Publications (20)85.88 Total impact
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Article: Carbon nanoparticles induce ceramide- and lipid raft-dependent signalling in lung epithelial cells: a target for a preventive strategy against environmentally-induced lung inflammation.
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ABSTRACT: BACKGROUND: Particulate air pollution in lung epithelial cells induces pathogenic endpoints like proliferation, apoptosis, and pro-inflammatory reactions. The activation of the epidermal growth factor receptor (EGFR) is a key event responsible for signalling events involving mitogen activated protein kinases specific for these endpoints. The molecular events leading to receptor activation however are not well understood. These events are relevant for the toxicological evaluation of inhalable particles as well as for potential preventive strategies in situations when particulate air pollution cannot be avoided. The current study therefore had the objective to elucidate membrane-coupled events leading to EGFR activation and the subsequent signalling cascade in lung epithelial cells. Furthermore, we aimed to identify the molecular target of ectoine, a biophysical active substance which we described to prevent carbon nanoparticle-induced lung inflammation. METHODS: Membrane signalling events were investigated in isolated lipid rafts from lung epithelial cells with regard to lipid and protein content of the signalling platforms. Using positive and negative intervention approaches, lipid raft changes, subsequent signalling events, and lung inflammation were investigated in vitro in lung epithelial cells (RLE-6TN) and in vivo in exposed animals. RESULTS: Carbon nanoparticle treatment specifically led to an accumulation of ceramides in lipid rafts. Detailed analyses demonstrated a causal link of ceramides and subsequent EGFR activation coupled with a loss of the receptor in the lipid raft fractions. In vitro and in vivo investigations demonstrate the relevance of these events for carbon nanoparticle-induced lung inflammation. Moreover, the compatible solute ectoine was able to prevent ceramide-mediated EGFR phosphorylation and subsequent signalling as well as lung inflammation in vivo. CONCLUSION: The data identify a so far unknown event in pro-inflammatory signalling and contribute to the understanding of particle cell interaction and therefore to risk identification and risk assessment of inhalable xenobiotics. Moreover, as this cellular reaction can be prevented by the well tolerated substance ectoine, a molecular preventive strategy for susceptible persons against airway inflammation is proposed.Particle and Fibre Toxicology 12/2012; 9(1):48. · 7.25 Impact Factor -
Article: Recovery of neutrophil apoptosis by ectoine: a new strategy against lung inflammation.
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ABSTRACT: The life span of neutrophilic granulocytes has determining impact on the intensity and duration of neutrophil driven lung inflammation. Based on the compatible solute ectoine, we aimed to prevent anti-apoptotic reactions in neutrophils triggered by the inflammatory microenvironment in the lung.Neutrophils from COPD patients and control individuals were exposed to inflammatory mediators and xenobiotics in the presence or absence of ectoine. The in vivo relevance of this approach was tested in xenobiotic-induced lung inflammation in rats.The reduction of apoptosis rates of ex vivo exposed neutrophils from persons of all study groups was significantly restored in the presence of ectoine. However, natural apoptosis rates not altered by inflammatory stimuli were not changed by ectoine. Mechanistic analyses demonstrated the preventive effect of ectoine on the induction of anti-apoptotic signalling. Neutrophilic lung inflammation induced by single or multiple exposition of animals to environmental particles was reduced after the therapeutic intervention with ectoine. Analyses of neutrophils from bronchoalveolar lavage indicate that the in vivo effect is due to the restoration of neutrophil apoptosis.Ectoine, a compound of the highly compliant group of compatible solutes, demonstrates a reproducible and robust effect on the resolution of lung inflammation.European Respiratory Journal 10/2012; · 5.89 Impact Factor -
Article: Unhealthy diet and ultrafine carbon black particles induce senescence and disease associated phenotypic changes.
