Antiphospholipid antibodies (Abs) are associated with thrombosis and are a risk factor for recurrent pregnancy loss and obstetric complications in patients with the antiphospholipid syndrome. It is generally accepted that the major autoantigen for aPL Abs is beta (2) glycoprotein I, which mediates the binding of aPL Abs to target cells (i.e., endothelial cells, monocytes, platelets, trophoblasts, etc.) leading to thrombosis and fetal loss. This article addresses molecular events triggered by aPL Abs on endothelial cells, platelets, and monocytes and complement activation, as well as a review of the current knowledge with regard to the putative receptor(s) recognized by aPL Abs on target cells as well as novel mechanisms that involve fibrinolytic processes. A section is devoted to the description of thrombotic and inflammatory processes that lead to obstetric complications mediated by aPL Abs. Based on experimental evidence using in vitro and in vivo models, new targeted therapies for treatment and/or prevention of thrombosis and pregnancy loss in antiphospholipid syndrome are proposed.

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The Mediterranean diet reduces the risk of coronary artery disease as a consequence of its high content of antioxidants, namely, hydroxytyrosol (HT) and oleuropein aglycone (OleA), typical of virgin olive oil. Because intercellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1) and E-selectin are crucial for endothelial activation, the role of the phenolic extract from extra virgin olive oil (OPE), OleA, HT, and homovanillyl alcohol (HVA) on cell surface and mRNA expression in human umbilical vascular endothelial cells (HUVEC) was evaluated. OPE strongly reduced cell surface expression of ICAM-1 and VCAM-1 at concentrations physiologically relevant (IC50 < 1 microM), linked to a reduction in mRNA levels. OleA and HT were the main components responsible for these effects. HVA inhibited cell surface expression of all the adhesion molecules, whereas the effect on mRNA expression was weaker. These results supply new insights on the protective role of olive oil against vascular risk through the down-regulation of adhesion molecules involved in early atherogenesis.

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The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose and lipid metabolism. They are activated by natural ligands, such as fatty acids, and are also targets of synthetic antidiabetic and hypolipidemic drugs. By using cell-based reporter assays, we studied the transactivation activity of two enantiomeric ureidofibrate-like derivatives. In particular, we show that the R-enantiomer, (R)-1, is a full agonist of PPAR␥, whereas the S-enantiomer, (S)-1, is a less potent partial agonist. Most importantly, we report the x-ray crystal struc- The peroxisome proliferator-activated receptors (PPARs), 4 members of the superfamily of nuclear receptors, are eukaryotic transcription factors that control the expression of genes involved in fatty acid metabolism (1, 2). They function as cellular lipid sensors that activate transcription in response to the binding of a cognate ligand, generally fatty acids and their eicosanoids metabolites (3). Ligand binding, by promoting the stabilization of the active conformation of the C-terminal activation function-2 helix (H12), triggers the recruitment of co-activator proteins (1, 4, 5) that locally remodel chromatin and activate the cellular transcriptional machinery (6, 7). The subtype PPAR␣ promotes fatty acid catabolism in the liver and skeletal muscle, whereas PPAR␥ regulates fatty acid storage in adipose tissues (1). PPARs are also targets of synthetic hypolipidemic and antidiabetic drugs. In particular, the fibrate class of lipid-lowering drugs (e.g. fenofibrate and gemfibrozil) are PPAR␣ ligands (8 -10). The thiazolidinedione (11, 12) antidiabetic agents (rosiglitazone and pioglitazone) are PPAR␥ agonists whose insulin-sensitizing action is well established (13). Selective PPAR␥ modulators (1, 14), acting in a cell type-selective manner and having lower adverse effects, such as edema, cardiomegaly, increased adiposity, and weight gain (14 -16), have been identified. These ligands, which may function as partial agonists, provide diminished conformational stability of receptor as opposed to full agonists (1, 5, 17). Furthermore, PPAR ligands with a dual activity on both PPAR␣ and PPAR␥ receptors improve hyperglycemia and dyslipidemic disorders in a coordinate manner (1). Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome. For this reason, the search for dual agonists with lower potency on PPAR␥ as compared with full agonists, but also active on PPAR␣, would be desirable.We synthesized the two enantiomers of the novel compound, 2-(4-{2-[1,3-benzoxazol-2-yl(heptyl)amino]ethyl}phenoxy)-2-methyl-butanoic acid, a conformationally constrained analogue of the well known PPAR␣/␥ agonist GW2331 (3, 18) (Fig. 1). The R-enantiomer, (R)-1, is able to activate both PPAR␣ and * This work was supported by Italian Ministry of University and ResearchGrant Progetti di Ricerca di Interesse Nazionale 2005033023. The costs of publication of this article were defrayed in part by the payment of page charges. This article m...

Myelin is a membrane characterized by high lipid content to facilitate impulse propagation. Changes in myelin fatty acid (FA) composition have been associated with peripheral neuropathy, but the specific role of peripheral nerve FA synthesis in myelin formation and function is poorly understood. We have found that mice lacking sterol regulatory element-binding factor-1c (Srebf1c) have blunted peripheral nerve FA synthesis that results in development of peripheral neuropathy. Srebf1c-null mice develop Remak bundle alterations and hypermyelination of small-caliber fibers that impair nerve function. Peripheral nerves lacking Srebf1c show decreased FA synthesis and glycolytic flux, but increased FA catabolism and mitochondrial function. These metabolic alterations are the result of local accumulation of two endogenous peroxisome proliferator-activated receptor-α (Pparα) ligands, 1-palmitoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine and 1-stearoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine. Treatment with a Pparα antagonist rescues the neuropathy of Srebf1c-null mice. These findings reveal the importance of peripheral nerve FA synthesis to sustain myelin structure and function.

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