Adiponectin, an adipocyte-derived insulin-sensitizing and anti-inflammatory hormone, is suppressed in obesity through mechanisms involving chronic inflammation and oxidative stress. Olive oil consumption is associated with beneficial cardiometabolic actions, with possible contributions from the antioxidant phenol hydroxytyrosol (HT) and the monounsaturated fatty acid oleic acid (OA, 18:1n-9 cis), both possessing anti-inflammatory and vasculo-protective properties. We determined the effects of HT and OA, alone and in combination, on adiponectin expression in human and murine adipocytes under pro-inflammatory conditions induced by the cytokine tumor necrosis factor(TNF)-?. We used human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes and murine 3T3-L1 adipocytes as cell model systems, and pretreated them with 1-100 ?mol/L OA, 0.1-20 ?mol/L HT or OA plus HT combination before stimulation with 10 ng/mL TNF-?. OA or HT significantly (P<0.05) prevented TNF-?-induced suppression of total adiponectin secretion (by 42% compared with TNF-? alone) as well as mRNA levels (by 30% compared with TNF-? alone). HT and OA also prevented-by 35%-TNF-?-induced downregulation of peroxisome proliferator-activated receptor PPAR?. Co-treatment with HT and OA restored adiponectin and PPAR? expression in an additive manner compared with single treatments. Exploring the activation of JNK, which is crucial for both adiponectin and PPAR? suppression by TNF-?, we found that HT and OA additively attenuated TNF-?-stimulated JNK phosphorylation (up to 55% inhibition). In conclusion, the virgin olive oil components OA and HT, at nutritionally relevant concentrations, have additive effects in preventing adiponectin downregulation in inflamed adipocytes through an attenuation of JNK-mediated PPAR? suppression.

Introduction: Polyphenols of wine have been extensively studied in relation to their health promoting properties. Red wine polyphenols consisted of different class of compounds belonging to flavonoid pathway, such as the resveratrol, quercetin, and anthocyanins which have long been considered to reduce the incidence of mortality and morbidity from cardiovascular diseases (CVD). Endothelial and monocyte activation is a pivotal event in atherosclerotic CVD, in this study was examined the anti-inflammatory effects of Italian red wines polyphenols in human vascular cells, such as endothelial and monocytoid cells. Since the wine polyhenols depend on different factors such as grape cultivar, and wine-making practices, aim of this study was to examine the anti-atherogenic effects of polyphenolic extracts from Italian red wines obtained by two Apulian grape cultivar: Primitivo and Negroamaro. Methods: Six Apulian red wines produced by the cv Negramaro and Primitivo grapes from the 2007-2008 vintage were analyzed. For each wine, triplicate lipophilic fraction analyses were carried out as per Giovinazzo et al., 2005. HPLC wine anthocyanin analysis was performed by direct injection of wine samples as reported by De Villiers et al. 2004. Human Umbilical Vein Endothelial Cells (HUVEC) and human monocytoid cells (U937) were pre-treated with chemically synthesised polyphenols, or with Primitivo and Negroamaro polyphenolic extracts and the corresponding de-alcoholised wines, at 0,2-2 % (v/v), before stimulation with 20 nmol/L phorbol myristate acetate (PMA) or 2 mg/mL lypopolysaccaride (LPS) for 24 h. Then, HUVEC were tested for the expression of Vascular Cell Adhesion Molecule(VCAM)-1 by enzyme immunoassays (EIA), and U937 supernatants were tested for the release of matrix metalloproteinases (MMP)-9 by gelatine zymography. Results: All chemically synthesized polyphenol tested reduced, in a concentration dependent manner, the stimulated expression of VCAM-1 in LPS triggered HUVEC. In the same conditions, lipophilic fraction extracted from both Primitivo and Negroamaro wines as well as the corresponding de-alcoholised wines exhibited an even higher inhibition of VCAM-1 expression (up to 50-70 fold higher than those expected on the base of individual polyphenol content). Similarly, either Primitivo and Negroamaro polyphenolic extracts reduced the PMA stimulated release of MMP-9 by PMA triggered U937.Conclusions: In this study different class of polyphenols from Primitivo and Negramaro red wines were characterised. These fractions, significantly inhibited the monocyte-derived extracellular matrix proteases release as well as the endothelial expression of athero-adhesion molecules. These inhibitory effects could explain, at least in part, the anti-inflammatory and cardio-protective properties of red wine polyphenols.

