Refine
Document Type
- Article (43)
Language
- English (43) (remove)
Has Fulltext
- yes (43)
Is part of the Bibliography
- no (43)
Keywords
- - (21)
- proteomics (4)
- Alzheimer’s disease (2)
- autophagy (2)
- heart failure (2)
- mass spectrometry (2)
- secretome (2)
- 3,5-Diiodothyronine (1)
- <i>Staphylococcus aureus</i> (1)
- ADCC (1)
- AICC (1)
- AKT/mTOR signaling (1)
- APOE ε4 (1)
- Affymetrix (1)
- BCL11B (1)
- BMD (1)
- CKD—chronic kidney disease (1)
- CNS (1)
- CRISPR/Cas (1)
- Clp proteolysis (1)
- Coagulation (1)
- Cortisol (1)
- Free thyroxine (1)
- GWA (1)
- GWAS (1)
- Glucocorticoid receptor (1)
- H9c2 cells (1)
- HLA (1)
- Hippocampus (1)
- IL-15 (1)
- IsdB (1)
- LC-MS/MS (1)
- Label-free quantification (1)
- MDD (1)
- MHC (1)
- McsB arginine kinase (1)
- MgsR activity (1)
- MgsR degradation (1)
- NLRP3 inflammasome (1)
- NMR metabolomics (1)
- NMR spectroscopy (1)
- NR3C1 (1)
- Plasma (1)
- SDS-SP3 protocol (1)
- SHIP (1)
- SLC22A9 (1)
- SP3 (1)
- Shotgun proteomics (1)
- SigB (1)
- Single nucleotide polymorphisms (1)
- Staphyloccus aureus (1)
- Staphylococcus aureus (1)
- Systemic infection (1)
- TAC (1)
- TGF-β (1)
- TLR4 (1)
- TNF-α (1)
- TREML2 (1)
- TSST-1 (1)
- Thyroid hormone (1)
- Trigonelline (1)
- UPS (1)
- Urine metabolome (1)
- Verbal memory (1)
- Warburg effect (1)
- acute pancreatitis (1)
- airway epithelial cells (1)
- alpha diversity (1)
- alpha- beta CD8+ T cells (1)
- alpha-toxin (1)
- amyloid beta (1)
- anti- (1)
- antibody (1)
- antibody repertoire (1)
- antibody response (1)
- antisense RNA (1)
- apolipoprotein E (1)
- arginine phosphorylation (1)
- bacterial cell disruption (1)
- bacterial infection (1)
- benzoate metabolism (1)
- brain atrophy (1)
- cardiac fibroblast (1)
- cardiac remodelling (1)
- cardiomyopathy (1)
- cathepsins (1)
- cellular sensitivity (1)
- cognition (1)
- compound (1)
- cytokine (1)
- cytokines (1)
- cytosolic renin (1)
- dental plaque (1)
- depression (1)
- differentiation (1)
- endothelial cells (1)
- energy metabolism (1)
- essential oil (1)
- estrone sulfate transporter (1)
- experimental pancreatitis (1)
- extracellular vesicle isolation (1)
- extracellular vesicles diagnostics (1)
- formalin fixed and embedded brain sample (1)
- gene expression (1)
- general population (1)
- glomerulus (1)
- healthy human oral microbiome (1)
- host-pathogen interaction (1)
- host-pathogen-interaction (1)
- human (1)
- human association studies (1)
- human breast milk (1)
- human cell lines (1)
- human induced pluripotent stem cell-derived cardiomyocytes (1)
- human umbilical vein endothelial cells (1)
- immune response (1)
- immune system (1)
- immunoproteasome (1)
- immunoproteomics (1)
- inflammasome (1)
- inherited cardiomyopathy (1)
- innate immunity (1)
- innateness (1)
- internalization (1)
- knock-out (1)
- label-free quantitation (1)
- lactoperoxidase (1)
- large cohort data (1)
- longitudinal cohort study (1)
- lysosomal biogenesis (1)
- macrophages (1)
- memory (1)
- metaproteomics (1)
- methods in liquid biopsy (1)
- miRNA (1)
- microRNA sequencing (1)
- microbiome (1)
- microglia (1)
- monocarboxylate transporter 8 (1)
- multi-omics (1)
- nLC-MS/MS (1)
- neurodegeneration (1)
- neuroinflammation (1)
