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Berlin Brandenburg

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  • 1
    Language: English
    In: Environmental Sciences Europe, 2011, Vol.23(1), pp.1-14
    Description: National and international governments are in the process of establishing testing programs and strategies to assess the safety of currently used chemicals with regard to their potential to interact with the endocrine system of man and wildlife, resulting in potential impacts on reproduction, growth, and/or development. Specifically, the USA, Japan, EU, and OECD have established testing approaches and regulatory frameworks with aim to assess the risks associated with chemicals that have endocrine disrupting properties (EDCs). While there has been a large amount of efforts over the past two decades in context with the assessment of chemical safety, no comparable attempts to harmonize and mutually accept testing strategies and decision-making criteria for environmental monitoring and assessment exist to date for EDCs. In fact, many of the current environmental programs such as the European Water Framework Directive (WFD) or the US Clean Water Act do not explicitly test for EDCs, and considering the unique requirements and endpoints required to assess the endocrine potential of a sample, these programs are unlikely to appropriately address exposure to these chemicals. This is of great concern since EDCs are ubiquitous in the environment, especially in aquatic ecosystems. One of most important sources for EDCs in the environment is the effluent from sewage treatment plants. Many EDCs such as the natural and synthetic estrogens 17β-estradiol and 17α-ethinylestradiol, respectively, are not completely removed with conventional wastewater treatment systems. In recognition of these concerns, in Europe, there is increasing pressure to further develop advanced wastewater treatment methods, such as ozonation and activated carbon treatment for a broad application in municipal wastewater treatment. Another issue is the continuing lack of understanding of the environmental relevance of the phenomenon of ED. A great number of studies have been conducted to describe potential ED in wild and laboratory animals. Most of these studies relied on biomarkers of estrogenicity such as vitellogenin induction in males and mild histological alterations (e.g. occurrence of testicular oocytes), and to date - with few exceptions - no convincing evidence of population relevant impacts of exposure to EDC in the wild exist. In conclusion, while there has been a great deal of research and efforts in context with the hazard assessment and regulation of EDCs, there is still a large number of remaining uncertainties and issues. These range from animal rights concerns due to significant increases in the use of animals to fulfill testing requirements, associated needs for alternative testing concepts such as in vitro , in silico , and modeling approaches, lack of understanding of the relevance of the exposure of man and wildlife to EDCs, and the need for inclusion of EDCs in current environmental programs such as the WFD. In this article we attempted to summarize the current state-of-the-art of regulatory and scientific approaches in context with EDCs, and to identify issues and future needs to address current shortcomings in the field.
    Keywords: Universities And Colleges -- Analysis ; Universities And Colleges -- Political Aspects ; Ethinyl Estradiol -- Analysis ; Ethinyl Estradiol -- Political Aspects ; Estrogens -- Analysis ; Estrogens -- Political Aspects ; Wastewater -- Analysis ; Wastewater -- Political Aspects ; Aquatic Ecosystems -- Analysis ; Aquatic Ecosystems -- Political Aspects ; Sex Hormones -- Analysis ; Sex Hormones -- Political Aspects ; Environmental Monitoring -- Analysis ; Environmental Monitoring -- Political Aspects ; Decision Making -- Analysis ; Decision Making -- Political Aspects ; Ozonization -- Analysis ; Ozonization -- Political Aspects ; Estradiol -- Analysis ; Estradiol -- Political Aspects ; Sewage Treatment -- Analysis ; Sewage Treatment -- Political Aspects ; Water Resource Management -- Analysis ; Water Resource Management -- Political Aspects;
    ISSN: 2190-4707
    E-ISSN: 1865-5084
    E-ISSN: 21904715
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  • 2
    Language: English
    In: Circulation, Nov 8, 2016, Vol.134(19)
    Keywords: Blood Pressure -- Health Aspects ; Heart Failure -- Risk Factors ; Pulmonary Hypertension -- Care And Treatment ; Smooth Muscle -- Research
    ISSN: 0009-7322
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  • 3
    Language: English
    In: Circulation, Nov 8, 2016, Vol.134(19)
    Keywords: Smooth Muscle -- Research ; Venous Thrombosis -- Patient Outcomes
    ISSN: 0009-7322
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  • 4
