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CKD712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, inhibits the lipopolysaccharide-stimulated secretion of HMGB1 by inhibiting PI3K and classical protein kinase C

Authors
 Young Joo Oh ; Ju Ho Youn ; Jeon-Soo Shin ; In-Hong Choi ; Sung-Sook Lee ; Dal-Hyun Kim ; Hyun Jin Min 
Citation
 International Immunopharmacology, Vol.11(9) : 1160~1165, 2011 
Journal Title
 International Immunopharmacology 
ISSN
 1567-5769 
Issue Date
2011
Abstract
CKD712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, was considered as a new effective drug candidate to sepsis, based on its anti-inflammatory activity. It was reported that CKD712 inhibited various signal pathways which play a key role in production of proinflammatory cytokines. Here, we examined the effect of CKD712 on the secretion of high mobility group box 1 (HMGB1), which is one of the proinflammatory cytokines. CKD712 can reduce Gram-negative lipopolysaccharide (LPS)- and Gram-positive lipoteichoic acid (LTA)-stimulated HMGB1 secretion in RAW264.7 and human peripheral blood monocytes (PBMo), and also reduce LPS-induced nucleocytoplasmic translocation of HMGB1 1h before or after LPS treatment. CKD712 could dose-dependently inhibit the activation of PI3K and PI3K-dependent kinase 1 (PDK1), which are involved in HMGB1 secretion signaling pathway. In addition, CKD712 inhibited classical protein kinase C (cPKC), the effective kinase for phosphorylation of HMGB1 for secretion, however, had no effect on histone acetyl-transferase activity, which is another mechanism known for HMGB1 secretion. Thus, we suggest that CKD712 could inhibit LPS- and LTA-stimulated HMGB1 secretion through the inhibition of HMGB1 phosphorylation by inhibiting PI3K-PKC signaling pathway.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/93529
DOI
10.1016/j.intimp.2011.03.013
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Microbiology
Yonsei Authors
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Link
 http://www.sciencedirect.com/science/article/pii/S1567576911001524
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