Mi-Sook Dong

Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells.

We investigated the molecular effect and signal pathway of icariin, a major flavonoid of Epimedium koreanum Nakai, on angiogenesis. Icariin stimulated in vitro endothelial cell proliferation, migration, and tubulogenesis, which are typical phenomena of angiogenesis, as well as increased in vivo angiogenesis. Icariin activated the angiogenic signal modulators, ERK, phosphatidylinositol 3-kinase (PI3K), Akt, and endothelial nitric oxide synthase (eNOS), and increased NO production, without affecting VEGF expression, indicating that icariin may directly stimulate angiogenesis. Icariin-induced ERK activation and angiogenic events were significantly inhibited by the MEK inhibitor PD98059, without affecting Akt and eNOS phosphorylation. The PI3K inhibitor Wortmannin suppressed icariin-mediated angiogenesis and Akt and eNOS activation without affecting ERK phosphorylation. Moreover, the NOS inhibitor NMA partially reduced the angiogenic activity of icariin. These results suggest that icariin stimulated angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways and may be a useful drug for angiogenic therapy.

Estrogenic/antiestrogenic activities of a Epimedium koreanum extract and its major components: in vitro and in vivo studies.

The estrogenic and antiestrogenic activities of Epimedii Herba, which is a traditional medicinal herb used in Korea and China were investigated in this study. The in vitro estrogen receptor (ER) mediated estrogenic/antiestrogenic activities of an Epimedii Herba extract (Epi ext) and its major components were determined using an estrogen responsive element driven reporter gene assay in MCF-7/ERE and HEK293T cells. The Epi ext exhibited ERα- and ERβ-mediated estrogenic activity with an EC(50) of 5.0 and 17.8 μM in HEK293T cells, respectively. Prenylflavonoid glycosides such as icariin (ICA), epimedin A, B, and C did not show any in vitro estrogenic or antiestrogenic activities. Icaritin (ICT) and quercetin exhibited in vitro ER mediated estrogenic activity with a more potent interaction with ERβ. In vivo estrogenic activities of the Epi ext, ICA and ICT were compared using an uterotrophic assay. Although the potency of in vitro estrogenic activity was in the order of ICT>Epi ext>ICA, ICA had the strongest estrogenic activity and next ICT in ovariectomized rats. These results collectively suggest that phytoestrogens possess both estrogenic and antiestrogenic activity, and that the differential expression of these two compounds with opposing activities is dependent on the physiological environment in terms of estrogen level, which may be the case in humans.

Anti-inflammatory effects of (Z)-ligustilide through suppression of mitogen-activated protein kinases and nuclear factor-κB activation pathways

AbstactThe roots of Angelica tenuissima have been commonly used for the treatment of cardiovascular diseases and menstrual discomfort in Asian countries, such as China and Korea. The primary volatile flavor components are essential oil ingredients, phthalide lactones. In this study, (Z)-ligustilide was tested for its anti-inflammatory activities in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We found that (Z)-ligustilide strongly inhibitis the induction of LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at both the mRNA and protein levels in a dose-dependent manner. The transcriptional activity of nuclear factor kappa B (NF-B) was also down-regulated in a concentration-dependent manner. Further study revealed that (Z)-ligustilide inhibited the phosphorylation and subsequent degradation of IBα, an inhibitor protein of NF-B. In addition, (Z)-ligustilide inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) in a dose-dependent manner. Taken together, these data suggest that (Z)-ligustilide can exert its antiinflammatory effects by regulating the NF-B and MAPK signal pathways.

Effects of hydroxyl group numbers on the B-ring of 5,7-dihydroxyflavones on the differential inhibition of human CYP 1A and CYP1B1 enzymes.

Flavonoids are polyphenols composed of two aromatic rings (A, B) and a heterocyclic ring (C). In order to determine the effects of the number of hydroxyl groups in the B-ring of the flavonoids on human cytochrome P450 (CYP) 1 family enzymes, we evaluated the inhibition of CYP1A-dependent 7-ethoxyresorufinO-deethylation activity by chrysin, apigenin and luteolin, using bacterial membrances that co-express human CYP1A1, CYP1A2, or CYP1B1 with human NADPH-cytochrome P450 reductase. Chrysin, which possesses no hydroxyl groups in its B-ring, exhibited the most pronounced inhibitory effects on CYP1A2-dependent EROD activity, followed by apigenin and luteolin. On the contray, CYP1A1-mediated EROD activity was most potently inhibited by luteolin, which is characterized by two hydroxyl groups in its B-ring, followed by apigenin and chrysin. However, all of the 5,7-dihydroxyflavones were determined to similarly inhibit CYP1B1 activity. Chrysin, apigenin, and luteolin exhibited a mixedtype mode of inhibition with regard to CYP1A2, CYP1B1, and CYP1A1, with apparent Ki values of 2.4, 0.5, and 2.0 μM, respectively. These findings suggested that the number of hydroxyl groups in the B-ring of 5,7-dihydroxyflavone might have some influence on the degree to which CYP1A enzymes were inhibited, but not on the degree to which CYP1B1 enzymes were inhibited.

