Iuf Leibniz Institute For Umweltmedizinische Forschung

Düsseldorf, Germany

Iuf Leibniz Institute For Umweltmedizinische Forschung

Düsseldorf, Germany

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Weber J.,Jacobs University Bremen | McInnes J.,Jacobs University Bremen | McInnes J.,Catholic University of Leuven | Kizilirmak C.,Jacobs University Bremen | And 7 more authors.
European Journal of Cell Biology | Year: 2017

Thyroid hormone (TH) target cells need to adopt mechanisms to maintain sufficient levels of TH to ensure regular functions. This includes thyroid epithelial cells, which generate TH in addition to being TH-responsive. However, the cellular and molecular pathways underlying thyroid auto-regulation are insufficiently understood. In order to investigate whether thyroglobulin processing and TH export are sensed by thyrocytes, we inactivated thyroglobulin-processing cathepsins and TH-exporting monocarboxylate transporters (Mct) in the mouse. The states of thyroglobulin storage and its protease-mediated processing and degradation were related to the levels of TH transporter molecules by immunoblotting and immunofluorescence microscopy. Thyroid epithelial cells of cathepsin-deficient mice showed increased Mct8 protein levels at the basolateral plasma membrane domains when compared to wild type controls. While the protein amounts of the thyroglobulin-degrading cathepsin D remained largely unaffected by Mct8 or Mct10 single-deficiencies, a significant increase in the amounts of the thyroglobulin-processing cathepsins B and L was detectable in particular in Mct8/Mct10 double deficiency. In addition, it was observed that larger endo-lysosomes containing cathepsins B, D, and L were typical for Mct8- and/or Mct10-deficient mouse thyroid epithelial cells. These data support the notion of a crosstalk between TH transporters and thyroglobulin-processing proteases in thyroid epithelial cells. We conclude that a defect in exporting thyroxine from thyroid follicles feeds back positively on its cathepsin-mediated proteolytic liberation from the precursor thyroglobulin, thereby adding to the development of auto-thyrotoxic states in Mct8 and/or Mct10 deficiencies. The data suggest TH sensing molecules within thyrocytes that contribute to thyroid auto-regulation. © 2017 The Authors.


PubMed | National Institute for Public Health and the Environment, Helmholtz Center Munich, University of Edinburgh, Copenhagen University and 12 more.
Type: | Journal: Environmental health perspectives | Year: 2016

A rich literature exists that has demonstrated adverse human health effects following exposure to ambient air particulate matter (PM), with strong support for an important role for ultrafine (nano-sized) particles. At present, relatively little human health or epidemiology data exists for engineered nanomaterials (NM) despite clear parallels in their physicochemical properties and biological actions in NMs are available in a range of physicochemical characteristics which allow a more systematic toxicological analysis. Therefore, the study of ultrafine particles (UFP, <100 nm in diameter) provides an opportunity to identify plausible health effects for NM, while the study of NM provides an opportunity to facilitate the understanding of the mechanism of toxicity of UFP.A workshop of experts systematically analysed the information available and identified 19 key Lessons that can facilitate knowledge exchange between these discipline areas.Key lessons range from the availability of specific techniques and standard protocols for physicochemical characterization and toxicology assessment, to understanding and defining dose and the molecular mechanisms of toxicity. This review identifies a number of key areas where additional research prioritisation would facilitate both research fields simultaneously.There is now an opportunity to apply knowledge from NM toxicology and use it to better inform PM health risk research and vice versa.


Krutmann J.,IUF Leibniz Institute for Umweltmedizinische Forschung | Krutmann J.,University of Dosseldorf | Berking C.,Ludwig Maximilians University of Munich | Berneburg M.,University of Regensburg | And 3 more authors.
Skin Pharmacology and Physiology | Year: 2015

Actinic keratosis (AK) or lesions of epidermal dysplasia occurring in skin chronically exposed to solar radiation is very prevalent in lighter skin persons, with chronic long-Term sun exposure being the major risk factor. With an aging population it is expected that the prevalence of AK will further increase. AK can progress to nonmelanoma skin cancer (NMSC) and is a public health concern. Six leading dermatologists with expertise in AK and NMSC from Germany met to discuss the nature of the disease and the prevention and treatment strategies available to dermatologists today. While cosmetic sunscreen products form an essential element of sun protection strategies, they are not adequate when damage has already been inflicted. Newly developed products of the medical device category offer DNA repair function paired with high sun protection factor (SPF) UV protection. An adjuvant treatment algorithm for various risk levels of AK was developed. For patients with low and moderate risk, sunscreen only is recommended. For patient groups with high and very high risk, a very high photoprotection and photorepair action (DNA repair enzymes) in medical device products all year round is recommended. © 2015 S. Karger AG, Basel.


