Isoflavones:Acute Response in Chronic Renal Failure

描述(由申请人提供)：高达40%的终末期肾病患者患有慢性炎症过程，目前不符合特定的 而且与高发病率和高死亡率有关。高循环 促炎细胞因子的水平和产生是这一过程的重要组成部分 持续的急性期反应，据信会加重终末期肾病的许多临床表现，包括肾性骨营养不良。就像所有人一样 其他经过更广泛调查的炎症过程， 核因子，核因子Kappa-B(NFKB)有望成为关键 这一急性时相反应的细胞中间体，既是介体，又是 炎性细胞因子作用的靶点。在当前搜索的代理中， 可能能够否定ESRD正在进行的急性期反应，大豆 异黄酮染料木素和大豆苷元已成为潜在的有用成分。这些 异黄酮类存在于许多豆类食品中，可作为非处方药购买。 营养补充剂，并因其 生物学特性和作为治疗剂的潜力。抑制效应 异黄酮类化合物对酪氨酸激酶和NFKB活性的影响 细胞因子的产生和对氧化应激的影响已经被证明 小组和许多其他调查人员，他们可能与 肾功能衰竭人群。此外，我们最近发现，摄入的 ESRD患者的大豆食物会导致血液中非常高的异黄酮和 这是可以容忍的。 我们的工作假设是，在慢性肾功能衰竭中，各种 内源性和外源性因素通过激活触发急性期反应 NFKB和促炎细胞因子的产生，以及干预 大豆异黄酮可抑制NFKB的激活和细胞因子的产生，从而 阻断正在进行的急性期反应并对临床产生积极影响 ESRD疾病活动性的相关参数。 这项建议的具体目标是进行随机、双盲 对血液透析患者进行饮食干预试验，以确定： 1.有临床症状的终末期肾病患者膳食中大豆异黄酮类的摄入量 正在进行的急性时相反应减少了促炎因子的产生 外周血中的细胞因子TNF-α、IL-1和IL-6，从而改变 这些细胞因子与它们的拮抗剂sTNFRI、sTNFRII和 IL-1ra。 2.大豆异黄酮抑制炎性细胞因子的产生 与改善临床相关疾病参数有关 活动，包括改善急性期反应的血液标记物，以及 降低血液中代谢性骨病标志物的水平。 3.摄入大豆异黄酮会抑制外周血中核因子-KB的活性 终末期肾病患者外周血单核细胞的变化 细胞因子水平和疾病的临床参数。

DESCRIPTION (provided by applicant): Up to 40 percent of ESRD patients suffer from a chronic inflammatory process which is not currently amenable to specific treatment and is associated with high morbidity and mortality. High circulating levels and production of pro-inflammatory cytokines are essential part of this ongoing acute-phase response and they are believed to exacerbate many of the clinical manifestations of ESRD, including renal osteodystrophy. Like in all other inflammatory processes that have undergone more extensive investigation, the nuclear factor, Nuclear Factor Kappa-B (NFKB) promises to be a critical cellular intermediate of this acute-phase response and to be both mediator and target of inflammatory cytokine effects. In the current search for agents that may be able to negate the ongoing acute-phase response of ESRD, the soy isoflavones genistein and daidzein have emerged as potentially useful. These isoflavones are present in many soyfoods, are available as over-the-counter nutritional supplements and have received growing attention due to their biological properties and potential as therapeutic agents. Inhibitory effects of the isoflavones on tyrosine kinase and NFKB activity, on inflammatory cytokine production and on oxidative stress have been demonstrated by this group and by many other investigators and they may be highly relevant to the renal failure population. Additionally, we have found recently that intake of soy food by ESRD patients results in very high blood levels of isoflavones and it is well tolerated. It is our working hypothesis that in chronic renal failure a variety of endogenous and exogenous factors trigger acute-phase response with activation of NFKB and production of pro-inflammatory cytokines, and that intervention with soy isoflavones inhibits NFKB activation and cytokines production, thus blocking the ongoing acute-phase response and affecting positively clinically relevant parameters of disease activity in ESRD. Specific objective of this proposal is to conduct a randomized, double-blinded dietary intervention trial in hemodialysis patients to determine whether: 1. Dietary intake of the soy isoflavones by ESRD patients with clinical signs of ongoing acute-phase response decreases the production of the proinflammatory cytokines TNF-alpha, IL-1 and IL-6 in peripheral blood, thus changing the balance between these cytokines and their antagonists sTNF RI, sTNF RII, and IL-1ra. 2. Suppression of inflammatory cytokine production by soy isoflavones is associated with improvement of clinically relevant parameters of disease activity, including improvement of blood markers of acute-phase response, and decreased blood levels of markers of metabolic bone disease. 3. Intake of soy isoflavones suppresses NF-KB activity in peripheral blood monocytic cells of ESRD patients, in a manner consistent with change of cytokine levels and of clinical parameters of disease.