    In: Circulation, 2016, Vol.134(Suppl_1 Suppl 1), pp.A14222-A14222
    Description: Introduction: Pulmonary artery hypertension (PAH) is a life-threatening cardiovascular disease with poor prognosis that is caused inter alia by constriction and inward remodeling of pulmonary arteries eliciting an increase in pulmonary blood pressure. We recently reported that a pressure-induced increase in biomechanical stress triggers the transcriptional activity of nuclear factor of activated T-cells 5 (NFAT5) in arterial smooth muscle cells (SMC) to control the expression of tenascin-C - a molecular marker of PAH.Hypothesis: NFAT5 activity promotes arterial remodeling during PAH.Methods & Results: Experimental PAH was evoked by exposing NFAT5 or inducible SMC-specific NFAT5-deficient mice (NFAT5) to hypoxia for 21 days. These conditions elevated the Fulton index (right/(left + septum) ventricular weight; 0.25 (control) vs. 0.42 (PAH), p〈0.001, n=8) and led to a weight loss (16%, p〈0.05, n=8) of NFAT5 but not NFAT5 mice. Telemetric assessment of the baseline blood pressure of NFAT5 and NFAT5 mice thereby revealed no significant difference. On the molecular level, PAH triggered the expression of NFAT5 in vascular but not airway SMC of NFAT5 mice (3.36-fold, p〈0.01, n=5) and was accompanied with thickening of pulmonary arterial walls (1.85-fold, p〈0.001, n=5) as well as local accumulation of tenascin-C (2.32-fold, p〈0.01, n=5). Upon SMC-specific genetic ablation of NFAT5 all of these effects were abolished. In vitro studies indicated that blocking palmitoylation processes by Etomoxir inhibits nuclear entry and transcriptional activity of NFAT5 by 80 percent (p〈0.05, n=5) in arterial SMCs exposed to biomechanical stretch as it occurs during PAH. Further mechanistic studies showed that phosphomimetic mutations at S1197, phosphodeficient mutations at T143 or treatment with the protein kinase inhibitor dasatinib blocked nuclear translocation and transcriptional activity of NFAT5.Conclusions: Collectively, our findings indicate that chronic exposure of arterial SMCs to hypertensive wall stress activates NFAT5 and controls its entry into the nucleus. During PAH, the transcriptional targets of NFAT5 support the remodeling of pulmonary arteries which may contribute to right heart failure.
    ISSN: 0009-7322
    Source: Copyright © 2013 Lippincott Williams & Wilkins. All rights reserved.〈img src=http://exlibris-pub.s3.amazonaws.com/LWW%20logo.png style="vertical-align:middle;margin-left:7px"〉
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  • 5
    In: Circulation, 2016, Vol.134(Suppl_1 Suppl 1), pp.A16017-A16017
    Description: Venous diseases such as deep vein thrombosis or chronic venous insufficiency constitute a substantial cause of morbidity in the western world. Although most of these diseases originate from varicose vein formation, animal models mimicking their development are scarce. Venous valve failure, pregnancy or obesity pose as main risk factors for varicose vein development due to impaired venous return and therefore increased venous filling pressure. Hence, we hypothesized that experimental venous hypertension is sufficient to elicit corresponding detrimental remodeling processes. To this end, we invented a model to evoke venous hypertension by occluding one large vein in the mouse auricle resulting in enhanced tortuosity and growth (~2.5-fold, p〈0.001, n=10) of the connected veins and venules within four days. While varicose remodeling was already visible after two days, (tortuous enlargement ~1.6-fold, p〈0.05, n=10), high resolution laser doppler perfusion analyses did not exhibit a significant increase in perfusion in corresponding vein segments. Moreover, the easily accessible, nearly two-dimensionally organized venous network allowed detailed immunofluorescence-based investigations of remodeling vein segments. This revealed an increase in MMP-2 abundance and proliferation of vascular cells (~18-fold, p〈0.001, n=5) and a decrease in the smooth muscle cell (SMC) differentiation marker myocardin (~2.4-fold, p〈0.001, n=6). Additionally, the morphological features of the auricle allowed for transdermal application of water- and DMSO-soluble drugs which have previously been proven to inhibit activation of venous SMCs in vitro. Thus, blockade of activator protein -1 (AP-1) transcriptional activity by specific decoy oligodeoxynucleotides or inhibition of the proteasome by bortezomib (Velcade®) abolished the aforementioned venous remodeling processes without provoking side effects. Based on this model, we demonstrated that therapeutic transdermal inhibition of the transcriptional activity of AP-1 or the proteasome block detrimental venous remodeling evoked by a chronic increase in filling pressure. As drugs are applied locally, the burden for the animal is substantially lower as compared to systemic drug administration.