Flexeder C.,Helmholtz Center for Environmental Research | Thiering E.,Helmholtz Center for Environmental Research | Bruske I.,Helmholtz Center for Environmental Research | Koletzko S.,Ludwig Maximilians University of Munich | And 11 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2012

Background: Growth velocities during infancy might affect the risk of asthma in childhood. This study examines the association between peak height and weight velocities during the first 2 years of life and onset of asthma and wheeze up to 10 years of age. Methods: Data from 9086 children who participated in the GINIplus and LISAplus birth cohorts were analyzed. Information on asthma was requested annually from 1 to 10 years and information on wheeze at 1, 2, 4, 6, and 10 years. Peak height and weight velocities were calculated using height and weight measurements obtained between birth and 2 years of age. Cox proportional hazards models and generalized linear mixed models were calculated after adjustment for potential confounding factors including birth weight and body mass index at 10 years of age. Results: Per interquartile range increase in peak weight velocity (PWV), the risk of asthma increased significantly (adjHR: 1.22; CI: 1.02-1.47). The relationship between peak height velocity (PHV) and onset of asthma was nonsignificant (adjHR: 1.08; CI: 0.88-1.31). Wheeze was not significantly associated with PHV or with PWV (adjOR: 1.07; CI: 0.64-1.77 and adjOR: 1.11; CI: 0.68-1.79, respectively). Conclusions: Weight gain during infancy is positively associated with physician-diagnosed asthma in school-aged children. © 2011 John Wiley & Sons A/S.


Standl M.,Helmholtz Center for Environmental Research | Sausenthaler S.,Helmholtz Center for Environmental Research | Lattka E.,Helmholtz Center for Environmental Research | Koletzko S.,Ludwig Maximilians University of Munich | And 12 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2012

Background: The protective effect of breastfeeding (BF) on the development of asthma has been widely recognized, even if not all results have been consistent. Gene variants of the FADS gene cluster have a major impact on fatty acid composition in blood and in breast milk. Therefore, we evaluated the influence of the FADS1 FADS2 gene cluster polymorphisms on the association between BF and asthma. Methods: The analysis was based on data (N = 2245) from two German prospective birth cohort studies. Information on asthma and BF during the first 6 months was collected using questionnaires completed by the parents. Logistic regression modelling was used to analyse the association between exclusive BF and ever having asthma stratified by genotype. Results: In the stratified analyses, BF for 3 or 4 months after birth had a protective effect for heterozygous and homozygous carriers of the minor allele (adjusted odds ratio between 0.37 (95% CI: 0.18-0.80) and 0.42 (95% CI: 0.20-0.88). Interaction terms of BF with genotype were significant and ranged from -1.17 (P-value: 0.015) to -1.33 (0.0066). Moreover, heterozygous and homozygous carriers of the minor allele who were exclusively breastfed for 5 or 6 months after birth had a reduced risk of asthma [0.32 (0.18-0.57) to 0.47 (0.27-0.81)] in the stratified analyses. For individuals carrying the homozygous major allele, BF showed no significant effect on the development of asthma. Conclusions: The association between exclusive BF and asthma is modified by the genetic variants of FADS genotypes in children. © 2011 John Wiley & Sons A/S.


