Evaluation of the Effect of Green Tea Polyphenols on IBD

描述(由申请人提供)： 在外行和科学文献中，绿茶作为一种改善健康和治疗疾病的药剂的兴趣都有所增加。绿茶由几种成分组成，大多数研究都集中在多酚成分上。绿茶多酚(GRTP)包括(-)-表儿茶素(EC)、(-)-表儿茶素(EGC)、(-)-表儿茶素-3-没食子酸酯(CG)和(-)-表儿茶素-3-没食子酸酯(EGCG)。其中，EGCG占多酚总量的40%以上。治疗和预防的好处被归因于多酚的强大抗氧化作用，包括降低癌症风险。GRTP还具有强大的抗炎特性。GRTP已被证明是核因子-kB(核因子-kB)的有效抑制剂，核因子-kB是控制肠道炎症的关键调节因子。核因子-kB的激活可由多种刺激因子诱导，如促炎细胞因子肿瘤坏死因子-α(TNF-a)或白介素1(IL-1)、细菌内毒素或氧化应激。在未受刺激的细胞中，核因子-kB以异源二聚体的形式存在，由p65和p50亚基组成，与抑制因子-kB(IKB)家族中的一个成员结合。核因子-kB激活剂通过IKB激酶(IKK)使IKB的N-末端调节域中的两个丝氨酸磷酸化，从而诱导26S蛋白小体对IKB的降解。释放出来的核因子-kB转位到细胞核，结合特定的启动子序列，诱导促炎细胞因子的表达。这些细胞因子在慢性炎症性肠病(IBD)中高水平表达。IL-1和TNF-a也在正向调节环路中激活了核因子-kB。这可能会导致炎症反应的放大。核因子-kB似乎在炎症中发挥重要作用，并且可能是抗炎治疗的靶点。应用GRTP可改善炎症动物模型。该提案的科学部分旨在评估GRTP在人类中的使用。特定目的1将证实GRTP抑制人外周血单核细胞中核因子-kB的激活。具体目标2将评估GRTP在静止期IBD志愿者中的安全性和耐受性，同时定义GRTP的药代动力学和药效学。具体目标3将进一步评估GRTP在IBD患者中的安全性，同时提供该疗法在活动期溃疡性结肠炎患者中的疗效的初步数据。

DESCRIPTION (provided by applicant): Interest in green tea as an agent for improving health and treating disease has increased in both the lay and scientific literature. Green tea consists of several components, with most research focusing on the polyphenol fraction. The green tea polyphenols (GrTP) include (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)- epicatechin-3-gatlate (ECG), and (-)-epigallocatechin-3-gallate (EGCG). Of these, EGCG accounts for greater than 40% of the total polyphenol content. Therapeutic and prophylactic benefits have been attributed to the potent anti-oxidant effects of the polyphenols, including reducing the risk of cancer. GrTP also have potent anti-inflammatory properties. GrTP have proven to be potent inhibitors of nuclear factor-kappa B (NF-kB), a key regutatory factor in the control of intestinal inflammation. Activation of NF-kB can be induced by a variety of stimulatory factors, such as the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-a) or interleukin-1 (IL-1), bacterial endotoxin, or oxidative stress. In unstimulated cells, NF-kB exists as a heterodimer comprised of p65 and p50 subunits, bound to a member of the inhibitor-kB (IkB) family of inhibitory proteins. NF-kB activators induce degradation of IkB by the 26s proteosome, by phosphorylation of two serines in the N-terminal regulatory domain of IkB by IkB kinase (IKK). The liberated NF-kB translocates to the nucleus, binds specific promoter sequences, and induces expression of proinflammatory cytokines. These cytokines are expressed at high levels in chronic inflammatory bowel disease (IBD). IL-1 and TNF-a also activate NF-kB in a positive regulatory loop. This may lead to amplification of the inflammatory response. NF-kB appears to play a significant role in inflammation, and is a likely target for anti-inflammatory therapies. Animal models of inflammation improved with GrTP administration. The scientific portion of this proposal intends to evaluate the use of GrTP in humans. Specific aim 1 will confirm that GrTP inhibit NF-kB activation in human peripheral blood monocytes. Specific aim 2 will evaluate the safety and tolerability of GrTP in volunteers with quiescent IBD, while defining the pharmacokinetics and pharmacodynamics of GrTP. Specific aim 3 will further evaluate the safety of GrTP in subjects with IBD, while providing preliminary data on the efficacy of this therapy in patients with active ulcerative colitis.