PDF(Pubmed)
Abstract：
20-Hydroxyecdysone and several of its oxidized derivatives exert cytoprotective effect in mammals including humans. Inspired by this bioactivity of ecdysteroids, in the current study it was our aim to prepare a set of sidechain-modified derivatives and to evaluate their potential to protect the blood-brain barrier (BBB) from oxidative stress. Six novel ecdysteroids, including an oxime and five oxime ethers, were obtained through regioselective synthesis from a sidechain-cleaved calonysterone derivative 2 and fully characterized by comprehensive NMR techniques revealing their complete 1H and 13C signal assignments. Surprisingly, several compounds sensitized hCMEC/D3 brain microvascular endothelial cells to tert-butyl hydroperoxide (tBHP)-induced oxidative damage as recorded by impedance measurements. Compound 8, containing a benzyloxime ether moiety in its sidechain, was the only one that exerted a protective effect at a higher, 10 μM concentration, while at lower (10 nM- 1 μM) concentrations it promoted tBHP-induced cellular damage. Brain endothelial cells were protected from tBHP-induced barrier integrity decrease by treatment with 10 μM of compound 8, which also mitigated the intracellular reactive oxygen species production elevated by tBHP. Based on our results, 17-oxime ethers of oxidized ecdysteroids modulate oxidative stress of the BBB in a way that may point towards unexpected toxicity. Further studies are needed to evaluate any possible risk connected to dietary ecdysteroid consumption and CNS pathologies in which BBB damage plays an important role.
摘要：
20-羟基蜕皮激素及其几种氧化衍生物在包括人类在内的哺乳动物中发挥细胞保护作用。受蜕皮类固醇生物活性的启发，在本研究中,我们的目标是制备一组侧链修饰的衍生物,并评估其保护血脑屏障(BBB)免受氧化应激的潜力.六种新颖的蜕皮类固醇，包括一个肟和五个肟醚，通过区域选择性合成从侧链切割的钙带酮衍生物2获得，并通过全面的NMR技术充分表征，揭示了它们完整的1H和13C信号分配。令人惊讶的是,通过阻抗测量记录，几种化合物使hCMEC/D3脑微血管内皮细胞对叔丁基过氧化氢（tBHP）诱导的氧化损伤敏感。化合物8，在其侧链中含有苄肟醚部分，是唯一一个在更高的温度下发挥保护作用的，10μM浓度,而在较低（10nM-1μM）浓度下，它促进了tBHP诱导的细胞损伤。通过用10μM化合物8处理,保护脑内皮细胞免受tBHP诱导的屏障完整性降低,这也减轻了由tBHP升高的细胞内活性氧的产生。根据我们的结果,氧化的蜕皮类固醇的17-肟醚以可能指向意外毒性的方式调节BBB的氧化应激。需要进一步的研究来评估与饮食中的蜕皮类固醇消耗和中枢神经系统病理有关的任何可能的风险，其中BBB损伤起着重要作用。
