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ABSTRACT: Leukocyte adhesion to the vascular endothelium is a critical initiating step in inflammation and atherosclerosis. We have
herein studied the effect of manassantin A (1) and B (2), dineolignans, on interaction of THP-1 monocytic cells and human umbilical vein endothelial cells (HUVEC) and expression
of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in HUVEC. When HUVEC
were pretreated with1 and2 followed by stimulation with TNF-α, adhesion of THP-1 cells to HUVEC decreased in dose-dependent manner with IC50 values of 5 ng/mL and 7 ng/mL, respectively, without cytotoxicity. Also,1 and2 inhibited TNF-α-induced up-regulation of ICAM-1, VCAM-1 and E-selectin. The present findings suggest that1 and2 prevent monocyte adhesion to HUVEC through the inhibition of ICAM-1, VCAM-1 and E-selectin expression stimulated by TNF-α,
and may imply their usefulness for the prevention of atherosclerosis relevant to endothelial activation.
Archives of Pharmacal Research 04/2012; 28(1):55-60. · 1.59 Impact Factor
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ABSTRACT: Inhibition of acyl CoA:diacylglycerol acyltransferase (DGAT) is proposed to be a drug target for the treatment of obesity and type 2 diabetes. Bioassay-guided fractionation of the CH(2)Cl(2)-soluble extract of the stem bark of Erythrina senegalensis, using an in vitro DGAT enzyme assay, resulted in the isolation of eight known prenylflavonoids, 8-prenylleutone (1), auriculatin (2), erysenegalensein O (3), erysenegalensein D (4), erysenegalensein N (5), derrone (6), alpinumisoflavone (7), and 6,8-diprenylgenistein (8). Compounds 1, 2-4, 6, and 8 inhibited DGAT activity, with IC(50) values ranging from 1.1 +/- 0.3 to 15.1 +/- 1.1 microg/mL. On the basis of the data obtained, we propose isoflavonoids with isoprenyl groups as a novel class of DGAT inhibitors.
Archives of Pharmacal Research 02/2009; 32(1):43-7. · 1.59 Impact Factor
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ABSTRACT: During the screening for diacylglycerol acyltransferase (DGAT) inhibitors from natural products, the lupane-type triterpenoid betulinic acid was isolated from the methanol extract of Alnus hirsuta. It potently inhibited DGAT in the rat liver microsomes with an IC (50) value of 9.6 microM. Enzyme kinetic studies showed apparent Km and Ki values of 13.3 microM and 8.1 microM using [(14)C]oleoyl-CoA as a substrate. A decrease in the apparent Vmax was observed with betulinic acid, whereas the apparent Km remained constant. Therefore, a Lineweaver-Burk plot of DGAT inhibition by betulinic acid showed a non-competitive type of inhibition. In the cell-based assay, betulinic acid inhibited triglyceride (TG) formation by human HepG2 cells. These findings suggest that betulinic acid may be a potential lead compound in the treatment of obesity.
Planta Medica 03/2006; 72(3):267-9. · 2.15 Impact Factor
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Mun-Chual Rho,
Young Kook Kim,
Jong Sun Chang,
Hyun Sun Lee,
Jin Ah Baek, Mi Yeon Chung,
Han Cheol Lee,
Hwan Woo Lee,
Byong Yong Rhim,
Michael A Reidy,
Koanhoi Kim
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ABSTRACT: Human vascular smooth muscle cells (HVSMCs) are resistant to Fas-mediated death under normal physiological conditions. However, HVSMC death by activation of the receptor pathway was reported in the atherosclerotic lesions. In this study, we investigated whether 7-ketocholesterol, one of the major cholesterol oxides in the lesions, altered resistance of HVSMC to Fas-mediated death pathway. Cross-linking of Fas receptor with agonistic anti-Fas antibody (CH11) in the presence of 7-ketocholesterol induced death in human aorta smooth muscle cells (HAoSMC) as detected by morphology, viability, and DNA fragmentation. The agonistic anti-Fas antibody, however, did not induce death in the presence of 7alpha-hydroxycholesterol or cholesterol. The HAoSMC death was significantly inhibited by an antagonistic Fas receptor (FasR) antibody and by expression of dominant negative Fas-associated death domain containing protein (DN-FADD) using adenoviruses. Activation of caspase-3 was observed in HAoSMC destined to death. HAoSMC death was significantly inhibited by pharmacological caspase inhibitor, z-VAD and z-DEVD, and baculovirus caspase inhibitor p35. 7-Ketocholesterol impaired mitochondrial transmembrane potential and ATP production. Overexpression of bcl-xL also significantly inhibited HAoSMC death. In dying HAoSMC, bax was translocated from the cytosol to mitochondria and cytochrome c was released from mitochondria into the cytosol. This is the first report demonstrating implication of the oxysterol in Fas-mediated death pathway. The present study proposes that 7-ketocholesterol would contribute to loss of HVSMC in the atherosclerotic lesions by altering resistance to receptor-mediated death pathway.
