Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress
Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress
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DOI：
10.1073/pnas.0500815102
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发表时间：
2005-03-22
影响因子：
11.1
通讯作者：
Talalay, P
中科院分区：
文献类型：
--
作者：
Dinkova-Kostova, AT;Liby, KT;Talalay, P
油酸的一系列合成三萜类（TP）类似物是细胞炎症过程的强力抑制剂，例如小鼠巨噬细胞中IFN-γ诱导的诱导型一氧化氮合酶（NOS）和环氧合酶2的诱导。在这里，我们表明，这些类似物也是非常有效的诱导剂的阶段2反应[例如，升高NAD（P）H-醌氧化还原酶和血红素加氧酶1]，这是细胞对抗氧化和亲电应激的主要保护剂。此外，与先前鉴定的2期诱导剂一样，TP类似物使用抗氧化反应元件-Nrf 2-Keap 1信号通路。因此，在nrf 2（-/-）和keap 1（-/-）小鼠胚胎成纤维细胞中，2期反应的诱导和NOS诱导的抑制被废除。TP类似物在诱导2相反应和阻断炎症方面的高效力取决于在环A和C中的关键位置处存在活化的迈克尔反应（烯酮）功能。最有效的TP使小鼠肝癌细胞中的NAD（P）H-醌氧化还原酶加倍，浓度为0.28 nM，抑制原代小鼠巨噬细胞中NOS诱导的IC 50为0.0035 nM。该TP与用于诱导剂的Keap 1传感器的硫醇基团的直接相互作用在光谱上被证明。在6个数量级的浓度范围内，18个TP的双相和2相诱导效力密切线性相关（r（2）= 0.91）。因此，除了阻断炎症和促进分化外，这些TP还表现出另一种非常重要的保护特性：诱导2期反应。
A series of synthetic triterpenoid (TP) analogues of oleanolic acid are powerful inhibitors of cellular inflammatory processes such as the induction by IFN-gamma of inducible nitric oxide synthase (NOS) and of cyclooxygenase 2 in mouse macrophages. Here, we show that these analogues are also extremely potent inducers of the phase 2 response [e.g., elevation of NAD(P)H-quinone oxidoreductase and heme oxygenase 1], which is a major protector of cells against oxidative and electrophile stress. Moreover, like previously identified phase 2 inducers, the TP analogues use the antioxidant response element-Nrf2-Keap1 signaling pathway. Thus, induction of the phase 2 response and suppression of the NOS induction was abrogated in nrf2(-/-) and keap1(-/-) mouse embryonic fibroblasts. The high potency of TP analogues in inducing the phase 2 response and blocking inflammation depends on the presence of activated Michael reaction (enone) functions at critical positions in rings A and C. The most potent TP doubles NAD(P)H-quinone oxidoreductase in murine hepatoma cells at 0.28 nM and has an IC50 for suppression of NOS induction in primary mouse macrophages of 0.0035 nM. The direct interaction of this TP with thiol groups of the Keap1 sensor for inducers is demonstrated spectroscopically. The antiinflammatory and phase 2 inducer potencies of 18 TP are closely linearly correlated (r(2) = 0.91) over 6 orders of magnitude of concentration. Thus, in addition to blocking inflammation and promoting differentiation, these TP exhibit another very important protective property: the induction of the phase 2 response.