Kanda Yusuke, Yamasaki Youhei, Shimura Satomi, Kamisuki Shinji, Sugawara Fumio, Nagumo Yoko, Usui Takeo
Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan.
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan.
J Antibiot (Tokyo). 2017 May;70(5):691-694. doi: 10.1038/ja.2016.168. Epub 2017 Jan 18.
MA026 is an antiviral natural compound against hepatitis C virus (HCV). It was recently reported that MA026 binds claudin-1 (CLDN1) and inhibits HCV infection. Although CLDN1 is an important component of tight junctions (TJ) in the epithelial cell layer, the effects of MA026 on the TJ barrier function remained to be revealed. Here we report that MA026 irreversibly opens the TJ. MA026 irreversibly increased FD4 permeability and decreased transepithelial electrical resistance (TER) for at least 5 h. Although MA026 increased Ca influx in layered MDCKII cells, the Ca influx was less than that of capsaicin, a reversible TJ opener. Moreover, MA026 did not induce the dephosphorylation of cofilin and reorganization of F-actin structure. Although the mechanism is left to be disclosed, these results suggest that MA026 is a novel irreversible TJ opener probably by targeting CLDN1.
MA026是一种抗丙型肝炎病毒（HCV）的抗病毒天然化合物。最近有报道称，MA026可结合紧密连接蛋白-1（CLDN1）并抑制HCV感染。尽管CLDN1是上皮细胞层紧密连接（TJ）的重要组成部分，但MA026对TJ屏障功能的影响仍有待揭示。在此我们报告，MA026可不可逆地打开TJ。MA026可使FD4通透性不可逆增加，并使跨上皮电阻（TER）至少降低5小时。尽管MA026可增加分层的MDCKII细胞中的钙离子内流，但该钙离子内流少于辣椒素（一种可逆的TJ开放剂）所引起的钙离子内流。此外，MA026不会诱导丝切蛋白的去磷酸化和F-肌动蛋白结构的重组。尽管其机制尚待揭示，但这些结果表明，MA026可能是一种通过靶向CLDN1的新型不可逆TJ开放剂。