Matrix metalloproteinase (MMP)-9 plays an important role in stroke by accelerating matrix degradation, disrupting the blood-brain barrier and increasing infarct size. Dipyridamole is an antiplatelet agent with recognised benefits in ischaemic stroke prevention. In addition to its antiplatelet properties, recent studies have reported that dipyridamole also features anti-inflammatory and anti-oxidant properties. We therefore investigated whether dipyridamole can ameliorate the proinflammatory profile of human monocytes, a source of MMP-9 in stroke, in terms of regulation of MMP-9 activity and expression, and explored underlying mechanisms. Human peripheral blood mononuclear cells (PBMC) and U937 cells were treated with increasing concentrations of dipyridamole (up to 10 mu g/ml) for 60 minutes before stimulation with tumour necrosis factor (TNF)-alpha or phorbol myristate acetate (PMA). Exposure of PBMC and U937 to dipyridamole reduced TNF-alpha- and PMA-induced MMP-9 activity and protein release as well as MMP-9 mRNA, without significantly affecting the release of TIMP-1. This inhibitory effect was independent of dipyridamole-induced cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) increase. Correspondingly, dipyridamole also significantly inhibited TNF-alpha-induced nuclear factor (NF)-kappa B activation and nuclear translocation of the p65 NF-kappa B subunit through a mechanism involving the inhibition of IkB alpha degradation and p38 MAPK activation. In conclusion, dipyridamole, at therapeutically achievable concentrations, reduces the expression and release of MMP-9 through a mechanism involving p38 MAPK and NF-kappa B inhibition. These results indicate that dipyridamole exerts anti-inflammatory properties in human monocytes that may favourably contribute to its actions in the secondary prevention of stroke, independent of its antiplatelet properties.

Epidemiological studies associate whole-grain consumption with several health benefits and increasing evidence suggests whole-grain wheat polyphenols as healthy agents with anti-inflammatory properties (1). However, many studies demonstrated the impact, usually negative, of wheat bran, rich in polyphenols, on bread quality. We have previously evaluated the bread making ability of meals composed of re-milled semolina biofortified with selected durum wheat milling by-products (200 g/kg) that were: i) residuals of the second and third debranning steps of durum wheat (DB), ii) the micronized and air-classified thin fraction obtained from the same residuals (MB), or iii) coarse bran obtained from conventional roller milling of non-debranned durum wheat (B) (2). We showed that total soluble phenolic compounds and antioxidant activity were significantly higher in MB and DB than in B (2), with acceptable bread quality in particular for MB. However, their biological anti-inflammatory potential was unknown. The aim of this study was to analyse the vascular anti-inflammatory properties of the phenolic extracts obtained from different biofortified bread by evaluating endothelium-monocyte adhesion and endothelial and monocytic inflammatory gene expression. Cultured human endothelial and monocytic cells were incubated with increasing concentrations (1, 5 or 10 ?g/mL) of phenolic acids extracts from biofortified bread (B, DB, MB) before stimulation with inflammatory challenge lipopolysaccharide (LPS 1 ?g/mL). All phenolic acids extracts inhibited, in a concentration-dependent manner, the stimulated endothelial leukocyte adhesion, and the protein expression of endothelial adhesion molecules. By real time PCR, we found that B, DB and MB phenolic extracts down-regulated the mRNA levels of adhesion molecules as well as pro-inflammatory cytokines and chemoattractants in stimulated endothelial cells and monocytes. Our findings appreciate the bread biofortified with selected durum wheat milling by-products as a source of phenolic acids with multiple anti-inflammatory properties.

