A5088288970- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Receptor Mechanisms and Signaling
- Mast cells and histamine
- Atherosclerosis and Cardiovascular Diseases
- Cell Adhesion Molecules Research
- T-cell and B-cell Immunology
- Blood Coagulation and Thrombosis Mechanisms
- Antifungal resistance and susceptibility
- Adenosine and Purinergic Signaling
- Click Chemistry and Applications
- Diet, Metabolism, and Disease
- Phytochemical compounds biological activities
- Cancer-related gene regulation
- Dietary Effects on Health
- Neuropeptides and Animal Physiology
- Wnt/β-catenin signaling in development and cancer
- Enzyme function and inhibition
- Cannabis and Cannabinoid Research
- Chemokine receptors and signaling
- Cytokine Signaling Pathways and Interactions
- Neurobiology and Insect Physiology Research
- Blood properties and coagulation
- Viral Infectious Diseases and Gene Expression in Insects
Ludwig-Maximilians-Universität München
2015-2024
Institute for Sports Medicine
2017-2024
Ontario Institute for Cancer Research
2012
Johns Hopkins University
1996-1999
Johns Hopkins Medicine
1997-1998
University of Baltimore
1996
University of Maryland, Baltimore
1996
München Klinik
1994
Johannes Gutenberg University Mainz
1991-1992
Nova Medical (United States)
1992
Chemokines orchestrate leukocyte trafficking and function in health disease. Heterophilic interactions between chemokines a given microenvironment may amplify, inhibit, or modulate their activity; however, systematic evaluation of the chemokine interactome has not been performed. We used immunoligand blotting surface plasmon resonance to obtain comprehensive map chemokine-chemokine confirm specificity. Structure-function analyses revealed that activity can be enhanced by CC-type heterodimers...
Chemokines and galectins are simultaneously upregulated mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability bind galectin-1 galectin-3, identified several interacting pairs, such as CXCL12 galectin-3. Based on NMR MD studies of CXCL12/galectin-3 heterodimer, contact sites between β-strand 1...
Abstract CCL17 is produced by conventional dendritic cells, signals through CCR4 on regulatory T (T reg ) cells and drives atherosclerosis suppressing functions yet undefined mechanisms. Here we show that from CCL17-deficient mice display a pro-tolerogenic phenotype transcriptome not phenocopied in lacking its cognate receptor CCR4. In the plasma of mice, CCL3 was only decreased cytokine/chemokine. We found signaled CCR8 as an alternate high-affinity receptor, which induced expression...
Glycoprotein VI (GPVI) is the essential platelet collagen receptor in atherothrombosis, but its inhibition causes only a mild bleeding tendency. Thus, targeting this has selective antithrombotic potential. This study sought to compare compounds interfering with GPVI–atherosclerotic plaque interaction improve current antiatherothrombotic therapy. Human atherosclerotic plaque–induced aggregation was measured anticoagulated blood under static and arterial flow conditions (550/s, 1,100/s,...
To determine the role of cytoplasmic carboxyl termini human B1 and B2 kinin receptors (B1KR B2KR, respectively) in internalization their respective ligands, des-Arg<sup>10</sup>-kallidin bradykinin (BK), both wild type receptors, as well truncated B2KRs, a mutated chimeric were stably expressed Chinese hamster ovary cells. Incubation [<sup>3</sup>H]BK at 37 °C with cells expressing B2KR resulted pronounced rapid ligand (∼80% after 10 min). By contrast, incubation of<sup>3</sup>H-labeled B1KR...
The co-stimulatory receptor CD27 modulates responses of T cells, B and NK cells. Various cell subsets participate in atherogenesis. However, the role atherosclerosis remains unexplored.Here we investigated effect bone marrow-derived systemic deficiency Apolipoprotein E-deficient (Apoe-/-) mice early advanced stages atherosclerosis. Lethally-irradiated Apoe-/- reconstituted with Cd27-/-Apoe-/- marrow consuming an atherogenic diet displayed a markedly increased plaque size lesional...
Bradykinin exerts a broad spectrum of cellular effects on different tissues. It is believed that these are predominantly mediated by the recently cloned B2 receptor. The mechanism post-receptor signal transduction not known in detail. Involvement protein kinase C (PKC) was suggested and activation classical PKC isoforms alpha beta demonstrated. aim present study to investigate whether receptor also activates new (delta, epsilon) atypical (zeta) isoforms. To this, chinese hamster ovary (CHO)...
Although the G protein-coupled receptors (GPCRs) share a similar seven-transmembrane domain structure, only limited number of amino acid residues is conserved in their protein sequences. One most highly sequences NPXXY motif located at cytosolic end transmembrane region-7 many GPCRs, particularly those belonging to family rhodopsin/beta-adrenergic-like receptors. Exchange Tyr(305) corresponding NPLVY sequence bradykinin B(2) receptor (B(2)R) for Ala resulted mutant, termed Y305A, that...
