School of Human Science and Environment, University of Hyogo, Himeji 670-0092, Japan.
Department of Food Science, Graduate School of Nutrition and Biosciences, The University of Tokushima, Tokushima 770-8503, Japan.
Arch Biochem Biophys. 2014 Sep 1;557:11-7. doi: 10.1016/j.abb.2014.05.025. Epub 2014 Jun 2.
In recent years, many papers have suggested that dietary flavonoids may exert beneficial effects in the brain tissue for the protection of neurons against oxidative stress and inflammation. However, the bioavailability of flavonoids across the blood-brain barrier and the localization in the brain remain controversial. Thus, we examined the localization of quercetin-3-O-glucuronide (Q3GA), a major phase-II metabolite of quercetin, in the human brain tissues with or without cerebral infarction by immunohistochemical staining using anti-Q3GA antibody. A significant immunoreactivity was observed in the epithelial cells of the choroid plexus, which constitute the structural basis of the blood-cerebrospinal fluid (CSF) barrier, and in the foamy macrophages of recent infarcts. The cellular accumulation of Q3GA was also reproduced in vitro in macrophage-like RAW264, microglial MG6, and brain capillary endothelial RBEC1. It is of interest that a common feature of these cell lines is the deconjugation of Q3GA, resulting in the cellular accumulation of non-conjugated quercetin and the methylated forms. We then examined the anti-inflammatory activity of Q3GA and the deconjugated forms in the lipopolysaccharide-stimulated macrophage cells and revealed that the deconjugated forms (quercetin and a methylated form isorhamnetin), but not Q3GA itself, exhibited inhibitory effects on the inflammatory responses through attenuation of the c-Jun N-terminal kinase pathway. These results suggested that a quercetin glucuronide can pass through the blood-brain barrier, perhaps the CSF barrier, accumulate in specific types of cells, such as macrophages, and act as anti-inflammatory agents in the brain through deconjugation into the bioactive non-conjugated forms.
近年来，许多论文表明，膳食类黄酮可能对神经元发挥有益作用，防止其受到氧化应激和炎症的损害。然而，类黄酮跨越血脑屏障的生物利用度以及在大脑中的定位仍然存在争议。因此，我们通过使用抗 Q3GA 抗体的免疫组织化学染色，研究了槲皮素-3-O-葡糖苷（Q3GA），槲皮素的主要 II 期代谢物，在有或没有脑梗死的人脑组织中的定位。在脉络丛的上皮细胞中观察到明显的免疫反应，脉络丛是血脑屏障的结构基础，在最近梗死的泡沫状巨噬细胞中也观察到了这种免疫反应。Q3GA 在体外也在巨噬细胞样 RAW264、小胶质细胞 MG6 和脑毛细血管内皮 RBEC1 中得到了细胞积累。有趣的是，这些细胞系的一个共同特征是 Q3GA 的去结合，导致非结合的槲皮素和甲基化形式的细胞积累。然后，我们研究了 Q3GA 和去结合形式在脂多糖刺激的巨噬细胞中的抗炎活性，并揭示了去结合形式（槲皮素和甲基化形式异鼠李素），而不是 Q3GA 本身，通过衰减 c-Jun N 端激酶途径，对炎症反应具有抑制作用。这些结果表明，槲皮素葡萄糖苷可以穿过血脑屏障，可能是脑脊液屏障，在特定类型的细胞中积累，如巨噬细胞，并通过去结合成生物活性的非结合形式在大脑中发挥抗炎作用。