Early atherosclerosis features functional and structural changes in the endothelial barrier function that affect the traffic of molecules and solutes between the vessel lumen and the vascular wall. Such changes are mechanistically related to the development of atherosclerosis. Proatherogenic stimuli and cardiovascular risk factors, such as dyslipidaemias, diabetes, obesity, and smoking, all increase endothelial permeability sharing a common signalling denominator: An imbalance in the production/disposal of reactive oxygen species (ROS), broadly termed oxidative stress. Mostly as a consequence of the activation of enzymatic systems leading to ROS overproduction, proatherogenic factors lead to a pro-inflammatory status that translates in changes in gene expression and functional rearrangements, including changes in the transendothelial transport of molecules, leading to the deposition of low-density lipoproteins (LDL) and the subsequent infiltration of circulating leucocytes in the intima. In this review, we focus on such early changes in atherogenesis and on the concept that proatherogenic stimuli and risk factors for cardiovascular disease, by altering the endothelial barrier properties, co-ordinately trigger the accumulation of LDL in the intima and ultimately plaque formation.

Iodinated radiocontrast media have been the most widely used pharmaceuticals for intravascular administration in diagnostic and interventional angiographic procedures. Although they are regarded as relatively safe drugs and vascular biocompatibility of contrast media has been progressively improved, severe adverse reactions may occur, among which acute nephropathy is one of the most clinically significant complications after intravascular administration of contrast media and a powerful predictor of poor early and long-term outcomes. Since radiocontrast media are given through the arterial or the venous circulation in vascular procedures, morphological and functional changes of the microvascular and macrovascular endothelial cells substantially contribute to the pathogenesis of organ-specific and systemic adverse reactions of contrast media. Endothelial toxicity of contrast media seems to be the result of both direct proapoptotic effects and morphological derangements, as well as endothelial dysfunction and induction of inflammation, oxidative stress, thrombosis, and altered vasomotor balance, with predominant vasoconstrictive response in atherosclerotic coronary arteries and kidney microcirculation. Further understanding of pathogenetic mechanisms underlying contrast media-induced adverse reactions in cellular targets, including endothelial cells, will hopefully lead to the development of novel preventive strategies appropriately curbing the pathogenesis of contrast media vasotoxicity. © 2012 Elsevier Inc.

Previous studies have shown the antiinflammatory, antioxidant and antiangiogenic properties by pure olive oil polyphenols; however, the effects of olive oil phenolic fraction on the inflammatory angiogenesis are unknown. In this study, we investigated the effects of the phenolic fraction ( olive oil polyphenolic extract, DOPE) from extra virgin olive oil and related circulating metabolites on the VEGF-induced angiogenic responses and NADPH oxidase activity and expression in human cultured endothelial cells. We found that DOPE (1-10 mu g/ml), at concentrations achievable nutritionally, significantly reduced, in a concentration-dependent manner, the VEGF-induced cell migration, invasiveness and tube-like structure formation through the inhibition of MMP-2 and MMP-9. DOPE significantly (P<0.05) reduced VEGF-induced intracellular reactive oxygen species by modulating NADPH oxidase activity, p47phox membrane translocation and the expression of Nox2 and Nox4. Moreover, the treatment of endothelial cells with serum obtained 4 h after acute intake of extra virgin olive oil, with high polyphenol content, decreased VEGF-induced NADPH oxidase activity and Nox4 expression, as well as, MMP-9 expression, as compared with fasting control serum. Overall, native polyphenols and serum metabolites of extra virgin olive oil rich in polyphenols are able to lower the VEGF-induced angiogenic responses by preventing endothelial NADPH oxidase activity and decreasing the expression of selective NADPH oxidase subunits. Our results provide an alternative mechanism by which the consumption of olive oil rich in polyphenols may account for a reduction of oxidative stress inflammatory-related sequelae associated with chronic degenerative diseases. (C) 2015 Elsevier Inc. All rights reserved.

