PMID- 26298005
OWN - NLM
STAT- MEDLINE
DCOM- 20160119
LR  - 20171116
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 288
IP  - 3
DP  - 2015 Nov 1
TI  - Anti-inflammatory effects of methylthiouracil in vitro and in vivo.
PG  - 374-86
LID - S0041-008X(15)30061-2 [pii]
LID - 10.1016/j.taap.2015.08.009 [doi]
AB  - The screening of bioactive compound libraries can be an effective approach for 
      repositioning FDA-approved drugs or discovering new treatments for human 
      diseases. Here, methylthiouracil (MTU), an antithyroid drug, was examined for its 
      effects on lipopolysaccharide (LPS)-mediated vascular inflammatory responses. The 
      anti-inflammatory activities of MTU were determined by measuring permeability, 
      human neutrophil adhesion and migration, and activation of pro-inflammatory 
      proteins in LPS-activated human umbilical vein endothelial cells and mice. We 
      found that post-treatment with MTU inhibited LPS-induced barrier disruption, 
      expression of cell adhesion molecules (CAMs), and adhesion/transendothelial 
      migration of human neutrophils to human endothelial cells. MTU induced potent 
      inhibition of LPS-induced endothelial cell protein C receptor (EPCR) shedding. It 
      also suppressed LPS-induced hyperpermeability and neutrophil migration in vivo. 
      Furthermore, MTU suppressed the production of tumor necrosis factor-alpha (TNF-alpha) and 
      interleukin (IL)-6, and the activation of nuclear factor-kappaB (NF-kappaB) and 
      extracellular regulated kinases (ERK) 1/2 by LPS. Moreover, post-treatment with 
      MTU resulted in reduced LPS-induced lethal endotoxemia. These results suggest 
      that MTU exerts anti-inflammatory effects by inhibiting hyperpermeability, 
      expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing 
      its usefulness as a therapy for vascular inflammatory diseases.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Ku, Sae-Kwang
AU  - Ku SK
AD  - Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany 
      University, Gyeongsan 712-715, Republic of Korea.
FAU - Baek, Moon-Chang
AU  - Baek MC
AD  - Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National 
      University, Daegu 700-422, Republic of Korea. Electronic address: 
      mcbaek@knu.ac.kr.
FAU - Bae, Jong-Sup
AU  - Bae JS
AD  - College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, 
      Kyungpook National University, Daegu 702-701, Republic of Korea. Electronic 
      address: baejs@knu.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150820
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Antigens, CD)
RN  - 0 (Antithyroid Agents)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Endothelial Protein C Receptor)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (PROCR protein, human)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (TLR4 protein, human)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - QW24888U5F (Methylthiouracil)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Antigens, CD/genetics/metabolism
MH  - Antithyroid Agents/pharmacology
MH  - Cell Adhesion/drug effects
MH  - Cell Adhesion Molecules/*metabolism
MH  - Cell Movement/drug effects
MH  - Cell Survival/drug effects
MH  - Endothelial Protein C Receptor
MH  - Endotoxemia/drug therapy
MH  - Human Umbilical Vein Endothelial Cells/drug effects/metabolism
MH  - Humans
MH  - Interleukin-6/metabolism
MH  - Lipopolysaccharides/adverse effects
MH  - Male
MH  - Methylthiouracil/*pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitogen-Activated Protein Kinase 1/genetics/metabolism
MH  - Mitogen-Activated Protein Kinase 3/genetics/metabolism
MH  - NF-kappa B/metabolism
MH  - Neutrophils/*drug effects/metabolism
MH  - Receptors, Cell Surface/genetics/metabolism
MH  - Toll-Like Receptor 4/genetics/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
OTO - NOTNLM
OT  - Barrier integrity
OT  - Drug repositioning
OT  - Lipopolysaccharide
OT  - Methylthiouracil
EDAT- 2015/08/25 06:00
MHDA- 2016/01/20 06:00
CRDT- 2015/08/23 06:00
PHST- 2015/06/23 00:00 [received]
PHST- 2015/07/25 00:00 [revised]
PHST- 2015/08/14 00:00 [accepted]
PHST- 2015/08/23 06:00 [entrez]
PHST- 2015/08/25 06:00 [pubmed]
PHST- 2016/01/20 06:00 [medline]
AID - S0041-008X(15)30061-2 [pii]
AID - 10.1016/j.taap.2015.08.009 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2015 Nov 1;288(3):374-86. doi: 
      10.1016/j.taap.2015.08.009. Epub 2015 Aug 20.