Pentagalloyl glucose as an inhibitor of monosodium urate induced inflammation

项目摘要 尿酸一钠诱导的炎症始于高尿酸血症导致尿酸一钠(MSU)结晶 关节和关节周围组织中的沉积。这些沉积物会引起炎症、疼痛和组织。 通过急性炎症性火焰或慢性疾病造成的破坏。在MSU诱导的炎症中，被激活 巨噬细胞产生多效性细胞因子白介素1β(IL-1β)，它被认为是 发病机制和其他促炎分子的关键诱因。炎症信号级联 首先激活巨噬细胞中的Toll-like/IL-1β受体(TIR)，从而触发前-IL-1β的产生 和其他炎性小体成分。然后，前体-IL-1β被从类NOD中切割的半胱氨酸酶激活 受体蛋白3(NLRP3)在出口前会产生炎症，并引发进一步的炎症。几个 痛风患者存在治疗选择，主要分为两类-降低循环水平 可溶的尿酸盐，或抑制疼痛和炎症。然而，这些疗法还有很多不尽如人意的地方。 因为它们有显著的不良反应，有害的药物-药物相互作用，高成本和低/无应答者 组。本项目研究一种潜在的治疗MSU引起的炎症的新型药物-- 五合金酰葡萄糖(PGG)-已知具有很强的抗氧化和抗炎作用。另外， 我们的初步数据显示，这种化合物抑制黄嘌呤氧化酶产生可溶性尿酸盐。我们也 前列腺素G抑制转化生长因子β激活的蛋白激酶在促炎症反应中的作用 对MSU引起的炎症至关重要的介质。最后，我们已经证明了PGG抑制了一种关键的 下游的激酶和致炎细胞因子。在第一个目标中，我们将研究PGG的机制 利用THP-1巨噬细胞体外减轻MSU诱导的炎症，研究THP-1巨噬细胞的原子相互作用 PGG与MSU嵌合，然后利用磷酸蛋白质组学鉴定MSU和pGG诱导的全球变化。在……里面 目的2我们将利用先前发表的痛风小鼠模型来确定PGG在体内的治疗效果 被我们这群人。综上所述，这些发现将提供对MSU诱导的更完整的知识 炎症信号，同时探索潜在的新的治疗方法，并为此提供训练机制 学生。

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.