Identification of 2,3,6-trisubstituted quinoxaline derivatives as a Wnt2/β-catenin pathway inhibitor in non-small-cell lung cancer cell lines.

We screened 1434 small heterocyclic molecules and identified thirteen 2,3,6-trisubstituted quinoxaline derivatives that were able to inhibit the Wnt/β-catenin signal pathway and cell proliferation. In the screen, some of the hit compounds such as the ethylene group-coupled quinoxaline derivatives were shown to hold promise for use as potential small-molecule inhibitors of the Wnt/β-catenin signal pathway in non-small-cell lung cancer cell lines.

Structure-related cytotoxicity and anti-hepatofibric effect of asiatic acid derivatives in rat hepatic stellate cell-line, HSC-T6.

The structural relationship of 16 asiatic acid (AA) derivatives, including AA and asiaticoside (AS) to cytotoxicity and anti-hepatofibrotic activity in HSC-T6 cells, were investigated. Cytotoxicities of AA derivatives varied from 5.5 μM to over 2000 μM of IC50 depending on AA functional group modifications. Substituting the hydroxyl group at the C(2) to N=C and substituting bulky groups for dihydroxyl groups at (3), (23) of the A-ring increased the cytotoxicity, but keto group at C(11) and benzoyl ester at C(2) were greatly reduced it. Modification of the carboxylic acid group at C28 also reduced the cytotoxicity. The collagen synthesis determined by hydroxyproline content in the cells was inhibited from a maximum of 48% (Zlx-i-85 and 87) to 15% (AS) by AA derivatives. The anti-hepatofibrotic effect of these compounds might be due to the reduced expression of prolyl 4-hydroxylase α and β subunits and TIMP2. However, the inhibition of collagen by asiaticoside derivatives did not show any structural-activity relationship.

Low-dose intravenous pantoprazole for optimal inhibition of gastric acid in Korean patients.

Background and Aim:  Proton‐pump inhibitor (PPI) therapy for bleeding ulcers is more efficacious in Asian patients than in non‐Asian patients. The aim of this study was to evaluate the efficacy of various doses of pantoprazole on intragastric acidity in Korean patients.

A novel 3-arylethynyl-substituted pyrido[2,3,-b]pyrazine derivatives and pharmacophore model as Wnt2/β-catenin pathway inhibitors in non-small-cell lung cancer cell lines.

We developed Wnt/β-catenin inhibitors by identifying 13 number of 3-arylethynyl-substituted pyrido[2,3,-b]pyrazine derivatives that were able to inhibit the Wnt/β-catenin signal pathway and cancer cell proliferation. In the optimization process, a series of 2,3,6-trisubstituted pyrido[2,3,-b]pyrazine core skeletons showed were shown to higher activity than 2,3,6-trisubstituted quinoxalines and thus hold promise for use as potential small-molecule inhibitors of the Wnt/β-catenin signal pathway in non-small-cell lung cancer cell (NSCLC) lines. And we have studied the pharmacophore mapping for compound 954, which presented the highest activity with a fit value of 2.81. The pharmacophore mapping for the compounds including 954, pyrido[2,3,-b]pyrazine core had hydrogen-bond acceptor site and hydrophobic center roles.

2,3,6-Trisubstituted quinoxaline derivative, a small molecule inhibitor of the Wnt/beta-catenin signaling pathway, suppresses cell proliferation and enhances radiosensitivity in A549/Wnt2 cells

GDK-100017, a 2,3,6-trisubstituted quinoxaline derivative, reduced β-catenin-T-cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcriptional activity and inhibited cell proliferation in a dose-dependent manner with an IC₅₀ value of about 10 μM in A549/Wnt2 cells. GDK-100017 down-regulated the expression of Wnt/β-catenin pathway target genes such as cyclin D1 and Dkk1 but not c-myc or survivin. GDK-100017 inhibited cell proliferation by arresting the cell cycle in the G1 phase not only in A549/wnt2 cells but also in SW480 colon cancer cells. In addition to its wnt signaling inhibitory properties, GDK-100017 also enhanced the radiosensitivity of the A549 human NSCLC line. These results suggest that GDK-100017 possesses potential anti-cancer activity by inhibiting the Wnt/β-catenin signal pathway, blocking the β-catenin-TCF/LEF interaction, and enhancing radiosensitivity.

Effects of CYP2C19 and MDR1 genotype on the eradication rate of Helicobacter pylori infection by triple therapy with pantoprazole, amoxycillin and clarithromycin

Backgrounds:  CYP2C19 polymorphism plays an important role in the metabolism of proton pump inhibitors. The multidrug resistance (MDR)1 genotype is associated with the successful eradication of Helicobacter pylori. The aim of the present study was to investigate the effects of CYP2C19 and MDR1 genotypes on the eradication rate of H. pylori using a pantoprazole‐based triple therapy.