Teresa Navarra

What is the role of the receptor for advanced glycation end products–ligand axis in liver injury?†

Multiligand receptor for advanced glycation end products (RAGE) is expressed in a wide variety of tissues, including the liver. Interactions with its ligands lead to cellular activation and thus prolonged inflammation and apoptosis. RAGE also exists in a soluble, truncated isoform called soluble RAGE, which has the same ligand‐binding specificity as membrane‐RAGE; acting as decoy, it can contribute to the removal/neutralization of circulating ligands and the resultant reduction of signaling pathway activation. Experimental and clinical studies have highlighted the idea that the RAGE‐ligand axis is involved in the development of liver fibrosis, inflammation, and regeneration after a massive injury and in the setting of liver transplantation. The involvement of the RAGE‐ligand axis in vascular disease, diabetes, cancer, and neurodegeneration is well established, but it still needs to be clarified in the setting of liver diseases. We present a review of the recent literature on this receptor in surgical and clinical settings involving the liver, and we highlight the open issues and possible directions of future research. Liver Transpl 17:633‐640, 2011.

Circulating soluble receptor for advanced glycation end-product levels are decreased in patients with calcific aortic valve stenosis

OBJECTIVE It has been suggested that atherosclerotic mechanisms are involved in the pathogenesis of aortic valve stenosis (AVS). We hypothesised that low levels of the soluble receptor for advanced glycation end-products (sRAGE) might be associated with AVS due to its clinical and pathological associations with atherosclerosis. METHODS We enrolled 75 consecutive patients with severe AVS scheduled for surgical aortic valve replacement and 39 controls without AVS matched for age and gender. Besides the traditional risk factors, we evaluated plasma levels of sRAGE, C-reactive protein (CRP) and IL-6. All patients underwent transthoracic echocardiography, carotid arteries ultrasound scan and coronary angiography. The aortic and coronary calcium by multislice computed tomography was assessed in AVS patients. RESULTS The values of sRAGE were significantly lower (p<0.01) in AVS patients than in controls, while the CRP levels were significantly higher (p<0.05) in AVS patients than in controls. In AVS patients the sRAGE levels correlated inversely with age, cholesterol levels and coronary calcification. In all study subjects, we found an inverse correlation between circulating sRAGE and the number of echographically assessed sites of calcification (ANOVA, p<0.0001). In multivariable logistic regression analysis after adjustment for potential confounders, the sRAGE levels were significantly and independently associated with the risk of AVS (OR=0.997, 95% CI=0.994-1.000, p=0.048). CONCLUSION Since sRAGE could exert antiatherogenic effects by preventing inflammatory responses mediated by cell surface RAGE activation, low levels in AVS patients indicate that ligand-RAGE axis could contribute to pathogenesis of AVS.

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 syndrome.

Increased FNDC5/Irisin expression in human hepatocellular carcinoma

HighlightsHepatic expression of FNDC5/Irisin mRNA is highly expressed in patients with HCC.There is correlation between FNDC5/Irisin mRNA and key regulators of lipogenesis.There is correlation between FNDC5/Irisin mRNA and inflammatory markers.There is correlation between FNDC5/Irisin mRNA and the oncogene NOTCH1 Abstract The fibronectin type III domain containing 5 (FNDC5)/Irisin, a novel energy‐regulating hormone, is associated with lipid and carbohydrate metabolism. It is produced in low amounts by normal hepatic tissue, while in human hepatocellular carcinoma (HCC), in which aberrant de novo lipogenesis (DNL) occurs, the hepatic expression of FNDC5/Irisin is still unknown. The gene expression of FNDC5/Irisin, associated to key regulators of DNL, inflammation and cancer progression was evaluated in liver tissue of 18 patients with HCC undergoing liver transplantation and of 18 deceased donors. Hepatic mRNA expression of FNDC5/Irisin and stearoyl‐CoA desaturase (SCD‐1), main enzymatic regulator of DNL, were significantly higher in HCC patients than in donors (p < 0.0001 and p = 0.015, respectively). The hepatic mRNA expression of the neurogenic locus notch homolog protein 1 (NOTCH1) tended to be higher in HCC patients than in donors (p = 0.06). Only in HCC patients, hepatic FNDC5/Irisin strongly correlated with the transcription factor sterol regulatory element–binding factor 1, SCD‐1, NOTCH1, tumor necrosis factor‐&agr; and Interleukin‐6 mRNA expression. Further, in HCC patients, FNDC5/Irisin mRNA tended to correlate to plasma lipid profile namely triglycerides, palmitic/linoleic acid and polyunsaturated fatty acid/saturated fatty acid ratios. In conclusion, HCC‐liver tissue over‐expressed FNDC5/Irisin in association with gene expression of mediators involved in lipogenesis, inflammation and cancer, suggesting a possible protective role of the hormone from the liver damage.