Kroker M.,Iuf Leibniz Institute For Umweltmedizinische Forschung | Sydlik U.,Iuf Leibniz Institute For Umweltmedizinische Forschung | Autengruber A.,Iuf Leibniz Institute For Umweltmedizinische Forschung | Cavelius C.,Leibniz Institute for New Materials | And 3 more authors.
Particle and Fibre Toxicology | Year: 2015

Background: Exposure of the airways to carbonaceous nanoparticles can contribute to the development of immune diseases both via the aggravation of the allergic immune response in sensitized individuals and by adjuvant mechanisms during the sensitization against allergens. The cellular and molecular mechanisms involved in these adverse pathways are not completely understood. We recently described that the reduction of carbon nanoparticle-induced lung inflammation by the application of the compatible solute ectoine reduced the aggravation of the allergic response in an animal system. In the current study we investigated the influence of carbon nanoparticles on the sensitization of animals to ovalbumin via the airways. Ectoine was used as a preventive strategy against nanoparticle-induced neutrophilic lung inflammation. Methods: Balb/c mice were repetitively exposed to the antigen ovalbumin after induction of airway inflammation by carbon nanoparticles, either in the presence or in the absence of ectoine. Allergic sensitization was monitored by measurement of immunoglobulin levels and immune responses in lung and lung draining lymph nodes after challenge. Furthermore the role of dendritic cells in the effect of carbon nanoparticles was studied in vivo in the lymph nodes but also in vitro using bone marrow derived dendritic cells. Results: Animals exposed to antigen in the presence of carbon nanoparticles showed increased effects with respect to ovalbumin sensitization, to the allergic airway inflammation after challenge, and to the specific TH2 response in the lymph nodes. The presence of ectoine during the sensitization significantly reduced these parameters. The number of antigen-loaded dendritic cells in the draining lymph nodes was identified as a possible cause for the adjuvant effect of the nanoparticles. In vitro assays indicate that the direct interaction of the particles with dendritic cells is not able to trigger CCR7 expression, while this endpoint is achieved by lung lavage fluid from nanoparticle-exposed animals. Conclusions: Using the intervention strategy of applying ectoine into the airways of animals we were able to demonstrate the relevance of neutrophilic lung inflammation for the adjuvant effect of carbon nanoparticles on allergic sensitization. © 2015 Kroker et al.


Vierkotter A.,Iuf Leibniz Institute For Umweltmedizinische Forschung
Hautarzt | Year: 2011

Extrinsic skin aging is the skin aging process induced by environmental factors. The most prominent environmental factor leading to extrinsic skin aging is the sun; therefore extrinsic skin aging is also known as photoaging. However, numerous studies in recent years have shown that smoking leads to extrinsic skin aging. Further, very recently it has been shown, that environmental pollution by traffic is also associated with the occurrence of signs of extrinsic skin aging. Thus, in preventive skin aging strategies the long-term exposure towards air pollution by traffic must also be considered. © 2011 Springer-Verlag.


Peuschel H.,Iuf Leibniz Institute For Umweltmedizinische Forschung | Sydlik U.,Iuf Leibniz Institute For Umweltmedizinische Forschung | Grether-Beck S.,Iuf Leibniz Institute For Umweltmedizinische Forschung | Felsner I.,Iuf Leibniz Institute For Umweltmedizinische Forschung | And 8 more authors.
Particle and Fibre Toxicology | Year: 2012

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. © 2012 Peuschel et al.; licensee BioMed Central Ltd.


Eckers A.,Iuf Leibniz Institute For Umweltmedizinische Forschung | Altschmied J.,Iuf Leibniz Institute For Umweltmedizinische Forschung | Haendeler J.,Iuf Leibniz Institute For Umweltmedizinische Forschung
Zeitschrift fur Gerontologie und Geriatrie | Year: 2012

Reactive oxygen species (ROS) are important signaling molecules in human cells. At physiological concentrations, they can for instance protect against apoptosis and act as secondary messengers in many different signaling pathways. Disturbance of redox homeostasis, i.e., the physiological balance between ROS generation and degradation, leads to not only increased ROS levels, so-called oxidative stress, but also results in damage to macromolecules and promotes the development of diseases and accelerates the aging process. The organism has various enzyme systems at hand to eliminate excess ROS. Their inactivation or degradation under conditions of oxidative stress is tightly linked to endothelial dysfunction due to endothelial cell apoptosis, a loss of telomerase activity, and telomere shortening. Restricted endothelial function causes cardiovascular diseases and diabetes type 2. © Springer-Verlag 2012.

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