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ABSTRACT: Diet and pollution are environmental factors known to compromise "healthy aging" of the cardiovascular and respiratory systems. The molecular consequences of this permanent burden in these cells are still unknown. Therefore, this study investigates the impact of unhealthy diet on aging-related signaling pathways of human, primary cardiovascular cells and of airborne particles on lung epithelial and human endothelial cells. Nutrition health reports have shown that the diet in industrialized countries contains more than 100mg/dl low density lipoprotein (LDL) and a high fraction of added sugars, especially fructose. Several studies demonstrated that ultrafine particles can enter the circulation and thus may interact with endothelial cells directly. Both, dietary compounds and pollution derived particles, have been shown to increase the risk for cardiovascular diseases. To simulate an unhealthy diet, we supplemented cell culture media of human primary endothelial cells, smooth muscle cells and cardiomyocytes with LDL and replaced 1/3 of glucose with fructose. We observed hypertrophy in cardiomyocytes, enhanced proliferation in smooth muscle cells and increased senescence, loss of endothelial nitric oxide synthase and increased nuclear FoxO3A in endothelial cells. With respect to pollution we have used ultrafine carbon black particles (ufCB), one of the major constituents of industrial and exhaust emissions, in concentrations our lungs and vessels are constantly exposed to. These concentrations of ufCB increased reactive oxygen species in lung epithelial and vascular endothelial cells and reduced the S-NO content, a marker for NO-bioavailability, in endothelial cells. NO increases activation of Telomerase Reverse Transcriptase (TERT), an enzyme essential for telomere maintenance. TERT is required for proper endothelial cell function and is inactivated by Src kinase under conditions of oxidative stress. ufCB significantly increased Src kinase activation and reduced Telomerase activity in endothelial and lung epithelial cells. As a consequence, ufCB increased senescence of endothelial cells. To investigate whether ufCB show also effects in vivo, we instilled ufCB in concentrations not inducing inflammation into mice. Indeed, eNOS expression was reduced in the abdominal aorta of animals treated with ufCB. Thus, a combination of fructose and LDL in the diet and ufCB, as a major constituent of air pollution, seem to accelerate respiratory and cardiovascular cellular changes, which may compromise "healthy aging" and can lead to cardiovascular and pulmonary diseases.Experimental gerontology 04/2012; · 3.34 Impact Factor -
Article: Endothelial NADPH oxidase 2: when does it matter in atherosclerosis?
Cardiovascular research 02/2012; 94(1):1-2. · 5.80 Impact Factor -
Article: c-Src-mediated activation of Erk1/2 is a reaction of epithelial cells to carbon nanoparticle treatment and may be a target for a molecular preventive strategy.
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ABSTRACT: Owing to their specific physico/chemical properties, engineered as well as environmental nanoparticles can induce pathogenic endpoints in humans. Earlier studies demonstrated that pure carbon nanoparticles induce cell signaling events at the level of membrane receptor activation in lung epithelial cells. As a possible link between receptor activation and subsequent MAP-kinase signaling, the involvement of Src family kinases was investigated in cell lines of organs potentially exposed to environmental nanoparticles. Human cells from bronchus, intestine, and skin (keratinocytes) as well as rat lung epithelial cells showed similar time patterns for the activation of mitogen-activated protein kinases Erk1/2 as well as Src family kinases (SFK) when treated with carbon nanoparticles. Moreover, c-Src was identified as an integral part of the signaling mediating the transfer of information from membrane receptors to members of the proliferative signaling cascade in lung epithelial cells. Pretreatment of cells with the compatible solute ectoine, which is known to stabilize macromolecules, reduced the nanoparticle specific phosphorylation of SFK. Together with earlier in vivo and in vitro data, this demonstrates that compatible solutes prevent nanoparticle-induced signaling steps at the level of membrane-coupled signaling.Biological Chemistry 11/2010; 391(11):1327-32. · 2.96 Impact Factor -
Article: Reactive oxygen species as mediators of membrane-dependent signaling induced by ultrafine particles.
