Endothelial antagonists syntheses

Gunasekera S, Foley FM, Clark RJ, Sando L, Fabri LJ, Craik D J, Daly NL (2008) Engineering stabilized vascular endothelial growth factor-A antagonists synthesis, structural characterization, and bioactivity of grafted analogues of cyclotides. J Med Chem 51 7697-7704... 

Cox-1 is constitutively expressed and responsible for most of the housekeeping functions of eicosanoids, including processes such as calcium metabolism in the bone, and stomach mucous membrane maintenance. It is also responsible for synthesis of thromboxanes in thrombocytes and of prostacyclin (PGI) in endothelial cells, which have antagonistic function in thrombocyte aggregation and activation (see later). 

It was observed that rats with a transient MCA occlusion have a larger brain infarction when recombinant human IL-1 P is injected into the lateral ventricle immediately after reperfusion [7,41]. Similar results have been obtained in rats with a permanent MCA occlusion [7,42]. The intraventricular injection of recombinant human IL-1 p also enhances the formation of brain edema and increases both the number of neutrophils in ischemic areas and neutrophil-endothelial cell adhesion. The most widely recognized functions of IL-1 appear to be the induction of endothelial cell adhesion molecule expression and the promotion of neutrophil tissue infiltration [7,41]. These observations suggest that IL-1 may play a deleterious role in cerebral ischemia. Studies showing a reduction in infarct size after the administration of IL-1 antagonists or inhibitors provide further evidence of the importance of IL-1 in cerebral ischemia [41,43-49]. The possible harmful mechanisms induced or activated by IL-1 include fever, increased heart rate and arterial blood pressure, enhancement of N-methyl-D-aspartate-mediated injury, proliferation of microglia, release of arachidonic acid, and stimulation of NO synthesis [7,50]. 

The evidence incriminating TNF in the pathogenesis of septic shock is now considerable. However, other cytokines may be involved, perhaps in amplifying TNF production or responses. TNF induces IL-1 synthesis in macrophages and endothelial cells and IL-1 administration enhances the lethal effects of recombinant TNF (W2). More recently it has been shown that the administration of recombinant human IL-1 receptor antagonist IL-lra improves survival in lethal endotoxemia in mice (A12). Indeed the administration of endotoxin alone induces inhibitors of both TNF and IL-1 in human plasma (S48). These findings yet again underline the complexity of the network of cytokines and their inhibition. 

ULRICH-MERZENICH, G METZNER, C SCHIERMEYER, B. VETTER, H. 2002. Vitamin C and vitamin E antagonistically modulate human vascular endothelial and smooth muscle cellDNA synthesis and proliferation. EurJ Nutr, 41, 27-34. 

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