Protective role of adiponectin on endothelial dysfunction induced by AGEs: A clinical and experimental approach

Objective: Obesity is characterized by low levels of adiponectin, an adipocytes derived hormone, and by an inflammatory component. Endothelial dysfunction is often found in overweight/obesity, diabetes, and atherosclerosis. Advanced glycation end products (AGEs) induce endothelial dysfunction and are linked to diabetes and increased atherogenicity and inflammation. The aim of the study was to investigate the possible link between adiponectin and N(epsilon)-(carboxymethyl) lysine (CML), the predominant adduct of circulating AGEs in overweight patients, and, in an in vitro model, to test the hypothesis that adiponectin acts as modulator of endothelial dysfunction, induced by AGEs. Results: In 108 overweight patients, plasma levels of CML correlated inversely with adiponectin levels. Preincubation of human vein endothelial cells (HUVECs) with physiological concentrations of adiponectin, followed by stimulation with AGEs, reduced vascular adhesion molecule-1 (VCAM-1) and E-selectin expression, as assessed by surface enzyme immunoassay. Conclusions: Taken together, these findings demonstrate an inverse correlation between CML and adiponectin levels in overweight patients and a protective role of adiponectin on endothelial dysfunction induced by AGEs, suggesting its key role in the treatment of the vascular complications of obesity/metabolic syndrome

Protective role of adiponectin on endothelial dysfunction induced by AGEs: a clinical and experimental approach

OBJECTIVE: Obesity is characterized by low levels of adiponectin, an adipocytes derived hormone, and by an inflammatory component. Endothelial dysfunction is often found in overweight/obesity, diabetes, and atherosclerosis. Advanced glycation end products (AGEs) induce endothelial dysfunction and are linked to diabetes and increased atherogenicity and inflammation. The aim of the study was to investigate the possible link between adiponectin and N(epsilon)-(carboxymethyl) lysine (CML), the predominant adduct of circulating AGEs in overweight patients, and, in an in vitro model, to test the hypothesis that adiponectin acts as modulator of endothelial dysfunction, induced by AGEs. RESULTS: In 108 overweight patients, plasma levels of CML correlated inversely with adiponectin levels. Pre-incubation of human vein endothelial cells (HUVECs) with physiological concentrations of adiponectin, followed by stimulation with AGEs, reduced vascular adhesion molecule-1 (VCAM-1) and E-selectin expression, as assessed by surface enzyme immunoassay. CONCLUSIONS: Taken together, these findings demonstrate an inverse correlation between CML and adiponectin levels in overweight patients and a protective role of adiponectin on endothelial dysfunction induced by AGEs, suggesting its key role in the treatment of the vascular complications of obesity/metabolic syndrom

Aspetti patogenetici comuni tra stenosi aortica calcifica e aterosclerosi: ruolo del recettore dei prodotti di glicosilazione avanzata

Clinical and experimental studies identified several similarities between calcific aortic stenosis and atherosclerosis, suggesting the involvement of similar pathogenic pathways in both conditions.There are severalmolecules involved in regulating the development, progression and calcification of the valve sclerosis and in growth and complications of atherosclerotic plaque. Among these molecules, the receptor of advanced glycation end-products , a multi-ligand receptor involved in the pathogenesis of several degenerative, inflammatory and immune diseases, could have an important regulatory role in both diseases and therefore worthy of study as a potential target therapeutic for both conditions.Studi sperimentali e clinici hanno individuato molte analogie fra la stenosi aortica calcifica e l\u27aterosclerosi,suggerendo una via patogenetica comune. Esistono diverse molecole coinvolte nella regolazione dello sviluppo, progressione della sclerosi e calcificazione della valvola,cos? come nella crescita e complicanze della placca aterosclerotica. Tra queste molecole, il recettore per i prodotti di glicosilazione avanzata, un recettoremulti-ligando che ? coinvolto nella patogenesi di diversemalattie degenerative infiammatorie e immunitarie, potrebbe avere un ruolo regolatore importante in entrambe le malattie, rappresentando un potenziale bersaglio terapeutico in ambedue le condizioni

ORGAN THERAPEUTICS DURING EX-SITU DYNAMIC PRESERVATION. A LOOK INTO THE FUTURE

editorial reviewe

A 2,3-diphenylpyrido[1,2-a] pyrimidin-4-one derivative inhibits specific angiogenic factors induced by TNF-\u3b1

Low-grade chronic inflammation is a key process of angiogenesis in tumour progression. We investigated whether a synthetic analogue of apigenin, the 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a] pyrimidin-4-one (called DB103), interfered with the mechanisms involved in the angiogenic process induced by the inflammatory cytokine tumour necrosis factor (TNF\u3b1). In endothelial cells, DB103 but not apigenin reduced the TNF\u3b1-induced oxidative stress. DB103 inhibited the activation of ERK1/2 but not JNK, p38 and Akt kinases, while apigenin was not so selective because it inhibited essentially all examined kinases. Similarly, apigenin inhibited the TNF\u3b1-induced transcription factors CREB, STAT3, STAT5 and NF-kB, while DB103 acted only on NFinhibited the induced-release of angiogenic factors such as monocyte chemotactic protein-1, interleukin-6 (IL-6) and angiopoietin-2 but not IL-8, while apigenin reduced the IL-6 and IL-8 release. DB103 revealed a better ability than apigenin to modulate proangiogenic responses induced by an inflammatory microenvironment

Elevated soluble receptor for advanced glycation end product levels in patients with acute coronary syndrome and positive cardiac troponin I

