Eupatolide

Phytochemistry. 2016 Sep;129:68-76.

Bioactive sesquiterpenoids from the flowers of Inula japonica.[Pubmed: 27452450]

METHODS AND RESULTS:
Phytochemical investigation of the flowers of Inula japonica led to isolation of nine sesquiterpenoids, inujaponins A-I, as well as eighteen known ones. These sesquiterpenoids belong to six skeletal-types, including eudesmane, 1,10-seco-eudesmane, germacrane, guaiane, 4,5-seco-guaiane, and pseudoguaiane sesquiterpenoids. Their structures were established by extensive spectroscopic analysis. The absolute configurations of inujaponin A, Eupatolide, and deacetylovatifolin were determined by Cu-Kα X-ray crystallographic analysis.
CONCLUSIONS:
Most of the isolated compounds exhibited potent cytotoxicity against HL-60, SMMC-7721, A-549, MCF-7, and SW-480 cancer cell lines, with IC50 values ranging from 1.57 to 22.58 μM. Some selected compounds also possessed significant inhibitory activity against LPS-induced NO production in RAW264.7 macrophages with IC50 values ranging from 1.42 to 8.99 μM.

Eur J Pharmacol. 2010 Jun 25;636(1-3):173-80.

Eupatolide inhibits lipopolysaccharide-induced COX-2 and iNOS expression in RAW264.7 cells by inducing proteasomal degradation of TRAF6.[Pubmed: 20353767 ]

Inula britannica is a traditional medicinal plant used to treat bronchitis, digestive disorders, and inflammation in Eastern Asia.
METHODS AND RESULTS:
Here, we identified Eupatolide, a sesquiterpene lactone from I. britannica, as an inhibitor of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. Eupatolide inhibited the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) as well as iNOS and COX-2 protein expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Eupatolide dose-dependently decreased the mRNA levels and the promoter activities of COX-2 and iNOS in LPS-stimulated RAW264.7 cells. Moreover, Eupatolide significantly suppressed the LPS-induced expression of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) reporter genes. Pretreatment of Eupatolide inhibited LPS-induced phosphorylation and degradation of I kappaB alpha, and phosphorylation of RelA/p65 on Ser-536 as well as the activation of mitogen-activated protein kinases (MAPKs) and Akt in LPS-stimulated RAW264.7 cells. Eupatolide induced proteasomal degradation of tumor necrosis factor receptor-associated factor-6 (TRAF6), and subsequently inhibited LPS-induced TRAF6 polyubiquitination.
CONCLUSIONS:
These results suggest that Eupatolide blocks LPS-induced COX-2 and iNOS expression at the transcriptional level through inhibiting the signaling pathways such as NF-kappaB and MAPKs via proteasomal degradation of TRAF6. Taken together, Eupatolide may be a novel anti-inflammatory agent that induces proteasomal degradation of TRAF6, and a valuable compound for modulating inflammatory conditions.

Phytother Res. 2013 Nov;27(11):1700-7.

Eupatolide inhibits PDGF-induced proliferation and migration of aortic smooth muscle cells through ROS-dependent heme oxygenase-1 induction.[Pubmed: 23297002]

The abnormal proliferation and migration of vascular smooth muscle cell (VSMC) contributes importantly to the pathogenesis of atherosclerosis and restenosis.
METHODS AND RESULTS:
Here, we investigated the effects of Eupatolide (EuTL), a sesquiterpene lactone isolated from the medicinal plant Inula britannica, on platelet-derived growth factor (PDGF)-induced proliferation and migration of primary rat aortic smooth muscle cells (RASMCs), as well as its underlying mechanisms. EuTL remarkably inhibited PDGF-induced proliferation and migration of RASMCs. Treatment of RASMCs with EuTL induced both protein and mRNA expression of heme oxygenase-1 (HO-1). SB203580 (a p38 inhibitor), SP600125 (a JNK inhibitor), U0126 (a MEK inhibitor) and LY294002 (a PI3K inhibitor) did not suppress EuTL-induced HO-1 expression; however, N-acetylcysteine (NAC, an antioxidant) blocked EuTL-induced HO-1 expression. Moreover, treatment of RASMCs with EuTL increased reactive oxygen species (ROS) accumulation and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2); however, this translocation was also inhibited by NAC. NAC or inhibition of HO-1 significantly attenuated the inhibitory effects of EuTL on PDGF-induced proliferation and migration of RASMCs.
CONCLUSIONS:
Taken together, these findings suggest that EuTL could suppress PDGF-induced proliferation and migration of VSMCs through HO-1 induction via ROS-Nrf2 pathway and may be a potential HO-1 inducer for preventing or treating vascular diseases.

Planta Med. 2006 Jan;72(1):40-5.

New sesquiterpene dimers from Inula britannica inhibit NF-kappaB activation and NO and TNF-alpha production in LPS-stimulated RAW264.7 cells.[Pubmed: 16450294 ]

METHODS AND RESULTS:
A bioassay-guided isolation of an ethyl acetate-soluble extract of the aerial parts of Inula britannica var. chinensis (Rupr.) Regel, using an in vitro NF-kappaB reporter gene assay, led to the isolation of four new sesquiterpene dimers bearing a norbornene moiety, inulanolides A-D, and three known sesquiterpenes, 1,6alpha-dihydroxyeriolanolide, 1-acetoxy-6alpha-hydroxyeriolanolide, and Eupatolide. The structures of the new compounds were elucidated by spectroscopic methods.
CONCLUSIONS:
Among these compounds, inulanolides B and D and Eupatolide, exhibited potent inhibitory activity on the LPS-induced NF-kappaB activation with IC50 values of 0.49 microM, 0.48 microM, and 1.54 microM, respectively. Consistent with their inhibitory effect on NF-kappaB activation, compounds and also strongly inhibited the production of NO and TNF-alpha in the LPS-stimulated RAW264.7 cells with IC50 values in the range of 2 microM.