- osmostress protectants (1)
- osteoporosis (1)
- pathogen-specific IgG (1)
- peptidome (1)
- phenotyping (1)
- plasma biomarker (1)
- podocyte (1)
- population-based imaging (1)
- protein aggregation (1)
- protein preparation (1)
- proteome (1)
- proteostasis (1)
- radiomics (1)
- riociguat (1)
- rs3747742 (1)
- rs56149945 (1)
- sarcomere (1)
- screening (1)
- sepsis (1)
- serology (1)
- serum biomarker (1)
- serum starvation (1)
- sex steroids (1)
- sex- specificity (1)
- small cell numbers (1)
- soluble guanylyl cyclase stimulator (1)
- storage conditions (1)
- stress response (1)
- superantigen (1)
- teeth (1)
- temperature (1)
- thyroid auto-regulation (1)
- toxic shock syndrome (1)
- transcriptome (1)
- transcriptome analysis (1)
- transmembrane pores (1)
- ubiquitin-proteasome system (1)
- virulence factors (1)
- vitamin D3 (1)
- white matter hyperintensity (1)
- whole-body magnetic resonance imaging (1)
- yolk sac (1)
- α-actinin-2 (1)
Institute
- Interfakultäres Institut für Genetik und Funktionelle Genomforschung (UMG) (10)
- Interfakultäres Institut für Genetik und Funktionelle Genomforschung (MNF) (5)
- Kliniken und Polikliniken für Innere Medizin (5)
- Institut für Immunologie u. Transfusionsmedizin - Abteilung Immunologie (4)
- Klinik für Psychiatrie und Psychotherapie (4)
- Institut für Biochemie (2)
- Institut für Community Medicine (2)
- Institut für Immunologie u. Transfusionsmedizin - Abteilung Transfusionsmedizin (2)
- Institut für Medizinische Psychologie (2)
- Institut für Mikrobiologie - Abteilung für Genetik & Biochemie (2)
Publisher
- MDPI (14)
- Frontiers Media S.A. (8)
- Nature Publishing Group (3)
- Springer Nature (3)
- Public Library of Science (PLoS) (2)
- S. Karger AG (2)
- Taylor & Francis (2)
- Wiley (2)
- AO Research Institute Davos (1)
- American Society for Microbiology (ASM) (1)
Although the common pathology of Alzheimer’s disease (AD) and white matter hyperintensities (WMH) is disputed, the gene TREML2 has been implicated in both conditions: its whole-blood gene expression was associated with WMH volume and its missense variant rs3747742 with AD risk. We re-examined those associations within one comprehensive dataset of the general population, additionally searched for cross-relations and illuminated the role of the apolipoprotein E (APOE) ε4 status in the associations. For our linear regression and linear mixed effect models, we used 1949 participants from the Study of Health in Pomerania (Germany). AD was assessed using a continuous pre-symptomatic MRI-based score evaluating a participant’s AD-related brain atrophy. In our study, increased whole-blood TREML2 gene expression was significantly associated with reduced WMH volume but not with the AD score. Conversely, rs3747742-C was significantly associated with a reduced AD score but not with WMH volume. The APOE status did not influence the associations. In sum, TREML2 robustly associated with WMH volume and AD-related brain atrophy on different molecular levels. Our results thus underpin TREML2’s role in neurodegeneration, might point to its involvement in AD and WMH via different biological mechanisms, and highlight TREML2 as a worthwhile target for disentangling the two pathologies.
