ArticleJournal of inflammation research2022
Shifting the Biosynthesis of Leukotrienes Toward Specialized Pro-Resolving Mediators by the 5-Lipoxygenase-Activating Protein (FLAP) Antagonist BRP-201.
Article in Journal of inflammation research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 28 citations in OpenAlex.
- Biosynthesis and analytics of specialized pro-resolving mediators: facts and faults.Journal of lipid research · 2026Review
- Tocotrienol metabolites redirect lipid mediator production in innate immune cells towards inflammation resolution.Acta pharmaceutica Sinica. B · 2026Article
- Reorganization of Innate Immune Cell Lipid Profiles by Bioinspired Meroterpenoids to Limit Inflammation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Microglial 5-LOX-activating protein antagonism alleviates leukotriene-driven neuroinflammation.Acta neuropathologica · 2026Article
- Unveiling the molecular dynamics of a nitrile-containing 5-lipoxygenase-activating protein antagonist in primary macrophages through Raman spectroscopy.Chemical science · 2026Article
- The role of ALOX15 in inflammation-related diseases.Frontiers in immunology · 2026Review
- Enhanced Efficiency of the Microsomal Prostaglandin EMolecular pharmaceutics · 2025Article
- KIF18A induces the EMT process of hepatoma cells through the 5-LOX-dependent arachidonic acid pathway.PloS one · 2025Article
- Dual anti-inflammatory activities of COX-2/5-LOX driven by kratom alkaloid extracts in lipopolysaccharide-induced RAW 264.7 cells.Scientific reports · 2024Article
- Intersecting Pathways: The Role of Metabolic Dysregulation, Gastrointestinal Microbiome, and Inflammation in Acute Ischemic Stroke Pathogenesis and Outcomes.Journal of clinical medicine · 2024Review
- PEG-Lipid-PLGA Hybrid Particles for Targeted Delivery of Anti-Inflammatory Drugs.Pharmaceutics · 2024Article
- Arachidonic acid-derived lipid mediators in multiple sclerosis pathogenesis: fueling or dampening disease progression?Journal of neuroinflammation · 2024Review
- Activation of pro-resolving pathways mediate the therapeutic effects of thymosin beta-4 duringFrontiers in immunology · 2024Article
- Ethoxy acetalated dextran nanoparticles for drug delivery: A comparative study of formulation methods.International journal of pharmaceutics: X · 2023Article
- Investigating the catalytic efficiency of C22-Fatty acids with LOX human isozymes and the platelet response of the C22-oxylipin products.Archives of biochemistry and biophysics · 2023Article
- Possibility of averting cytokine storm in SARS-COV 2 patients using specialized pro-resolving lipid mediators.Biochemical pharmacology · 2023Review
- Differential impact of 5-lipoxygenase-activating protein antagonists on the biosynthesis of leukotrienes and of specialized pro-resolving mediators.Frontiers in pharmacology · 2023Article
- Frankincense preparation promotes formation of inflammation-resolving lipid mediators by manipulating lipoxygenases in human innate immune cells.Frontiers in pharmacology · 2023Article
- Intestinal epithelial BLT1 promotes mucosal repair.JCI insight · 2022Article
- Molecular Pharmacology of Inflammation Resolution in Atherosclerosis.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeLipid mediators (LM) play crucial roles in the complex inflammation process with respect to initiation, maintenance, and resolution. Proinflammatory leukotrienes (LTs), generated by 5-lipoxygenase (LOX) and the 5-LOX-activating protein (FLAP), initiate and maintain inflammation while specialized pro-resolving mediators (SPMs) formed by various LOXs as key enzymes promote inflammation resolution and the return to homeostasis. Since 5-LOX also contributes to SPM biosynthesis, smart pharmacological manipulation of the 5-LOX pathway and accompanied activation of 12-/15-LOXs may accomplish suppression of LT formation but maintain or even elevate SPM formation. Here, we demonstrated that the FLAP antagonist BRP-201 possesses such pharmacological profile and causes a switch from LT toward SPM formation. METHODS AND
resultsComprehensive LM metabololipidomics with activated human monocyte-derived macrophages (MDM) of M1 or M2 phenotype showed that BRP-201 strongly inhibits LT formation induced by bacterial exotoxins. In parallel, SPM levels and 12/15-LOX-derived products were markedly elevated, in particular in M2-MDM. Intriguingly, in unstimulated MDM, BRP-201 induced formation of 12/15-LOX products including SPM and caused 15-LOX-1 subcellular redistribution without affecting 5-LOX. Experiments with HEK293 cells stably expressing either 5-LOX with or without FLAP, 15-LOX-1 or 15-LOX-2 confirmed suppression of 5-LOX product formation due to FLAP antagonism by BRP-201 but activated 15-LOX-1 in the absence of FLAP. Finally, in zymosan-induced murine peritonitis, BRP-201 (2 mg/kg, ip) lowered LT levels but elevated 12/15-LOX products including SPMs.
conclusionBRP-201 acts as FLAP antagonist but also as 12/15-LOX activator switching formation of pro-inflammatory LTs toward inflammation-resolving SPM, which reflects a beneficial pharmacological profile for intervention in inflammation.
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