| 1. |
- Azimzadeh, Omid, et al.
(author)
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Label-free protein profiling of formalin-fixed paraffin-embedded (FFPE) heart tissue reveals immediatemitochondrial impairment after ionising radiation
- 2012
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In: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 75:8, s. 2384-2395
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Journal article (peer-reviewed)abstract
- Qualitative proteome profiling of formalin-fixed, paraffin-embedded (FFPE) tissue is advancing the field of clinical proteomics. However, quantitative proteome analysis of FFPE tissue is hampered by the lack of an efficient labelling method. The usage of conventional protein labelling on FFPE tissue has turned out to be inefficient. Classical labelling targets lysine residues that are blocked by the formalin treatment. The aim of this study was to establish a quantitative proteomics analysis of FFPE tissue by combining the label-free approach with optimised protein extraction and separation conditions. As a model system we used FFPE heart tissue of control and exposed C57BL/6 mice after total body irradiation using a gamma ray dose of 3 gray. We identified 32 deregulated proteins (p <= 0.05) in irradiated hearts 24 h after the exposure. The proteomics data were further evaluated and validated by bioinformatics and immunoblotting investigation. In good agreement with our previous results using fresh-frozen tissue, the analysis indicated radiation-induced alterations in three main biological pathways: respiratory chain, lipid metabolism and pyruvate metabolism. The label-free approach enables the quantitative measurement of radiation-induced alterations in FFPE tissue and facilitates retrospective biomarker identification using clinical archives.
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| 2. |
- Eisenberg, Tobias, et al.
(author)
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Cardioprotection and lifespan extension by the natural polyamine spermidine
- 2016
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 22:12, s. 1428-1438
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Journal article (peer-reviewed)abstract
- Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
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| 3. |
- Kempf, Stefan J., et al.
(author)
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The cognitive defects of neonatally irradiated miceare accompanied by changed synaptic plasticity,adult neurogenesis and neuroinflammation
- 2014
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In: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 9, s. 57-
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Journal article (peer-reviewed)abstract
- Background/purpose of the study: Epidemiological evidence suggests that low doses of ionising radiation(≤1.0 Gy) produce persistent alterations in cognition if the exposure occurs at a young age. The mechanismsunderlying such alterations are unknown. We investigated the long-term effects of low doses of total body gammaradiation on neonatally exposed NMRI mice on the molecular and cellular level to elucidate neurodegeneration.Results: Significant alterations in spontaneous behaviour were observed at 2 and 4 months following a single 0.5or 1.0 Gy exposure. Alterations in the brain proteome, transcriptome, and several miRNAs were analysed 6–7months post-irradiation in the hippocampus, dentate gyrus (DG) and cortex. Signalling pathways related to synapticactin remodelling such as the Rac1-Cofilin pathway were altered in the cortex and hippocampus. Further, synapticproteins MAP-2 and PSD-95 were increased in the DG and hippocampus (1.0 Gy). The expression of synapticplasticity genes Arc, c-Fos and CREB was persistently reduced at 1.0 Gy in the hippocampus and cortex. Thesechanges were coupled to epigenetic modulation via increased levels of microRNAs (miR-132/miR-212, miR-134).Astrogliosis, activation of insulin-growth factor/insulin signalling and increased level of microglial cytokine TNFαindicated radiation-induced neuroinflammation. In addition, adult neurogenesis within the DG was persistentlynegatively affected after irradiation, particularly at 1.0 Gy.Conclusion: These data suggest that neurocognitive disorders may be induced in adults when exposed at a youngage to low and moderate cranial doses of radiation. This raises concerns about radiation safety standards andregulatory practices.
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| 4. |
- Vogel, Katharina U, et al.
(author)
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Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation
- 2013
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In: Immunity. - Cambridge, USA : Cell Press. - 1074-7613 .- 1097-4180. ; 38:4, s. 655-68
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Journal article (peer-reviewed)abstract
- The Roquin-1 protein binds to messenger RNAs (mRNAs) and regulates gene expression posttranscriptionally. A single point mutation in Roquin-1, but not gene ablation, increases follicular helper T (Tfh) cell numbers and causes lupus-like autoimmune disease in mice. In T cells, we did not identify a unique role for the much lower expressed paralog Roquin-2. However, combined ablation of both genes induced accumulation of T cells with an effector and follicular helper phenotype. We showed that Roquin-1 and Roquin-2 proteins redundantly repressed the mRNA of inducible costimulator (Icos) and identified the Ox40 costimulatory receptor as another shared mRNA target. Combined acute deletion increased Ox40 signaling, as well as Irf4 expression, and imposed Tfh differentiation on CD4(+) T cells. These data imply that both proteins maintain tolerance by preventing inappropriate T cell activation and Tfh cell differentiation, and that Roquin-2 compensates in the absence of Roquin-1, but not in the presence of its mutated form.
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| 5. |
- Xie, Kan, et al.
(author)
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Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice
- 2018
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 115:10, s. E2348-E2357
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Journal article (peer-reviewed)abstract
- Advanced age is not only a major risk factor for a range of disorders within an aging individual but may also enhance susceptibility for disease in the next generation. In humans, advanced paternal age has been associated with increased risk for a number of diseases. Experiments in rodent models have provided initial evidence that paternal age can influence behavioral traits in offspring animals, but the overall scope and extent of paternal age effects on health and disease across the life span remain underexplored. Here, we report that old father offspring mice showed a reduced life span and an exacerbated development of aging traits compared with young father offspring mice. Genome-wide epigenetic analyses of sperm from aging males and old father offspring tissue identified differentially methylated promoters, enriched for genes involved in the regulation of evolutionarily conserved longevity pathways. Gene expression analyses, biochemical experiments, and functional studies revealed evidence for an overactive mTORC1 signaling pathway in old father offspring mice. Pharmacological mTOR inhibition during the course of normal aging ameliorated many of the aging traits that were exacerbated in old father offspring mice. These findings raise the possibility that inherited alterations in longevity pathways contribute to intergenerational effects of aging in old father offspring mice.
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