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Pentagalloyl glucose as an inhibitor of monosodium urate induced inflammation

五没食子酰葡萄糖作为尿酸钠诱导炎症的抑制剂

基本信息

批准号：
10535379
负责人：
Paul Panipinto
金额：
$ 3.82万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10535379
关键词：
Acute Address Adverse effects Affect Allopurinol American Anti-Inflammatory Agents Antiinflammatory Effect Antioxidants Attenuated Binding Binding Sites Bone Resorption C57BL/6 Mouse CASP1 gene Caspase Categories Chronic Disease Colchicine Crystal Formation Crystallization Data Deposition Disease Docking Drug Interactions Enzymes Flare Global Change Glucose Gout Human Hyperuricemia IL8 gene Immunology In Vitro Inflammasome Inflammation Inflammation Mediators Inflammatory Interleukin-1 beta Intra-Articular Injections Investigation JUN gene Joints Knowledge Lipopolysaccharides MAPK8 gene Mediating Mediator of activation protein Mitogen-Activated Protein Kinases Modeling Molecular N-terminal Non-Steroidal Anti-Inflammatory Agents Pain Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Probenecid Process Production Publishing Regulation Research Personnel Rheumatism Role Signal Transduction Structure-Activity Relationship Students TNF gene Testing Therapeutic Therapeutic Agents Tissues Training Transforming Growth Factor beta Up-Regulation Urate Uric Acid Work Xanthine Oxidase base chemokine compliance behavior cost cytokine disability effective therapy falls febuxostat in silico in vivo in vivo evaluation inhibitor intense pain macrophage marenostrin molecular dynamics mouse model neutrophil new therapeutic target novel novel therapeutics phosphoproteomics receptor simulation training opportunity uptake

项目摘要

Project Summary Monosodium urate-induced inflammation begins with hyperuricemia leading to monosodium urate (MSU) crystal deposition in the joints and periarticular tissues. These deposits can cause inflammation, pain, and tissue destruction through either acute inflammatory flares or chronic disease. In MSU-induced inflammation, activated macrophages produce the pleiotropic cytokine Interleukin-1β (IL-1β) which is recognized as the major driver of pathogenesis and a key inducer of other pro-inflammatory molecules. The inflammatory signaling cascade begins with activation of Toll-like/IL-1β receptors (TIRs) in macrophages, which triggers production of pro-IL-1β and other inflammasome components. Pro-IL-1β is then activated by cleaved caspase from the NOD-Like Receptor Protein 3 (NLRP3) inflammasome before being exported and initiating further inflammation. Several treatment options exist for gout patients, mostly falling into two categories – reduction of circulating levels of soluble urate, or the suppression of pain and inflammation. These therapies, however, leave much to be desired as they have significant adverse effects, deleterious drug-drug interactions, high cost and low/non-responder groups. This project investigates a potential novel therapeutic agent for MSU-induced inflammation – pentagalloyl glucose (PGG) – that is known to have strong antioxidant and anti-inflammatory effects. Additionally, our preliminary data shows that this compound inhibits xanthine oxidase which produces soluble urate. We also demonstrate that PGG inhibits TGFβ-activated kinase which plays a role in the upregulation of proinflammatory mediators critical to MSU-induced inflammation. Finally, we have demonstrated that PGG inhibits both a critical downstream kinase and proinflammatory cytokines. In Aim one we will investigate the mechanism by which PGG reduces MSU-induced inflammation in vitro using THP-1 macrophages, investigate the atomistic interactions of PGG with MSU in-silico, then use phosphoproteomics to identify global changes induced by MSU and PGG. In Aim two we will determine the effects of PGG treatment in vivo using mouse models of gout previously published by our group. Taken together, these findings will provide a more complete knowledge of MSU-induced inflammatory signaling while exploring a potential novel therapeutic and providing a training mechanism for this student.

项目总结