Objectives High levels of soluble receptor for advanced glycation end products (sRAGE) have been shown to have an atheroprotective role; however, no data are available on this molecule in acute coronary syndromes (ACS). We evaluated sRAGE levels in patients with non-ST segment elevation ACS (NSTE-ACS) or with chronic stable angina. Methods We studied 265 patients, 190 of whom had NSTE-ACS and 75 had chronic stable angina. Results Plasma sRAGE values were comparable in the two groups (P= 0.19). However, in the patients with NSTEACS,sRAGE levels were significantly higher in patients with cardiac troponin-I (cTnI) of more than or equal to 0.04 lg/l compared with those with cTnI of less than 0.04 lg/l [758 pg/ml (493-1536 pg/ml) vs. 454 pg/ml (167-899 pg/ml); P = 0.0037]. A significant correlation(r= 0.323, P = 0.0045) was found between sRAGE and cTnI levels in patients with NSTE-ACS.Conclusion Plasma sRAGE levels are elevated in patients with NSTE-ACS with positive cTnI, suggesting that they could be related to myocardial cell damage

Effect of the administration of n-3 polyunsaturated fatty acids on circulating levels of microparticles in patients with a previous myocardial infarction

Udgivelsesdato: 2008-Jun BACKGROUND: Increased levels of microparticles exposing tissue factor circulate in the blood of patients with coronary heart disease, possibly disseminating their pro-thrombotic and pro-inflammatory potential. Because diets rich in n-3 (polyunsaturated) fatty acids have been associated with reduced incidence of coronary heart disease-related events, we investigated the in vivo effects of treatments with n-3 fatty acids on levels of circulating microparticles and their tissue factor- dependent procoagulant activity in patients with a previous myocardial infarction. DESIGN AND METHODS: Forty-six post-myocardial infarction patients were assigned to receive either 5.2 g of n-3 fatty acids daily (n=23) or an olive oil placebo (n = 23) for 12 weeks. Circulating microparticles were isolated from peripheral blood. The number of microparticles, their cellular source and tissue factor antigen were determined by flow cytometry, and their procoagulant potential assayed by a fibrin generation test. RESULTS: The total number of microparticles, endothelium-derived microparticles and microparticle tissue factor antigen were not significantly different between the two groups. However, the number of platelet-derived microparticles [from a median of 431 (126-1796, range) x 10(6)/L to a median of 226 (87-677, range)] x 10(6)/L and monocyte-derived microparticles [from a median of 388 (9-1681, range) x 10(6)/L to a median of 265 (7-984, range) x 10(6)/L] in plasma were significantly (p < 0.05) decreased by n-3 fatty acids, while they were unchanged in the placebo group. Total microparticle tissue factor-procoagulant activity was also reduced in the n-3 fatty acid group compared to that in the placebo group. CONCLUSIONS: Treatment with n-3 fatty acids after myocardial infarction exerts favorable effects on levels of platelet- and monocyte-derived microparticles, thus possibly explaining some of the anti-inflammatory and anti-thrombotic properties of these natural compounds

The Mediterranean Lifestyle as a Non-Pharmacological and Natural Antioxidant for Healthy Aging

Oxidative stress has been suggested to affect age-associated physiological dysfunction. Therefore, it is speculated that antioxidant supplements could have a potential role in preventing age-related diseases and death. Among different dietary habits, the highly antioxidant Mediterranean dietary pattern, which includes high vegetable and fruit intake, consumption of legumes, cereals, and fish, low intake of meat and dairy derivatives, moderate red wine consumption, and use of extra-virgin olive oil, is characterized by other aspects than food, such as conviviality, sensory stimulation, socialization, biodiversity, and seasonality that can reinforce the Mediterranean diet’s (MeD) beneficial effects on wellbeing, quality of life, and healthy aging. The present review aims to discuss available data on the relationship between oxidative stress and aging, biomarkers of oxidative stress status, protective effects of the MeD, and the adoption of the Mediterranean lifestyle as a non-pharmacological and natural tool to cope with oxidative stress damage for a longer life span, and—even more important—healthy aging beyond the biological, psychological, and social challenges that old age entails

miRNA and long non-coding RNA transcriptional expression in hepatocellular carcinoma cell line-secreted extracellular vesicles

Extracellular vesicles (EVs) are membrane-released vesicles acting as transporters of proteins, lipids and short/long non-coding RNA (miRNAs and lncRNAs). They are released by normal and pathological cells, including hepatocellular carcinoma (HCC). To date, studies focused on miRNAs and lncRNAs contained in EVs derived from HCC are limited. Our aim was to analyze the transcriptional profile of potential regulating miRNAs and lncRNAs in EVs secreted by HCC tumor cell line (HepG2, n = 6), and from a non-tumorigenic hepatocyte cell line (WRL68, n = 6), to compare their differential expression profile and to identify novel molecular diagnostic markers of HCC. EVs were isolated from the conditioned medium, through differential centrifugations. The expression profile of miRNAs (miR-23a, miR-16-2, miR-181a, miR-373, miR-205, miR-27a, miR-1323, and miR-532) and lncRNAs (HULC, HOTAIR, XIST, MALAT-1, GAS-5, H19) was performed in Real-time PCR, and their transcript was found both in HepG2 and WRL68 EVs. Lower miR-181a, miR-205 and miR-1323 expression were detected in EVs secreted by HepG2 compared to WRL68, while an opposite trend was observed for miR-23a, miR-16-2, miR-373, miR-27a, and miR-532. Several significant correlations were found between miRNA and lncRNA. An in silico analysis was also performed. The results obtained could identified them as new potential diagnostic and prognostic biomarkers of HCC