    ISSN: 0009-7322
    Source: Copyright © 2013 Lippincott Williams & Wilkins. All rights reserved.〈img src=http://exlibris-pub.s3.amazonaws.com/LWW%20logo.png style="vertical-align:middle;margin-left:7px"〉
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  • 6
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, December 2012, Vol.26(12), pp.4864-75
    Description: Zinc finger motif-1 (ZFM1) represses proinflammatory gene expression in vascular smooth muscle cells (SMCs) at a global level and thus may also be involved in the attenuation of growth factor-induced phenotype changes in these cells. Using human primary cultured thymus vein SMCs, we have investigated the molecular mechanism by which a potent SMC mitogen, platelet-derived growth factor-BB (PDGF-BB), causes a rapid decrease in ZFM1 expression in a concentration-dependent manner and consequences thereof. Reporter gene analyses and chromatin immunoprecipitation showed that PDGF-BB-induced ZFM1 repression occurs at the level of transcription through replacement of the activating transcription factor Sp1 by Egr-1. The subsequent drop in ZFM1 abundance disinhibits SMC proliferation, migration, and synthetic gene expression in a concerted manner. Stabilizing ZFM1 levels in a PDGF-BB-independent way with a GFP-ZFM1 expression construct or by using Egr-1-specific decoy oligonucleotides abrogates all PDGF-BB effects. Conversely, siRNA-mediated knockdown of ZFM1 alone not only increases the sensitivity of SMCs for PDGF-BB, but even mimics PDGF-BB-induced proliferation and gene expression. Our findings suggest that ZFM1 is an important factor for the stabilization of a contractile SMC phenotype under basal or mildly activating conditions and that, as a prerequisite for efficient action, PDGF-BB must repress ZFM1 expression to alter the SMC phenotype.
    Keywords: Cell Dedifferentiation -- Drug Effects ; Cell Proliferation -- Drug Effects ; DNA-Binding Proteins -- Metabolism ; Myocytes, Smooth Muscle -- Drug Effects ; Proto-Oncogene Proteins C-Sis -- Pharmacology ; Transcription Factors -- Metabolism
    E-ISSN: 1530-6860
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  • 7
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, October 2011, Vol.25(10), pp.3613-21
    Description: An increase in circumferential wall tension (CWT) is an important determinant of vascular remodeling during hypertension or arteriosclerosis but also arteriogenesis. Although pivotal for such processes, the effect of this biomechanical force on venous remodeling has not yet been delineated. To this end, we raised the filling pressure in veins of the mouse auricle, which led to a 2.5-fold enlargement of these blood vessels within 4 d along with an increase in smooth muscle cell proliferation, matrix metalloproteinase 2 (MMP-2) expression and gelatinase activity. These changes were likewise observed in tissue samples of human varicose veins. Topical treatment of the auricles with a decoy oligonucleotide-neutralizing activator protein 1 (AP-1) inhibited these effects. Likewise, proliferation, MMP-2 expression, and gelatinase activity in both native and cultured venous smooth muscle cells exposed to enhanced stretch was decreased by up to 80% through inhibiting AP-1. In contrast, mutant control oligonucleotides had no effect on smooth muscle cell activation. These findings indicate that an increase in venous filling pressure and thus CWT is sufficient to activate AP-1, which, in turn, triggers varicose remodeling through fuelling MMP-2 activity and smooth muscle cell hyperplasia in the venous vessel wall.
    Keywords: Myocytes, Smooth Muscle -- Metabolism ; Neovascularization, Pathologic -- Metabolism ; Transcription Factor AP-1 -- Metabolism
    ISSN: 08926638
    E-ISSN: 1530-6860
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  • 8
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, February 2016, Vol.30(2), pp.923-32
    Description: Subcutaneously growing tumors are widely utilized to study tumor angiogenesis and the efficacy of antiangiogenic therapies in mice. To additionally assess functional and morphologic alterations of the vasculature in the periphery of a growing tumor, we exploited the easily accessible and hierarchically organized vasculature of the mouse auricle. By site-specific subcutaneous implantation of a defined preformed mouse B16/F0 melanoma aggregate, a solid tumor nodule developed within 14 d. Growth of the tumor nodule was accompanied by a 4-fold increase in its perfusion as well as a 2- to 4-fold elevated diameter and perfusion of peripheral blood vessels that had connected to the tumor capillary microvasculature. By transdermal application of the anticancer drug bortezomib, tumor growth was significantly diminished by about 50% without provoking side effects. Moreover, perfusion and tumor microvessel diameter as well as growth and perfusion of arterial or venous blood vessels supplying or draining the tumor microvasculature were decreased under these conditions by up to 80%. Collectively, we observed that the progressive tumor growth is accompanied by the enlargement of supplying and draining extratumoral blood vessels. This process was effectively suppressed by bortezomib, thereby restricting the perfusion capacity of both extra and intratumoral blood vessels.
