A5066031416- Sphingolipid Metabolism and Signaling
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Pulmonary Hypertension Research and Treatments
- Receptor Mechanisms and Signaling
- Lipid Membrane Structure and Behavior
- RNA Research and Splicing
- PI3K/AKT/mTOR signaling in cancer
- Sleep and Wakefulness Research
- Nitric Oxide and Endothelin Effects
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Inflammasome and immune disorders
- Protein Kinase Regulation and GTPase Signaling
- Crystallography and molecular interactions
- Genomics and Chromatin Dynamics
- Apelin-related biomedical research
- Photochromic and Fluorescence Chemistry
- Neonatal Respiratory Health Research
- Hormonal Regulation and Hypertension
- RNA and protein synthesis mechanisms
- Cystic Fibrosis Research Advances
- Phosphodiesterase function and regulation
- Renin-Angiotensin System Studies
- Cardiovascular Issues in Pregnancy
Idorsia (Switzerland)
2017-2025
Idera Pharmaceuticals (United States)
2021
Actelion (Switzerland)
2008-2017
Max Planck Institute of Biochemistry
1997-2000
Max Planck Institute of Neurobiology
1999-2000
Max Planck Society
1998-1999
MRC Laboratory of Molecular Biology
1992-1995
Medical Research Council
1993
Sphingosine-1-phosphate (S1P) is a widespread lysophospholipid which displays wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P(1) S1P(5). Agonists the receptor block egress T-lymphocytes from thymus and lymphoid organs hold promise for oral treatment autoimmune disorders. Here, we report on discovery detailed structure-activity relationships novel class agonists based 2-imino-thiazolidin-4-one scaffold....
The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of and test potential therapeutic interventions, despite the well recognized dissimilarities human idiopathic pulmonary (IPF). Therefore, in this study, we sought identify genomic commonalities between gene expression profiles from 100 IPF lungs 108 control that were obtained Lung Tissue Research Consortium, rat harvested at Days 3, 7, 14, 21, 28, 42, 56 after bleomycin instillation. Surprisingly, highest...
Two endothelin receptor antagonists (ERAs), bosentan and ambrisentan, are currently approved for the treatment of pulmonary arterial hypertension (PAH), a devastating disease involving an activated system aberrant contraction proliferation smooth muscle cells (PASMC). The novel ERA macitentan has recently concluded testing in Phase III morbidity/mortality clinical trial PAH patients. Since association dissociation rates G protein-coupled can influence their pharmacological activity vivo, we...
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis, which characterised by destruction of normal architecture and excessive deposition extracellular matrix. The heterogeneity progression in patients IPF poses significant obstacles to patient care prevents efficient development novel therapeutic interventions. Blood biomarkers, reflecting pathobiological processes the lung, could provide objective evidence underlying disease. Longitudinally...
Alternative pre-mRNA splicing patterns can change an extracellular stimulus, but the signaling pathways leading to these changes are still poorly characterized. Here, we describe a tyrosine-phosphorylated nuclear protein, YT521-B, and show that it interacts with transcriptosomal component scaffold attachment factor B, 68-kDa Src substrate associated during mitosis, Sam68. Northern blot analysis demonstrated ubiquitous expression, detailed RNA in situ revealed cell type specificity brain....
Interphase chromatin is arranged into topologically separated domains comprising gene expression and replication units through genomic sequence elements, so-called MAR or SAR regions (for matrix- scaffoldassociating regions). S/MAR are located near the boundaries of actively transcribed genes were shown to influence their activity. We show that scaffold attachment factor B (SAF-B), which specifically binds regions, interacts with RNA polymerase II (RNA pol II) a subset serine-/arginine-rich...
Phosphorylated serine- and arginine-rich (SR) proteins are components of the spliceosomal complex, have been implicated in control alternative splicing. Kinases that regulate phosphorylation possibly intranuclear distribution SR may therefore contribute to changes choice splice site. We cloned three mouse cDNAs with high sequence identity family LAMMER kinases (i.e. carrying conserved signature EHLAMMERILG catalytic domain). A comparison their amino acid sequences revealed two related...
Hereditary pancreatitis has been found to be associated with germline mutations in the cationic trypsinogen (PRSS1) gene. Here we report a family hereditary that carries novel PRSS1 mutation (R122C). This cannot diagnosed conventional screening method using <i>Afl</i>III restriction enzyme digest. We therefore propose new assay based on digest <i>Bst</i>UI, technique permits detection of R122C addition most common R122H mutation, and even presence recently reported neutral polymorphism...
