Metabolomic profiling of rapid cold hardening and cold shock in Drosophila melanogaster

A short exposure to a mild cold stress is sufficient to increase cold tolerance in many insects. This phenomenon, termed rapid cold hardening (RCH) expands the thermal interval that can be exploited by the insect. To investigate the possible role of altered metabolite levels during RCH, the present study used untargeted (1)H NMR metabolomic profiling to examine the metabolomic response in Drosophila melanogaster during the 72 h following RCH and cold shock treatment. These findings are discussed in relation to the costs and benefits of RCH that are measured in terms of survival and reproductive output. Cold shock caused a persistent disturbance of the metabolite profile that correlated well with a delayed onset of cold shock mortality. The disruption of metabolite homeostasis was smaller following RCH, where control levels were fully recovered after 72 h. RCH improved both survival and reproductive output after a subsequent cold shock but the RCH treatment alone was associated with costs in terms of reduced survival and reproductive output. The most pronounced changes following the RCH treatment were elevated levels of glucose and trehalose. Although, it is difficult to discern if a change in a specific metabolite is linked to physiological processes of adaptive, neutral or detrimental nature we observed that the onset and magnitude of the increased sugar levels correlated tightly with the improved chill tolerance following RCH. These findings suggest a putative role of cryoprotectants during RCH which are discussed in the light of the existing literature on the mechanistic background of RCH.     

Manual pressure distension of the human saphenous vein changes its biomechanical properties-implication for coronary artery bypass grafting

Patency rates of saphenous vein grafts following coronary artery bypass grafting (CABG) depend on multiple factors. Information regarding the impact of biomechanical properties of vein grafts on patency rates is not available. The objective of the present study was to evaluate whether uncontrolled manual pressure distension during routine preparation of the saphenous vein in CABG-induced changes in the biomechanical properties of the vein. The morphometric and stress-strain properties were studied in isolated segments of the saphenous vein from 12 patients undergoing elective CABG. Six segments were manually distended without pressure control and six were not distended. The mechanical test was performed as a ramp inflation using syringe pump. The vein dimensions were obtained from digitised images at different pressures as well as at the no-load and zero-stress states. The circumferences, the wall and lumen area, the wall thickness, and the outer diameter as function of the applied pressure were largest in the segments with uncontrolled manual distension compared to those without distension (P<0.05). The opening angle and the absolute value of the residual strains were lower (P<0.01) and the circumferential stress-strain curve shifted to the left, indicating the wall became stiffer with uncontrolled manual distension compared to those without distension (P<0.05). In conclusion, manual pressure distension changed the morphometric and biomechanical properties of the saphenous vein. The perspective is that studies on biomechanical properties on the saphenous vein may guide surgeons how to handle graft material without causing major changes of the biomechanical properties during harvesting and preparation.     

Small molecule ago-allosteric modulators of the human glucagon-like peptide-1 (hGLP-1) receptor

Following our previous publication describing the biological profiles, we herein describe the structure-activity relationships of a core set of quinoxalines as the hGLP-1 receptor agonists. The most potent and efficacious compounds are 6,7-dichloroquinoxalines bearing an alkyl sulfonyl group at the C-2 position and a secondary alkyl amino group at the C-3 position. These findings serve as a valuable starting point for the discovery of more drug-like small molecule agonists for the hGLP-1 receptor.     

Endothelium-dependent vascular responses induced by leukotriene B4

Leukotriene B(4) (LTB(4)) is an inflammatory mediator derived from the 5-lipoxygenase pathway of arachidonic acid metabolism and has recently implicated in the pathogenesis of atherosclerosis. There are two membrane bound receptors for LTB(4): BLT(1) and BLT(2), which represent the high and low affinity receptors, respectively. BLT receptors are expressed on leukocytes, and LTB(4) is a potent chemoattractant for neutrophils, eosinophils, and T lymphocytes. Recent studies have in addition shown that LTB(4) is an indirectly acting vasoconstrictor of isolated vascular preparations. In the guinea pig aorta, the LTB(4)-induced contractions were inhibited by endothelium-denudation. In addition, pre-treatment with the NO synthase inhibitor, L-NOARG, significantly enhanced the contractions induced by LTB(4). The contractile response induced by LTB(4) in the guinea pig aorta was abolished by the selective BLT(1) receptor antagonist U75302 and the expression of BLT(1) receptor mRNA in the guinea pig aorta was established by RT-PCR. Taken together, these results suggest that LTB(4) activates BLT(1) receptors on the endothelium of the guinea pig aorta, associated with the release of both contractile factors and NO.     

Helicobacter pylori infection and gastroesophageal reflux in a population-based study (The HUNT Study)

BACKGROUND AND AIM: It has been suggested that Helicobacter pylori infection may prevent gastroesophageal reflux, possibly through gastric atrophy. Since, however, previous results are contradictory and no population-based studies are available, the relationship between H. pylori and reflux remains uncertain. The aim of this study was to investigate this relationship in a population-based, nested, case-control study. METHODS: From a cohort of 65,363 individuals, representing 71.2% of the adult population in the Norwegian county of Nord-Trondelag, we randomly selected 472 persons with recurrent reflux symptoms (cases) and 472 without such symptoms (controls). Occurrence of H. pylori and its virulence factor cagA was determined serologically, using an immunoblot assay. Gastric atrophy was assessed through serum levels of pepsinogen I. Odds ratios (OR) with 95% confidence intervals (CI), adjusted for potential confounding factors, represented relative risks. RESULTS: H. pylori infection was not associated with a decreased risk of reflux symptoms (OR 1.1, 95% CI 0.8-1.6), irrespective of positive cagA status (OR 1.1, 95% CI 0.8-1.5). Gastric atrophy reduced the risk of reflux symptoms (OR 0.2, 95% CI 0.0-0.6). Infection with H. pylori entailed a ninefold increase in the risk of gastric atrophy compared to non-infection (OR 8.9, 95% CI 2.0-39.9). CONCLUSIONS: H. pylori infection, irrespective of cagA status, did not affect the occurrence of reflux symptoms in this population-based setting. Infected individuals are at increased risk of gastric atrophy, which in turn reduces reflux symptoms, but due to the low frequency of gastric atrophy among infected individuals overall, there was no association with reflux symptoms on a population level.     

Quantitative proteomic assessment of very early cellular signaling events

Technical limitations have prevented proteomic analyses of events occurring less than 30 s after signal initiation. We developed an automated, continuous quench-flow system allowing quantitative proteomic assessment of very early cellular signaling events (qPACE) with a time resolution of 1 s. Using this technique, we determined that autophosphorylation of the epidermal growth factor receptor occurs within 1 s after ligand stimulation and is followed rapidly by phosphorylation of the downstream signaling intermediates Src homologous and collagen-like protein and phospholipase C gamma 1.