Serum proprotein convertase subtilisin/Kexin type 9 and vascular disease in type 2 diabetic patients

BackgroundProprotein Convertase Subtilisin/Kexin type 9 (PCSK9) levels have been suggested as novel atherosclerotic biomarker. PCSK9 plays important roles in the pathogenesis of atherosclerosis by regulating the degradation of low-density lipoprotein receptor as well as different inflammatory pathways. Considering the important prognostic role of arterial stiffness in cardiovascular disease (CVD), the aim of the study is to investigate the correlation between PCSK9 levels and arterial stiffness in a cohort of diabetic patients, without previous CV events. MethodsThis cross-sectional analysis enrolled 401 Caucasian patients with type II diabetes mellitus (T2DM). PCSK9 levels were measured by ELISA test, arterial stiffness was estimated by measuring carotid-femoral pulse wave velocity (PWV). ResultsPatients were divided in three tertiles according to increasing value of PCSK9. From the I to the III tertiles, there was a significant increase in high sensitivity C-reactive protein (hs-CRP), fibrinogen and white blood cells (WBC) and a reduction in estimated glomerular filtration rate (e-GFR). Patients with higher levels of PCSK9 presented increased systolic, diastolic blood pressure, pulse pressure and PWV. PWV was significantly and directly correlated with PCSK9, fibrinogen, age, BMI and PP, and indirectly correlated with diet, lifestyle and e-GFR. Serum PCSK9 was the major predictor of PWV, justifying a 16.9% of its variation. ConclusionOur study demonstrates a close association between circulating PCSK9 levels and PWV in T2DM subjects without previous CV events even after adjusting for well-known CV risk factor and pharmacological medications. Serum PCSK9 could be a useful biomarker for CV risk stratification in diabetic subjects

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

A review of the emerging profile of the anti-inflammatory drug oxaprozin.

Oxaprozin is a nonsteroidal anti-inflammatory drug characterised by a propionic acid-based structure. It is able to diffuse easily into inflamed synovial tissues after oral administration. Although discovered > 20 years ago, it is now under intensive investigation because of its unusual pharmacodynamic properties. Other than being a nonselective cyclooxygenase inhibitor, the drug is capable of inhibiting both anandamide hydrolase in neurons (median inhibitory concentration [IC50] = 85 micromol/l), with consequent potent analgesic activity, and NF-kappaB activation in inflammatory cells (IC50 = 50 micromol/l). Moreover, oxaprozin induces apoptosis of activated monocytes in a dose-dependent manner, with the effect being detectable at a concentration of 5 micromol/l and reaching the maximum activity at 50 micromol/l. As monocyte-macrophages and NF-kappaB pathways are crucial for synthesis of proinflammatory and histotoxic mediators in inflamed joints, oxaprozin appears to be endowed with pharmacodynamic properties exceeding those presently assumed as markers of classical nonsteroidal anti-inflammatory drug

Immune complexes induce monocyte survival through defined intracellular pathways

Monocytes recruitment and survival at sites of inflammation are determinant for the persistence of inflammatory reactions. Immune-complexes (ICs), whose tissue deposition is involved in a variety of autoimmune diseases, activate monocytes through the interaction with Fcgamma-receptor triggering the secretion of several inflammatory modulators and favoring their tissue accumulation by inhibiting the apoptosis. To elucidate the intracellular pathways governing this process, on the basis of our previous findings regarding the dose-dependent inhibition of apoptosis in IC-activated monocytes, we have investigated the role of PI3K/Akt pathway, MAP kinases, nuclear factor-kappaB (NF-kappaB), and caspase 3, 8, and 9. Here we show that IC-activated monocytes underwent apoptosis at a rate comparable to that of resting monocytes in the presence of LY294002, a selective inhibitor of PI3K, as well in the presence of Akt inhibitor, PD98059 inhibitor of ERK1/2, and SB203580 inhibitor of p38. Moreover, IC-triggered phosphorylation of Akt, ERK1/2, and p38 MAP kinase was demonstrated on Western blot analysis. SN50, an inhibitor of NF-kappaB translocation and BMS345541, a specific inhibitor of IKK, also abolished the apoptosis protection conferred by ICs. In parallel, ICs induced an increase in NF-kappaB activation, as shown by EMSA, together with the expression of XIAP, as shown by Western blot, though indicating that in monocytes IC protection from apoptosis is NF-kappaB dependent. Finally, the activity of caspase 3, 8, and 9 resulted inhibited in IC-activated monocytes. These results disclose a signaling route triggered by ICs which can be involved in the pathophysiology of inflammatory diseases and can represent a target for therapy of IC-mediated diseases

Dexamethasone-induced apoptosis of human monocytes exposed to immune complexes. Intervention of CD95-and XIAP-dependent pathways.

Monocytes and macrophages play a key role in the initiation and persistence of inflammatory reactions. The possibility to interfere with the survival of these cells, once recruited and activated at sites of inflammation, is an attractive therapeutic option. Although resting monocytes are susceptible to pharmacologically induced apoptosis, no data are available about the possibility to modulate the survival of activated monocytes. The present work was planned to investigate if dexamethasone is able to promote apoptosis of human monocytes activated by immune complexes. When monocytes were cultured with immune complexes, a dose-dependent inhibition of apoptosis was observed. Dexamethasone stimulated apoptosis of resting and activated monocytes in a dose-dependent manner. Both the immune complex inhibitory activity and dexamethasone stimulatory properties depend on NF-kappaB/XIAP and Ras/MEK/ERK/CD95 pathways. In fact, the exposure of monocytes to immune complexes increased NF-kB activation and XIAP expression, which in turn were inhibited by dexamethasone. On the other hand, immune complex-stimulated monocytes displayed a reduced expression of CD95, which is prevented by dexamethasone, as well as by MEK inhibitor U0126. Furthermore, anti-CD95 ZB4 mAb prevented dexamethasone-induced apoptosis in immune complex stimulated monocytes. Similarly, ZB4 inhibited dexamethasone-mediated augmentation of caspase 3 activity. The present findings suggest that Fc triggering by insoluble immune complexes result in the activation of two intracellular pathways crucial for the survival of monocytes: 1. Ras/MEK/ERK pathway responsible for the down-regulation of CD95 expression; 2. NF-kappaB pathway governing the expression of XIAP. Both the pathways are susceptible to inhibition by monocyte treatment with pharmacologic concentrations of dexamethasone