Objective: In acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death. Understanding how immunological host defence mechanisms fail to protect the intestinal barrier is of great importance in reducing the mortality risk of the disease. Here, we studied the role of the Treg/Th17 balance for maintaining the intestinal barrier function in a mouse model of severe AP.
Design: AP was induced by partial duct ligation in C57Bl/6 or DEREG mice, in which regulatory T-cells (Treg) were depleted by intraperitoneal injection of diphtheria toxin. By flow cytometry, functional suppression assays and transcriptional profiling we analysed Treg activation and characterised T-cells of the lamina propria as well as intraepithelial lymphocytes (IELs) regarding their activation and differentiation. Microbiota composition was examined in intestinal samples as well as in murine and human pancreatic necrosis by 16S rRNA gene sequencing.
Results: The prophylactic Treg-depletion enhanced the proinflammatory response in an experimental mouse model of AP but stabilised the intestinal immunological barrier function of Th17 cells and CD8+/γδTCR+ IELs. Treg depleted animals developed less bacterial translocation to the pancreas. Duodenal overgrowth of the facultative pathogenic taxa Escherichia/Shigella which associates with severe disease and infected necrosis was diminished in Treg depleted animals.
Conclusion: Tregs play a crucial role in the counterbalance against systemic inflammatory response syndrome. In AP, Treg-activation disturbs the duodenal barrier function and permits translocation of commensal bacteria into pancreatic necrosis. Targeting Tregs in AP may help to ameliorate the disease course.
Osteoporosis, a complex chronic disease with increasing prevalence, is characterised by reduced bone mineral density (BMD) and increased fracture risk. The high heritability of BMD suggests substantial impact of the individual genetic disposition on bone phenotypes and the development of osteoporosis. In the past years, genome-wide association studies (GWAS) identified hundreds of genetic variants associated with BMD or osteoporosis. Here, we analysed 1103 single nucleotide polymorphisms (SNPs), previously identified as associated with estimated BMD (eBMD) in the UK Biobank. We assessed whether these SNPs are related to heel stiffness index obtained by quantitative ultrasound in 5665 adult participants of the Study of Health in Pomerania (SHIP). We confirmed 45 significant associations after correction for multiple testing. Next, we analysed six selected SNPs in 631 patients evaluated for osteoporosis [rs2707518 (CPED1/WNT16), rs3779381 (WNT16), rs115242848 (LOC101927709/EN1), rs10239787 (JAZF1), rs603424 (PKD2L1) and rs6968704 (JAZF1)]. Differences in minor allele frequencies (MAF) of rs2707518 and rs3779381 between SHIP participants (higher MAF) and patients evaluated for osteoporosis (lower MAF) indicated a protective effect of the minor allele on bone integrity. In contrast, differences in MAF of rs603424 indicated a harmful effect. Co-localisation analyses indicated that the rs603424 effect may be mediated via stearoyl-CoA desaturase (SCD) expression, an enzyme highly expressed in adipose tissue with a crucial role in lipogenesis. Taken together, our results support the role of the WNT16 pathway in the regulation of bone properties and indicate a novel causal role of SCD expression in adipose tissue on bone integrity.
Background and Purpose
Development and progression of heart failure involve endothelial and myocardial dysfunction as well as a dysregulation of the NO-sGC-cGMP signalling pathway. Recently, we reported that the sGC stimulator riociguat has beneficial effects on cardiac remodelling and progression of heart failure in response to chronic pressure overload. Here, we examined if these beneficial effects of riociguat were also reflected in alterations of the myocardial proteome and microRNA profiles.
Experimental Approach
Male C57BL/6N mice underwent transverse aortic constriction (TAC) and sham-operated mice served as controls. TAC and sham animals were randomised and treated with either riociguat or vehicle for 5 weeks, starting 3 weeks after surgery, when cardiac hypertrophy was established. Afterwards, we performed mass spectrometric proteome analyses and microRNA sequencing of proteins and RNAs, respectively, isolated from left ventricles (LVs).