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ABSTRACT: Cell-membrane-dependent proliferative signal transduction activated by ultrafine carbon particles in lung epithelial cells involves the specific induction of Akt and ERK1/2 phosphorylation. Particle-induced generation of reactive oxygen species (ROS) and oxidative stress are regarded as initial molecular mechanisms leading to the induction of diverse cellular responses. Therefore, we aimed to analyze the ROS dependence of the induced activation of the Akt/ERK1/2 signaling pathway upon exposure to ultrafine particulate matter (UPM). For this, ultrafine carbon black (ufCB) and ferric sulfate (FS) were used as a model representing the carbonaceous core and a nonparticulate Fenton-reactive transition metal salt often found in combustion-derived UPM. Cell-free as well as intracellular particle-induced ROS generation was assessed and related to the induced Akt and ERK1/2 phosphorylation by inhibiting oxidative stress with catalase, superoxide dismutase, and N-acetylcysteine. We show here that the activation of this signal transduction pathway was mainly due to intracellular, rather than extracellular, ROS production induced by both ufCB and FS. Further inhibitor studies on the role of cell membrane receptors pointed to the epidermal growth factor receptor as a common mediator for particle- as well as transition metal-induced signaling, whereas integrin-dependent Akt and ERK1/2 activation seems to be particle-specific.Free radical biology & medicine 08/2010; 49(4):597-605. · 5.42 Impact Factor -
Article: Cellular responses to nanoparticles: Target structures and mechanisms
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ABSTRACT: Nanotechnology makes use of the special surface properties of extremely small particles. In this rapidly growing field, many different materials are produced for a multitude of diverse applications. Possible adverse health effects of these materials however are so far scarcely investigated and are therefore a special task of toxicology. Although strategies for risk assessment have been suggested, the authors of the current review emphasize the fact that on the cellular, subcellular and molecular levels, interactions between nanoparticles (NP) and target cells relevant for the induction of possible adverse health effects are poorly understood. On the basis of existing literature, the potentially most relevant cellular target sites of NP as well as the so far known major molecular events specifically induced by these xenobiotics are reviewed. Starting with NP uptake across the cell membrane, mechanisms of generation of reactive oxygen species and the activation of redox-sensitive signalling cascades are described. Besides the cell membrane, mitochondria and cell nucleus are considered as major cell compartments relevant for possible NP-induced toxicity. Finally, an integrated research protocol is proposed to identify fundamental cellular responses to NP in order to complement current toxicological screening strategies with a mechanism-based approach.07/2009; 1(1):52-71. -
Article: The compatible solute ectoine protects against nanoparticle-induced neutrophilic lung inflammation.
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ABSTRACT: Inflammatory reactions of the airways induced by nanoparticles of occupational and environmental origin contribute to organ-specific and systemic human diseases. Because this kind of exposure in modern societies is often unavoidable, a strategy of molecular prevention on an individual level could help to prevent inflammation-derived secondary diseases. To test whether the compatible solute ectoine [(S)-2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid], which is known to reduce cell stress effects on a molecular level, prevents nanoparticle-induced lung inflammation. Inflammatory parameters were studied in Fischer 344 rats treated with model carbon nanoparticles. The molecular effects of ectoin on proinflammatory signal transduction were demonstrated in the rat and in the human system using cultured lung epithelial cells. Ectoine, given with or before the nanoparticles, dose-dependently reduced neutrophil inflammation in the lung. This preventive effect was not observed when lung inflammation was induced by bacterial lipopolysaccharide. Analyses of the underlying mode of action revealed that ectoine acted on lung epithelial cells. Ectoine administration inhibited nanoparticle-induced signaling, which is known to be responsible for proinflammatory reactions in rat lung epithelial cells in vitro as well as in vivo. These findings were corroborated and extended in experiments with cultured human bronchial epithelial cells in which ectoine inhibited nanoparticle-triggered cell signaling and IL-8 induction. Because compatible solutes are compliant natural products without known toxic potential, we propose that this group of substances may be used for the prevention of particle-induced airway inflammation in humans.American Journal of Respiratory and Critical Care Medicine 04/2009; 180(1):29-35. · 11.08 Impact Factor -
Article: Changes of lipid raft membrane composition as early events in nanoparticle-induced signalling
Toxicology Letters - TOXICOL LETT. 01/2009; 189. -
Article: The forkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicin-mediated cytotoxicity.
