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Kosir R.,University of Ljubljana | Zmrzljak U.P.,University of Ljubljana | Bele T.,University of Ljubljana | Acimovic J.,University of Ljubljana | And 6 more authors.
FEBS Journal | Year: 2012

The cytochrome P450 (CYP) genes Cyp51, Cyp11a1, Cyp17a1, Cyb11b1, Cyp11b2 and Cyp21a1 are involved in the adrenal production of corticosteroids, whose circulating levels are circadian. cAMP signaling plays an important role in adrenal steroidogenesis. By using cAMP responsive element modulator (Crem) knockout mice, we show that CREM isoforms contribute to circadian expression of steroidogenic CYPs in the mouse adrenal gland. Most striking was the CREM-dependent hypomethylation of the Cyp17a1 promoter at zeitgeber time 12, which resulted in higher Cyp17a1 mRNA and protein expression in the knockout adrenal glands. The data indicate that products of the Crem gene control the epigenetic repression of Cyp17 in mouse adrenal glands. © 2012 FEBS.


Balasubramanian S.K.,National University of Singapore | Poh K.-W.,National University of Singapore | Ong C.-N.,National University of Singapore | Kreyling W.G.,German Research Center for Environmental Health GmbH | And 2 more authors.
Biomaterials | Year: 2013

Airborne engineered nanoparticles undergo agglomeration, and careful distinction must be made between primary and agglomerate size of particles, when assessing their health effects. This study compares the effects on rats undergoing 15-day inhalation exposure to airborne agglomerates of gold nanoparticles (AuNPs) of similar size distribution and number concentration (1×106particles/cm3), but two different primary diameters of 7nm or 20nm. Inhalation of agglomerates containing 7-nm AuNPs resulted in highest deposition by mass concentration in the lungs, followed by brain regions including the olfactory bulb, hippocampus, striatum, frontal cortex, entorhinal cortex, septum, cerebellum; aorta, esophagus, and kidney. Eight organs/tissues especially the brain retained greater mass concentration of Au after inhalation exposure to agglomerates of 7-nm than 20-nm AuNPs. Macrophage mediated escalation followed by fecal excretion is the major pathway of clearing inhaled AuNPs in the lungs. Microarray analyses of the hippocampus showed mostly downregulated genes, related to the cytoskeleton and neurite outgrowth. Together, results in this study indicate disintegration of nanosized agglomerates after inhalation and show impact of primary size of particles on subsequent biodistribution. © 2013 Elsevier Ltd.


Beyerle A.,German Research Center for Environmental Health GmbH | Beyerle A.,University of Marburg | Long A.S.,Environmental Health science and Research Bureau | White P.A.,Environmental Health science and Research Bureau | And 2 more authors.
Molecular Pharmaceutics | Year: 2011

Genotoxicity information on polymers used for gene delivery is scant, but of great concern, especially when developing polymeric nanocarriers as nonviral vector systems for cancer treatment. The genotoxicity of some engineered nanomaterials, e.g., metal oxides like ZnO, TiO 2, and CuO but also carbon based materials like carbon black or nanotubes, has commonly been related to oxidative stress, and subsequent inflammation. Recent studies of poly(ethylene imine) (PEI)-based polymers, important nonviral vector systems for pDNA and siRNA, might raise concerns because of their toxic effects dominated by cellular oxidative stress and inflammatory responses, similar to the mentioned effects of engineered nanoparticles. In this study, we employed a FE1-MutaMouse lung epithelial cell line based mutation assay to determine the genotoxicity of three PEI-based polymers and nanosized zinc oxide particles (NZO), all of which have previously been shown to trigger oxidative stress and inflammation. In addition, oxidative DNA damage (8-OH-dG) in FE1 cells was assessed by ELISA. The well-known carcinogen benzo[a]pyrene (B[a]P) was used as positive control. FE1 lung epithelial cells were exposed for eight sequential 72 h incubations, and reporter-gene mutation frequency or 8-OH-dG formation was determined to assess mutagenicity and oxidative DNA damage, respectively. No cytotoxic effects were detected at the exposure levels examined, which are representative of PEI concentrations normally used in in vitro transfection studies. In contrast to B[a]P, neither PEI-polymers nor NZO showed any significant mutagenic activity or oxidative DNA damage in the exposed cells, although PEI-based polymers have been shown to generate significant levels of cellular stress and inflammatory responses. We suggest that the lack of any detectable mutagenic/genotoxic activity of the PEI-based polymers studied here is a crucial step toward a safe use of such nanocarriers in clinical trials. © 2011 American Chemical Society.


