Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study

Animal studies implicate the AP-1 (activator protein-1) pro-inflammatory pathway as a promising target in the treatment of atherosclerotic disease. It is, however, unclear whether these observations apply to human atherosclerosis. Therefore we evaluated the profile of AP-1 activation through histological analysis and tested the potential benefit of AP-1 inhibition in a clinical trial. AP-1 activation was quantified by phospho-c-Jun nuclear translocation (immunohistochemistry) on a biobank of aortic wall samples from organ donors. The effect of AP-1 inhibition on vascular parameters was tested through a double blind placebo-controlled cross-over study of 28 days doxycycline or placebo in patients with symptomatic peripheral artery disease. Vascular function was assessed by brachial dilation as well as by plasma samples analysed for hs-CRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6), IL-8, ICAM-1 (intercellular adhesion molecule-1), vWF (von Willebrand factor), MCP-1 (monocyte chemoattractant protein-1), PAI-1 (plasminogen activator inhibitor-1) and fibrinogen. Histological evaluation of human atherosclerosis showed minimal AP-1 activation in non-diseased arterial wall (i.e. vessel wall without any signs of atherosclerotic disease). A gradual increase of AP-1 activation was found in non-progressive and progressive phases of atherosclerosis respectively (P<0.044). No significant difference was found between progressive and vulnerable lesions. The expression of phospho-c-Jun diminished as the lesion stabilized (P<0.016) and does not significantly differ from the normal aortic wall (P<0.33). Evaluation of the doxycycline intervention only revealed a borderline-significant reduction of circulating hs-CRP levels (−0.51 μg/ml, P=0.05) and did not affect any of the other markers of systemic inflammation and vascular function. Our studies do not characterize AP-1 as a therapeutic target for progressive human atherosclerotic disease

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Effect of dietary restraint during and following pegylated recombinant leptin (PEG-OB) treatment of overweight men

Effect of dietary restraint during and following pegylated recombinant leptin (PEG-OB) treatment of overweight men. Lejeune MP, Hukshorn CJ, Saris WH, Westerterp-Plantenga MS. Department of Human Biology, Maastricht University, Maastricht, The Netherlands. [email protected] OBJECTIVE: To examine the effect of dietary restraint during and following pegylated recombinant leptin (PEG-OB protein) treatment in overweight men. DESIGN: A randomized double-blind placebo-controlled trial in 24 overweight men (BMI: 28.8+/-0.3 kg/m(2); age: 34.8+/-0.9 y). PEG-OB protein (80 mg) or placebo was administered subcutaneously weekly for 6 weeks, combined with a 2.1 MJ/day energy restriction program. Dietary restraint was determined by the Three-Factor Eating Questionnaire before and after treatment, and after 8 weeks follow-up. RESULTS: During treatment dietary restraint increased, and general hunger, resting energy expenditure and respiratory quotient decreased similarly in the PEG-OB and the placebo group. With PEG-OB treatment, additional weight loss (P<0.03) was observed. During 8 weeks follow-up, body weight increase was larger in the PEG-OB group compared to placebo (P<0.05), and body weight regain was faster. Body weight regain was inversely correlated with the increase in cognitive dietary restraint during treatment (PEG-OB group: r(2)=0.49, P<0.02; placebo group: r(2)=0.60, P=0.01). CONCLUSION: Although treatment with PEG-OB protein led to a greater body weight loss relative to placebo, weight maintenance thereafter was mainly supported by dietary restraint, which was more effective in the placebo-treated group, resulting in a slower regain of body weight

In-depth assessment of health-related quality of life after in-hospital cardiac arrest

Introduction: Evidence on physical and psychological well-being of in-hospital cardiac arrest (IHCA) survivors is scarce. The aim of this study is to describe long-term health-related quality of life (HRQoL), functional independence and psychological distress 3 and 12 months post-IHCA. Methods: A multicenter prospective cohort study in 25 hospitals between January 2017 – May 2018. Adult IHCA survivors were included. HRQoL (EQ-5D-5L, SF-12), psychological distress (HADS, CSI) and functional independence (mRS) were assessed at 3 and 12 months post-IHCA. Results: At 3-month follow-up 136 of 212 survivors responded to the questionnaire and at 12 months 110 of 198 responded. The median (IQR) EQ-utility Index score was 0.77 (0.65–0.87) at 3 months and 0.81 (0.70–0.91) at 12 months. At 3 months, patients reported a median SF-12 (IQR) physical component scale (PCS) of 38.9 (32.8–46.5) and mental component scale (MCS) of 43.5 (34.0–39.7) and at 12 months a PCS of 43.1 (34.6–52.3) and MCS 46.9 (38.5–54.5). Discussion: Using various tools most IHCA survivors report an acceptable HRQoL and a substantial part experiences lower HRQoL compared to population norms. Our data suggest that younger (male) patients and those with poor functional status prior to admission are at highest risk of impaired HRQoL

Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans

To elucidate whether the role of leptin in regulating neuroendocrine and immune function during short-term starvation in healthy humans is permissive, i.e., occurs only when circulating leptin levels are below a critical threshold level, we studied seven normal-weight women during a normoleptinemic-fed state and two states of relative hypoleptinemia induced by 72-h fasting during which we administered either placebo or recombinant methionyl human leptin (r-metHuLeptin) in replacement doses. Fasting for 72 h decreased leptin levels by ≈80% from a midphysiologic (14.7 ± 2.6 ng/ml) to a low-physiologic (2.8 ± 0.3 ng/ml) level. Administration of r-metHuLeptin during fasting fully restored leptin to physiologic levels (28.8 ± 2.0 ng/ml) and reversed the fasting-associated decrease in overnight luteinizing hormone pulse frequency but had no effect on fasting-induced changes in thyroid-stimulating hormone pulsatility, thyroid and IGF-1 hormone levels, hypothalamic–pituitary–adrenal and renin–aldosterone activity. FSH and sex steroid levels were not altered. Short-term reduction of leptin levels decreased the number of circulating cells of the adaptive immune response, but r-metHuLeptin did not have major effects on their number or in vitro function. Thus, changes of leptin levels within the physiologic range have no major physiologic effects in leptin-replete humans. Studies involving more severe and/or chronic leptin deficiency are needed to precisely define the lower limit of normal leptin levels for each of leptin’s physiologic targets