Hydroxytyrosol (HT), the major olive oil antioxidant polyphenol in cardioprotective Mediterranean diets, is endowed with anti-inflammatory and anti-atherosclerotic activity. The production of cyclooxygenase (COX)-2-dependent inflammatory eicosanoids and the functionally linked release of matrix metalloproteinase (MMP)-9 by macrophages likely contribute to plaque instability leading to acute coronary events. Objective of the study was to examine the HT effects on inflammatory markers in human activated monocytes, including MMP-9 and COX-2 activity and expression and explore HT underlying mechanisms.METHODS AND RESULTS: Human peripheral blood mononuclear cells (PBMC) and U937 monocytes were treated with 1-10 ?mol/L HT before activation with phorbol myristate acetate (PMA). HT blunted monocyte matrix invasive potential and reduced MMP-9 release and expression at zymography, ELISA and RT-PCR, with an IC50 = 10 ?mol/L ( P< 0.05), without affecting tissue inhibitor of metalloproteinase (TIMP)-1. Moreover, HT inhibited prostaglandin (PG)E2 production and COX-2 expression, without affecting COX-1. These effects were mediated by inhibition of transcription factor nuclear factor (NF)-?B and protein kinase C (PKC)? and PKC?1 activation.CONCLUSION: HT, at nutritionally relevant concentrations, reduces MMP-9 and COX-2 induction in activated human monocytes via PKC? and PKC?1 inhibition, thus featuring novel anti-inflammatory properties. Overall, such results contribute to explaining the vascular protective effects by olive oil polyphenols in Mediterranean diets.

Diets with high content of antioxidant polyphenols are associated with low prevalence of cardiovascular diseases and cancer. Inflammatory angiogenesis is a key pathogenic process both in cancer and atherosclerosis, and is tightly regulated by the proinflammatory enzyme cyclooxygenase (COX)-2 and the matrix degrading enzymes matrix metalloproteinases (MMPs). We studied the effects of antioxidant polyphenols from virgin olive oil (oleuropein and hydroxytyrosol) and red wine (resveratrol and quercetin) on endothelial cell angiogenic response in vitro, and explored underlying mechanisms. Cultured endothelial cells were pre-incubated with 0.1-50 mu mol/L polyphenols before stimulation with phorbol myristate acetate (PMA). All tested polyphenols reduced endothelial cell tube formation on matrigel and migration in wound healing assays. The reduced angiogenesis was associated with the inhibition of PMA-induced COX-2 protein expression and prostanoid production, as well as MMP-9 protein release and gelatinolytic activity. These effects were accompanied by a significant reduction in the stimulated intracellular reactive oxygen species levels and in the activation of the redox-sensitive transcription factor nuclear factor (NF)-kappa B. Our findings reveal that olive oil and red wine polyphenols reduce inflammatory angiogenesis in cultured endothelial cells, through MMP-9 and COX-2 inhibition, supporting a potential protective role for dietary polyphenols in atherosclerotic vascular disease and cancer. (C) 2012 Elsevier Inc. All rights reserved.

Purpose: The aim of the study was to evaluate the vascular anti-inflammatory effects of polyphenolic extracts from two typical South Italy red wines, the specific contribution of individual polyphenols and the underlying mechanisms of action.Methods: Human endothelial cells were incubated with increasing concentrations (1-50 ?g/mL) of Primitivo and Negroamaro polyphenolic extracts (PWPE and NWPE, respectively) or pure polyphenols (1-25 ?mol/L), including hydroxycinnamic acids (p-coumaric, caffeic and caftaric acids), flavonols (kaempferol, quercetin, myricetin) or stilbenes (trans-resveratrol, trans-piceid) before stimulation withlipopolysaccharide. Through multiple assays, we analyzed the endothelial-monocyte adhesion, theendothelial expression of adhesion molecules (ICAM-1, VCAM-1 and E-Selectin), monocytechemoattractant protein-1 (MCP-1) and macrophage colony-stimulating factor (M-CSF), as well as ROSintracellular levels and the activation of NF-?B and AP-1.Results: Both PWPE and NWPE, already at 1 ?g/mL, inhibited monocyte adhesion to stimulated endothelial cells, a key event in triggering vascular inflammation. They down-regulated the expression of adhesion molecules, ICAM-1, VCAM-1, E-Selectin, as well as MCP-1 and M-CSF, at mRNA and protein levels. All polyphenols reduced intracellular ROS, and everything, except caftaric acid, inhibited the endothelial expression of adhesion molecules and MCP-1, although with different potency. Flavonols and resveratrol significantly reduced also the endothelial expression and release of M-CSF. The decrease in endothelial inflammatory gene expression was related to the inhibition of NF-?B and AP-1 activation but not to intracellular oxidative stress.Conclusions: This study showed multiple anti-inflammatory and anti-atherosclerotic properties of red wine polyphenolic extracts and indentified specific bioactive polyphenols which could counteract inflammatory diseases including atherosclerosis.

