Wiser Jessica, Alexis Neil E, Jiang Qing, Wu Weidong, Robinette Carole, Roubey Robert, Peden David B
The Center for Environmental Medicine, Asthma and Lung Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7310, USA.
Free Radic Biol Med. 2008 Jul 1;45(1):40-9. doi: 10.1016/j.freeradbiomed.2008.03.002. Epub 2008 Mar 12.
We have recently reported that gamma-tocopherol (gammaT) reduces allergen- and zymosan-induced inflammation using rodent models. As an initial step in extending these observations to humans, we conducted an open-label, Phase I dosing study of two doses (one or two capsules daily for 1 week) of a gamma-tocopherol-rich preparation containing 623 mg of gamma-tocopherol, 61.1 mg of d-alpha-tocopherol, 11.1 mg of d-beta-tocopherol (11.1 mg), and 231 mg of d-sigma-tocopherol per capsule. Endpoints for this study include serum levels of 5-nitro-gamma-tocopherol, as a marker of oxidative stress, and changes in serum gamma-, alpha-, and delta-tocopherol and gamma-2'-carboxyethyl-6-hydroxychroman (CEHC) 6 and 24 h after the first dose and after 1 week of treatment. To assess the biological activity of this treatment, we obtained peripheral blood mononuclear cells at baseline and after 1 week of treatment with two capsules of a gamma-tocopherol-rich preparation/day and examined the inflammatory cytokine response of these cells in culture to ex vivo endotoxin/LPS (0.01 ng/ml) challenge. We also monitored a number of safety endpoints to examine how well this preparation is tolerated in eight normal volunteers (four allergic and four nonallergic) and eight allergic asthmatics. We further obtained human monocytes from a subset of these volunteers and treated them ex vivo with gammaT, alphaT, gamma-CEHC, and alpha-CEHC and assessed their actions on LPS-induced degradation of IkappaBalpha and JNK signaling and ROS generation. As detailed herein, this open-label study demonstrates that gamma-tocopherol-enriched supplementation decreased systemic oxidative stress, increased serum levels of gamma-tocopherol, and inhibited monocyte responses to LPS without any adverse health effects. Further, in vitro treatment of human monocytes with gamma-CEHC and alpha-CEHC inhibits ROS generation and LPS-induced degradation of IkappaB and JNK activation.
我们最近报道，使用啮齿动物模型发现γ-生育酚（γT）可减轻变应原和酵母聚糖诱导的炎症。作为将这些观察结果扩展至人类的第一步，我们进行了一项开放标签的I期剂量研究，给予两种剂量（每日1粒或2粒胶囊，共1周）富含γ-生育酚的制剂，每粒胶囊含623mgγ-生育酚、61.1mg d-α-生育酚、11.1mg d-β-生育酚（11.1mg）和231mg d-δ-生育酚。该研究的终点包括血清5-硝基-γ-生育酚水平（作为氧化应激的标志物），以及首次给药后和治疗1周后6小时及24小时血清γ-、α-和δ-生育酚以及γ-2'-羧乙基-6-羟基色满（CEHC）的变化。为评估该治疗的生物学活性，我们在基线时以及每天服用2粒富含γ-生育酚制剂治疗1周后获取外周血单个核细胞，并检测这些细胞在体外培养中对离体内毒素/LPS（0.01ng/ml）刺激的炎性细胞因子反应。我们还监测了多个安全性终点，以检查该制剂在8名正常志愿者（4名变应性和4名非变应性）和8名变应性哮喘患者中的耐受性。我们还从这些志愿者的一个亚组中获取人单核细胞，并用γT、αT、γ-CEHC和α-CEHC进行离体处理，并评估它们对LPS诱导的IκBα降解、JNK信号传导和ROS生成的作用。如本文详细所述，这项开放标签研究表明，富含γ-生育酚的补充剂可降低全身氧化应激，提高血清γ-生育酚水平，并抑制单核细胞对LPS的反应，且无任何不良健康影响。此外，用γ-CEHC和α-CEHC对人单核细胞进行体外处理可抑制ROS生成以及LPS诱导的IκB降解和JNK激活。
