Piperazine Derivatives Enhance Epithelial Cell Monolayer Permeability by Increased Cell Force Generation and Loss of Cadherin Structures
Piperazine Derivatives Enhance Epithelial Cell Monolayer Permeability by Increased Cell Force Generation and Loss of Cadherin Structures
复制标题
哌嗪衍生物通过增加细胞力的产生和钙粘蛋白结构的损失来增强上皮细胞单层通透性
DOI：
10.1021/acsbiomaterials.9b01660
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发表时间：
2019
影响因子：
5.8
通讯作者：
Dahl, Kris Noel
中科院分区：
文献类型：
--
作者：
Zheng, Shiyuan;Lavrenyuk, Kirill;Lamson, Nicholas G.;Fein, Katherine C.;Whitehead, Kathryn A.;Dahl, Kris Noel
A major obstacle for topical and enteral drug delivery is the poor transport of macromolecular drugs through the epithelium. One potential solution is the use of permeation enhancers that alter epithelial structures. Piperazine derivatives are known permeation enhancers that modulate epithelial structures, reduce transepithelial electrical resistance, and augment the absorption of macromolecular drugs. The mechanism by which piperazine derivatives disrupt the structures of epithelial monolayers is not well understood. Here, the effects of 1-phenylpiperazine and 1-methyl-4-phenylpiperazine are modeled in the epithelial cell line NRK-52E. Live-cell imaging reveals a dose-dependent gross reorganization of monolayers at high concentrations, but reorganization differs based on the piperazine molecule. Results show that low concentrations of piperazine derivatives increase myosin force generation within the cells and do not disrupt the cytoskeletal structure. Also, cytoskeletally attached cadherin junctions are disrupted before tight junctions. In summary, piperazines appear to increase myosin-mediated contraction followed by disruption of cell–cell contacts. These results provide new mechanistic insight into how transient epithelial permeation enhancers act and will inform of the development of future generations of transepithelial delivery systems.