Nutraceuticals are potentially healthful foods that play a role in maintaining human wellbeing, enhancing health and preventing, or even treating, specific diseases. More than forany other diseases, cardiovascular diseases occur in association with risk factors that areamenable to prevention or treatment by nutraceutical interventions. Several ingredientsmarketed for use in dietary supplements address such risk factors. The ability of nutraceu-ticals to favorably influence cardiovascular risk factors and atherosclerotic vascular diseaseshould be recognized as an enormous opportunity for the prevention or treatment of thiscommon condition. In this review, we attempt at summarizing some of the recent researchfindings on ? -3-polyunsaturated fatty acids and antioxidant polyphenols that have bene-ficial cardiovascular effects to update the practicing clinicians on the potential benefits ofnutraceuticals in this area

INTRODUCTION:Obstructive sleep apnea syndrome (OSAS) is a highly prevalent sleep disorder associated with severe cardiovascular events, morbidity and mortality. Recent evidence has highlighted OSAS as an independent risk factor for an excessive platelet activation and arterial thrombosis, but the underlying mechanisms have not yet been determined. Studies in cell culture and animal models have significantly increased our understanding of the mechanisms of inflammation in OSAS. Hypoxia is a critical pathophysiological element that leads to an intense sympathetic activity, in association with systemic inflammation, oxidative stress and procoagulant activity. While platelet dysfunction and/or hypercoagulability play an important role in the pathogenesis of vascular disease, there are limited studies on the potential role of blood viscosity in the development of vascular disease in OSAS.CONCLUSION:Further studies are required to determine the precise role of hypercoagulability in the cardiovascular pathogenesis of OSAS, particularly its interaction with oxidative stress, thrombotic tendency and endothelial dysfunction. Nasal continuous positive airway pressure (nCPAP), the gold standard treatment for OSAS, not only significantly reduced apnea-hypopnoea indices but also markers of hypercoagulability, thus representing a potential mechanisms by which CPAP reduces the rate of cardiovascular morbidity and mortality in OSAS patients.

Introduction: Obstructive sleep apnea (OSA) is a serious and prevalent medical condition with major consequences for health and safety. Excessive daytime sleepiness (EDS) is a common-but not universal- accompanying symptom. The purpose of this literature analysis is to understand whether the presence/absence of EDS is associated with different physiopathologic, prognostic, and therapeutic outcomes in OSA patients.

Obstructive sleep apnoea syndrome (OSAS) is associated with severe cerebro-cardiovascular morbidity and mortality. It is an independent risk factor for atherosclerosis, arterial thrombosis and metabolic syndrome, and recently has been associated with an increased incidence of cancer and death. A causal link between OSAS and atherosclerosis has been partially established. Recent research on atherosclerosis in OSAS has focused on thrombotic tendency and blood viscosity, providing new insight into disease mechanisms. Hypoxia is a critical pathophysiological element in OSAS that leads to intensive sympathetic activity, in association with inflammation, oxidative stress and procoagulant activity. Hypoxia and the induction of oxidative stress can simultaneously represent an underlying mechanism in the pathogenesis of cancer development and progression. This mini-review will discuss the latest findings on the association and potential relationship between OSA and pathological vascular sequelae.