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ABSTRACT: The forkhead superfamily of transcription factors, which play major roles in control of cellular proliferation, oxidative stress and apoptosis, are becoming more and more considered as crucial therapeutic targets in cancer. In this study, we addressed the contribution of class O of forkhead box transcription factor (FOXO) 4 transcription factor, a forkhead superfamily member, to cytotoxicity mediated by the anthracyclic drug doxorubicin. FOXO4 can be phosphorylated by phosphatidylinositol-3-kinase/AKT signaling resulting in its inactivation and nuclear exclusion. Under stress conditions, FOXO4 can be phosphorylated via jun N-terminal kinase (JNK) leading to increased transcriptional activation of the transcription factor. Our results show that doxorubicin incubation led to phosphorylation of AKT and concomitantly to AKT-dependent inactivation and nuclear exclusion of the tumor suppressor FOXO4 in Hct-116 cells. We found that inhibition of FOXO4 nuclear exclusion by blockage of AKT phosphorylation following overexpression of dominant-negative AKT enhanced doxorubicin-mediated cytotoxicity. Overexpression of wild-type FOXO4 led to an increase in doxorubicin-mediated cytotoxicity, which was further exacerbated by overexpression of a solely nuclear-localized FOXO4 mutant. In contrast, though doxorubicin resulted in JNK activation, modulation of JNK-dependent regulation of FOXO4 was of no effect to doxorubicin cytotoxicity. These results show for the first time that in Hct-116 cells sustained nuclear localization of FOXO4 seems to be one crucial point enhancing doxorubicin-induced cytotoxicity and apoptosis. Targeting FOXO4 or AKT may lead to new chances in sensitizing cancer cells to cytostatic drugs thereby allowing use of lower drug concentrations and minimizing drug-induced adverse effects in patients.Carcinogenesis 09/2008; 29(11):2045-52. · 5.70 Impact Factor -
Article: Carbon nanoparticle-induced lung epithelial cell proliferation is mediated by receptor-dependent Akt activation.
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ABSTRACT: Treatment of lung epithelial cells with different kinds of nano-sized particles leads to cell proliferation. Because bigger particles fail to induce this reaction, it is suggested that the special surface properties, due to the extremely small size of these kinds of materials, is the common principle responsible for this specific cell reaction. Here the activation of the protein kinase B (Akt) signaling cascade by carbon nanoparticles was investigated with regard to its relevance for proliferation. Kinetics and dose-response experiments demonstrated that Akt is specifically activated by nanoparticulate carbon particles in rat alveolar type II epithelial cells as well as in human bronchial epithelial cells. This pathway appeared to be dependent on epidermal growth factor receptor and beta(1)-integrins. The activation of Akt by these receptors is known to be a feature of adhesion-dependent signaling. However, intracellular proteins described in this context (focal adhesion kinase pp125(FAK) and integrin-linked kinase) were not activated, indicating a specific signaling mechanism. Inhibitor studies demonstrate that nanoparticle-induced proliferation is mediated by phosphoinositide 3-kinases and Akt. Moreover, overexpression of mutant Akt, as well as pretreatment with an Akt inhibitor, reduced nanoparticle-specific ERK1/2 phosphorylation, which is decisive for nanoparticle-induced proliferation. With this report, we describe the activation of a pathway by carbon nanoparticles that was so far known to be triggered by ligand receptor binding or on cell adhesion to extracellular matrix proteins.AJP Lung Cellular and Molecular Physiology 03/2008; 294(2):L358-67. · 3.66 Impact Factor -
Article: Lack of association of delta-aminolevulinate dehydratase polymorphisms with blood lead levels and hemoglobin in Romanian women from a lead-contaminated region.
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ABSTRACT: As part of a project on environmental pollution, this study aimed to evaluate associations between blood lead (BPb) levels, hemoglobin (Hb) content, and single-nucleotide polymorphisms (SNPs) of delta-aminolevulinic acid dehydratase (ALAD) gene in 129 unrelated women from Romania. Five SNPs (rs1805313, rs2228083, rs1805312, rs1800435, rs1139488) were analyzed with respect to haplotype structure and impact on BPb levels and Hb content with proportional odds and analysis of covariance models. Combinations of SNPs were rare (16%). Low haplotype diversity was found with seven haplotypes. One rare haplotype implied the C allele of rs1800435, often referred to as the ALAD2 allele (frequency 8.6%). The putative risk genotype (CC) occurred in only one woman with BPb below 0.5 microg/dl. Median BPb was 4.8 microg/dl and differed markedly by community with a level of 12.5 microg/dl near a mining-spill region. Hb was regular (interquartile range 12.3-13.7 g/dl) and not correlated with BPb, although quantitatively lower in women living near the spill region. No significant associations were found for BPb or Hb with SNPs, haplotypes, or diplotypes. BPb levels were higher in this region than in populations from industrialized countries but without hematotoxic effects. An impact of ALAD2 on BPb or Hb was not seen in these women.Journal of Toxicology and Environmental Health Part A 02/2008; 71(11-12):716-24. · 1.83 Impact Factor -
Article: Ultrafine carbon particles induce apoptosis and proliferation in rat lung epithelial cells via specific signaling pathways both using EGF-R.
