Colestilan decreases weight gain by enhanced NEFA incorporation in biliary lipids and fecal lipid excretion.

Bile acid sequestrants (BASs) are cholesterol-lowering drugs that also affect hyperglycemia. The mechanism by which BASs exert these and other metabolic effects beyond cholesterol lowering remains poorly understood. The present study aimed to investigate the effects of a BAS, colestilan, on body weight, energy expenditure, and glucose and lipid metabolism and its mechanisms of action in high-fat-fed hyperlipidemic APOE*3 Leiden (E3L) transgenic mice.

Inhibitors of protein: geranylgeranyl transferases.

The enzyme protein:geranylgeranyl transferase-1 (PGGT-1 or GGTase-I) catalyzes the geranylgeranylation of cysteine residues near the C-termini of a variety of proteins, including most monomeric GTP binding precursor proteins belonging to the Rho, Rac and Rap subfamilies. These proteins are involved in signaling pathways controlling important processes such as cell differentiation and growth. In the framework of the development of therapeutics against disorders associated with aberrant cell proliferation, the interference with these signal transduction cascades has been a major focus of investigation.

Novel non-systemic inhibitor of ileal apical Na+-dependent bile acid transporter reduces serum cholesterol levels in hamsters and monkeys.

1-{7-[(1-(3,5-Diethoxyphenyl)-3-{[(3,5-difluorophenyl)(ethyl)amino]carbonyl}-4-oxo-1,4-dihydroquinolin-7-yl)oxy]heptyl}-1-methylpiperidinium bromide, R-146224, is a potent, specific ileum apical sodium-dependent bile acid transporter (ASBT) inhibitor; concentrations required for 50% inhibition of [3H]taurocholate uptake in human ASBT-expressing HEK-293 cells and hamster ileum tissues were 0.023 and 0.73 microM, respectively.

A combinatorial approach toward the generation of ambiphilic peptide-based inhibitors of protein:geranylgeranyl transferase-1.

A combinatorial synthesis of oligopeptide analogues and their evaluation as protein:geranylgeranyl transferase inhibitors is presented. The combinatorial strategy is based on the random mutation, in each new generation, of one of any of the four amino acid building blocks of which the most effective compounds of the previous generation are assembled. In this way, a progressive improvement of the average inhibitory activity was observed until the fifth generation.

Synthesis and biological evaluation of lipophilic Ca(1)a(2)L analogues as potential bisubstrate inhibitors of protein:geranylgeranyl transferase-1.

Ca(1)a(2)L analogues, having the central dipeptide a(1)a(2) replaced by a sugar amino acid, were provided at the N-terminal end directly or via a spacer with a lipid. The inhibitory potency toward PGGT-1 of the set of lipophilic Ca(1)a(2)L analogues was improved in comparison with the original analogues, 1 and 2. The most potent inhibitors, 39 and 40, were found to inhibit PGGT-1 with an IC(50)-value of 12.

Design, synthesis, and evaluation of sugar amino acid based inhibitors of protein prenyl transferases PFT and PGGT-1.

Eleven analogues of the C-terminal Ca(1)a(2)X motif found in natural substrates of the prenyl transferases PFT and PGGT-1 were synthesized and evaluated for their inhibition potency and selectivity against PFT and PGGT-1. Replacement of the central dipeptide part a(1)a(2) by a benzylated sugar amino acid resulted in a good and highly selective PFT inhibitor (8, IC(50) = 250 +/- 20 nM). The methyl ester of 8 (13) selectively inhibited protein farnesylation in cultured cells.

Synthesis and antimicrobial evaluation of farnesyl diphosphate mimetics.

The synthesis and first antimicrobial evaluation of farnesyl diphosphate mimetics are described. Several analogues (10, 12, 13, and 20) are inhibitors of Candida albicans, Shizosaccharomyces pombe, and Saccharomyces cerevisiae. The activities of analogues 10, 12, and 13, which contain a omega-phenyl moiety and a diphosphate isostere, are not attributable to inhibition of sterol biosynthesis via squalene synthase.

Differential effect of simvastatin on activation of Rac(1) vs. activation of the heat shock protein 27-mediated pathway upon oxidative stress, in human smooth muscle cells.

In the present study, we have analyzed the response of human smooth muscle cell (SMC)s to oxidative stress, in terms of recruitment of key elements of the stress-activated protein kinase (SAPK) pathway, such as Rac(1), p38, and the small heat shock protein (HSP)27. The level of expression of three small HSPs, alphaB-crystallin, HSP20, HSP27, as well as the phosphorylation levels of HSP27 and p38, were higher in cultured, asynchronously growing SMCs originating from left interior mammary artery (LIMA) than those originating from aorta, saphenous vein, and umbilical vein, validating the choice of SMCs from LIMA as a model system in our study. In synchronized, quiescent SMCs from LIMA, oxidative stress (H(2)O(2) stimulation)-induced membrane translocation of Rac(1), p38 phosphorylation, membrane translocation, and phosphorylation of HSP27.