Seaweed extracts and unsaturated fatty acid constituents from the green alga Ulva lactuca as activators of the cytoprotective Nrf2-ARE pathway.
Seaweed extracts and unsaturated fatty acid constituents from the green alga Ulva lactuca as activators of the cytoprotective Nrf2-ARE pathway.
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DOI：
10.1016/j.freeradbiomed.2012.12.019
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发表时间：
2013-04
影响因子：
7.4
通讯作者：
Luesch, Hendrik
中科院分区：
文献类型：
--
作者：
Wang, Rui;Paul, Valerie J.;Luesch, Hendrik
关键词：
活性氧（ROS）的增加量已涉及许多病理条件，包括癌症。细胞用来中和过量ROS的主要机制是通过激活抗氧化反应元件（ARE）来控制许多II期解毒酶的激活。识别ARE的转录因子Nrf 2可以被多种小分子激活，其中大多数含有α，β-不饱和羰基系统。在追求化学预防剂从海洋生物，我们建立，分馏，并筛选了一个图书馆的30个现场收集的真核藻类从佛罗里达。利用ARE-荧光素酶报告基因检测技术，对一种可食用的绿色植物石莼（Ulva lactuca）进行了活性检测。我们分离了三种单不饱和脂肪酸（MUFA）衍生物作为活性成分，包括一种新的酮型C18脂肪酸（1）、相应的短链C16酸（2）和C18酸的酰胺衍生物（3）。通过核磁共振和质谱鉴定了它们的化学结构。所有三种都含有C7和C9之间的共轭烯酮基序，这被认为是ARE活性的原因。随后的生物学研究集中在1，分离的最活跃和丰富的ARE激活剂。在IMR-32人神经母细胞瘤细胞中，C18酸1诱导ARE调节的细胞保护基因的表达，包括NAD（P）H：醌氧化还原酶1、血红素加氧酶1、硫氧还蛋白还原酶1、谷氨酸-半胱氨酸连接酶的两个亚基（催化亚基和修饰亚基）和胱氨酸/谷氨酸交换转运蛋白。其细胞活性需要Nrf 2和PI 3 K功能的存在，分别基于RNA干扰和药理学抑制剂研究。用1处理仅导致Nrf 2活化，而不是NRF 2 mRNA产生的增加。为了测试其ARE活性和体内细胞保护潜力，我们用单剂量的U。富含1的莴苣组分，其显示出与体外观察到的相似的ARE活化作用。这可能是由于该组分通过抑制Keap 1介导的Nrf 2泛素化以及随后的Nrf 2积累和核转位来稳定Nrf 2的能力。许多ARE驱动的抗氧化基因在体内的诱导，最突出的是在心脏同意公认的心脏保护特性的MUFA。在其他小鼠组织如脑、肺和胃中也发现了Nqo 1转录水平的显著增加。总的来说，这项研究为为什么食用海藻可能对健康有益提供了新的见解，并且确定的化合物添加到化学预防膳食不饱和脂肪酸的列表中。
Increased amounts of reactive oxygen species (ROS) have been implicated in many pathological conditions, including cancer. The major machinery that the cell employs to neutralize excess ROS is through the activation of the antioxidant-response element (ARE) that controls the activation of many phase II detoxification enzymes. The transcription factor that recognizes the ARE, Nrf2, can be activated by a variety of small molecules, most of which contain an α,β-unsaturated carbonyl system. In the pursuit of chemopreventive agents from marine organisms, we built, fractionated, and screened a library of 30 field-collected eukaryotic algae from Florida. An edible green alga, Ulva lactuca, yielded multiple active fractions by ARE–luciferase reporter assay. We isolated three monounsaturated fatty acid (MUFA) derivatives as active components, including a new keto-type C18 fatty acid (1), the corresponding shorter chain C16 acid (2), and an amide derivative (3) of the C18 acid. Their chemical structures were elucidated by NMR and mass spectrometry. All three contain the conjugated enone motif between C7 and C9, which is thought to be responsible for the ARE activity. Subsequent biological studies focused on 1, the most active and abundant ARE activator isolated. C18 acid 1 induced the expression of ARE-regulated cytoprotective genes, including NAD(P)H:quinone oxidoreductase 1, heme oxygenase 1, thioredoxin reductase 1, both subunits of the glutamate–cysteine ligase (catalytic subunit and modifier subunit), and the cystine/glutamate exchange transporter, in IMR-32 human neuroblastoma cells. Its cellular activity requires the presence of Nrf2 and PI3K function, based on RNA interference and pharmacological inhibitor studies, respectively. Treatment with 1 led only to Nrf2 activation, and not the increase in production of NRF2 mRNA. To test its ARE activity and cytoprotective potential in vivo, we treated mice with a single dose of a U. lactuca fraction that was enriched with 1, which showed ARE-activating effects similar to those observed in vitro. This could be owing to this fraction's ability to stabilize Nrf2 through inhibition of Keap1-mediated Nrf2 ubiquitination and the subsequent accumulation and nuclear translocation of Nrf2. The induction of many ARE-driven antioxidant genes in vivo and most prominently in the heart agreed with the commonly recognized cardioprotective properties of MUFAs. A significant increase in Nqo1 transcript levels was also found in other mouse tissues such as the brain, lung, and stomach. Collectively, this study provides new insight into why consumption of dietary seaweed may have health benefits, and the identified compounds add to the list of chemopreventive dietary unsaturated fatty acids.
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