Abstract |
Dehydroglyasperin D (DHGA-D), a compound present in licorice, has been found to exhibit anti- obesity, antioxidant and anti- aldose reductase effects. However, the direct molecular mechanism and molecular targets of DHGA-D during skin inflammation remain unknown. In the present study, we investigated the effect of DHGA-D on inflammation and its mechanism of action on UVB-induced skin inflammation in HaCaT human keratinocytes and SKH-1 hairless mice. DHGA-D treatment strongly suppressed UVB-induced COX-2 expression, PGE2 generation and AP-1 transactivity in HaCaT cells without affecting cell viability. DHGA-D also inhibited phosphorylation of the mitogen-activated protein kinase kinase (MKK) 3/6/ p38, MAPK/Elk-1, MKK4/ c-Jun N-terminal kinase (JNK) 1/2/c-Jun/ mitogen, and stress-activated protein kinase (MSK), whereas phosphorylation of the mixed-lineage kinase (MLK) 3 remained unaffected. Kinase and co-precipitation assays with DHGA-D Sepharose 4B beads showed that DHGA-D significantly suppressed MLK3 activity through direct binding to MLK3. Knockdown of MLK3 suppressed COX-2 expression as well as phosphorylation of MKK4/p38 and MKK3/6/JNK1/2 in HaCaT cells. Furthermore, Western blot assay and immunohistochemistry results showed that DHGA-D pre-treatment significantly inhibits UVB-induced COX-2 expression in vivo. Taken together, these results indicate that DHGA-D may be a promising anti-inflammatory agent that mediates suppression of both COX-2 expression and the MLK3 signalling pathway through direct binding and inhibition of MLK3.
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Authors | Sung Keun Jung, Su Jeong Ha, Yeong A Kim, Jihoon Lee, Tae-Gyu Lim, Yun Tai Kim, Nam Hyouck Lee, Jun Seong Park, Myeong-Hun Yeom, Hyong Joo Lee, Ki Won Lee |
Journal | Journal of cellular and molecular medicine
(J Cell Mol Med)
Vol. 19
Issue 1
Pg. 135-42
(Jan 2015)
ISSN: 1582-4934 [Electronic] England |
PMID | 25176057
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. |
Chemical References |
- Flavonoids
- Transcription Factor AP-1
- Cyclooxygenase 2
- MAP Kinase Kinase Kinases
- mitogen-activated protein kinase kinase kinase 11
- MAP Kinase Kinase 3
- MAP Kinase Kinase 6
- Dinoprostone
- dehydroglyasperin D
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Topics |
- Animals
- Cell Survival
(drug effects, radiation effects)
- Cyclooxygenase 2
(metabolism)
- Dinoprostone
(biosynthesis)
- Female
- Flavonoids
(chemistry, pharmacology)
- Gene Knockdown Techniques
- Humans
- Keratinocytes
(drug effects, enzymology, radiation effects)
- MAP Kinase Kinase 3
(metabolism)
- MAP Kinase Kinase 6
(metabolism)
- MAP Kinase Kinase Kinases
(metabolism)
- MAP Kinase Signaling System
(drug effects, radiation effects)
- Mice, Hairless
- Phosphorylation
(drug effects, radiation effects)
- Protein Binding
(drug effects, radiation effects)
- Transcription Factor AP-1
(metabolism)
- Ultraviolet Rays
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