Key Results
TAC-induced changes of the LV proteome were significantly reduced by treatment with riociguat. Bioinformatics analyses revealed that riociguat improved TAC-induced cardiovascular disease-related pathways, metabolism and energy production, for example, reversed alterations in the levels of myosin heavy chain 7, cardiac phospholamban and ankyrin repeat domain-containing protein 1. Riociguat also attenuated TAC-induced changes of microRNA levels in the LV.
Conclusion and Implications
The sGC stimulator riociguat exerted beneficial effects on cardiac structure and function during pressure overload, which was accompanied by a reversal of TAC-induced changes of the cardiac proteome and microRNA profile. Our data support the potential of riociguat as a novel therapeutic agent for heart failure.
Introduction
Respiratory tract infections are a worldwide health problem for humans and animals. Different cell types produce lipid mediators in response to infections, which consist of eicosanoids like hydroxyeicosatetraenoic acids (HETEs) or oxylipins like hydroxydocosahexaenoic acids (HDHAs). Both substance classes possess immunomodulatory functions. However, little is known about their role in respiratory infections.
Objectives
Here, we aimed to analyze the lipid mediator imprint of different organs of C57BL/6J mice after intranasal mono-infections with Streptococcus pneumoniae (pneumococcus), Staphylococcus aureus or Influenza A virus (IAV) as wells as pneumococcal-IAV co-infection.
Methods
C57BL/6J mice were infected with different pathogens and lungs, spleen, and plasma were collected. Lipid mediators were analyzed using HPLC-MS/MS. In addition, spatial-distribution of sphingosine 1-phosphate (S1P) and ceramide 1-phosphates (C1P) in tissue samples was examined using MALDI-MS-Imaging. The presence of bacterial pathogens in the lung was confirmed via immunofluorescence staining.
Results
We found IAV specific changes for different HDHAs and HETEs in mouse lungs as well as enhanced levels of 20-HETE in severe S. aureus infection. Moreover, MALDI-MS-Imaging analysis showed an accumulation of C1P and a decrease of S1P during co-infection in lung and spleen. Long chain C1P was enriched in the red and not in the white pulp of the spleen.
Conclusions
Lipid mediator analysis showed that host synthesis of bioactive lipids is in part specific for a certain pathogen, in particular for IAV infection. Furthermore, MS-Imaging displayed great potential to study infections and revealed changes of S1P and C1P in lungs and spleen of co-infected animals, which was not described before.
The iron-regulated surface determinant protein B (IsdB) of Staphylococcus aureus is involved in the acquisition of iron from hemoglobin. Moreover, IsdB elicits an adaptive immune response in mice and humans. Here, we show that IsdB also has impact on innate immunity. IsdB induces the release of proinflammatory cytokines, including IL-6 and IL-1β, in innate immune cells of humans and mice. In silico analysis and thermophoresis show that IsdB directly binds to TLR4 with high affinity. TLR4 sensing was essential for the IsdB-mediated production of IL-6, IL-1β, and other cytokines as it was abolished by blocking of TLR4-MyD88-IRAK1/4-NF-κB signaling. The release of IL-1β additionally required activation of the NLRP3 inflammasome. In human monocytes infected with live S. aureus, IsdB was necessary for maximal IL-1β release. Our studies identify S. aureus IsdB as a novel pathogen-associated molecular pattern that triggers innate immune defense mechanisms.
