Sesamin is a major lignan constituent of sesame and possesses multiple functions such as antihypertensive, cholesterol-lowering, lipid-lowering and anticancer activities. Several groups have previously reported that sesamin induces growth inhibition in human cancer cells. However, the nature of this growth inhibitory mechanism remains unknown. The authors here report that sesamin induces growth arrest at the G1 phase in cell cycle progression in the human breast cancer cell line MCF-7. Furthermore, sesamin dephosphorylates tumor-suppressor retinoblastoma protein (RB). It is also shown that inhibition of MCF-7 cell proliferation by sesamin is correlated with down-regulated cyclin D1 protein expression, a proto-oncogene that is overexpressed in many human cancer cells. It was found that sesamin-induced down-regulation of cyclin D1 was inhibited by proteasome inhibitors, suggesting that sesamin suppresses cyclin D1 protein expression by promoting proteasome degradation of cyclin D1 protein. S esamin is a major lignan constituent of sesame and sesame oil, which have been traditional health foods in eastern countries for thousands of years. Many studies have revealed that sesamin is effective in preventing hypertension, thrombogenesis, (1) and hypercholesteremia by increasing hepatic fatty acid oxidation. (2,3) Additionally, sesamin exhibits antioxidative properties, by reducing peroxidation products in the plasma and liver of rats, (4 -6) and exerts an inhibitory effect on chemically induced cancers. Several groups have previously reported that treatment with sesamin induces growth inhibition and apoptosis in human lymphoid leukemia Molt 4B cells and human stomach cancer KATO III cells, respectively.(8,9) Furthermore, sesamin inhibits the incorporation of tritiated thymidine into human leukemia (HL-60) cells.(10) However, the growth inhibitory mechanism of sesamin remains to be elucidated.Cell cycle progression is regulated by cyclin-dependent kinases (CDK) that form complexes with cyclin in a phase-specific manner during the cell cycle.(11) Cyclin D1/D2/D3-CDK4/6 and cyclin E/A-CDK2 play important roles in promoting the G1-to-S phase transition of the cell cycle by phosphorylating tumor-suppressor retinoblastoma protein (RB). (11,12) Activation of cyclins/ CDK is counterbalanced by CDK inhibitors (CKI). The first family of CKI, referred to as the CIP/ KIP family, consists of the related proteins known as p21 WAF1/Cip1 , p27 Kip1 and p57 Kip2 , and each member inhibits cyclin E /A-CDK2 complexes. (13,14) The second family of CDK inhibitors is called the INK4 family of proteins. The four members of the INK4 family, p16INK4a , p15 INK4b , p18INK4c and p19 INK4d , specifically and directly bind to CDK4/6 and inhibit their activities. (14)(15)(16) In the present study, it is shown that sesamin induces growth arrest at the G1 phase and dephosphorylates RB protein in the human breast cancer cell line MCF-7. It is also shown that sesamin specifically down-regulates the expression of cyclin D1 protein among the cell-cycl...

The INK4 family members p16INK4a and p15 INK4b negatively regulate cell cycle progression by inhibition of cyclin-dependent kinase (CDK) 4/6. Loss of p16INK4a functional activity is frequently observed in tumor cells, and is thought to be one of the primary causes of carcinogenesis. In contrast, despite the biochemical similarity to p16 INK4a, the frequency of defects in p15INK4b was found to be lower than in p16 INK4a, suggesting that p15 INK4b-inductive agents may be useful for tumor suppression. Here we report the discovery of a novel pyrido-pyrimidine derivative, JTP-70902, which exhibits p15

G protein-coupled receptors (GPCRs) are major drug targets, and their ligands are currently being explored and developed by many pharmaceutical companies and independent researchers. Class A (rhodopsin-like) GPCRs compose a predominant GPCR family; therefore, class A GPCR ligands are in demand. Growth hormone secretagogue receptor (GHS-R) is a class A GPCR that stimulates food intake by binding to its peptide ligand, ghrelin. Therefore, antagonists of GHS-R are expected to exert antiobesity function. In this article, we describe the use of cDNA display to screen for successfully and identify an antagonistic peptide of GHS-R. The antagonistic peptide inhibited the ghrelin-induced increase in intracellular Ca 2þ in vitro (IC 50 ¼ approximately 10 μM) and repressed the contraction of isolated animal stomach in response to ghrelin. Furthermore, peripheral administration of the peptide inhibited the food intake of mice. This work provides new insight into the development of antiobesity drugs and describes a method for the discovery of unique peptide ligands for class A GPCRs.aptamer | in vitro display | peptide drug | ligand screening | cell-based selection

To elucidate the anti-atherogenic effect of probucol, high-density lipoprotein (HDL) was isolated from probucol-treated patients (n = 14) and compared with that from control subjects (n = 12). The HDL obtained from probucol-treated patients was low in cholesteryl ester (CE) in comparison with that from control subjects (21.3 +/- 3.9 mol per cent vs. 27.6 +/- 3.2 mol% of total lipids. P < 0.001), and the peak diameters of patients' HDL were significantly smaller than those of control subjects on 4-30% non-denaturing polyacrylamide gradient gel electrophoresis (10.6 +/- 0.6 nm vs. 12.1 +/- 0.4 nm, P < 0.001). These data may be explained by the increased cholesteryl ester transfer protein (CETP) activities of probucol-treated patients (129 +/- 12% of control subjects, P < 0.001). The in vitro ability of HDL to remove CE from lipid-laden macrophages induced by incubation with acetylated low-density lipoprotein (Ac-LDL) was studied. The small and CE-poor HDL obtained from probucol-treated patients had a greater capacity to promote CE efflux from macrophages than did control HDL (59.8 +/- 6.9% vs. 44.2 +/- 5.4%, P < 0.01). Furthermore, the ability of HDL to promote cholesterol efflux correlated negatively with the CE content and particle diameter of HDL (r = -0.561 and r = -0.583 respectively; P < 0.01). When the inhibitory effect of HDL on the incorporation of [14C]-oleate into cellular cholesteryl ester was compared, the HDL from patients and control subjects inhibited CE formation to a similar extent. The enhanced ability of probucol-treated patients' HDL may, therefore, be involved in the acceleration of hydrolysis of the CE pool in macrophages. Taken together, we conclude that CETP plays a crucial role in making HDL more active in its anti-atherogenic function by reducing CE and making HDL smaller, and that probucol may enhance reverse cholesterol transport by activating CE transfer in vivo. The current study demonstrated, for the first time, that HDL modified by enhanced CETP activity in vivo is potentially anti-atherogenic.