Leukocyte migration to sites of inflammation is regulated by several endothelial adhesion molecules. Vascular adhesion protein-1 (VAP-1) is unique among the homing-associated molecules as it is both an enzyme that oxidizes primary amines and an adhesin. Although granulocytes can bind to endothelium via a VAP-1-dependent manner, the counter-receptor(s) on this leukocyte population is(are) not known. Here we used a phage display approach and identified Siglec-9 as a candidate ligand on granulocytes. The binding between Siglec-9 and VAP-1 was confirmed by in vitro and ex vivo adhesion assays. The interaction sites between VAP-1 and Siglec-9 were identified by molecular modeling and confirmed by further binding assays with mutated proteins. Although the binding takes place in the enzymatic groove of VAP-1, it is only partially dependent on the enzymatic activity of VAP-1. In positron emission tomography, the 68 Gallium-labeled peptide of Siglec-9 specifically detected VAP-1 in vasculature at sites of inflammation and cancer. Thus, the peptide binding to the enzymatic groove of VAP-1 can be used for imaging conditions, such as inflammation and cancer. (Blood. 2011;118(13):3725-3733) IntroductionLeukocyte migration from the blood into the nonlymphoid tissues is a hallmark of inflammation. Several molecules on the endothelial cell surface and their counter-receptors on leukocytes mediate a multistep adhesion cascade featuring tethering, rolling, activation, adhesion, crawling, and transmigration phases. 1,2 Vascular adhesion protein-1 (VAP-1/AOC3) is an endothelial cell molecule that is rapidly translocated from the intracellular storage granules to the endothelial cell surface on inflammation. It contributes to several steps in the extravasation cascade and controls trafficking of lymphocytes, granulocytes, and monocytes to sites of inflammation. VAP-1 has unique features distinct from other conventional adhesion molecules because, besides being an adhesin, it is also an enzyme. It catalyzes oxidative deamination of primary amines and produces hydrogen peroxide, aldehyde, and ammonium. 3 The end products of the enzymatic activity are highly potent inflammatory mediators and can up-regulate other adhesion molecules, such as E-and P-selectin, ICAM-1, and VCAM-1. 4,5 We recently found the first lymphocyte ligand for VAP-1, Siglec-10. 6 It is expressed on B cells, monocytes, and eosinophils but is absent from granulocytes. 7 However, VAP-1 is also involved in granulocyte migration to sites of inflammation. This has been demonstrated in studies with acute inflammation models (peritonitis, lung, and air pouch inflammation) in mouse. In these studies, significant reduction in granulocyte migration to sites of inflammation was obtained with a function blocking anti-VAP-1 antibody and a small molecular inhibitor against VAP-1. [8][9][10] Contribution of VAP-1 both at the rolling and transmigration steps during leukocyte extravasation has been demonstrated, and the enzymatic activity of VAP-1 seems to be important in these proc...

Central opioidergic mechanisms may modulate the positive effects of physical exercise such as mood elevation and stress reduction. How exercise intensity and concomitant effective changes affect central opioidergic responses is unknown. We studied the effects of acute physical exercise on the cerebral μ-opioid receptors (MOR) of 22 healthy recreationally active males using positron emission tomography (PET) and the MOR-selective radioligand [C]carfentanil. MOR binding was measured in three conditions on separate days: after a 60-min aerobic moderate-intensity exercise session, after a high-intensity interval training (HIIT) session, and after rest. Mood was measured repeatedly throughout the experiment. HIIT significantly decreased MOR binding selectively in the frontolimbic regions involved in pain, reward, and emotional processing (thalamus, insula, orbitofrontal cortex, hippocampus, and anterior cingulate cortex). Decreased binding correlated with increased negative emotionality. Moderate-intensity exercise did not change MOR binding, although increased euphoria correlated with decreased receptor binding. These observations, consistent with endogenous opioid release, highlight the role of the μ-opioid system in mediating affective responses to high-intensity training as opposed to recreational moderate physical exercise.

Short-term HIT and MIT are equally effective in improving aerobic fitness, but HIT increases experience of negative emotions and exertion in sedentary middle-age men. This may limit the adherence to this time-effective training mode, even though displeasure lessens over time and suggests similar mental adaptations to both MIT and HIT.