PMID- 24632454
OWN - NLM
STAT- MEDLINE
DCOM- 20150105
LR  - 20161125
IS  - 1873-6351 (Electronic)
IS  - 0278-6915 (Linking)
VI  - 68
DP  - 2014 Jun
TI  - Withaferin A is an inhibitor of endothelial protein C receptor shedding in vitro 
      and in vivo.
PG  - 23-9
LID - S0278-6915(14)00138-0 [pii]
LID - 10.1016/j.fct.2014.03.009 [doi]
AB  - Withaferin A (WFA), an active compound from Withania somnifera, has been widely 
      researched for its anti-inflammatory and cardioactive properties and effects on 
      the central nervous system. The endothelial cell protein C receptor (EPCR) plays 
      important roles in blood coagulation and inflammation. EPCR activity is markedly 
      changed by ectodomain cleavage and release as the soluble EPCR. EPCR is shed from 
      the cell surface, mediated by tumor necrosis factor-alpha converting enzyme (TACE). 
      In this study, we investigated the effects of WFA on the EPCR shedding in human 
      umbilical vein endothelial cells (HUVECs) and in mice and the associated 
      signaling pathways. WFA was found to induce inhibition of phorbol-12-myristate 
      13-acetate (PMA), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and on 
      cecal ligation and puncture (CLP)-induced EPCR shedding and WFA suppressed the 
      expression and activity of TACE. In addition, treatment with WFA resulted in 
      reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases 
      (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate a 
      therapeutic potentiality of WFA as an anti-sEPCR shedding reagent against PMA and 
      CLP-mediated EPCR shedding.
CI  - Copyright (c) 2014 Elsevier Ltd. 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 - Han, Min-Su
AU  - Han MS
AD  - Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu 
      Fatima Hospital, Daegu 701-724, Republic of Korea.
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 - 20140313
PL  - England
TA  - Food Chem Toxicol
JT  - Food and chemical toxicology : an international journal published for the British 
      Industrial Biological Research Association
JID - 8207483
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Blood Coagulation Factors)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Withanolides)
RN  - 0 (activated protein C receptor)
RN  - 56937-68-9 (phorbolol myristate acetate)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.86 (ADAM17 Protein)
RN  - EC 3.4.24.86 (ADAM17 protein, human)
RN  - EC 3.4.24.86 (Adam17 protein, mouse)
RN  - L6DO3QW4K5 (withaferin A)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - ADAM Proteins/metabolism
MH  - ADAM17 Protein
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Blood Coagulation Factors/*antagonists & inhibitors/metabolism
MH  - Human Umbilical Vein Endothelial Cells/drug effects
MH  - Humans
MH  - Interleukin-1beta/antagonists & inhibitors/metabolism
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phosphorylation
MH  - Receptors, Cell Surface/*antagonists & inhibitors/metabolism
MH  - Signal Transduction
MH  - Tetradecanoylphorbol Acetate/analogs & derivatives/antagonists & 
      inhibitors/metabolism
MH  - Tumor Necrosis Factor-alpha/antagonists & inhibitors/metabolism
MH  - Withanolides/*pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
OTO - NOTNLM
OT  - CLP
OT  - EPCR shedding
OT  - PMA
OT  - Withaferin A
EDAT- 2014/03/19 06:00
MHDA- 2015/01/06 06:00
CRDT- 2014/03/18 06:00
PHST- 2013/10/28 00:00 [received]
PHST- 2014/03/04 00:00 [revised]
PHST- 2014/03/05 00:00 [accepted]
PHST- 2014/03/18 06:00 [entrez]
PHST- 2014/03/19 06:00 [pubmed]
PHST- 2015/01/06 06:00 [medline]
AID - S0278-6915(14)00138-0 [pii]
AID - 10.1016/j.fct.2014.03.009 [doi]
PST - ppublish
SO  - Food Chem Toxicol. 2014 Jun;68:23-9. doi: 10.1016/j.fct.2014.03.009. Epub 2014 
      Mar 13.