A5024379262- Immune Response and Inflammation
- Immunotherapy and Immune Responses
- Inflammatory mediators and NSAID effects
- Cell Adhesion Molecules Research
- Asthma and respiratory diseases
- Immune cells in cancer
- Monoclonal and Polyclonal Antibodies Research
- Rheumatoid Arthritis Research and Therapies
- Psoriasis: Treatment and Pathogenesis
- IL-33, ST2, and ILC Pathways
- NF-κB Signaling Pathways
- Chemokine receptors and signaling
- Immune Cell Function and Interaction
- Ion Channels and Receptors
- Osteoarthritis Treatment and Mechanisms
- Toxin Mechanisms and Immunotoxins
- Synthesis and biological activity
- Receptor Mechanisms and Signaling
- Cytokine Signaling Pathways and Interactions
- Pharmacological Effects of Natural Compounds
- Phosphodiesterase function and regulation
- Multiple Myeloma Research and Treatments
- Veterinary Equine Medical Research
- Sphingolipid Metabolism and Signaling
- Cholinesterase and Neurodegenerative Diseases
Novartis (Switzerland)
2013-2024
Novartis Institutes for BioMedical Research
2009-2022
Institut thématique Immunologie, inflammation, infectiologie et microbiologie
2017
Royal Veterinary College
1986-1992
University of London
1987-1992
Howard College
1986-1987
When SUCNR1/GPR91-expressing macrophages are activated by inflammatory signals, they change their metabolism and accumulate succinate. In this study, we show that during activation, release succinate into the extracellular milieu. They simultaneously up-regulate GPR91, which functions as an autocrine paracrine sensor for to enhance IL-1β production. GPR91-deficient mice lack metabolic reduced macrophage activation production of antigen-induced arthritis. Succinate is abundant in synovial...
NLRP3 is a molecular sensor recognizing wide range of danger signals. Its activation leads to the assembly an inflammasome that allows for caspase-1 and subsequent maturation IL-1β IL-18, as well cleavage Gasdermin-d pyroptotic cell death. The has been implicated in plethora diseases including gout, type 2 diabetes, atherosclerosis, Alzheimer's disease, cancer. In this publication, we describe discovery novel, tricyclic, NLRP3-binding scaffold by high-throughput screening. hit (1) could be...
Abstract The paracaspase MALT1 plays an important role in immune receptor-driven signaling pathways leading to NF-κB activation. promotes by acting as a scaffold, recruiting downstream proteins, well proteolytic cleavage of multiple substrates. However, the relative contributions these two different activities T and B cell function are not understood. To investigate how activity contributes overall regulation, we generated protease-deficient mice (Malt1PD/PD) compared their phenotype with...
Bruton's tyrosine kinase (BTK), a cytoplasmic kinase, plays central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors limited to oncology indications based on their suboptimal selectivity. We describe the discovery preclinical profile LOU064 (remibrutinib, 25), potent, highly selective inhibitor. exhibits exquisite selectivity due binding inactive conformation has potential best-in-class inhibitor...
The acute-phase reactant rabbit serum amyloid A 3 (SAA3) was identified as the major difference product in Ag-induced arthritis rabbit, a model resembling many aspects clinical characteristics of rheumatoid (RA) humans. In arthritis, up-regulated SAA3 transcription vivo detected cells infiltrating into inflamed joint, area where pannus formation starts and, most notably, also chondrocytes. proinflammatory cytokine IL-1beta induced primary chondrocytes vitro. Furthermore, rSAA3 protein matrix...
1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified COX-1 and COX-2 with K(i) values 3 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition at concentrations up to 30 (HEK 293 cells transfected human COX-1). 3. whole blood assay, for were 0.13 67 (COX-1/COX-2 selectivity ratio 515). 4. was...
The identification of a natural ligand the orphan chemoattractant receptor GPR15 provides mechanistic insight into migration lymphocytes in skin.
This manuscript reports the results of preclinical studies in rat with robenacoxib, a novel selective cyclooxygenase (COX)-2 inhibitor. Robenacoxib selectively inhibited COX-2 vitro as evidenced from COX-1:COX-2 IC50 ratios 27:1 purified enzyme preparations and >967:1 isolated cell assays. Binding to COX-1 was rapid readily reversible (dissociation t(1/2) << 1 min), whilst binding slowly (t(1/2) = 25 min). In vivo, robenacoxib PGE2 production (an index inhibition) lipopolysaccharide...
Retinoic acid receptor-related-orphan-receptor-C (RORγt) is the key transcription factor that driving differentiation of IL-17 producing T-helper 17 (Th17) cells are implicated in pathology various autoimmune and inflammatory diseases. Based on importance RORγt promoting Th17-driven pathology, there considerable interest to develop low-molecular-weight compounds with aim inhibiting transcriptional activity this nuclear hormone receptor. In article, we describe vitro vivo pharmacology a...
Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic Rorc deficiency mice, while preventing autoimmunity, causes early lethality due to metastatic thymic T cell lymphomas. We sought determine whether pharmacological RORC inhibition could be an effective and safe therapy for diseases by evaluating its effects on functions intrathymic development. inhibitors effectively inhibited differentiation IL-17A...
A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well hERG channel prevented it further development. Therefore, new round of optimization addressing the key liabilities performed led discovery with an improved profile. Compound significant rat antigen induced arthritis hyperalgesia angiogenesis model at well-tolerated dose 30 mg/kg.
In mammals, ceramide kinase (CerK)-mediated phosphorylation of is the only known pathway to ceramide-1-phosphate (C1P), a recently identified signaling sphingolipid metabolite. To help delineate roles CerK and C1P, we knocked out gene in BALB/c mice by homologous recombination. All vitro as well cell-based assays indicated that activity completely abolished Cerk-/- mice. Labeling with radioactive orthophosphate showed profound reduction levels de novo C1P formed macrophages. Consistently,...
This article describes the use of a fluorescent nanoprobe as functional biomarker for identification increased vascular permeability in cancer/arthritis disease models. Synthesis was achieved by passive loading fluorophore inside nanoparticle using thin film hydration method. The outer layer decorated with poly(ethylene glycol) arms to increase bioavailability fluorophore. Stability studies showed that particles were stable up 70 days. uptake and internalization target cells confirmed...
Abstract Three‐dimensional (3D) MR images were obtained from the knees of rats in a model antigen‐induced arthritis, elicited by intraarticular administration methylated bovine serum albumin (mBSA) to previously immunized rats. Superparamagnetic particles iron oxide (SPIO) administered i.v. 24 hr before each imaging session. Starting 4 days postantigen injection, arthritic exhibited distinctive signal attenuation synovium. This was significantly smaller animals treated with dexamethasone,...
The integrin lymphocyte function-associated antigen-1 (LFA-1) (αLβ2; CD11a/CD18) plays an important role in leukocyte migration and T cell activation. LFA-1 is inhibited by the cholesterol-lowering drug lovastatin, which binds to allosteric site of αL I domain termed lovastatin (L-site). Here we report for first time x-ray structures complexed with derivatives optimized inhibition. This analysis identified two new subpockets within L-site occupied chemical groups statin but not itself....
Background Succinate, in addition to its role as an intermediary of the citric acid cycle, acts alarmin, initiating and propagating danger signals resulting from tissue injury or inflammatory stimuli. The contribution this immune sensing pathway development allergic responses is unknown. Methods Ear thickness wild-type (wt) Sucnr1-deficient (Sucnr1−/−) mice, sensitized challenged with oxazolone, was used a criterion assess relevance SUCNR1/GPR91 expression mediating contact dermatitis (ACD)....
The cytosolic metalloenzyme leukotriene A
Abstract Objective We have previously reported that the kinase activity of interleukin‐1 receptor–associated 4 (IRAK‐4) is important for Toll‐like receptor and signaling in vitro. Using mice devoid IRAK‐4 (IRAK‐4 KD mice), we undertook this study to determine importance function complex disease models joint inflammation. Methods were subjected serum transfer–induced (K/BxN) arthritis, migration transferred spleen lymphocytes into joints cartilage bone degradation assessed. T cell response...
Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites. The function of the enzyme catalyzes biosynthesis pro-inflammatory lipid mediator leukotriene (LT) B4. Recent literature suggests LTA4H responsible for degradation tripeptide Pro-Gly-Pro (PGP) which neutrophil chemotactic activity has been postulated. It speculated design selective inhibitors spare pocket may...
Retinoic-acid-related orphan receptor γt (RORγt) is a key transcription factor implicated in the production of pro-inflammatory Th17 cytokines, which drive number autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with good physicochemical profile has very challenging task RORγt inhibitor field. Based on available structures and incorporating in-house knowledge, new triazolo- imidazopyridine inverse agonists was designed. In addition,...
Chronic pain resulting from metastatic bone cancer remains poorly understood and resistant to treatment. Here we have examined the effect of novel COX-2 enzyme inhibitor lumiracoxib in a model rat. Lumiracoxib was administered orally twice daily day 10 20 after injection MRMT-1 tumour cells into one tibia. Mechanical hyperalgesia, measured as reduction weight-bearing ipsilateral limb, development static dynamic allodynia were significantly inhibited by repeated lumaricoxib administration. A...