Urotensin-II (U-II) is a cyclic peptide now described as the most potent vasoconstrictor known. U-II binds to specific G protein-coupled receptor, formerly orphan receptor GPR14, renamed urotensin (UT receptor), and present in mammalian species. Palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt) new antagonist of human UT receptor. ACT-058362 antagonizes binding <sup>125</sup>I-labeled on natural recombinant cells carrying...
Lymphocyte exit from lymph nodes and their recirculation into blood is controlled by the sphingolipid sphingosine 1-phosphate (S1P). The cellular receptor mediating lymphocyte S1P<sub>1</sub>, one of five S1P receptors. Nonselective agonists for receptors lead to count reduction. effects selective S1P<sub>1</sub> on impact in models lymphocyte-mediated tissue inflammation have been less investigated. We describe here general pharmacology ponesimod,...
Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment and improved patient outcomes. Blood-based biomarkers that reliably identify patients at risk PAH, or with disease, would significantly improve screening, potentially leading to survival, provide novel mechanistic insights into disease. The main objective this study was proteomic biomarker signature could discriminate...
The characterization of distinct subnuclear domains suggests a dynamic nuclear framework supporting gene expression and DNA replication. Here, we show that the glutamic acid/arginine-rich domain protein YT521-B localizes to novel structure, YT bodies. bodies are compartments, which first appear at beginning S-phase in cell cycle disperse during mitosis. Furthermore, untreated cells human line MCF7 they were undetectable appeared only after drug- induced differentiation. contain...
Intratracheal administration of bleomycin induces fibrosis in the lung, which is mainly assessed by histopathological grading that subjective. Current literature highlights need reproducible and quantitative pulmonary analysis. If some studies looked at parameters separately, none them quantitatively both aspects: lung tissue remodeling collagenization. To ensure reliable quantification, support vector machine learning was used on digitalized images to design a fully automated method...
Idiopathic pulmonary fibrosis is a life-threatening progressive disease characterized by loss of alveolar epithelial cells, inflammation, and aberrant fibroblast activation. The two currently approved therapies do not halt or reverse tissue remodeling, therefore novel disease-modifying mechanisms are needed. Our results describe YAP/TAZ inhibition through prostacyclin (IP) receptor activation as mechanism that suppresses profibrotic (myo)fibroblast activity. We investigated the antifibrotic...
The biogenic amine serotonin (5-HT) is a multi-faceted hormone that synthesized from dietary tryptophan with the rate limiting step being catalyzed by enzyme hydroxylase (TPH). therapeutic potential of peripheral 5-HT synthesis inhibitors has been demonstrated in number clinical and pre-clinical studies diseases including carcinoid syndrome, lung fibrosis, ulcerative colitis obesity. Due to long half-life blood lung, changes steady-state levels are slow manifest themselves. Here,...
In the progression phase of idiopathic pulmonary fibrosis (IPF), normal alveolar structure lung is lost and replaced by remodeled fibrotic tissue bronchiolized cystic airspaces. Although these are characteristic features IPF, knowledge specific interactions between pathological processes limited. Here, interaction epithelial mesenchymal cells was investigated in a coculture model human primary airway (EC) fibroblasts (FB). Single-cell RNA sequencing revealed that starting EC population...
Three distinct pharmacological corrector types (I, II, III) with different binding sites and additive behavior only partially rescue the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding trafficking defect observed in cystic fibrosis. We describe uniquely effective, macrocyclic CFTR correctors that were to known types, exerting a complementary “type IV” mechanism. Macrocycles achieved wild-type–like efficiency of F508del-CFTR at endoplasmic reticulum normalized...
We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that another bosentan, in rat model non-vasoreactive pulmonary hypertension (PH) particular emphasis on right ventricular (RV) remodeling.Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented PH characterized by absence dilatation to adenosine. therefore chose bleomycin compare effects maximally effective doses macitentan and bosentan vascular RV remodeling....
Piperidine
Urotensin-II (U-II), a vasoactive cyclic neuropeptide, was recently identified as the natural ligand for G-protein coupled receptor GPR14. The expression pattern of U-II and GPR14 are consistent with role neurohormonal regulatory system in cardiovascular homeostasis. induces rapid short-lasting rise intracellular calcium recombinant expressing cells. In present study we show that signal transduction pathways leading to long-lasting activation extracellular signal-regulated kinase 1/2...