Glabrol, an acyl-coenzyme A: cholesterol acyltransferase inhibitor from licorice roots.

Acyl-coenzyme A: cholesterol acyltransferase (ACAT) esterifies free cholesterol in the liver and the intestine. It has relations with production of lipoproteins and accumulation of cholesteryl esters of the atheroma. Therefore, ACAT inhibitors may act as antihypercholesterolemic and antiatherosclerotic agents. One isoprenyl flavonoid was isolated from ethanol extract of licorice roots. On the basis of spectral evidences, the compound was identified as glabrol (1). Compound 1 inhibited rat liver microsomal ACAT activity with an IC(50) value of 24.6 microM and decreased cholesteryl ester formation with an IC(50) value of 26.0 microM in HepG2 cells. In addition, 1 showed a non-competitive type of inhibition against ACAT.

Dimeric sesquiterpenoids isolated from Chloranthus japonicus inhibited the expression of cell adhesion molecules.

In the search for cell adhesion inhibitors from natural sources, three active compounds were isolated from Chloranthus japonicus Sieb. (Chloranthaceae) roots. The compounds were identified as dimeric sesquiterpenoids of shizukaol B (1), cycloshizukaol A (2) and shizukaol F (3). These compounds inhibited PMA-induced homotypic aggregation of HL-60 cells without cytotoxicity with MIC values of 34.1 nM (1), 0.9 microM (2) and 27.3 nM (3), respectively. Although 1-3 did not affect the direct binding of LFA-1 to ICAM-1, these compounds markedly inhibited ICAM-1 expression in HL-60 cells in a dose-dependent fashion. On the other hand, when HUVEC were pretreated with 1-3 and stimulated with TNF-alpha, adhesion of THP-1 cells to HUVEC decreased in dose-dependent manner with IC(50) values of 54.6 nM, 1.2 microM and 34.1 nM, respectively. In fact, 1 inhibited TNF-alpha-induced surface expression of the ICAM-1, VCAM-1 and E-selectin in HUVEC with IC(50) values of 5.4 nM, 13.6 microM and 95.6 nM, respectively. The present findings suggest that 1-3 prevent monocyte adhesion to HUVEC through the inhibition of cell adhesion molecules expression stimulated by TNF-alpha.

Manassantin A and B isolated from Saururus chinensis inhibit TNF-alpha-induced cell adhesion molecule expression of human umbilical vein endothelial cells.

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.

Kurarinone isolated from Sophora flavescens Ait inhibited MCP-1-induced chemotaxis.

The accumulation of circulating monocytes in the arterial wall is an early in atherosclerotic plaque formation. Monocyte chemoattractant protein-1 (MCP-1) promotes the migration of monocytes and would play a role in the development of atherosclerotic lesions. Searching for inhibitors of MCP-1-induced cell migration from natural sources, we isolated one active compound through active-guided fractionations from the MeOH extracts of Sophora flavescens Ait (Leguminosae). On the basis of spectral evidence, the structure of active compound was identified as kurarinone. It inhibited the migration of THP-1 cells induced by MCP-1 with IC50 value of 19.2 microg/mL. In addition, it inhibited the binding of MCP-1 to THP-1 cells and phosphorylation of p42/44 MARK.

Polyacetylenic compounds, ACAT inhibitors from the roots of Panax ginseng.

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.

Guineensine, an Acyl-CoA: cholesterol acyltransferase inhibitor, from the fruits of Piper longum.

Bioactivity-guided fractionations for ACAT inhibitor led to the isolation of guineensine from the CHCl (3) extract of Piper longum. Its structure was identified by spectroscopic means (IR, UV, MS and NMR). Guineensine inhibited ACAT activity in a dose-dependent manner with an IC (50) value of 3.12 micro M.

Pheophorbide A-methyl ester, Acyl-CoA: cholesterol acyltransferase inhibitor from Diospyros kaki.

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.

Inhibitory effects of manassantin A and B isolated from the roots of Saururus chinensis on PMA-induced ICAM-1 expression.

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.

Isolation of Acyl-CoA:cholesterol acyltransferase inhibitor from Persicaria vulgaris.

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 the methanol extract of Persicaria vulgaris. On the basis of spectral evidence, the structure of the active compound was identified as pheophorbide A. Pheophorbide A inhibited ACAT activity with an IC 50 value of 1.1 microg/ml in an enzyme assay using rat liver microsomes with a dose dependent fashion.