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ABSTRACT: Apoptosis and proliferation are important causes of adverse health effects induced by inhaled ultrafine particles. The molecular mechanisms of particle cell interactions mediating these end points are therefore a major topic of current particle toxicology and molecular preventive medicine. Initial studies revealed that ultrafine particles induce apoptosis and proliferation in parallel in rat lung epithelial cells, dependent on time and dosage. With these end points, two antagonistic reactions seem to be induced by the same extracellular stimulus. It was therefore investigated whether proliferation is induced directly by the particles or as a compensation of particle-caused cell death. Experimental conditions excluding compensatory proliferation demonstrated that both end points are induced independently by specific signaling pathways. Events eliciting signaling cascades leading to apoptosis and proliferation were studied with specific inhibitors of membrane receptors. Epidermal growth factor receptor (EGF-R) kinase activity was identified as essential for apoptosis as well as for proliferation. As ultrafine particle-induced proliferation alone was dependent on the activation of beta1-integrins, these membrane receptors are suggested to mediate the specificity of EGF-R signaling concerning the decision as to whether apoptosis or proliferation is triggered. Accordingly, MAP kinase signaling downstream of EGF-R showed comparable specificity with regard to receptor-dependent induction of apoptosis and proliferation. As key mediators of signaling cascades, the activation of extracellular signal-regulated kinases 1 and 2 proved to be specific for proliferation in a beta1-integrin-dependent manner, whereas phosphorylation of c-Jun NH2-terminal kinases 1 and 2 was correlated with the induction of apoptosis.AJP Lung Cellular and Molecular Physiology 11/2006; 291(4):L725-33. · 3.66 Impact Factor -
Article: Variation of the N-acetyltransferase 2 gene in a Romanian and a Kyrgyz population.
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ABSTRACT: As part of a project on environmental disasters in minority populations, this study aimed to evaluate differences in the sequence of N-acetyltransferase 2 (NAT2) as a metabolic susceptibility gene in yet unexplored ethnicities. Eight single nucleotide polymorphisms (SNP) in the NAT2 coding region and a variant in the 3' flanking region were analyzed in 290 unrelated Kyrgyz and 140 unrelated Romanians by SNP-specific PCR analysis. The variants 341C, 481T, and 803G were less and 857A more prevalent in Kyrgyz (P < 0.0001). The variant at site 857 indicates Asian descent. 282C>T and 590G>A showed no significant variation by ethnicity. 364G>A and 411A>T turned out to be monomorphic. Database comparisons of the NAT2 minor allele frequencies support that Romanians belong to Caucasians and Kyrgyz are in between Caucasians and East Asians. The distributions of predicted haplotypes differed significantly between the two ethnicities where the Kyrgyz showed a higher genetic diversity. The haplotype without mutations was more common in Kyrgyz (40.1% in Kyrgyz, 29.3% in Romanians). Accordingly, the imputed slow acetylator phenotype was less prevalent in Kyrgyz (35.2% versus 51.4% in Romanians). We found pronounced ethnic differences in NAT2 genotypes with yet unknown effect on the health risks for environmental or occupational exposures in minority populations.Cancer Epidemiology Biomarkers & Prevention 01/2006; 15(1):138-41. · 4.12 Impact Factor -
Article: Induction of 8-hydroxydeoxyguanosine by man made vitreous fibres and crocidolite asbestos administered intraperitoneally in rats.