Journal of Molecular and Cellular Cardiology 12/2005; 39(5):823-32. · 5.17 Impact Factor
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ABSTRACT: This study was undertaken to investigate whether a physiologically compatible concentration of 7-ketocholesterol had any effect on human vascular smooth muscle cells (HVSMCs). We found that 7-ketocholesterol changed the viability of human aorta smooth muscle cells (HAoSMC) not by cytotoxicity but by activation of tumor necrosis factor-alpha receptor (TNFR)-mediated death. Whereas TNF-alpha did not affect the viability in the presence of 7alpha-hydroxycholesterol or cholesterol, the cytokine induced HAoSMC death in the presence of 7-ketocholesterol as detected by morphology, viability, and fragmentation of chromosomal DNA. The HAoSMC death was inhibited by a neutralizing anti-TNF receptor 1 (TNFR1) antibody and by the caspase inhibitors of z-VAD and z-DEVD. Activations of caspase-8 and -3 were detected from dying HAoSMCs. 7-Ketocholesterol inhibited translocation of the nuclear factor kappaB (NF-kappaB) subunits of p65 and p50 from the cytosol into the nucleus, increase of NF-kappaB activity, and expression of caspase-8 homolog Fas ligand interleukin-1-converting enzyme inhibitory protein by TNF-alpha. We also found that X-chromosome-linked inhibitor of apoptosis protein was degraded in dying HAoSMC. The present study proposes that 7-ketocholesterol would contribute to the disappearance of HVSMC in the atherosclerotic lesions by enhancing receptor-mediated death. This is the first report demonstrating induction of TNF-alpha-mediated death by oxysterol in cells.
Biochemical and Biophysical Research Communications 09/2005; 333(4):1093-9. · 2.48 Impact Factor
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ABSTRACT: Acyl-CoA: cholesterol acyltransferase (ACAT), which plays a role in the absorption, storage, and production of cholesterol, has been explored as a potential target for pharmacological intervention of hyperlipidemia and atherosclerotic disease. In our search for ACAT inhibitors from natural sources, the petroleum ether extract of Panax ginseng showed moderate inhibition of ACAT enzyme from rat liver microsomes. Bioactivity-guided fractionations led to the isolation of one new polyacetylenic compound, (9R,10S)-epoxy-16-heptadecene-4, 6-diyne-3-one (1), in addition to the previously reported polyacetylenic compounds 2 and 3. Their chemical structures were elucidated on the basis of spectroscopic evidence (UV, IR, NMR, and MS). The compounds 1, 2, and 3 showed significant ACAT inhibition with IC(50) values of 35, 47, and 21 microM, respectively.
Journal of Agricultural and Food Chemistry 03/2005; 53(4):919-22. · 2.82 Impact Factor
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ABSTRACT: Leukocyte adhesion to the vascular endothelium is a critical initiating step in inflammation and atherosclerosis. We have herein studied the effect of manassantin A (1) and B (2), dineolignans, on interaction of THP-1 monocytic cells and human umbilical vein endothelial cells (HUVEC) and expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in HUVEC. When HUVEC were pretreated with 1 and 2 followed by stimulation with TNF-alpha, adhesion of THP-1 cells to HUVEC decreased in dose-dependent manner with IC50 values of 5 ng/mL and 7 ng/mL, respectively, without cytotoxicity. Also, 1 and 2 inhibited TNF-alpha-induced up-regulation of ICAM-1, VCAM-1 and E-selectin. The present findings suggest that 1 and 2 prevent monocyte adhesion to HUVEC through the inhibition of ICAM-1, VCAM-1 and E-selectin expression stimulated by TNF-alpha, and may imply their usefulness for the prevention of atherosclerosis relevant to endothelial activation.
