A5055523748- Barrier Structure and Function Studies
- Connexins and lens biology
- Neurological Disease Mechanisms and Treatments
- Gut microbiota and health
- Drug Transport and Resistance Mechanisms
- Caveolin-1 and cellular processes
- Bone Tissue Engineering Materials
- Advanced Glycation End Products research
- Yersinia bacterium, plague, ectoparasites research
- Advanced MRI Techniques and Applications
- Periodontal Regeneration and Treatments
- Dental Implant Techniques and Outcomes
- Cancer, Hypoxia, and Metabolism
- Glioma Diagnosis and Treatment
- 3D Printing in Biomedical Research
- Advanced NMR Techniques and Applications
- Atomic and Subatomic Physics Research
- Pharmacogenetics and Drug Metabolism
- Hereditary Neurological Disorders
- Cervical Cancer and HPV Research
- Adenosine and Purinergic Signaling
- Phytochemical compounds biological activities
- Biochemical and Molecular Research
- Cutaneous lymphoproliferative disorders research
- Plant-based Medicinal Research
Leibniz-Forschungsinstitut für Molekulare Pharmakologie
2006-2021
Leibniz Association
2014-2019
Forschungsverbund Berlin
2017
Helios Hospital Berlin-Buch
2013
Leibniz Institute for Neurobiology
2007
University of Duisburg-Essen
2002-2006
Freie Universität Berlin
2005
Johannes Gutenberg University Mainz
1996-1997
Claudins are the critical transmembrane proteins in tight junctions. Claudin-5, for instance, prevents paracellular permeation of small molecules. However, molecular interaction mechanism is unknown. Hence, claudin-claudin and junction strand formation were investigated using systematic single mutations. Claudin-5 mutants transfected into junction-free cells demonstrated that extracellular loop 2 involved via trans-interaction, but not polymerization, along plasma membrane one cell. Three...
The outcome of stroke is greatly influenced by the state blood–brain barrier (BBB). BBB endothelium sealed paracellularly tight junction (TJ) proteins, i.e., claudins (Cldns) and redox regulator occludin. Functions Cldn3 occludin at are largely unknown, particularly after stroke. We address effects deficiency stress factors on its TJs. tightened for small molecules ions, limited endothelial endocytosis, strengthened TJ structure controlled Cldn1 expression. After middle cerebral artery...
Clostridium perfringens enterotoxin (CPE) binds to the extracellular loop 2 of a subset claudins, e.g. claudin-3. Here, molecular mechanism CPE-claudin interaction was analyzed. Using peptide arrays, recombinant CPE-(116-319) bound peptides mouse claudin-3, -6, -7, -9, and -14 but not 1, 2, 4, 5, 8, 10-13, 15, 16, 18-20, 22. Substitution mapping identified central motif (148)NPL(150)VP, supposed represent turn region in as essential for between CPE murine claudin-3 peptides. CPE-binding...
Most claudins are tight junction (TJ)-forming proteins. However, their interaction on the molecular level remains unresolved. It is hypothesized that extracellular loops specify these claudin functions. assumed first loop (ECL1) critical for determining paracellular tightness and selective ion permeability, second may cause narrowing of cleft. Using a combination site-directed mutagenesis homology modeling (ECL2) claudin-5, we found several amino acids important folding and/or...
The blood–brain barrier (BBB) formed by the microvascular endothelium limits cerebral drug delivery. paraendothelial cleft is sealed tight junctions (TJs) with a major contribution from claudin‐5, which we selected as target to modulate BBB permeability. For this purpose, drug‐enhancer peptides were designed based on first extracellular loop (ECL) of claudin‐5 allow transient permeabilization. Peptidomimetics (C5C2 and derivatives, nanomolar affinity claudin‐5) size‐selectively (≤40 kDa)...
Claudin-5 is a tight junction (TJ) protein which limits the diffusion of small hydrophilic molecules. Thus, it represents potential pharmacological target to improve drug delivery tissues protected by claudin-5-dependent barriers. Sodium caprate known as an absorption enhancer opens paracellular space acting on TJ proteins and actin cytoskeleton. Its action claudin-5 not understood so far. Epithelial endothelial systems were used evaluate effect in TJ-free cells fully integrated TJ. To this...
Glioblastoma (GBM) heterogeneity, aggressiveness and infiltrative growth drastically limit success of current standard care drugs efficacy various new therapeutic approaches. There is a need for therapies models reflecting the complex biology these tumors to analyze molecular mechanisms tumor formation resistance, as well identify targets. We established screened panel 26 patient-derived subcutaneous (s.c.) xenograft (PDX) GBM on immunodeficient mice, which 15 were also orthotopic models....
Cutaneous T-cell lymphomas (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), are rare hematological malignancies with limited curative treatment options. Despite early-stage responsiveness, these often relapse in advanced stages, highlighting the need for novel, durable therapies. As other non-Hodgkin lymphoma (NHL) MF SS have a greater incidence rate males than females. The endocrine contribution to this gender difference is unknown. Although several studies could show...