Atherosclerosis is now widely accepted to be an inflammatory disease, characterized by degenerative as well as proliferative changes and extracellular accumulation of lipid and cholesterol, in which an ongoing inflammatory reaction plays an important role both in initiation and progression/destabilization, converting a chronic process into an acute disorder. Neovascularization has also been recognized as an important process for the progression/destabilization of atherosclerotic plaques. In fact, vulnerable atherosclerotic plaques prone to rupture are characterized by an enlarged necrotic core, containing an increased number of vasa vasorum, apoptotic macrophages, and more frequent intraplaque haemorrhage. Various functional roles have been assigned to intimal microvessels, however the relationship between the process of angiogenesis and its causal association with the progression and complications of atherosclerosis are still challenging and controversial. In the past 30 years, the dietary intake of omega-3 (n-3) polyunsaturated fatty acids - mainly derived from fish - has emerged as an important way to modify cardiovascular risk through beneficial effects on all stages of atherosclerosis, including plaque angiogenesis. This review specifically focuses on the modulating effects of n-3 fatty acids on molecular events involved in early and late atherogenesis, including effects on endothelial expression of adhesion molecules, as well as pro-inflammatory and pro-angiogenic enzymes. By accumulating in endothelial membrane phospholipids, omega-3 fatty acids have been shown to decrease the transcriptional activation of several genes through an attenuation of activation of the nuclear factor-?B system of transcription factors. This occurs secondary to decreased generation of intracellular reactive oxygen species. This series of investigations configures a clear example of nutrigenomics - i.e., how nutrients may affect gene expression, ultimately affecting a wide spectrum of human diseases.

Vascular inflammation, especially at the level of endothelial cells, has been shown to play a pivotal role in theinception, progression, and clinical complications of atherosclerosis. The common denominators for the activationof inflammatory genes appear to be a small subset of transcription factors--among which include nuclear factor-?B,activator protein-1 (AP-1), and GATA--that function as the central hub of vascular inflammation. Strategies directedto inhibit both the secondary mediators and the primary triggers (atherosclerosis risk factors) appear viable to inhibitatherosclerosis. However, attempts have now been made to address the central hub of vascular inflammation. "Old"drugs, such as dipyridamole, can also now be revisited for properties related to inhibition of vascular inflammation,probably by acting on the common hub of inflammation.

Red wine is a treasured source of polyphenols, such as stilbenes, flavonols and hydroxycinnamic acids, depending on different factors, such as grape cultivar and wine-making practices. The red wine polyphenols (RWPs) have long been associated to reduced mortality and morbidity from cardiovascular diseases and cancer. Since matrix metalloproteinase (MMP) activity is involved in extracellular matrix degradation, a crucial step both in inflammation and cell migration, aim of this study was to examine the effects of specific classes of polyphenols from Primitivo and Negroamaro grapes and wines produced in the Apulian region (Southern Italy), on the release and activity of MMP-9 in human monocytoid cells.U937 monocitoid cells were pre-treated with increasing concentrations of polyphenolic extracts (PE) of Primitivo and Negramaro grape and wine, before stimulation with 30 nM phorbol myristate acetate (PMA) for 24 h. The release and activity of MMP-9 in culture medium was tested by ELISA and zymography, respectively. Both Primitivo and Negroamaro PE exhibited a concentration-dependent inhibition of MMP-9 release and activity, without any reduction in cell viability. The inhibitory effect was higher than that produced by individual chemically synthesized polyphenols.. In this study, the PE from Primitivo and Negramaro grapes and red wines were characterized, and shown to significantly and synergistically inhibit the monocyte-derived release and activity of extracellular matrix proteases. These inhibitory effects could explain, at least in part, the anti-inflammatory and anti-cancerogenic properties of RWP.

The activation of peroxisome proliferator-activated receptor (PPAR)? is known to inhibit angiogenesis. As a potential mechanism for this, we aimed at examining the effects of PPAR? agonists on the pro-angiogenic enzyme cyclooxygenase (COX)-2 in human endothelium.Methods and results Cultured endothelial cells were pre-incubated with the PPAR? agonists rosiglitazone (RSG) or GW1929 before stimulation with vascular endothelial growth factor (VEGF) or phorbol myristate acetate (PMA). RSG and GW1929 attenuated VEGF- and PMA-stimulated COX-2 activity, as well as protein and mRNA expression. This effect was abolished by the PPAR? antagonists bisphenol A diglycidyl ether and GW9662 as well as by PPAR? small-interfering RNAs (siRNAs). Transient transfection experiments revealed that the induction of COX-2 promoter was significantly inhibited by RSG through an interference with the cAMP response element (CRE) site. COX-2 downregulation after siRNA targeting CRE-binding protein (CREB) confirmed the role of CREB in mediating COX-2 transcription. Correspondingly, PPAR? agonists attenuated CREB activation. As both protein kinase C (PKC)? and ? are involved in VEGF-induced COX-2 expression and CREB activation, we investigated which isoform(s) of PKC was affected by RSG. RSG only reduced VEGF- and PMA-stimulated PKC? membrane translocation.Conclusion VEGF induces CREB-mediated COX-2 expression through a PKC?-dependent pathway in human endothelium. The anti-angiogenic effect of PPAR? agonists is due, at least in part, to an interference with the VEGF-stimulated PKC?-mediated activation of CREB and the related expression of COX-2.

