Lysophosphatidylcholine and Carotid Intima-Media Thickness in Young Smokers: A Role for Oxidized LDL-Induced Expression of PBMC Lipoprotein-Associated Phospholipase A2?

Although cigarette smoking has been associated with carotid intima-media thickness (CIMT) the mechanisms are yet not completely known. Lysophosphatidylcholine (lysoPC), a main product of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, appears to be a major determinant of the pro-atherogenic properties of oxidized LDL (oxLDL) and to induce proteoglycan synthesis, a main player in intimal thickening. In this study we assessed whether cigarette smoking-induced oxidative stress may influence plasma Lp-PLA2 and lysoPC and Lp-PLA2 expression in peripheral blood mononuclear cells (PBMC), as well as the relationship between lysoPC and CIMT.45 healthy smokers and 45 age and sex-matched subjects participated in this study. Smokers, compared to non-smokers, showed increased plasma concentrations of oxLDL, Lp-PLA2 and lysoPC together with up-regulation of Lp-PLA2 (mRNA and protein) expression in PBMC (P<0.001). Plasma Lp-PLA2 positively correlated with both lysoPC (r=0.639, P<0.001) and PBMC mRNA Lp-PLA2 (r=0.484, P<0.001) in all subjects. Moreover CIMT that was higher in smokers (P<0.001), positively correlated with lysoPC (r=0.55, P<0.001). Then in in vitro study we demonstrated that both oxLDL (at concentrations similar to those found in smoker's serum) and oxidized phospholipids contained in oxLDL, were able to up-regulate mRNA Lp-PLA2 in PBMC. This effect was likely due, at least in part, to the enrichment in oxidized phospholipids found in PBMC after exposure to oxLDL. Our results also showed that in human aortic smooth muscle cells lysoPC, at concentrations similar to those found in smokers, increased the expression of biglycan and versican, two main proteoglycans.In smokers a further effect of raised oxidative stress is the up-regulation of Lp-PLA2 expression in PBMC with subsequent increase of plasma Lp-PLA2 and lysoPC. Moreover the correlation between lysoPC and CIMT together with the finding that lysoPC up-regulates proteoglycan synthesis suggests that lysoPC may be a link between smoking and intimal thickening

Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases

Various cellular perturbations implicated in the pathophysiology of human diseases, including cardiovascular and neurodegenerative diseases, diabetes mellitus, obesity, and liver diseases, can alter endoplasmic reticulum (ER) function and lead to the abnormal accumulation of misfolded proteins. This situation configures the so-called ER stress, a form of intracellular stress that occurs whenever the protein-folding capacity of the ER is overwhelmed. Reduction in blood flow as a result of atherosclerotic coronary artery disease causes tissue hypoxia, a condition that induces protein misfolding and ER stress. In addition, ER stress has an important role in cardiac hypertrophy mainly in the transition to heart failure (HF). ER transmembrane sensors detect the accumulation of unfolded proteins and activate transcriptional and translational pathways that deal with unfolded and misfolded proteins, known as the unfolded protein response (UPR). Once the UPR fails to control the level of unfolded and misfolded proteins in the ER, ER-initiated apoptotic signaling is induced. Furthermore, there is considerable evidence that implicates the presence of oxidative stress and subsequent related cellular damage as an initial cause of injury to the myocardium after ischemia/reperfusion (I/R) and in cardiac hypertrophy secondary to pressure overload. Oxidative stress is counterbalanced by complex antioxidant defense systems regulated by a series of multiple pathways, including the UPR, to ensure that the response to oxidants is adequate. Nuclear factor-E2-related factor (Nrf2) is an emerging regulator of cellular resistance to oxidants; Nrf2 is strictly interrelated with the UPR sensor called pancreatic endoplasmic reticulum kinase. A series of studies has shown that interventions against ER stress and Nrf2 activation reduce myocardial infarct size and cardiac hypertrophy in the transition to HF in animals exposed to I/R injury and pressure overload, respectively. Finally, recent data showed that Nrf2/antioxidant-response element pathway activation may be of importance also in ischemic preconditioning, a phenomenon in which the heart is subjected to one or more episodes of nonlethal myocardial I/R before the sustained coronary artery occlusion

Are they in or out? The elusive interaction between Qtracker(\uae)800 vascular labels and brain endothelial cells

AIM:Qtracker\uae800 Vascular labels (Qtracker\uae800) are promising biomedical tools for high-resolution vasculature imaging; their effects on mouse and human endothelia, however, are still unknown.MATERIALS &amp; METHODS:Qtracker\uae800 were injected in Balb/c mice, and brain endothelium uptake was investigated by transmission electron microscopy 3-h post injection. We then investigated, in vitro, the effects of Qtracker\uae800 exposure on mouse and human endothelial cells by calcium imaging.RESULTS:Transmission electron microscopy images showed nanoparticle accumulation in mouse brain endothelia. A subset of mouse and human endothelial cells generated intracellular calcium transients in response to Qtracker\uae800.CONCLUSION:Qtracker\uae800 nanoparticles elicit endothelial functional responses, which prompts biomedical safety evaluations and may bias the interpretation of experimental studies involving vascular imaging

