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

• 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
• 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

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.

项目摘要 尿酸单钠诱导的炎症开始于高尿酸血症，导致尿酸盐（MSU）结晶 在关节和关节周围组织中沉积。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的破坏。在MSU诱导的炎症中， 巨噬细胞产生多效性细胞因子白细胞介素-1 β（IL-1β），其被认为是巨噬细胞增殖的主要驱动因子。 发病机制和其他促炎分子的关键诱导物。炎症信号级联 开始于巨噬细胞中Toll样/IL-1β受体（TIR）的激活，其触发pro-IL-1β的产生 和其他炎性体成分。然后Pro-IL-1β被NOD样蛋白中切割的半胱天冬酶激活 受体蛋白3（NLRP 3）在被输出并引发进一步炎症之前的炎性小体。几 痛风患者存在治疗选择，主要分为两类-降低痛风的循环水平， 可溶性尿酸盐或抑制疼痛和炎症。然而，这些疗法仍有许多不足之处 因为它们具有显著的副作用、有害的药物-药物相互作用、高成本和低/无应答 组该项目研究了一种潜在的新型治疗MSU诱导的炎症的药物- 五镓酰葡萄糖（PGG）-已知具有强抗氧化和抗炎作用。此外，本发明还 我们的初步数据显示该化合物抑制产生可溶性尿酸盐的黄嘌呤氧化酶。我们也 表明PGG抑制TGFβ激活的激酶，该激酶在促炎性细胞因子的上调中起作用。 对MSU诱导的炎症至关重要的介质。最后，我们已经证明，PGG抑制两个关键的 下游激酶和促炎细胞因子。目的一是研究PGG在体内的作用机制， 使用THP-1巨噬细胞在体外减少MSU诱导的炎症，研究 PGG与MSU的计算机模拟，然后使用磷酸化蛋白质组学来鉴定MSU和PGG诱导的全局变化。在 目的二，我们将使用先前发表的小鼠痛风模型来确定PGG治疗的体内效果 我们的团队。总之，这些发现将提供一个更完整的知识MSU诱导 炎症信号，同时探索潜在的新型治疗方法并为此提供训练机制。 学生.