Objective-Leukotriene B 4 (LTB 4 ), a product of the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism, has been implicated in atherosclerosis. However, the molecular mechanisms for the atherogenic effect of LTB 4 are not well understood. This study is to determine candidate mechanisms. Method and Results-Primary human monocytes were treated with LTB 4 and the supernatant was analyzed for cytokine/chemokine production by an immuno-protein array. This analysis revealed a strong increase of the monocyte chemoattractant protein-1 (MCP-1), a proinflammatory cytokine. See page 1748Recent studies suggest a strong link between LTB 4 pathways with atherosclerosis. For example, human atherogenic plaques produce LTB 4 , 7 and expression of both BLT 1 and BLT 2 increases with the progression of atherosclerotic lesions. 8 Treatment of atherosclerosis-prone mice (apolipoprotein E [ApoE] or low-density lipoprotein receptor [LDLR]-deficient mice) with the BLT 1 -specific antagonist CP-105,696 9,10 markedly decreased lesion size. 11 Interestingly, the anti-atherogenic effects of CP-105,696 were diminished in mice deficient in the chemoattractant monocyte chemotactic protein-1 (MCP-1), 11 indicating a critical role for MCP-1 in mediating the LTB 4 atherogenic signals.MCP-1 is a prototype of the C-C chemokine ␤ subfamily and exhibits the most potent chemotactic activity for monocytes. 12 Overexpression of MCP-1 contributes to the development of atherosclerosis in mouse models. 13 Deficiency of either MCP-1 or its cognate high-affinity receptor C-C chemokine receptor 2 (CCR2) results in a marked decrease in atheromas and fewer monocytes in vascular lesions. 14,15 Additionally, therapeutic gene transfer of a dominantnegative MCP-1 mutant attenuated the development of early atherosclerosis and also limited progression of preexisting atherosclerotic lesions in ApoE-null mice. 16 Despite the critical role played by LTB 4 in atherogenesis, the molecular mechanisms for these activities are poorly understood. In this study, we investigated specifically whether LTB 4 regulates MCP-1 production in primary human monocytes to broaden the mechanistic understanding for LTB 4 -induced atherosclerosis. Our study shows that LTB 4 induced MCP-1 protein by several hundred-fold in primary human monocytes. LTB 4 induced MCP-1 mRNA by 500-fold Original

We describe a new program called cryptic splice finder (CSF) that can reliably identify cryptic splice sites (css), so providing a useful tool to help investigate splicing mutations in genetic disease. We report that many css are not entirely dormant and are often already active at low levels in normal genes prior to their enhancement in genetic disease. We also report a fascinating correlation between the positions of css and introns, whereby css within the exons of one species frequently match the exact position of introns in equivalent genes from another species. These results strongly indicate that many introns were inserted into css during evolution and they also imply that the splicing information that lies outside some introns can be independently recognized by the splicing machinery and was in place prior to intron insertion. This indicates that non-intronic splicing information had a key role in shaping the split structure of eukaryote genes.

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Ausgehend von dem Ascorbinsäurederivat (I) wird das Epoxid (VII) dargestellt, dessen Kondensation mit dem Phosphoniumbromid (IX) den Epoxyester (X) liefert.

Altogether, these data indicate a modest but definite improvement in the therapeutic index for indolyl-ASC compared with tacrolimus in rodent models.