Tight junctions (TJ) are intercellular barriers between epithelial cells that separate the internal and external environments of cellular sheets, and control the invasion of foreign substances and the diffusion of solutes and water across the epithelium. Biologics with high molecular weight and hydrophilicity are unable to diffuse through the lipid bilayer of the cell membrane. Control of TJ opening by attenuating the barrier function of TJ has proved to be attractive because it could allow safe and controllable transmucosal/transdermal administration of biologics. However, TJ prevent foreign substances from entering the body and are essential for maintaining homeostasis in the body, sustained opening of TJ is risky. Therefore, we have focused on the chemicals that induce reversible opening of TJ, i.e., chemicals that temporarily open the TJ and restore the barrier function of TJ after a few hours.
Here, we show our investigations on reversible TJ openers identified from food ingredients and natural products. Capsaicin is a famous TRPV1 agonist, however we found this compound opens TJ reversibly via non-TRPV1-mediated mechanism. MA026 is a natural product targeting claudin-1, a most important TJ components, and we found this chemical enhances transdermal penetration of large hydrophilic material. Our results not only reveal the new targets of TJ regulators with novel mechanisms but also might be useful for transmucosal/transdermal administration of large hydrophilic biologics.