Tight junctions (TJs) seal paracellular clefts in epithelia/endothelia and form tissue barriers for proper organ function. TJ-associated marvel proteins (TAMPs; tricellulin, occludin, marvelD3) are thought to be relevant regulation. Under normal conditions, tricellulin tightens tricellular against macromolecules. Traces of occur bicellular junctions.As pathological disturbances have not been analyzed, the structure function human including potentially redox-sensitive Cys sites, were...
Mammalian soluble and microsomal epoxide hydrolases have been proposed to belong the family of αlβ‐hydrolase‐fold enzymes. These enzymes hydrolyse their substrates by a catalytic triad, with first step enzymatic reaction being formation covalent enzyme‐substrate ester. In present paper, we describe direct visualization ester between rat hydrolase its substrate. Microsomal was precipitated acetone after brief incubation |l‐ 14 C]epoxystearic acid. After denaturing SDS gel electrophoresis...
The transcription factor RovA of Yersinia pseudotuberculosis and analogous proteins in other Enterobacteriaceae activate the expression virulence genes that play a crucial role stress adaptation pathogenesis. In this study, we demonstrate protein forms dimers independent DNA binding, stimulates RNA polymerase, most likely via its C-terminal domain, counteracts transcriptional repression by histone-like H-NS. As molecular function family is largely uncharacterized, random mutagenesis terminal...
Claudins regulate paracellular permeability, contribute to epithelial polarization and are dysregulated during inflammation carcinogenesis. Variants of the claudin-binding domain Clostridium perfringens enterotoxin (cCPE) highly sensitive protein ligands for generic detection a broad spectrum claudins. Here, we investigated preferential binding YFP- or GST-cCPE fusion proteins non-junctional claudin molecules. Plate reader assays, flow cytometry microscopy were used assess claudins in...
Abstract The majority of tight junction (TJ) proteins restrict the paracellular permeation solutes via their extracellular loops (ECLs). Tricellulin tightens tricellular TJs (tTJs) and regulates bicellular TJ (bTJ) proteins. We demonstrate that addition recombinantly produced loop 2 (ECL2) tricellulin opens cellular barriers. peptidomimetic trictide, a synthetic peptide derived from ECL2, increases passage ions, as well small larger molecules up to 10 kDa, between 16 30 h after application...
Abstract Improving diagnostic imaging and therapy by targeted compound delivery to pathological areas across biological barriers is of urgent need. A lipopeptide, P‐CrA‐A2, composed a highly cationic peptide sequence (A2), an N‐terminally attached palmitoyl chain (P) cryptophane molecule (CrA) for preferred uptake into blood–brain barrier (BBB) capillary endothelial cells, was generated. CrA allows reversible binding Xe NMR detection with hyperpolarized nuclei. The lipopeptide forms...
Fluids and Barriers of the CNS 2017, 14(Supp 2):A3The loss blood-brain barrier (BBB) integrity primarily occurs in cerebral venules veins during acute hypertensive conditions.Methyl-beta-cyclodextrin (MBCD) causes cholesterol depletion from cell plasma membrane leads to caveolar transport disruption.The present study was intended examine effects MBCD 14(Suppl 2):27 on functional structural properties type brain microvessels angiotensin (ANG) II-induced hypertension rats.The experimental...
Abstract Human recombinant bone morphogenetic protein‐2 (rhBMP‐2) immobilized on the surface of metal implants can facilitate osseointegration. Here, we describe a cell reporter assay useful for quantifying small amounts rhBMP‐2 various materials. The peptide was dotted and heat‐fixed titanium, 316L stainless steel, nitrocellulose, or glass, its distribution monitored by in situ biotinylation followed detection with avidin–biotin method. Bioactivity demonstrated means confluent layer...
Tryptophan hydroxylases catalyze the first and rate-limiting step in biosynthesis of serotonin, a well-known neurotransmitter that plays an important role multiple physiological functions. A reduction serotonin levels, especially brain, can cause dysregulation leading to depression or insomnia. In contrast, overproduction peripheral is associated with symptoms like carcinoid syndrome pulmonary arterial hypertension. Recently, we developed class TPH inhibitors based on...
Abstract Background Claudins, a family of protein localized in tight junctions, are essential for the control paracellular permeation epithelia and endothelia. The interaction several claudins with Clostridium perfringens enterotoxin (CPE) has been exploited an affinity-based enrichment CPE-binding from lysates normal rat cholangiocytes. Results Immunoblotting mass spectrometry (MS) experiments demonstrate strong -3, -4 -7, indicating specific association glutathione-S-transferase (GST)-CPE...
Drug delivery to the brain is limited for most pharmaceuticals by blood-brain barrier (BBB) where claudin-5 dominates paraendothelial tightening. For circumventing BBB, we identified compound M01 as a interaction inhibitor. causes transient permeabilisation of BBB depending on concentration small molecules in different cell culture models within 3 48 h. In mice, uptake fluorescein peaked first h after injection and normalised Compared cytostatic paclitaxel alone, improved mouse reduced...