Marcon A.,University of Verona | Cerveri I.,University of Pavia | Wjst M.,German Research Center for Environmental Health GmbH | Wjst M.,TU Munich | And 14 more authors.
Journal of Allergy and Clinical Immunology | Year: 2014

Background: Evidence on the longitudinal association of airway responsiveness with respiratory diseases is scarce. The best indicator of responsiveness is still undetermined. Objective: We investigated the association of airway responsiveness with the incidence of asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis. Methods: We studied 3851 subjects who underwent spirometry and methacholine challenge tests both at baseline (1991-1993), when they were 20 to 44 years old, and at follow-up (1999-2002) in the European Community Respiratory Health Survey. Airway responsiveness was defined based on the methacholine dose-response slope on both occasions. Incidence rate ratios for the association of airway responsiveness with disease occurrence were computed by using Poisson regression. Results: With respect to reference (slope of the fourth quintile or greater), subjects with the greatest degree of airway responsiveness (slope less than the first quintile) showed the greatest risk of developing asthma, COPD, and allergic rhinitis (incidence rate ratios of 10.82, 5.53, and 4.84, respectively; all P <.01). A low slope predicted disease occurrence, even in subjects who did not reach a 20% decrease in FEV1 at the cumulative dose of 1 mg of methacholine (PD20 >1 mg). A decrease in slope over time was an independent predictor of disease risk. Conclusion: Airway responsiveness predicted new-onset asthma, COPD, and allergic rhinitis. Our study supports the use of a continuous noncensored indicator of airway responsiveness, such as the slope of the methacholine dose-response curve, in clinical practice and research because it showed clear advantages over PD20. © 2013 American Academy of Allergy, Asthma & Immunology.


Kl A.,University of Marburg | Sonar S.S.,University of Marburg | Sonar S.S.,ETH Zurich | Yildirim A.O.,German Research Center for Environmental Health GmbH | And 3 more authors.
Journal of Allergy and Clinical Immunology | Year: 2011

Background: Excessive extracellular matrix deposition occurs as a result of repetitive injury-repair cycles and plays a central role in the pathogenesis of chronic inflammatory diseases, such as allergic asthma. The molecular mechanism leading to aberrant collagen deposition is not fully understood. Objective: We sought to test the hypothesis that increased nerve growth factor (NGF) production contributes to collagen deposition in the airways during chronic allergic airway inflammation. Methods: Antibody-blocking experiments were performed in an in vivo model for chronic allergic airway inflammation (allergic asthma), which is accompanied by matrix deposition in the subepithelial compartment of the airways, to study the profibrotic effect of NGF. The signaling pathways were delineated with in vivo and in vitro studies in primary lung fibroblasts. Results: Functional blocking of NGF in chronically affected mice markedly prevented subepithelial fibrosis. Transgenic overexpression of NGF in murine airways resulted in altered airway wall morphology with increased peribronchial collagen deposition and impaired lung physiology in the absence of inflammation. NGF exerted a direct effect on collagen expression in murine lung fibroblasts, which was mainly mediated through the activation of the receptor tropomyosin-related kinase A. NGF-induced collagen expression was dependent on downstream activation of p38 mitogen-activated protein kinase independent of the TGF-β1/mothers against decapentaplegic homolog (SMAD) pathway. Conclusion: The results of this study demonstrate that NGF exerts profibrotic activities in the airways by inducing type III collagen production in fibroblasts independently of TGF-β1. © 2011 American Academy of Allergy, Asthma & Immunology.