The hypothalamus–pituitary–adrenal axis is the main physiological stress response system and regulating the release of cortisol. The two corticoid receptors encoded by the genes NR3C1 and NR3C2 are the main players in regulating the physiological response to cortisol. This biological system has been linked to neurocognitive processes and memory, yet the mechanisms remain largely unclear. In two independent general population studies (SHIP, total sample size > 5500), we aim to diseantangle the effects of genetic variation, gene expression and cortisol on verbal memory and memory associated brain volume. Especially for NR3C1 results exhibited a consistent pattern of direct an interactive effects. All three biological layers, genetic variation (rs56149945), gene expression for NR3C1 and cortisol levels, were directly associated with verbal memory. Interactions between these components showed significant effects on verbal memory as well as hippocampal volume. For NR3C2 such a complex association pattern could not be observed. Our analyses revealed that different components of the stress response system are acting together on different aspects of cognition. Complex phenotypes, such as cognition and memory function are regulated by a complex interplay between different genetic and epigenetic features. We promote the glucocorticoid receptor NR3C1 as a main target to focus in the context of verbal memory and provided a mechanistic concept of the interaction between various biological layers spanning NR3C1 function and its effects on memory. Especially the NR3C1 transcript seemed to be a key element in this complex system.
There is growing evidence for sex and gender differences in the clinical manifestation and outcomes of human diseases. Human primary endothelial cells represent a useful cardiovascular model to study sexual dimorphisms at the cellular level. Here, we analyzed sexual dimorphisms of the secretome after serum starvation using human umbilical vein endothelial cells (HUVECs) from twin pairs of the opposite sex to minimize the impact of varying genetic background. HUVECs were starved for 5 and 16 h, respectively, and proteins of the cell culture supernatants were analyzed by tandem mass spectrometry. Altogether, 960 extracellular proteins were identified of which 683 were amendable to stringent quantification. Significant alterations were observed for 455 proteins between long-term and short-term starvation and the majority were similar in both sexes. Only 5 proteins showed significant sex-specific regulation between long-versus short-term starvation. Furthermore, 19 unique proteins with significant sexual dimorphisms at the same time points of serum starvation were observed. A larger number of proteins, for example tissue factor inhibitor 2 (TFPI2), displayed higher levels in the supernatants of females compared to male cells after long term serum starvation that might point to higher adaptation capacity of female cells. The overall results demonstrate that male and female cells differ in their secretome.
Tissue sections, which are widely used in research and diagnostic laboratories and have already been examined by immunohistochemistry (IHC), may subsequently provide a resource for proteomic studies, even though only small amount of protein is available. Therefore, we established a workflow for tandem mass spectrometry-based protein profiling of IHC specimens and characterized defined brain area sections. We investigated the CA1 region of the hippocampus dissected from brain slices of adult C57BL/6J mice. The workflow contains detailed information on sample preparation from brain slices, including removal of antibodies and cover matrices, dissection of region(s) of interest, protein extraction and digestion, mass spectrometry measurement, and data analysis. The Gene Ontology (GO) knowledge base was used for further annotation. Literature searches and Gene Ontology annotation of the detected proteins verify the applicability of this method for global protein profiling using formalin-fixed and embedded material and previously used IHC slides.
Life-threatening toxic shock syndrome is often caused by the superantigen toxic shock syndrome toxin-1 (TSST-1) produced by Staphylococcus aureus. A well-known risk factor is the lack of neutralizing antibodies. To identify determinants of the anti-TSST-1 antibody response, we examined 976 participants of the German population-based epidemiological Study of Health in Pomerania (SHIP-TREND-0). We measured anti-TSST-1 antibody levels, analyzed the colonization with TSST-1-encoding S. aureus strains, and performed a genome-wide association analysis of genetic risk factors. TSST-1-specific serum IgG levels varied over a range of 4.2 logs and were elevated by a factor of 12.3 upon nasal colonization with TSST-1-encoding S. aureus. Moreover, the anti-TSST-1 antibody levels were strongly associated with HLA class II gene loci. HLA-DRB1*03:01 and HLA-DQB1*02:01 were positively, and HLA-DRB1*01:01 as well as HLA-DQB1*05:01 negatively associated with the anti-TSST-1 antibody levels. Thus, both toxin exposure and HLA alleles affect the human antibody response to TSST-1.