A5085908396- Alzheimer's disease research and treatments
- Crystal structures of chemical compounds
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- Cholinesterase and Neurodegenerative Diseases
- Ubiquitin and proteasome pathways
- Synthesis and biological activity
- Metal complexes synthesis and properties
- Neuroscience and Neuropharmacology Research
- Peptidase Inhibition and Analysis
- Oxidative Organic Chemistry Reactions
- Synthesis of Organic Compounds
- Calpain Protease Function and Regulation
- Receptor Mechanisms and Signaling
- Protein Degradation and Inhibitors
- Carbohydrate Chemistry and Synthesis
- Asymmetric Synthesis and Catalysis
- Click Chemistry and Applications
- Drug Transport and Resistance Mechanisms
- Synthetic Organic Chemistry Methods
- Synthesis and Characterization of Heterocyclic Compounds
- Phenothiazines and Benzothiazines Synthesis and Activities
- Wnt/β-catenin signaling in development and cancer
- Pharmacogenetics and Drug Metabolism
- Synthesis and Biological Evaluation
Agaplesion Bethanien Krankenhaus
2022-2025
Agaplesion Markus Hospital
2022-2025
Technical University of Darmstadt
2013-2023
Cardiovascular Center Bethanien
2017
Université Libre de Bruxelles
2014-2015
King's College London
2012-2013
William Harvey Research Institute
2012-2013
Queen Mary University of London
2012-2013
University of Naples Federico II
2013
Peking University People's Hospital
2013
The formation of a covalent bond with the target is essential for number successful drugs, yet tools docking without significant restrictions regarding warhead or receptor classes are rare and limited in use. In this work we present DOCKTITE, highly versatile workflow Molecular Operating Environment (MOE) combining automated screening, nucleophilic side chain attachment, pharmacophore-based docking, novel consensus scoring approach. comprehensive validation study includes pose predictions 35...
Abstract Curcumin binds to the amyloid β peptide (Aβ) and inhibits or modulates precursor protein (APP) metabolism. Therefore, curcumin‐derived isoxazoles pyrazoles were synthesized minimize metal chelation properties of curcumin. The decreased rotational freedom absence stereoisomers was predicted enhance affinity toward Aβ 42 aggregates. Accordingly, replacement 1,3‐dicarbonyl moiety with isosteric heterocycles turned curcumin analogue into potent ligands fibrillar Additionally, several...
Tauopathies are widespread neurodegenerative disorders characterised by the intracellular accumulation of hyperphosphorylated tau. Especially in Alzheimer's disease, pathological alterations retina discussed as potential biomarkers to improve early diagnosis disease. Using mice expressing human mutant P301S tau, we demonstrate for first time a straightforward optical approach vivo detection fibrillar tau retina. Longitudinal examinations individual animals revealed fate single cells...
Syndecans are cell surface proteoglycans that bind and modulate various proinflammatory mediators can be proteolytically shed from the surface. Within lung, syndecan-1 -4 expressed as transmembrane proteins on epithelial cells released in bronchoalveolar fluid during inflammation. We here characterize mechanism leading to generation of soluble cultured murine lung tissue. show bladder carcinoma line ECV304, A459 primary alveolar express constitutively release -4. This involves activity...
The world health organization (WHO) estimated that 18 million people are struck by Alzheimer's disease (AD). USA, France, Germany, and other countries launched major programmes targeting the identification of risk factors, improvement caretaking, fundamental research aiming to postpone onset AD. glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes has been linked pathogenesis several diseases including diabetes mellitus, cancer, Inhibition GSK-3 leads...
Angiotensin II (Ang II) type 1 receptor (AT ) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory antiaggregatory in vitro patients, although underlying mechanism unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, LOS metabolite EXP3179 is generated, which shows homology to indomethacin, a cyclooxygenase inhibitor with properties. Subsequently, serum-levels were determined 8...
One of the key pathological features Alzheimer's disease is aggregation tau protein. We are therefore searching for compounds capable inhibiting this reaction. On basis an initial screen 200000 [Pickhardt, M., Gazova, Z., von Bergen, Khlistunova, I., Wang, Y., Hascher, A., Mandelkow, E. Biernat, J., and (2005) Anthraquinones inhibit dissolve paired helical filaments in vitro cells, J. Biol. Chem. 280, 3628−3635], we performed silico predicted a new phenylthiazolyl-hydrazide (PTH) compound as...