Ditengou F.A.,Albert Ludwigs University of Freiburg | Muller A.,University of Gottingen | Rosenkranz M.,German Research Center for Environmental Health GmbH | Felten J.,Swedish University of Agricultural Sciences | And 7 more authors.
Nature Communications | Year: 2015

The mutualistic association of roots with ectomycorrhizal fungi promotes plant health and is a hallmark of boreal and temperate forests worldwide. In the pre-colonization phase, before direct contact, lateral root (LR) production is massively stimulated, yet little is known about the signals exchanged during this step. Here, we identify sesquiterpenes (SQTs) as biologically active agents emitted by Laccaria bicolor while interacting with Populus or Arabidopsis. We show that inhibition of fungal SQT production by lovastatin strongly reduces LR proliferation and that (-)-thujopsene, a low-abundance SQT, is sufficient to stimulate LR formation in the absence of the fungus. Further, we show that the ectomycorrhizal ascomycote, Cenococcum geophilum, which cannot synthesize SQTs, does not promote LRs. We propose that the LR-promoting SQT signal creates a win-win situation by enhancing the root surface area for plant nutrient uptake and by improving fungal access to plant-derived carbon via root exudates. © 2015 Macmillan Publishers Limited.


PubMed | Karlsruhe Institute of Technology and German Research Center for Environmental Health GmbH
Type: Journal Article | Journal: Global change biology | Year: 2016

The carbon- and nitrogen-rich soils of montane grasslands are exposed to above-average warming and to altered precipitation patterns as a result of global change. To investigate the consequences of climatic change for soil nitrogen turnover, we translocated intact plant-soil mesocosms along an elevational gradient, resulting in an increase of the mean annual temperature by approx. 2C while decreasing precipitation from approx. 1500 to 1000mm. Following three years of equilibration, we monitored the dynamics of gross nitrogen turnover and ammonia-oxidizing bacteria (AOB) and archaea (AOA) in soils over an entire year. Gross nitrogen turnover and gene levels of AOB and AOA showed pronounced seasonal dynamics. Both summer and winter periods equally contributed to cumulative annual N turnover. However, highest gross N turnover and abundance of ammonia oxidizers were observed in frozen soil of the climate change site, likely due to physical liberation of organic substrates and their rapid turnover in the unfrozen soil water film. This effect was not observed at the control site, where soil freezing did not occur due to a significant insulating snowpack. Climate change conditions accelerated gross nitrogen mineralization by 250% on average. Increased N mineralization significantly stimulated gross nitrification by AOB rather than by AOA. However, climate change impacts were restricted to the 2-6cm topsoil and rarely occurred at 12-16cm depth, where generally much lower N turnover was observed. Our study shows that significant mineralization pulses occur under changing climate, which is likely to result in soil organic matter losses with their associated negative impacts on key soil functions. We also show that N cycling processes in frozen soil can be hot moments for N turnover and thus are of paramount importance for understanding seasonal patterns, annual sum of N turnover and possible climate change feedbacks.


Kremmer E.,Molecular Health GmbH | Meyer K.,Universitatsklinikum des Saarlandes | Meyer K.,AG Sarikas | Grasser F.A.,Universitatsklinikum des Saarlandes | And 4 more authors.
Analytical and Bioanalytical Chemistry | Year: 2012

Procalcitonin (PCT)-a diagnostic serum parameter for bacterial infection and sepsis-is of great interest in the field of biosensors for point-of-care testing. Its detection needs specific biological recognition elements, such as antibodies. Herein, we describe the development and characterization of rat monoclonal antibodies (mAbs) for PCT, and their application in enzyme-linked immunosorbent assays (ELISAs) for the determination of PCT in patient serum samples. From about 50 mAbs, two mAbs, CALCA 2F3 and CALCA 4A6, were selected as a pair with high affinity for PCT in sandwich immunoassays. Both mAbs could be used either as capture or as detection mAb. They were Protein G-purified and biotinylated when used as detection mAb. The setup of two sandwich ELISAs with standards of human recombinant (hr) PCT, using either CALCA 2F3 (assay A) or CALCA 4A6 (assay B) as capture mAbs and the biotinylated mAbs CALCA 4A6 or CALCA 2F3, respectively, as detection mAbs, led to highly specific determinations of PCT without cross-reactivity to calcitonin and katacalcin. Test midpoints (IC 50) of both assays were determined for hrPCT standards in 4% (w/v) human serum albumin and found with 2.5 (assay A) and 2.7 μg L -1 (assay B). With both sandwich ELISAs a collection of eight patient serum samples have been determined in comparison to the determination by the Elecsys BRAHMS PCT assay. Good correlations between our prototype ELISAs and the BRAHMS assay could be demonstrated (R 2: assay A, 0.996 and assay B, 0.990). The use of these newly developed anti-PCT mAbs should find broad applications in immunosensors for point-of-care diagnostics of sepsis and systemic inflammation processes. © 2011 Springer-Verlag.