Cardiovascular diseases and depression are the leading causes of disability in Western countries. Clinical data on potential cardiovascular effects serotonin reuptake inhibitors (SSRIs), most commonly used antidepressant drugs, controversial. In addition to blocking transporter brain, SSRIs deplete major peripheral (5-hydroxytryptamine [5-HT]) storage by inhibiting transporter-mediated uptake platelets. this study, we aimed investigate effect chronic SSRI intake development...
PHA-022121 is a novel small molecule bradykinin B2 receptor antagonist, in clinical development for the treatment and prevention of hereditary angioedema attacks. The present study describes vitro pharmacological characteristics its active metabolite, PHA-022484 (M2-D). In mammalian cell lines, show high affinity recombinant human with Ki values 0.47 0.70 nM, respectively, potent antagonism Kb 0.15 0.26 respectively (calcium mobilization assay). Antagonist potency at cynomolgus monkey...
Abstract Dissecting the pathways regulating adaptive immune response in atherosclerosis is of particular therapeutic interest. Here we report that lipid G-protein-coupled receptor GPR55 highly expressed by splenic plasma cells (PCs), upregulated mouse spleens during atherogenesis and human unstable or ruptured compared to stable plaques. Gpr55 -deficient mice developed larger atherosclerotic plaques with increased necrotic core size their corresponding controls. Lack hyperactivated B cells,...
The human B2 kinin receptor (B2KR), stably expressed in chinese hamster ovary cells, responded to bradykinin stimulation with rapid (within minutes) ligand internalization and loss of cell surface receptors (sequestration). By contrast, B1 (B1KR) showed almost no or sequestration upon des-Arg10-Kallidin (DAK). ability the B2KR internalize sequester is conferred by information cytoplasmic tail receptor. It normally impossible determine affinity at 37°C because processes. We created a mutant...
Blockade of the bradykinin B2 receptor provides therapeutic benefit in hereditary angioedema (HAE) and potentially many other diseases. Herein, we describe development highly potent antagonists with a molecular weight approximately 500 g/mol. First, known quinoline-based were stripped down to their shared core motif 53, which turned out be minimum pharmacophore. Targeted modifications 53 resulted water-soluble lead compound 8a. Extensive exploration its structure−activity relationship series...
Abstract The secretion of proteolytic enzymes by pathogenic microorganisms is one the most successful strategies used pathogens to colonize and infect host organism. extracellular microbial proteinases can seriously deregulate homeostatic cascades host, including kinin-forming system, repeatedly reported be activated during bacterial infection. current study assigns a kinin-releasing activity secreted Candida spp. yeasts, major fungal humans. Of several species studied, C. parapsilosis...
Abstract Bradykinin-related peptides, universal mediators of inflammation collectively referred to as the kinins, are often produced in excessive amounts during microbial infections. We have recently shown that yeast Candida albicans , major fungal pathogen humans, can exploit two mechanisms enhance kinin levels at sites candidial infection, one depending on adsorption and activation endogenous kinin-generating system host cell wall other relying cleavage precursors, kininogens, by...
Candida albicans yeast produces 10 distinct secreted aspartic proteases (Saps), which are some of the most important virulence factors this pathogenic fungus. One suggested roles Saps is their deregulating effect on various proteolytic cascades that constitute major homeostatic systems in human hosts, including blood coagulation, fibrinolysis, and kallikrein-kinin systems. This study compared characteristics action all kininogens, results generating proinflammatory bradykinin-related...
Active B2 bradykinin (BK) receptors were solubilized in high yields from intact monolayers or particulate fractions of cultured human foreskin fibroblasts using 4 mM the non-denaturing zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS). Other detergents showed only minor (digitonin) no (Triton X-100, n-octyl glucopyranosid) efficacy at all. The stability CHAPS-solubilized BK binding activity was temperature dependent being reduced to 30% initial...
Determinants for desensitization and sequestration of G protein-coupled receptors often contain serine or threonine residues located in their C-termini. The sequence context, however, which these have to appear, the receptor specificity motifs are largely unknown. Mutagenesis studies with B(2) bradykinin (B(2)wt), stably expressed HEK 293 cells, identified a distal N338 (NSMGTLRTSI, including I347 but not basally phosphorylated S348) particular TSI therein, as major determinant rapid...
The DRY motif with the highly conserved R3.50 is a hallmark of family A G protein-coupled receptors (GPCRs). crystal structure rhodopsin revealed salt bridge between R135<sup>3.50</sup> and another residue, E247<sup>6.30</sup>, in helix 6. This ionic lock was shown to maintain its inactive state. Thus far, little information available on how interruption this bond affects signaling properties nonrhodopsin GPCRs, because focus has been mutations R3.50, although residue indispensable for...