Leukotriene B 4 (LTB 4 ) has been implicated in ischemic stroke pathology. We examined the prognostic significance of LTB 4 levels in patients with acute middle cerebral artery (MCA) infarction and their mechanisms in rat stroke models. In ischemic stroke patients with middle cerebral artery infarction, plasma LTB 4 levels were found to increase rapidly, roughly doubling within 24 h when compared to initial post-stroke levels. Further analyses indicate that poor functional recovery is associated with early and more sustained increase in LTB 4 rather than the peak levels. Results from studies using a rat embolic stroke model showed increased 5-lipoxygenase (5-LOX) expression in the ipsilateral infarcted cortex compared with sham control or respective contralateral regions at 24 h post-stroke with a concomitant increase in LTB 4 levels. In addition, neutrophil influx was also observed in the infarcted cortex. Double immunostaining indicated that neutrophils express 5-LOX and leukotriene A 4 hydrolase (LTA 4 H), highlighting the pivotal contributions of neutrophils as a source of LTB 4 . Importantly, rise in plasma LTB 4 levels corresponded with an increase in LTB 4 amount in the infarcted cortex, thereby supporting the use of plasma as a surrogate for brain LTB 4 levels. Pre-stroke LTB 4 loading increased brain infarct volume in tMCAO rats. Conversely, administration of the 5-LOX-activating protein (FLAP) inhibitor BAY-X1005 or B-leukotriene receptor (BLTR) antagonist LY255283 decreased the infarct volume by a similar extent. To conclude, targeted interruption of the LTB 4 pathway might be a viable treatment strategy for acute ischemic stroke.
Three insulin-like compounds consisting of two disulfide-linked polypeptide chains have been synthesized. The A-chains of these compounds correspond either to the A- or to the A + D-domain of the putative amphioxus insulin-like peptide (amphioxus ILP), and their B-chains correspond either to the B-chain of insulin or to a slightly modified (i.e., [1-Thr]) B-domain of amphioxus ILP. The biological potency of these compounds was evaluated in mammalian cells or cell fractions containing either human or rat insulin receptors or human or mouse insulin-like growth factor I (IGF-I) receptors, with respect to binding affinity, insulin-like metabolic activity (lipogenesis), and growth factor activity (mitogenesis). Amphioxus ILP A/bovine insulin B and amphioxus ILP A + D/bovine insulin B exhibited potencies ranging from 2.0 to 9.8% relative to natural insulin, and both compounds were full agonists in lipogenesis assays, stimulating lipogenesis to the same maximal extent as seen with natural insulin. Amphioxus ILP A/amphioxus ILP [1-Thr]B stimulated lipogenesis with a potency of 0.01% relative to natural insulin. We consider this compound also likely to be a full agonist. In assays measuring binding to IGF-I receptors and stimulation of mitogenesis, these compounds displayed some activity although the activity was too low for exact quantification. These results suggest that amphioxus ILP has retained an overall structural similarity to mammalian insulin and IGF-I but has also accumulated substantial mutations which markedly reduce its ability to bind and activate their cognate receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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