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ABSTRACT: Inhaled fibres with certain physico-chemical properties are known to induce mesothelioma in humans. The induction of reactive oxygen (ROS) or nitrogen species (RNS) have been suggested as molecular mechanism of fibre induced carcinogenesis. In earlier studies we were able to demonstrate that crocidolite asbestos in vivo induces mutations in transgenic rats with a specific molecular spectrum that indicates the involvement of 8-hydroxydeoxyguanosine (8-OHdG) as pre-mutagenic adduct. 8-OHdG may be induced by primary (direct) and/or secondary (cellular mediated) mechanisms. Therefore, the induction of 8-OHdG as well as the inflammatory response of animals treated with fibre samples significantly differing in their physico-chemical characteristics was investigated. As appropriate system to study mesothelioma carcinogenesis, intraperitoneal injection in rats was used with samples of UICC crocidolite, crocidolite with reduced iron content, and a vitreous fibre (MMVF 11). Equal numbers of carcinogenic fibres from each sample revealed significant comparable increases in 8-OHdG induction. Parameters of inflammation (percentage of macrophages and TNF-alpha secretion) correlated significantly with the induction of 8-OHdG, 10 weeks after treatment.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 10/2004; 553(1-2):59-65. · 2.85 Impact Factor -
Article: Signal transduction pathways relevant for neoplastic effects of fibrous and non-fibrous particles.
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ABSTRACT: Apart from their genotoxic effects, both fibrous and non-fibrous particles are known to induce signalling pathways involved in the development of malignant lung diseases. Different direct effects of particles as well as indirect cellular effects are believed to induce changes in apoptosis or proliferation in target cells. Signalling events, e.g. the induction of mitogen-activated protein kinase (MAPK) cascades resulting in the activation of the transcription factor AP-1, as well as the induction of the transcription factor NFkappaB which mainly mediates the expression of pro-inflammatory genes are discussed. There is some insight into the molecular mechanisms eliciting these pathways. Therefore, this review aims to give an overview on signalling pathways as well as initial events including effects of reactive oxygen and nitrogen species, membrane receptors and particle uptake.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 10/2004; 553(1-2):23-35. · 2.85 Impact Factor -
Article: beta1-integrin mediates asbestos-induced phosphorylation of AKT and ERK1/2 in a rat pleural mesothelial cell line.
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ABSTRACT: Integrin-mediated signalling has been implicated in asbestos-induced carcinogenesis. In studies here, we examined signal transduction events associated with integrin-directed cell reactions triggered by crocidolite asbestos in the pleural mesothelial cell line 4/4 RM-4. Crocidolite fibres induced a significant time- and dose-dependent activation of the extracellular-signal-regulated kinases ERK1 and ERK2. ERK activation was specifically inhibited by integrin-blocking agents, that are integrin-binding peptides containing the sequence arginine-glycine-aspartic acid (RGD), and monoclonal antibodies against the integrin beta1-chain. Integrin-dependent activation of ERK1/2 in response to asbestos appeared to be independent of focal adhesion kinase pp125FAK (FAK) since FAK autophosphorylation remained unaffected in crocidolite-exposed mesothelial cells. Instead, we observed striking similarities in the kinetics of asbestos-induced ERK1/2 responses and phosphorylation of protein kinase B (AKT) at serine 473, a possible target residue for integrin-linked kinase. As with ERK activation, asbestos-induced AKT stimulation was significantly blocked by both the RGD-peptide and the beta1-integrin antibodies. These studies are the first to establish that in mesothelial cells ERK1/2 and AKT are simultaneously phosphorylated upon asbestos exposure in a beta1-integrin-dependent manner.Oncogene 12/2003; 22(52):8524-8. · 6.37 Impact Factor -
Article: Environmental arsenic exposure from a coal-burning power plant as a potential risk factor for nonmelanoma skin carcinoma: results from a case-control study in the district of Prievidza, Slovakia.
