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.

项目概要尿酸钠诱发的炎症始于高尿酸血症，导致尿酸钠 (MSU) 结晶沉积在关节和关节周围组织中，这些沉积物会引起炎症、疼痛和组织损伤。通过急性炎症发作或慢性疾病造成的破坏在密歇根州立大学诱发的炎症中被激活。巨噬细胞产生多效性细胞因子白细胞介素-1β (IL-1β)，它被认为是发病机制和其他促炎症分子的关键诱导物。首先是巨噬细胞中 Toll 样/IL-1β 受体 (TIR) 的激活，从而触发 pro-IL-1β 的产生然后，Pro-IL-1β 和其他炎性小体成分被 NOD-Like 中裂解的 caspase 激活。受体蛋白 3 (NLRP3) 炎性体在被输出并引发进一步炎症之前。痛风患者存在治疗选择，主要分为两类——降低循环水平然而，这些疗法还有很多不足之处。因为它们具有显着的副作用、有害的药物间相互作用、高成本和低/无反应该项目研究了一种潜在的新型治疗剂，用于治疗密歇根州立大学引起的炎症—— 五没食子酰葡萄糖 (PGG) – 已知具有强大的抗氧化和抗炎作用。我们的初步数据表明，该化合物可抑制产生可溶性尿酸盐的黄嘌呤氧化酶。证明 PGG 抑制 TGFβ 激活激酶，该激酶在促炎性上调中发挥作用最后，我们证明 PGG 可以抑制这两种关键介质。在目标一中，我们将研究 PGG 的下游激酶和促炎细胞因子。使用 THP-1 巨噬细胞在体外减少 MSU 诱导的炎症，研究 PGG 与 MSU 计算机模拟，然后使用磷酸蛋白质组学来识别 MSU 和 PGG 诱导的全局变化。目标二，我们将使用先前发表的痛风小鼠模型确定 PGG 治疗的体内效果总而言之，这些发现将提供对密歇根州立大学诱发的更完整的了解。炎症信号传导，同时探索潜在的新型治疗方法并为此提供训练机制学生。