TY - JOUR
T1 - Synergistic effect of baicalein, wogonin and oroxylin A mixture
T2 - multistep inhibition of the NF-κB signalling pathway contributes to an anti-inflammatory effect of Scutellaria root flavonoids
AU - Shimizu, Tomofumi
AU - Shibuya, Nobuhiko
AU - Narukawa, Yuji
AU - Oshima, Naohiro
AU - Hada, Noriyasu
AU - Kiuchi, Fumiyuki
N1 - Funding Information:
Acknowledgements This work was supported by JSPS KAKENHI grant number JP26460130, Keio Gijuku Academic Development Funds and MEXT-Supported Program for the Strategic Research Foundation at Private Universities. The authors thank Dr. Megumi Funakoshi-Tago for the valuable discussions.
Publisher Copyright:
© 2017, The Japanese Society of Pharmacognosy and Springer Japan KK.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Scutellaria root, the root of Scutellaria baicalensis Georgi, is a crude drug used for inflammatory diseases. In our previous report, the combination of flavonoids contained in Scutellaria root have been found to inhibit PGE2 production more strongly than individual flavonoids. Here, to investigate the mechanism of the synergistic effect, we examined the effects of an equimolar mixture (F-mix) of baicalein (1), wogonin (2) and oroxylin A (3) on the production of PGE2 in LPS-treated J774.1 cells. Although 1 and 3 inhibited COX-2 activity, the F-mix showed no synergistic effect on COX-2 inhibition. Therefore, we investigated the steps leading to the activation of COX-2 protein. Compounds 1–3 and F-mix inhibited the expression of COX-2 protein. However, only 2 inhibited the expression of COX-2 mRNA among the flavonoids, and the F-mix showed no synergistic effect. Only 1 inhibited NF-κB translocation into the nucleus, and the F-mix showed no synergistic effect. Although 2 did not affect NF-κB translocation, it strongly inhibited NF-κB-dependent transcriptional activity, and the F-mix inhibited the activity slightly more than 2. Compounds 1–3 also inhibited NO production, and the F-mix showed a synergistic effect. However, the effects of each flavonoid on the expression of iNOS mRNA were not consistent with those on COX-2 mRNA. Because the flavonoids inhibit different steps in the production of PGE2 and NO, and their mixture did not show apparent synergistic effects in each step, we conclude that the synergistic effect of the flavonoid mixture reflects the total effect of the flavonoids inhibiting different steps in the NF-κB signalling pathway.
AB - Scutellaria root, the root of Scutellaria baicalensis Georgi, is a crude drug used for inflammatory diseases. In our previous report, the combination of flavonoids contained in Scutellaria root have been found to inhibit PGE2 production more strongly than individual flavonoids. Here, to investigate the mechanism of the synergistic effect, we examined the effects of an equimolar mixture (F-mix) of baicalein (1), wogonin (2) and oroxylin A (3) on the production of PGE2 in LPS-treated J774.1 cells. Although 1 and 3 inhibited COX-2 activity, the F-mix showed no synergistic effect on COX-2 inhibition. Therefore, we investigated the steps leading to the activation of COX-2 protein. Compounds 1–3 and F-mix inhibited the expression of COX-2 protein. However, only 2 inhibited the expression of COX-2 mRNA among the flavonoids, and the F-mix showed no synergistic effect. Only 1 inhibited NF-κB translocation into the nucleus, and the F-mix showed no synergistic effect. Although 2 did not affect NF-κB translocation, it strongly inhibited NF-κB-dependent transcriptional activity, and the F-mix inhibited the activity slightly more than 2. Compounds 1–3 also inhibited NO production, and the F-mix showed a synergistic effect. However, the effects of each flavonoid on the expression of iNOS mRNA were not consistent with those on COX-2 mRNA. Because the flavonoids inhibit different steps in the production of PGE2 and NO, and their mixture did not show apparent synergistic effects in each step, we conclude that the synergistic effect of the flavonoid mixture reflects the total effect of the flavonoids inhibiting different steps in the NF-κB signalling pathway.
KW - Flavonoid
KW - Inflammation
KW - Nuclear factor-kappa B
KW - Prostaglandin E
KW - Scutellaria baicalensis
KW - Synergistic effect
UR - http://www.scopus.com/inward/record.url?scp=85029591256&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029591256&partnerID=8YFLogxK
U2 - 10.1007/s11418-017-1129-y
DO - 10.1007/s11418-017-1129-y
M3 - Article
C2 - 28921127
AN - SCOPUS:85029591256
VL - 72
SP - 181
EP - 191
JO - Journal of Natural Medicines
JF - Journal of Natural Medicines
SN - 1861-0293
IS - 1
ER -