title: Suppressive effects of methylthiouracil on polyphosphate-mediated vascular inflammatory responses.
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.
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu, Korea.
authors.forename: Gahee
authors.initials: G
authors.lastname: Min
authors.affiliation: Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan, Korea.
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu, Korea.
authors.forename: Seongdo
authors.initials: S
authors.lastname: Jeong
authors.affiliation: Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University, Daegu, Korea.
authors.forename: Moon-Chang
authors.initials: MC
authors.lastname: Baek
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu, Korea.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology*; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis; D008779:Methylthiouracil / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D011122:Polyphosphates; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015815:Cell Adhesion Molecules; D015850:Interleukin-6; D016328:NF-kappa B; D011122:Polyphosphates; D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D008779:Methylthiouracil
keywords: barrier integrity; drug repositinging; inflammation; methylthiouracil; polyphosphate