Cha, H. J. | bioRxiv Science

bioRxiv2020

Antifungal benzimidazoles disrupt vasculature by targeting one of nine β-tubulins

Thiabendazole (TBZ) is an FDA-approved benzimidazole widely used for its antifungal and antihelminthic properties. We showed previously that TBZ is also a potent vascular disrupting agent and inhibits angiogenesis at the tissue level by dissociating vascular endothelial cells in newly formed blood vessels. Here, we uncover TBZs molecular target and mechanism of action. Using human cell culture, molecular modeling, and humanized yeast, we find that TBZ selectively targets only 1 of 9 human {beta}-tubulin isotypes (TUBB8) to specifically disrupt endothelial cell microtubules. By leveraging epidemiological pesticide resistance data and mining chemical features of commercially used benzimidazoles, we discover that a broader class of benzimidazole compounds, in extensive use for 50 years, also potently disrupt immature blood vessels and inhibit angiogenesis. Thus, besides identifying the molecular mechanism of benzimidazole-mediated vascular disruption, this study presents evidence relevant to the widespread use of these compounds while offering potential new clinical applications.

systems biology↗

bioRxiv2020

Rapid Establishment of Tracheal Stenosis in Pigs Using Endotracheal Tube Cuff Overpressure and Electrocautery

BackgroundCentral airway obstruction can be caused by cancer, tracheal intubation, or tuberculosis, among others. If surgery is contraindicated, bronchoscopic therapy may be performed. Bronchoscopic treatment for airway obstruction is continuously evolving. In particular, attempts to overcome the current shortcomings of airway stents (stent migration, mucostasis, and granulation tissue formation) are currently ongoing. To apply a new airway stent to humans, preclinical studies in an appropriate animal model is needed. Canine and porcine tracheas have been used as animal airway stenosis models. However, existing models take a long time to develop (3-8 weeks) and have a disadvantage that the mechanism of stenosis is different from that in humans. PurposeTo establish a new and fast tracheal stenosis model in pigs using a combination of cuff overpressure intubation and electrocautery. MethodsFourteen pigs were divided into three groups: tracheal cautery (TC) group (n = 3), cuff overpressure intubation (COI) group (n = 3), and COI-TC combination group (n = 8). Cuff overpressure (200/400/500 mmHg) was applied using a 9-mm internal diameter endotracheal tube. Tracheal cautery (40/60 watts) was performed using a rigid bronchoscopic electrocoagulator. After intervention, the pigs were observed for 3 weeks and bronchoscopy was performed every 7 days. When the cross-sectional area decreased by > 50%, it was judged that tracheal stenosis was established. ResultsThe time for tracheal stenosis was 14 days in the TC group and 7 days in the COI-TC combination group. In the COI group, no stenosis occurred. In the COI-TC group, electrocautery (40 watts) immediately after intubation for > 1 hour with a cuff pressure of 200 mmHg or more resulted in sufficient tracheal stenosis within 7 days. Moreover, the degree of tracheal stenosis increased in proportion to the cuff pressure and tracheal intubation time. ConclusionsThe combined use of cuff overpressure and electrocautery helped to establish tracheal stenosis in pigs rapidly. This animal model was technically simple and reproducible, and used a mechanism similar to that in human tracheal stenosis. It is expected to help develop new treatments for airway stenosis

physiology↗