Red wine polyphenols have long been associated to a reduced morbidity and mortality from atherosclerotic disease in part by reducing inflammation, however the effects of different polyphenolic compounds are not clear. The aim of this study was to evaluate the anti-inflammatory and anti-oxidant effects of polyphenolic extracts from two red wines typical of Southern Italy, and to dissect the specific contribute of hydroxycinnamic acids, flavonols and stilbenes and to investigate underlying mechanisms of action in endothelial cells.Methodology and Results: Through multiple assays, we showed that both Primitivo and Negroamaro Wine Polyphenolic Extracts significantly inhibited monocyte adhesion to endothelium, endothelial expression of adhesion molecules, monocyte chemoattractant protein-1 and macrophage colony-stimulating factor as well as intracellular oxidative stress and the activation of NF-?B and AP-1, without any reduction in cell viability. We also showed that all tested polyphenols exhibited a strong antioxidant action in stimulated human endothelial cells but not all significantly exhibited anti-inflammatory activity which in turn was related to the inhibition of NF-?B and AP-1 activation.Conclusions: The present study provides new evidences on specifc anti-inflammatory and anti-atherosclerotic role of red wine polyphenols including hydroxycinnamic acids, flavonols and stilbenes.

Matrix metalloproteinases (MMPs) are endopeptidases responsible for the hydrolysis of various components of extracellular matrix. MMPs, namely gelatinases MMP-2 and MMP-9, contribute to the progression of chronic and degenerative diseases. Since gelatinases' activity and expression are regulated by oxidative stress, we sought to evaluate whether supplementation with polyphenol-rich red grape skin extracts modulated the matrix-degrading capacity in cell models of vascular inflammation. Human endothelial and monocytic cells were incubated with increasing concentrations (0.5-25 ?g/mL) of Negroamaro and Primitivo red grape skin polyphenolic extracts (NSPE and PSPE, respectively) or their specific components (0.5-25 ?mol/L), before stimulation with inflammatory challenge. NSPE and PSPE inhibited, in a concentration-dependent manner, endothelial invasion as well as the MMP-9 and MMP-2 release in stimulated endothelial cells, and MMP-9 production in inflamed monocytes, without affecting tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2. The matrix degrading inhibitory capacity was the same for both NSPE and PSPE, despite their different polyphenolic profiles. Among the main polyphenols of grape skin extracts, trans-resveratrol, trans-piceid, kaempferol and quercetin exhibited the most significant inhibitory effects on matrix-degrading enzyme activities. Our findings appreciate the grape skins as rich source of polyphenols able to prevent the dysregulation of vascular remodelling affecting degenerative and inflammatory diseases.

Adipose tissue inflammation is a mechanistic link between obesity and its related sequelae, including insulin resistance and type 2 diabetes. Dual ligands of peroxisome proliferator activated receptor (PPAR)? and ?, combining in a single molecule the metabolic and inflammatory-regulatory properties of ? and ? agonists, have been proposed as a promising therapeutic strategy to antagonize adipose tissue inflammation. Here we investigated the effects of the dual PPAR?/? agonist aleglitazar on human adipocytes challenged with inflammatory stimuli. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with aleglitazar or - for comparison - the selective agonists for PPAR? or ? fenofibrate or rosiglitazone, respectively, for 24 h before stimulation with TNF-?. Aleglitazar, at concentrations as low as 10 nmol/L, providing the half-maximal transcriptional activation of both PPAR? and PPAR?, reduced the stimulated expression of several pro-inflammatory mediators including interleukin (IL)-6, the chemokine CXC-L10, and monocyte chemoattractant protein (MCP)-1. Correspondingly, media from adipocytes treated with aleglitazar reduced monocyte migration, consistent with suppression of MCP-1 secretion. Under the same conditions, aleglitazar also reversed the TNF-?-mediated suppression of insulin-stimulated ser473 Akt phosphorylation and decreased the TNF-?-induced ser312 IRS1 phosphorylation, two major switches in insulin-mediated metabolic activities, restoring glucose uptake in insulin-resistant adipocytes. Such effects were similar to those obtainable with a combination of single PPAR? and ? agonists. In conclusion, aleglitazar reduces inflammatory activation and dysfunction in insulin signaling in activated adipocytes, properties that may benefit diabetic and obese patients. The effect of aleglitazar was consistent with dual PPAR? and ? agonism, but with no evidence of synergism.

