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 单钠尿酸诱导的炎症始于高尿酸血症，导致尿酸单钠（MSU）晶体 关节和周围组织中的沉积。这些沉积物会引起炎症，疼痛和组织 通过急性炎性耀斑或慢性疾病的破坏。在MSU引起的炎症中，激活 巨噬细胞产生多效性细胞因子白细胞介素1β（IL-1β），被认为是 发病机理和其他促炎分子的关键诱导剂。炎症信号级联 从巨噬细胞中的Toll样/IL-1β受体（TIR）激活开始，这会触发Pro-IL-1β的产生 和其他炎性组件。然后，通过从点头样的caspase激活pro-il-1β 受体蛋白3（NLRP3）炎性体在出口并启动进一步感染之前。一些 痛风患者存在治疗选择，主要分为两类 - 循环水平降低 可溶性尿酸盐或抑制疼痛和注射。但是，这些疗法有很多不足之处 由于它们具有明显的不良影响，有害的药物相互作用，高成本和低反应者 组。该项目研究了一种潜在的新型热剂，用于MSU诱导的注射 - pentagalloyl葡萄糖（PGG） - 已知具有强抗氧化剂和抗炎作用。此外， 我们的初步数据表明，这种化合物抑制了产生固体尿酸盐的黄嘌呤氧化物。我们也是 证明PGG抑制了TGFβ激活的激酶，该激酶在促炎的上调中起作用 对MSU引起的炎症至关重要的介体。最后，我们证明了PGG抑制了两个关键 下游激酶和促炎细胞因子。在目标中，我们将研究PGG的机制 使用THP-1巨噬细胞减少MSU诱导的体外炎症，研究 使用MSU INILICO的PGG，然后使用磷酸化蛋白质组学来识别MSU和PGG诱导的全局变化。在 目标两个我们将使用先前发表的痛风的鼠标模型来确定体内PGG治疗的效果 由我们的小组。综上所述，这些发现将为MSU引起的更完整的了解 在探索潜在的新型疗法并为此提供训练机制的同时，炎症信号传导 学生。