Anti-AMOTL1 monoclonal antibody, clone FQS22914-65

Background: Statin use in individuals with chronic obstructive pulmonary disease (COPD) with coexisting cardiovascular disease is associated with a reduced risk of exacerbations. The mechanisms by which statin plays a role in the pathophysiology of COPD have not been defined. To explore the mechanisms involved, we investigated the effect of statin on endothelial cell function, especially endothelial cell tight junctions. Method: We primarily assessed whether pitavastatin could help mitigate the development of emphysema induced by continuous cigarette smoking (CS) exposure. We also investigated the activation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling, which plays a role in maintaining endothelial functions, important tight junction proteins, zonula occludens (ZO)-1 and claudin-5 expression, and lung microvascular endothelial cell permeability. Results: We found that pitavastatin prevented the CS-induced decrease in angiomotin-like protein I (AmotL1)-positive vessels via the activation of LKB1/AMPK signaling and IFN-gamma-induced hyper permeability of cultured human lung microvascular endothelial cells by maintaining the levels of AmotL1, ZO-1, and claudin-5 expression at the tight junctions. Conclusion: Our results indicate that the maintenance of lung microvascular endothelial cells by pitavastatin prevents tight junction protein dysfunctions induced by CS. These findings may ultimately lead to new and novel therapeutic targets for patients with COPD. (C) 2016 Elsevier Ltd. All rights reserved.

Previous data indicate that Tankyrase inhibitors exert anti-growth functions in many cancer cell lines due to their ability to inactivate the YAP protooncogene. In the present manuscript, we investigated the effect of Tankyrase inhibitors on the growth of hepatocellular carcinoma (HCC) cell lines and the molecular mechanisms involved. For this purpose, we performed cell proliferation assay by colony-forming ability in seven human HCC cells subjected to XAV-939 and G007-LK Tankyrase inhibitors. Noticeably, the two Tankyrase inhibitors suppressed the HCC cell growth in a dose-dependent manner. Furthermore, we found that Tankyrase inhibitors synergized with MEK and AKT inhibitors to suppress HCC cell proliferation. At the molecular level, Tankyrase inhibitors significantly decreased YAP protein levels, reduced the expression of YAP target genes, and inhibited YAP/TEAD luciferase reporter activity. In addition, Tankyrase inhibitors administration was accompanied by upregulation of Angiomotin-like 1 (AMOTL1) and Angiomotin-like 2 (AMOTL2) proteins, two major negative regulators of YAP. Altogether, the present data indicate that XAV-939 and G007-LK Tankyrase inhibitors could suppress proliferation of hepatocellular carcinoma cells and downregulate YAP/TAZ by stabilizing AMOTL1 and AMOTL2 proteins, thus representing new potential anticancer drugs against hepatocellular carcinoma.