Puk O.,German Research Center for Environmental Health GmbH | De Angelis M.H.,German Research Center for Environmental Health GmbH | De Angelis M.H.,TU Munich | Graw J.,German Research Center for Environmental Health GmbH
Mammalian Genome | Year: 2013

Scheimpflug imaging has recently been established for in vivo imaging of the anterior eye segment and quantitative determination of lens transparency in the mouse. This enables more effective investigations of cataract formation with the mouse model, including longitudinal studies. In order to enable recognition of disease-associated irregularities, we performed Scheimpflug measurements with the common laboratory inbred lines C57BL/6J, C3HeB/FeJ, FVB/NCrl, BALB/cByJ, and 129/SvJ in a period between 2 and 12 months of age. C57BL/6J mice showed lowest mean lens densities during the test period. Progressive cortical lens opacification was generally observed, with the earliest onset in C57BBL/6J, C3HeB/FeJ, and 129/SvJ, between 2 and 6 months after birth. Moreover, lenses of these inbred lines developed nuclear opacities. Calculated mean lens density significantly increased between 6 and 12 months of age in all inbred strains except 129/SvJ. Lens densities (and the corresponding standard deviations) of FVB/NCrl and 129/SvJ increased most likely because of differences in the genetic background. Albinism as confounder might be excluded since the albino Balb/cByJ mice are more similar to the C57BL/6J or C3Heb/FeJ mice. We further identified strain-specific anterior lens opacities (C57BL/6J) and cloudy corneal lesions (C57BL/6J, FVB/NCrl, and BALB/cByJ) at later stages. In conclusion, our results indicate that there are lifelong opacification processes in the mouse lens. The highest lens transparency and a dark coat color, which prevents interference from light reflections, make mice with the C57BL/6J background most suitable for cataract research by Scheimpflug imaging. We show that lens densitometry by Scheimpflug imaging in mouse eyes can resolve differences of less than 1 %, making it possible to detect differences in cataract development in different mouse strains, even if they are small. © 2013 Springer Science+Business Media New York.


Puk O.,German Research Center for Environmental Health GmbH | De Angelis M.H.,German Research Center for Environmental Health GmbH | De Angelis M.H.,TU Munich | Graw J.,German Research Center for Environmental Health GmbH
Mammalian Genome | Year: 2013

Spectral domain optical coherence tomography (SD-OCT) has recently been established as a method for in vivo imaging of fundus and retina in the mouse. It enables more effective studies of retinal diseases including investigations of etiopathologic mechanisms. In order to learn more about longitudinal fundus development and to enable recognition of disease-associated irregularities, we performed confocal scanning laser ophthalmoscopy (cSLO) and SD-OCT measurements in the inbred strains C57BL/6J, C3HeB/FeJ, FVB/NCrl, BALB/cByJ, and 129S2/SvJ when they were between 2 and 6 months of age. In general, cSLO and SD-OCT data did not reveal sex-specific or unilateral differences. C3HeB/FeJ and FVB/NCrl mice showed diffuse choroidal dysplasia. Choroidal vein-like structures appeared as dark fundus stripes in C3HeB/FeJ. In FVB/NCrl, fundus fleck accumulation was found. In contrast, only minor time-dependent changes of fundus appearance were observed in C57BL/6J, BALB/cByJ, and 129S2/SvJ. This was also found for individual fundic main blood vessel patterns in all inbred strains. Vessel numbers varied between 6 and 13 in C57BL/6J. This was comparable in most cases. We further found that retinae were significantly thicker in C57BL/6J compared to the other strains. Total retinal thickness generally did not change between 2 and 6 months of age. As a conclusion, our results indicate lifelong pathologic processes in C3HeB/FeJ and FVB/NCrl that affect choroid and orbital tissues. Inbred strains with regular retinal development did not reveal major time-dependent variations of fundus appearance, blood vessel pattern, or retinal thickness. Consequently, progressive changes of these parameters are suitable indicators for pathologic outliers. © 2013 Springer Science+Business Media New York.

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