    Keywords: Angiogenesis ; Blood Vessel Growth ; Bortezomib ; Mouse Model ; Perfusion ; Ear Neoplasms ; Melanoma ; Neovascularization, Pathologic ; Bortezomib -- Pharmacology ; Drug Delivery Systems -- Methods
    ISSN: 08926638
    E-ISSN: 1530-6860
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  • 9
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 12 June 2018, Vol.115(24), pp.E5556-E5565
    Description: Monocyte extravasation into the vessel wall is a key step in atherogenesis. It is still elusive how monocytes transmigrate through the endothelial cell (EC) monolayer at atherosclerosis predilection sites. Platelets tethered to ultra-large von Willebrand factor (ULVWF) multimers deposited on the luminal EC surface following CD40 ligand (CD154) stimulation may facilitate monocyte diapedesis. Human ECs grown in a parallel plate flow chamber for live-cell imaging or Transwell permeable supports for transmigration assay were exposed to fluid or orbital shear stress and CD154. Human isolated platelets and/or monocytes were superfused over or added on top of the EC monolayer. Plasma levels and activity of the ULVWF multimer-cleaving protease ADAMTS13 were compared between coronary artery disease (CAD) patients and controls and were verified by the bioassay. Two-photon intravital microscopy was performed to monitor CD154-dependent leukocyte recruitment in the cremaster microcirculation of ADAMTS13-deficient versus wild-type mice. CD154-induced ULVWF multimer-platelet string formation on the EC surface trapped monocytes and facilitated transmigration through the EC monolayer despite high shear stress. Two-photon intravital microscopy revealed CD154-induced ULVWF multimer-platelet string formation preferentially in venules, due to strong EC expression of CD40, causing prominent downstream leukocyte extravasation. Plasma ADAMTS13 abundance and activity were significantly reduced in CAD patients and strongly facilitated both ULVWF multimer-platelet string formation and monocyte trapping in vitro. Moderate ADAMTS13 deficiency in CAD patients augments CD154-mediated deposition of platelet-decorated ULVWF multimers on the luminal EC surface, reinforcing the trapping of circulating monocytes at atherosclerosis predilection sites and promoting their diapedesis.
    Keywords: Adamts13 ; Cd40 ; Coronary Artery Disease ; Endothelial Cells ; Von Willebrand Factor ; Adamts13 Protein -- Metabolism ; Blood Platelets -- Metabolism ; Cd40 Antigens -- Metabolism ; Cell Communication -- Physiology ; Endothelial Cells -- Metabolism ; Von Willebrand Factor -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 10
    In: Circulation, 2017, Vol.136(Suppl_1 Suppl 1), pp.A20950-A20950
    Description: Cardiac remodeling and heart failure are characterized by misaligned adaptations in protein synthesis and degradation, harboring the therapeutic potential for interventional harmonization. Partial inhibition of protein degradation via the ubiquitin-proteasome system was reported to reduce acute hypertrophic remodeling as well as recover systolic function. The studies are suggestive of an inadequate gain in proteasome activity, contributing to cardiac remodeling and heart failure.Aim was to identify a common mechanism promoting proteasome activity during cardiac remodeling and heart failure and to test whether it contributes to the pathogenesis.Incorporation of the inducible proteasome subunit Lmp2 has been described to increase proteasome activity. In fact, it is increasingly expressed and incorporated in proteasome complexes during isoproterenol-induced hypertrophic remodeling, which is associated with a gain in proteasome activity. We found that Lmp2 is also increasingly expressed upon transverse aortic constriction and in a murine model of familial hypertrophic cardiomyopathy. Knock-out (KO) of Lmp2 in mice increased the caspase-like proteasome activity by 19% (n=5, p〈0.05), but had no apparent influence on cardiac morphology or function. As predicted, lack of Lmp2 confined the regulatory capacity of proteasomes to gain activity during hypertrophic remodeling induced by isoproterenol. Unexpectedly, the restriction in additional activity did not reduce cardiac remodeling as previously described for proteasome inhibition. In contrast, lack of Lmp2 exacerbated hypertrophic remodeling and caused loss of systolic function (fractional shortening: -32% vs. wildtype, n≥8, p〈0.01). Cardiomyocyte-specific expression of Lmp2 via gene transfer into adult Lmp2 KO mice completely rescued the isoproterenol-induced deterioration of cardiac remodeling and function. Interestingly, the deprived gain in proteasome activity in Lmp2 KO hearts rather affected a specific subset than the general pool of ubiquitinated proteins.In conclusion, a gain in proteasome activity during acute cardiac remodeling is not entirely maladaptive. At least in part, it is dependent on Lmp2, controlling remodeling and preserving cardiac function.
    ISSN: 0009-7322
    Source: Copyright © 2013 Lippincott Williams & Wilkins. All rights reserved.〈img src=http://exlibris-pub.s3.amazonaws.com/LWW%20logo.png style="vertical-align:middle;margin-left:7px"〉
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