Dietary macronutrients and the aging liver sinusoidal endothelial cell.

Fenestrations are pores within the liver sinusoidal endothelial cells (LSECs) that line the sinusoids of the highly vascularized liver. Fenestrations facilitate the transfer of substrates between blood and hepatocytes. With pseudocapillarization of the hepatic sinusoid in old age, there is a loss of fenestrations. LSECs are uniquely exposed to gut-derived dietary and microbial substrates delivered by the portal circulation to the liver. Here we studied the effect of 25 diets varying in content of macronutrients and energy on LSEC fenestrations using the Geometric Framework method in a large cohort of mice aged 15 mo. Macronutrient distribution rather than total food or energy intake was associated with changes in fenestrations. Porosity and frequency were inversely associated with dietary fat intake, while fenestration diameter was inversely associated with protein or carbohydrate intake. Fenestrations were also linked to diet-induced changes in gut microbiome, with increased fenestrations associated with higher abundance of Firmicutes and reduced abundance of Bacteroidetes Diet-induced changes in levels of several fatty acids (C16:0, C19:0, and C20:4) were also significantly inversely associated with fenestrations, suggesting a link between dietary fat and modulation of lipid rafts in the LSECs. Diet influences fenestrations and these data reflect both the key role of the LSECs in clearing gut-derived molecules from the vascular circulation and the impact these molecules have on LSEC morphology.

ICAM-1 in acute myocardial infarction: a potential therapeutic target.

Current treatments for AMI centre on prompt restoration of epicardial coronary blood flow. Despite improvements, AMI is still associated with significant morbidity and mortality. Novel approaches are therefore keenly sought. Intercellular adhesion molecule-1 (ICAM-1, CD54) is a member of the immunoglobulin superfamily. It is implicated in neutrophil and monocyte-endothelial cell adhesion, processes contributing to myocardial neutrophil infiltration and microvascular coronary slow flow, both viewed as important to the pathophysiologic responses in AMI. ICAM-1 would therefore appear an important potential therapeutic target in this context, and is the subject of this review.

Is there potential for antioxidants to enhance thrombolysis therapy in patients with ischemic stroke?

The medical and socio-economic burden of ischemic stroke is vast. Current thrombolytic therapies have a time-limited therapeutic window and do not provide significant benefits beyond tissue reperfusion. The detrimental effect of oxidative stress caused by excessive oxidant production due to cerebral reperfusion injury is a neglected consequence of ischemic stroke and warrants special consideration. Strategies directed at preventing or reducing oxidative damage in the brain post-ischemic stroke have the potential to improve neurological outcome and reduce morbidity and mortality from this common disease. Significantly, the prospect of increasing the size of the treatment window for thrombolytic therapies, perhaps by synergistic effects with other medications given in parallel, is also an avenue worthy of further investigation. This perspective outlines the current status of thrombolytic therapy for the treatment of ischemic stroke and explores the possibility of improving and expanding this potential therapy. Furthermore, the implications of directly treating damage caused by oxidative stress with novel antioxidant therapy are discussed.