanced recruitment of POLeta to the replication machinery of the K63R-Ub expressing cells, where it co-localized with PCNA. Suppression of POLeta expression by using siRNA resulted in a 50% reduction of BPDE-induced mutations in the K63R cells. In conclusion, we demonstrated that formation of K63-polyUb chains protects BPDE-exposed human cells against translesion synthesis-mediated mutagenesis. These findings indicate that K63-polyubiquitination guards against chemical carcinogenesis by preventing mutagenesis and thus contributing to genomic stability. 相似文献
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Hong Zhao Jinmin Zhu Kemi Cui Xiaoyin Xu Megan O'Brien Kelvin K Wong Santosh Kesari Weiming Xia Stephen TC Wong 《Cancer cell international》2009,9(1):15
Background
Cancer and Alzheimer's disease (AD) are two seemingly distinct diseases and rarely occur simultaneously in patients. To explore molecular determinants differentiating pathogenic routes towards AD or cancer, we investigate the role of amyloid β protein (Aβ) on multiple tumor cell lines that are stably expressing luciferase (human glioblastoma U87; human breast adenocarcinoma MDA-MB231; and mouse melanoma B16F). 相似文献36.
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Tobamoviruses, mostly isolated from solanaceous plants, may represent
ancient virus lineages that have codiverged with their hosts. Recently
completed nucleotide sequences of six nonsolanaceous tobamoviruses allowed
assessment of the codivergence hypothesis and support a third subgroup
within tobamoviruses. The genomic sequences of 12 tobamoviruses and the
partial sequences of 11 others have been analyzed. Comparisons of the
predicted protein sequences revealed three clusters of tobamoviruses,
corresponding to those infecting solanaceous species (subgroup 1), those
infecting cucurbits and legumes (subgroup 2), and those infecting
crucifers. The orchid-infecting odontoglossum ringspot tobamovirus was
associated with subgroup 1 genomes by its coat and movement protein
sequences, but with the crucifer-pathogenic tobamoviruses by the remainder
of its genome, suggesting that it is the progeny of a recombinant. For four
of five genomic regions, subgroup 1 and 3 genomes were equidistant from a
subgroup 2 genome chosen for comparison, suggesting uniform rates of
evolution. A phylogenetic tree of plant families based on the tobamoviruses
they harbor was congruent with that based on rubisco sequences but had a
different root, suggesting that codivergence was tempered by rare events of
viruses of one family colonizing another family. The proposed subgroup 3
viruses probably have an origin of virion assembly in the movement protein
gene, a large (25-codon) overlap of movement and coat protein open reading
frames, and a comparably shorter genome. Codon-position- dependent base
compositions and codon prevalences suggested that the coat protein frame of
the overlap region was ancestral. Bootstrapped parsimony analysis of the
nucleotides in the overlap region and of the sequences translated from the
-1 frame (the subgroup 3 movement protein frame) of this region produced
trees inconsistent with those deduced from other regions. The results are
consistent with a model in which a no or short overlap organization was
ancestral. Despite encoding of subgroup 2 and 3 movement protein C-termini
by nonhomologous nucleotides, weak similarities between their amino acid
sequences suggested convergent sequence evolution.
相似文献