Amyloid-beta plaque deposition represents a major neuropathological hallmark of Alzheimer's disease. While numerous studies have described dendritic spine loss in proximity to plaques, much less is known about the kinetics these processes. In particular, question as whether synapse precedes or follows formation remains unanswered. To address this question, and learn more underlying kinetics, we simultaneously imaged amyloid by applying two-photon vivo microscopy through cranial window double...
The kinetics of amyloid plaque formation and growth as one the characteristic hallmarks Alzheimer's disease (AD) are fundamental issues in AD research. Especially question how fast plaques grow to their final size after they born remains controversial. By long-term two-photon vivo imaging we monitored individual methoxy-X04-stained over 6 weeks 12 18 months old Tg2576 mice. We found that mice, newly appearing were initially small volume subsequently grew time. rate was inversely proportional...
Abstract The ubiquitin–proteasome system (UPS) has been successfully targeted by both academia and the pharmaceutical industry for oncological immunological applications. Typical proteasome inhibitors are based on a peptidic backbone endowed with an electrophilic C‐terminus which they react active proteolytic sites. Although peptide moiety attracted much attention in terms of subunit selectivity, target specificity biological stability compounds largely determined reactive warheads. In this...
The in vivo diagnosis of Alzheimer's disease (AD) is high socioeconomic interest and remains a demanding field research. biopathological hallmarks the are extracellular plaques consisting aggregated β-amyloid peptides (Aβ) tau protein derived intracellular tangles. Here we report synthesis evaluation fluorescent pyrazine, pyrimidine,and pyridazine derivatives vitro aiming at tau-based AD. probes were pre-evaluated on human brain tissue by fluorescence microscopy found to label all known...
Two active metabolites of the angiotensin type 1 (AT1) receptor blocker losartan have been described previously, EXP3174 and EXP3179. Whereas is main antihypertensive AT1 receptor-blocking metabolite, role EXP3179 widely unknown. Recently, a subgroup blockers has identified as ligands for peroxisome proliferator-activated gamma (PPAR-gamma). Here we characterize PPAR-gamma-activating properties 2 metabolites. PPAR-gamma activity was measured with chimeric Gal4-DNA-binding...
CD23, the low-affinity receptor for IgE, exists in membrane and soluble forms. Soluble CD23 (sCD23) fragments are released from (m)CD23 by endogenous metalloprotease a disintegrin 10. When purified tonsil B cells incubated with IL-4 anti-CD40 to induce class switching IgE vitro, mCD23 is upregulated, sCD23 accumulates medium prior synthesis. We have uncoupled effects of cleavage accumulation on synthesis this system. show that small interfering RNA inhibition or an 10 inhibitor, GI254023X,...
We investigated the role of matrix metalloproteinase-8 (MMP8) in neointima formation and vascular smooth muscle cell (VSMC) migration proliferation.After carotid artery wire injuring, MMP8(-/-)/apoE(-/-) mice had fewer proliferating cells neointimal lesions smaller lesion sizes. Ex vivo assays comparing VSMCs isolated from MMP8 knockout wild-type showed that decreased proliferation migration. Proteomics analysis revealed a disintegrin metalloproteinase domain-containing protein 10 (ADAM10)...
A major neuropathological hallmark of Alzheimer's disease is the deposition amyloid plaques in brains affected individuals. Amyloid mainly consist fibrillar β-amyloid, which a cleavage product precursor protein. The amyloid-cascade-hypothesis postulates Aβ accumulation as central event initiating toxic cascade leading to pathology and, ultimately, loss cognitive function. We studied kinetics β-amyloid Tg2576 mice, overexpress human protein with Swedish mutation. Utilizing long-term...
Accumulating evidence indicates that stem/progenitor cells (SPCs) represent an important source of in atheromas and contribute to lesion formation progression.We investigated whether matrix metalloproteinase-8 (MMP8) played a role SPC migration their recruitment into atheromas.We found SPCs expressed MMP8 knockout significantly reduced numbers atherosclerotic lesions apolipoprotein E (ApoE)-deficient mice fed Western diet. Further vivo experiments showed ApoE(-/-)/MMP8(-/-) injected with...
Abstract DiC14-amidine is a cationic lipid that was originally designed as nanocarrier for nucleic acid transport, and turned out to be Toll-like receptor 4 (TLR4) agonist well. We found while E. coli lipopolysaccharide (LPS) TLR4 in all species, diC14-amidine nanoliposomes are full agonists human, mouse cat receptors but weak horse agonists. Taking advantage of this unusual species specificity, we used chimeric constructs based on the human sequences identified two regions modulate activity...