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ABSTRACT: To investigate the risk of arsenic exposure from a coal-burning power plant in Slovakia on nonmelanoma skin cancer (NMSC) development, a 1996-1999 population-based case-control study was conducted with 264 cases and 286 controls. Exposure assessment was based on residential history and annual emissions (Asres1, Asres2) and on nutritional habits and arsenic content in food (Asnut1, Asnut2). Asres1 was assessed as a function of the distance of places of residence to the plant. Asres2 additionally considered workplace locations. Asnut1 was used to calculate arsenic uptake by weighting food frequencies with arsenic concentrations and annual consumption of food items. Asnut2 additionally considered consumption of local products. Age- and gender-adjusted risk estimates for NMSC in the highest exposure category (90th vs. 30th percentile) were 1.90 (95% confidence interval (CI): 1.39, 2.60) for Asres1, 1.90 (95% CI: 1.38, 2.62) for Asres2, 1.19 (95% CI: 0.64, 2.12) for Asnut1, and 1.83 (95% CI: 0.98, 3.43) for Asnut2. No interaction was found between arsenic exposure and dietary and residential data. Other plant emissions could have confounded the distance-based exposure variables. Consumption of contaminated vegetables and fruits could be confounded by the protective effects of such a diet. Nevertheless, the authors found an excess NMSC risk for environmental arsenic exposure.American Journal of Epidemiology 06/2002; 155(9):798-809. · 5.22 Impact Factor -
Article: Distinct spectrum of mutations induced by crocidolite asbestos: clue for 8-hydroxydeoxyguanosine-dependent mutagenesis in vivo.
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ABSTRACT: DNA damage due to reactive oxygen or nitrogen species is proposed to be involved in the molecular mechanism of asbestos-induced carcinogenicity. However, indications for this hypothesis came mainly from in vitro assays using cultured cells or cell-free systems. In the present study, the mutagenicity of crocidolite fibers and the underlying molecular mechanisms were investigated in vivo. Mutation frequencies were determined in DNA of omenta, a relevant target tissue for mesothelioma carcinogenesis, using lacI transgenic rats. The mutagenic effect of 2 and 5 mg of crocidolite asbestos was demonstrated, with a maximal relative increase in mutation frequency of 3.4 compared with the control group. The molecular analysis of the mutations revealed striking differences according to mutation types between asbestos-induced mutations and spontaneous mutations. Therefore, a specific molecular mechanism induced by crocidolite that differs from that induced by the generation of spontaneous mutations can be proposed. G to T transversions, which are known to be induced by the premutagenic DNA adduct 8-hydroxydeoxyguanosine (8-OHdG), were the most prominent mutation type (29%) within crocidolite-induced mutations. In additional experiments, 8-OHdG in DNA of omenta from rats treated with 1 or 2 mg of crocidolite asbestos was determined. Levels of 8-OHdG in animals treated with crocidolite were significantly increased compared with negative controls. These data give strong evidence for the involvement of reactive oxygen or nitrogen species in crocidolite-induced mutagenesis in vivo.Cancer Research 02/2002; 62(1):99-104. · 7.86 Impact Factor -
Article: Importance of Surface Characteristics of Quartz DQ12 for Acute Inflammation
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ABSTRACT: Although quartz is known to induce inflammation in rat lungs, the mechanisms by which it does so are not yet fully understood. The importance of particle surface characteristics was investigated in vivo after intratracheal instillation of different preparations of quartz in rat lungs. Three days after instillation of 2 mg of DQ12 quartz, or DQ12-coated with polyvinylpyridine- N -oxide or aluminium lactate (AL), lungs of female Wistar rats were lavaged in situ to determine markers of inflammation. Control rats received saline or the coating substances alone. DQ12 induced a marked inflammatory response, as indicated by a significant increase in the number of neutrophils and macrophages, as well as in the levels of β-glucuronidase and myeloperoxidase. None of these inflammatory markers was increased for both coated quartz preparations, with the exception of neutrophil influx, which was increased after treatment with AL quartz. Our results indicate that surface characteristics are important in the onset of quartz-induced lung inflammation and, by implication, the development of persistent inflammation. This will be investigated in later follow-up time points of the same animal study.
Top co-authors
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Institutions
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2004–2010
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Leibniz-Institut für Umweltmedizinische Forschung
Düsseldorf, North Rhine-Westphalia, Germany
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2003–2009
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Heinrich-Heine-Universität Düsseldorf
- Institut für Umweltmedizinische Forschung (IUF) an der HHU
Düsseldorf, North Rhine-Westphalia, Germany
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