Abstract
Drug repositioning is used to discover drug candidates to treat human diseases, through the application of drugs or compounds that are approved for the treatment of other diseases. This method can significantly reduce the time required and cost of discovering new drug candidates for human diseases. Previous studies have reported pro‐inflammatory responses of endothelial cells to the release of polyphosphate (PolyP). In this study, we examined the anti‐inflammatory responses and mechanisms of methylthiouracil (MTU), which is an antithyroid drug, and its effects on PolyP‐induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behaviour of human neutrophils and vascular permeability were determined in PolyP‐activated HUVECs and mice. MTU suppressed the PolyP‐mediated vascular barrier permeability, up‐regulation of inflammatory biomarkers, adhesion/migration of leucocytes, and activation and/or production of nuclear factor‐κB, tumour necrosis factor‐α and interleukin‐6. Furthermore, MTU demonstrated protective effects on PolyP‐mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of MTU on various systemic inflammatory diseases, such as sepsis or septic shock.
Highlights
Finding new molecular targets or mechanistic pathways provides unique ways to translate research findings into new drugs
A high-content screening system (Operetta, PerkinElmer, Inc., Waltham, MA, USA) was used to select the compounds that modulated the PolyP-mediated disruption of the vascular endothelium, and we found that methylthiouracil (MTU), which is an antithyroid drug, had suppressive effects on the a 2016 The Authors
Based on our previous findings that demonstrated the potential effects of PolyP on vascular inflammatory responses [9,10,11], this study was conducted to investigate the mechanisms underlying the suppressive actions of MTU on PolyP-induced septic responses in human endothelial cells and mice
Summary
Finding new molecular targets or mechanistic pathways provides unique ways to translate research findings into new drugs. Our recent studies indicated pro-inflammatory activities of PolyP, such as mediating vascular hyperpermeability, increasing the adhesion and migration of leucocytes, and up-regulating the expression of cell adhesion molecules (CAMs), including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin [9,10,11]. Based on our previous findings that demonstrated the potential effects of PolyP on vascular inflammatory responses [9,10,11], this study was conducted to investigate the mechanisms underlying the suppressive actions of MTU on PolyP-induced septic responses in human endothelial cells and mice.
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