Scope: High intakes of n-3 fatty acids exert anti-inflammatory effects and cardiovascular protection, but the underlying molecular basis is incompletely defined. By genome-wide analysis we searched for novel effects of docosahexaenoic acid (DHA) on gene expression and pathways in human vascular endothelium under pro-inflammatory conditions. Methods and Results: Human umbilical vein endothelial cells were treated with DHA and then stimulated with interleukin(IL)-1?. Total RNA was extracted, and gene expression examined by DNA microarray. DHA alone altered the expression of 188 genes, decreasing 92 and increasing 96. IL- 1? changed the expression of 2031 genes, decreasing 997 and increasing 1034. Treatment with DHA before stimulation significantly affected the expression of 116 IL-1?-deregulated genes, counter-regulating the expression of 55 genes among those decreased and of 61 among those increased. Functional and network analyses identified immunological, inflammatory and metabolic pathways as the most affected. Newly identified DHA-regulated genes are involved in stemness, cellular growth, cardiovascular system function and cancer, and included cytochrome p450 4F2(CYP4F2), transforming growth factor(TGF)-?2, Cluster of Differentiation (CD)47, caspase recruitment domain(CARD)11 and phosphodiesterase(PDE)5?. Conclusions: Endothelial exposure to DHA regulates novel genes and related pathways. Such unbiased identification should increase our understanding of mechanisms by which n-3 fatty acids affect human diseases.

The lower occurrence of cardiovascular disease and cancer in populations around the Mediterranean basin as detected in the 1950s was correctly attributed to the peculiar dietary habits of those populations. Essentially, until the mid-20th century, typical Mediterranean diets were rich in fruits, vegetables, legumes, whole-wheat bread, nuts, fish, and, as a common culinary trait, the routine use of extra-virgin olive oil. Nowadays, the regular adoption of such dietary patterns is still thought to result in healthful benefits. Such patterns ensure the assumption of molecules with antioxidant and anti-inflammatory actions, among which ?-3 polyunsaturated fatty acids (PUFAs), ?-9 monounsaturated fatty acids (oleic acid), and phenolic compounds. The aim of this review is to provide an update of the vasculo-protective pathways mediated by ?-3 PUFAs and polyphenols in the context of the modern Mediterranean dietary habits, including the possible cross-talk and synergy between these typical components. This review complements a parallel one focusing on the role of dietary nitrates and alimentary fats.

This review summarizes available evidence on the beneficial effects of inorganic nitrates and the monounsaturated fatty acid (MUFA) oleic acid, largely contained in Mediterranean diet, on blood pressure and coagulation activity.Inorganic nitrate. Normal vascular function requires NO production from the 1-arginine-NO synthase (NOS) pathway. This process is defective in conditions of local hypoxia, and here nitrite can substitute for 1-arginine-NOS derived NO. In this context, NO generation from the nitrate-nitrite-NO pathway mostly derived from green leafy vegetables appears to be an alternative source for NOS-dependent NO production, ensuring NO bioavailability also in situations when the endogenous 1-arginine/NO synthase pathway is dysfunctional or physiologically reduced in local hypoxic conditions.Olive oil and oleic acid. In addition to effects on lipoprotein metabolism and oxidation, the beneficial effects of oleic acid occur also on coagulation activity, namely on coagulation factor VII (FVII). Normally, a substantial increase of FVII coagulant activity (FVIIc) occurs within 2-3. h after a fatty meal and persists for several hours thereafter. When a background diet high in MUFA is consumed, a lower post-prandial increase of FVIIc takes place.