PDF(Pubmed)
Abstract：
The modulation of tight junction (TJ) integrity with small molecules is important for drug delivery. High-dose baicalin (BLI), baicalein (BLE), quercetin (QUE), and hesperetin (HST) have been shown to open TJs in Madin-Darby canine kidney (MDCK) II cells, but the mechanisms for HST and QUE remain unclear. In this study, we compared the effects of HST and QUE on cell proliferation, morphological changes, and TJ integrity. HST and QUE were found to have opposing effects on the MDCK II cell viability, promotion, and suppression, respectively. Only QUE, but not HST, induced a morphological change in MDCK II into a slenderer cell shape. Both HST and QUE downregulated the subcellular localization of claudin (CLD)-2. However, only QUE, but not HST, downregulated CLD-2 expression. Conversely, only HST was shown to directly bind to the first PDZ domain of ZO-1, a key molecule to promote TJ biogenesis. The TGFβ pathway partially contributed to the HST-induced cell proliferation, since SB431541 ameliorated the effect. In contrast, the MEK pathway was not involved by both the flavonoids, since U0126 did not revert their TJ-opening effect. The results offer insight for using HST or QUE as naturally occurring absorption enhancers through the paracellular route.
摘要：
用小分子调节紧密连接(TJ)完整性对于药物递送是重要的。大剂量黄芩苷(BLI),黄芩素（BLE），槲皮素（QUE），和橙皮素（HST）已被证明在Madin-Darby犬肾（MDCK）II细胞中打开TJ，但HST和QUE的作用机制尚不清楚.在这项研究中,我们比较了HST和QUE对细胞增殖的影响，形态变化,和TJ的完整性。发现HST和QUE对MDCKII细胞活力具有相反的作用，促销,和压制，分别。仅QUE,但不是HST,诱导MDCKII的形态变化为更细的细胞形状。HST和QUE均下调claudin（CLD）-2的亚细胞定位。然而,只有QUE，但不是HST,CLD-2表达下调。相反，只有HST显示直接结合ZO-1的第一个PDZ结构域，ZO-1是促进TJ生物发生的关键分子。TGFβ途径部分参与了HST诱导的细胞增殖,因为SB431541改善了效果。相比之下,这两种类黄酮都不涉及MEK途径，因为U0126没有恢复其TJ开放效应。结果提供了通过细胞旁途径使用HST或QUE作为天然存在的吸收增强剂的见解。