Archives of Pharmacal Research 02/2005; 28(1):55-60. · 1.59 Impact Factor
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ABSTRACT: Four prenylflavonoids, kurarinone ( 1), a chalcone of 1, kuraridin ( 2), kurarinol ( 3), kushenol H ( 4) and kushenol K ( 5) isolated from the roots of Sophora flavescens were investigated for their inhibitory effects on diacylglycerol acyltransferase (DGAT). The flavonoids inhibited DGAT activity in a dose-dependent manner with IC50 values of 10.9 microM ( 1), 9.8 microM ( 2), 8.6 microM ( 3), 142.0 microM ( 4) and 250 microM ( 5). The prenylflavonoids without C3-OH ( 1, 2, 3) showed stronger inhibition than those with C3-OH ( 4, 5). On the other hand, flavonoids without side chains (hesperetin, naringenin, quercetin and kaempferol) did not inhibit the enzyme activity at a final concentration of 800 microM. These data suggest that the lavandulyl side chain and the position of the hydroxy group are important for high DGAT inhibitory activity. Compound 1 also inhibited de novo synthesis of triacylglycerol (TG) in Raji cells.
Planta Medica 04/2004; 70(3):258-60. · 2.15 Impact Factor
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ABSTRACT: The petroleum ether extract of Panax ginseng showed a significant inhibition of the diacylglycerol acyltransferase (DGAT) enzyme from rat liver microsomes. Bioactivity-guided fractionation led to the isolation of two new polyacetylenic compounds, (9 R,10 S)-epoxyheptadecan-4,6-diyn-3-one ( 1) and 1-methoxy-(9 R,10 S)-epoxyheptadecan-4,6-diyn-3-one ( 2). Their chemical structures were elucidated on the basis of spectroscopic evidence and asymmetric synthesis. IC50 values of 9 microg/mL ( 1) and 32 microg/mL ( 2) were obtained.
Planta Medica 04/2004; 70(3):197-200. · 2.15 Impact Factor
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ABSTRACT: Cell adhesion inhibitors were isolated from the methanol extract of Saururus chinensis roots by bioactivity-guided fractionation. The active compounds were identified as manassantin A ( 1) and B ( 2), dineolignan compounds. Compounds 1 and 2 inhibited PMA-induced ICAM-1/LFA-1-mediated homotypic aggregation of the HL-60 cells without cytotoxicity with MIC values of 1.0 and 5.5 nM, respectively. Even though 1 and 2 did not affect the adhesion of ICAM-1 to LFA-1, these compounds inhibited PMA-induced ICAM-1 expression in HL-60 cells in a dose-dependent fashion. These results suggest that 1 and 2 inhibit cell aggregation through down-regulation of ICAM-1 expression.
Planta Medica 01/2004; 69(12):1147-9. · 2.15 Impact Factor
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ABSTRACT: In the course of our search for Acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors from natural sources, a new type of ACAT inhibitor was isolated from a methanol extract of Diospyros kaki. On the basis of spectral and structural evidence, the compound was identified as pheophorbide A-methyl ester. Pheophorbide A-methyl ester inhibited ACAT activity in a dose dependent manner with an IC50 value of 1.85 microg/mL.
Archives of Pharmacal Research 10/2003; 26(9):716-8. · 1.59 Impact Factor
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ABSTRACT: From the diacylglycerol acyltransferase (DGAT) activity-guided fractionation, a new quinolone alkaloid, 1-methyl-2-tetradecyl-4(1H)-quinolone (1) was isolated from the fruits of Evodia rutaecarpa together with three known quinolone alkaloids, evocarpine (2), 1-methyl-2-[(4 Z,7 Z)-4,7-decadienyl]-4(1H)-quinolone (3) and 1-methyl-2-[(6 Z,9 Z)-6,9-pentadecadienyl]-4(1 H)-quinolone (4). They showed a dose-dependent DGAT inhibition with IC 50 values of 69.5 microM ( 1), 23.8 microM (2), 20.1 microM (3) and 13.5 mu (4).
Planta Medica 01/2003; 68(12):1131-3. · 2.15 Impact Factor
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The Journal of Antibiotics 12/2002; 55(11):1004-8. · 1.65 Impact Factor
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ABSTRACT: The inhibitory activity of tanshinones from Salvia miltiorrhiza was tested on rat liver diacylglycerol acyltransferase (DGAT). Cryptotanshinone (1) and 15,16-dihydrotanshinone I (3) exhibited potent DGAT inhibitory activities dose-dependently with IC50 values of 10.5 microg/ml and 11.1 microg/ml. However, tanshinone IIA (2) and tanshinone I (4) showed very weak inhibition (IC50 value: > 250 microg/ml). A dihydrofuran moiety was seemed to be responsible for the stronger inhibitory activity.
Archives of Pharmacal Research 08/2002; 25(4):446-8. · 1.59 Impact Factor