EFFETTO DEL MODERATO ESERCIZIO FISICO SUL SISTEMA Nrf2-ARE IN PAZIENTI CON CLAUDICATIO INTERMITTENS

Recenti evidenze suggeriscono che l'esercizio fisico pu\uf2 migliorare lo stress ossidativo nei pazienti con arteriopatia obliterante degli arti inferiori (AOP) con claudicatio intermittens (CI), ridurre l'infiammazione e aumentare l\u2019abilit\ue0 di marcia. Sebbene inequivocabili evidenze dimostrino che il training di esercizio fisico migliora significativamente il dolore nei pazienti con CI i meccanismi sono complessi e non ancora completamente chiariti. I radicali liberi dell\u2019ossigeno (ROS) prodotti durante i ripetuti episodi di ischemia-riperfusione (I/R) nei pazienti AOP con CI che svolgono un esercizio fisico massimale sono la principale causa dello stress del reticolo endoteliale che attiva l\u2019\u201cUnfolded protein response\u201d (UPR). Nrf2 (Nuclear factor-erythroid 2-related factor 2) gioca un ruolo chiave nel regolare le risposte antiossidanti innescate dall\u2019UPR. Lo scopo di questo studio \ue8 di valutare se, un periodo di tre settimane di esercizio fisico controllato in 24 pazienti con AOP (Fontaine fase II) e CI, migliora l\u2019intervallo di marcia libero e assoluto valutato con Treadmill Test, migliora lo stress ossidativo misurato come malondialdeide plasmatica (MDA) e influenza l\u2019espressione genica della via di segnale antiossidante Nrf2/ARE nei linfomonociti circolanti dei soggetti in esame.Recent evidence suggests that exercise training can improve oxidative stress in patients with (PAD) with peripheral arterial disease (PAD) and intermittent claudication (IC), reducing inflammation and increasing walking ability. Although evidences demonstrating that exercise training significantly improves calf pain in patients with CI, the mechanisms are complex and not yet clear. The reactive oxygen species (ROS) produced during repeated episodes of ischemia-reperfusion (I / R) in patients with PAD and IC who undergo maximal exercise are the main cause of the endothelial reticulum stress and activate the '' Unfolded protein response "(UPR). Nrf2 (Nuclear factor-erythroid 2-related factor 2) plays a key role in regulating the antioxidant responses. The aim of this study is to evaluate if a period of three weeks of controlled exercise training in 24 patients with PAD (Fontaine stage II) and IC can improve the pain free walking distance and the maximal walking distance evaluated with Treadmill Test; improve oxidative stress measured as plasma malondialdehyde (MDA) and affect the Nrf2 / ARE signaling pathway in circulating PBMC of these subjects

Adipogenic effect of mild ozonisation on human adipose-derived adult stem cells

Effects of low ozone concentrations on human adipose-derived adult stem (hADAS) cells by combining light and electron microscop

Adipogenic effect of mild ozonisation on human adipose-derived adult stem cells

Effects of low ozone concentrations on human adipose-derived adult stem (hADAS) cells by combining light and electron microscop

The atherosclerotic plaque vulnerability: focus on the oxidative and endoplasmic reticulum stress in orchestrating the macrophage apoptosis in the formation of the necrotic core

Although the understanding the pathophysiology of atherogenesis and atherosclerosis progression has been one of the major goals of cardiovascular research during the last decades, the precise mechanisms underlying plaque destabilization are still unknown. The disruption of the plaque and the thrombosis in the lumen that are mostly determined by the expansion of the necrotic core (NC) are driven by various mechanisms, including accelerated macrophage apoptosis and defective phagocytic clearance (defective efferocytosis). Oxidative stress is implicated in the expansion of the NC: in fact, many oxidized compounds and processes contribute to the macrophage apoptosis; in addition, the oxidized derivatives of polyunsatured fatty acids promote defective efferocytosis, with the final result of NC expansion. In the last years the role of the endoplasmic reticulum (ER) stress is under investigation to better define its possible contribution in affecting the NC expansion. The abnormal amount of apoptotic cells in the vulnerable plaque has been demonstrated to be related both to the sustained ER stress and to the expression of survival and protective genes, such as the unfolded protein response or/and the nuclear erytroid- related factor 2. In this review the authors focus on the promising results of the oxidative and ER stress in contributing to triggering and orchestrating the atherosclerotic plaque vulnerability

Oxygenator Is the Main Responsible for Leukocyte Activation in Experimental Model of Extracorporeal Circulation: A Cautionary Tale

In order to assess mechanisms underlying inflammatory activation during extracorporeal circulation (ECC), several small animal models of ECC have been proposed recently. The majority of them are based on home-made, nonstandardized, and hardly reproducible oxygenators. The present study has generated fundamental information on the role of oxygenator of ECC in activating inflammatory signaling pathways on leukocytes, leading to systemic inflammatory response, and organ dysfunction. The present results suggest that experimental animal models of ECC used in translational research on inflammatory response should be based on standardized, reproducible oxygenators with clinical characteristics

Correlation between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) and oxidized LDL (oxLDL) and between plasma LpPLA2 and lysophosphatidylcholine (lysoPC).

<p>(A) Correlation between plasma Lp-PLA2 and oxLDL and (B) correlation between plasma Lp-PLA2 and lysoPC concentrations in the whole population of subjects studied.</p