. (2016) Protective actions of des-acylated ghrelin on brain injury and blood-brain barrier disruption after stroke in mice. Clinical Science, 130(17), pp. 1545-1558. (doi:10.1042 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/135040/ AbstractThe major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, emerging evidence indicates that these peptides may have other functions including neuro-and vaso-protection. Here, we investigated whether post-stroke treatment with acylated ghrelin or des-acylated ghrelin could improve functional and histological endpoints of stroke outcome in mice after transient middle cerebral artery occlusion. We found that des-acylated ghrelin (1 mg/kg) improved neurological and functional performance, reduced infarct and swelling, and decreased apoptosis. In addition, it reduced BBB disruption in vivo and attenuated the hyper-permeability of mouse cerebral microvascular endothelial cells after oxygen glucose deprivation and reoxygenation (OGD + RO). By contrast, acylated ghrelin (1 mg/kg or 5 mg/kg) had no significant effect on these endpoints of stroke outcome. Next we found that des-acylated ghrelin's vasoprotective actions were associated with increased expression of tight junction proteins (occludin and claudin-5), and decreased cell death. Moreover, it attenuated superoxide production, Nox activity, and expression of 3-nitrotyrosine. Collectively, these results demonstrate that poststroke treatment with des-acylated ghrelin, but not acylated ghrelin, protects against ischemia/reperfusion-induced brain injury and swelling, and BBB disruption by reducing oxidative and/or nitrosative damage. Summary statementStroke is a leading cause of death, but treatments are limited. This experimental study reveals that the hormone ghrelin powerfully protects the brain and its blood vessels against injury after stroke, raising the possibility that it could be exploited therapeutically. Short titleDes-acylated ghrelin protects against stroke. KeywordsIschemia, reperfusion, ghrelin, neuroprotection, blood-brain barrier. Abbreviations listBlood-brain barrier (BBB); ghrelin O-acyltransferase (GOAT); growth hormone secretagogue receptor 1a (GHSR1a); oxygen glucose deprivation and reoxygenation (OGD + Clinical perspectives• Ischemic stroke is a leading cause of mortality and long-term disability, but treatment options are limited. The major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, recent evidence indicates these peptides may have neuroprotective and vasoprotective actions, and thus may protective actions in ischemic stroke.• In this study we tested whether the peptides could mediate protection in a clinically relevant mouse model of ischemic stroke.• Our findings reveal protective actions of des-acylated ghrelin whe...

Background and Purpose The NO redox sibling nitroxyl (HNO) elicits soluble guanylyl cyclase (sGC)‐dependent vasodilatation. HNO has high reactivity with thiols, which is attributed with HNO‐enhanced left ventricular (LV) function. Here, we tested the hypothesis that the concomitant vasodilatation and inotropic actions induced by a HNO donor, Angeli's salt (sodium trioxodinitrate), were sGC‐dependent and sGC‐independent respectively. Experimental Approach Haemodynamic responses to Angeli's salt (10 pmol–10 μmol), alone and in the presence of scavengers of HNO (L‐cysteine, 4 mM) or of NO [hydroxocobalamin (HXC), 100 μM] or a selective inhibitor of sGC [1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ), 10 μM], a CGRP receptor antagonist (CGRP8–37, 0.1 μM) or a blocker of voltage‐dependent potassium channels [4‐aminopyridine (4‐AP), 1 mM] were determined in isolated hearts from male rats. Key Results Angeli's salt elicited concomitant, dose‐dependent increases in coronary flow and LV systolic and diastolic function. Both L‐cysteine and ODQ shifted (but did not abolish) the dose–response curve of each of these effects to the right, implying contributions from HNO and sGC in both the vasodilator and inotropic actions. In contrast, neither HXC, CGRP8–37 nor 4‐AP affected these actions. Conclusions and Implications Both vasodilator and inotropic actions of the HNO donor Angeli's salt were mediated in part by sGC‐dependent mechanisms, representing the first evidence that sGC contributes to the inotropic and lusitropic action of HNO in the intact heart. Thus, HNO acutely enhances LV contraction and relaxation, while concomitantly unloading the heart, potentially beneficial actions in failing hearts.

The processes involved in reperfusion injury might provide targets for improved outcomes after myocardial infarction but thus far that aim has not been met in the clinic.

Studies have utilised immortalised mouse cerebral endothelial cells (bEnd.3) exposed to oxygen glucose deprivation (OGD) to study blood-brain barrier (BBB) disruption after ischaemia. However, there is a paucity of literature describing the duration of OGD (and reoxygenation [RO]) required to best simulate BBB disruption in vivo. In this study we assessed BBB disruption in bEnd.3 cells after exposure to a range of OGD periods, and also after OGD + RO. Exposure of bEnd.3 monolayers to 4, 6, 16, or 24 hours of OGD resulted in a significant increase in permeability. The hyperpermeability after 16 or 24 hours was associated with decreased expression of tight junction proteins (occludin and claudin-5). Furthermore, there was a decrease in cell viability and increased expression of the pro-apoptotic protein, cleaved caspase-3. Exposure of bEnd.3 monolayers to 1 hour OGD+ 23 hours RO exacerbated hyperpermeability relative to 1 hour OGD, which was associated with decreased expression levels of occludin and ZO-1, but no change in cell viability or caspase-3. 4 hours OGD + 23 hours RO exacerbated hyperpermeability, decreased expression levels of tight junction proteins, decreased cell viability, and increased caspase-3 expression. Thus, bEnd.3 cells exhibit hyperpermeability, a loss of tight junction proteins, and undergo cell death, after exposure to prolonged periods of OGD. Moreover, they exhibit exacerbated hyperpermeability, a loss of tight junction proteins, and increased expression of caspase-3 after OGD + RO. These findings will facilitate the use of this cell line in studies of BBB disruption and for the testing of therapeutics.

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In acute myocardial infarction (AMI) the first line of treatment is to rapidly restore blood flow to the ischemic myocardium to limit infarct size. It is now well established that though clearly beneficial the positive outcomes of this intervention are limited by injury in response to the reperfusion itself in addition to the prior ischemia. This process is described as reperfusion injury and is considered to contribute to the arrhythmias, microvascular dysfunction and impaired cardiac contractility that is observed even after the restoration of coronary blood flow. Thus an important, currently unmet, therapeutic challenge is to address the outcomes of this reperfusion injury. In this article we review the evidence that flavonols and flavones may prove useful in preserving cardiac function after ischemia and reperfusion and consider the possible mechanisms, in particular the inhibition of kinases, by which they may exert protection.

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McDonald's is one of the most successful fast food companies around the world. It has approximately 32,000 outlets located in 119 countries. Being a global and modern fast food company, McDonald's has a clear vision, "to be the world's best quick service restaurant experience". This paper presents the contributing factors which drive McDonald's success being a global and modern fast food company. McDonald's top management believes that job satisfaction and motivation are the contributing factors to the success of McDonald's. McDonald's has won many awards over the years for its employees' engagement programs.