Circulating levels of soluble receptor for advanced glycation end products and ligands of the receptor for advanced glycation end products in patients with acute liver failure

Animal studies suggest that receptor for advanced glycation end products (RAGE)–dependent mechanisms contribute to acetaminophen‐induced liver damage. We examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) or RAGE ligands, including extracellular newly identified receptor for advanced glycation end products binding protein (EN‐RAGE), high‐mobility group box 1 (HMGB1), and Nε‐(Carboxymethyl)lysine adducts (CML), could aid in prognostication after an acetaminophen overdose. Sixty well‐characterized acetaminophen‐related acute liver failure (ALF) patients (30 spontaneous survivors and 30 patients who underwent transplantation and/or died) who were enrolled in the National Institutes of Health–sponsored Acute Liver Failure Study Group, were matched by age, met standard criteria for encephalopathy, and had an international normalized ratio > 1.5 were retrospectively studied. HMGB1, EN‐RAGE, CML, and sRAGE were detected by enzyme‐linked immunosorbent assay methods in sera from ALF patients and 30 healthy controls. Levels of sRAGE, EN‐RAGE, and HMGB1 (but not CML) were significantly greater (P < 0.001) in ALF patients versus normal controls. The levels of sRAGE, HMGB1, and EN‐RAGE were significantly higher (P = 0.03, P < 0.01, and P = 0.03) in patients with a systemic inflammatory response syndrome (SIRS) score > 2 versus patients with a SIRS score ≤ 2. Nevertheless, only sRAGE levels were significantly higher in patients who underwent transplantation and/or died versus spontaneous survivors (P < 0.001), and they were positively associated with conventional markers of liver disease severity. Multivariate logistic regression identified an encephalopathy grade > 2 as an independent predictor of an adverse outcome on admission (odds ratio, 13; 95% confidence interval, 2.3‐73; P < 0.001). The RAGE‐ligand axis may interfere with liver regeneration and should be a promising objective for further research. Liver Transpl 21:847‐854, 2015.

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

ObjectivesHigh 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. MethodsWe studied 265 patients, 190 of whom had NSTE-ACS and 75 had chronic stable angina. ResultsPlasma sRAGE values were comparable in the two groups (P=0.19). However, in the patients with NSTE-ACS, sRAGE levels were significantly higher in patients with cardiac troponin-I (cTnI) of more than or equal to 0.04 µg/l compared with those with cTnI of less than 0.04 µg/l [758 (493–1536 ) pg/ml vs. 454 (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. ConclusionPlasma sRAGE levels are elevated in patients with NSTE-ACS with positive cTnI, suggesting that they could be related to myocardial cell damage.

CIRCULATING LEVELS OF SOLUBLE RAGE AND RAGE-LIGANDS IN PATIENTS WITH ACUTE LIVER FAILURE

Animal studies suggest that receptor for advanced glycation end products (RAGE)–dependent mechanisms contribute to acetaminophen‐induced liver damage. We examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) or RAGE ligands, including extracellular newly identified receptor for advanced glycation end products binding protein (EN‐RAGE), high‐mobility group box 1 (HMGB1), and Nε‐(Carboxymethyl)lysine adducts (CML), could aid in prognostication after an acetaminophen overdose. Sixty well‐characterized acetaminophen‐related acute liver failure (ALF) patients (30 spontaneous survivors and 30 patients who underwent transplantation and/or died) who were enrolled in the National Institutes of Health–sponsored Acute Liver Failure Study Group, were matched by age, met standard criteria for encephalopathy, and had an international normalized ratio > 1.5 were retrospectively studied. HMGB1, EN‐RAGE, CML, and sRAGE were detected by enzyme‐linked immunosorbent assay methods in sera from ALF patients and 30 healthy controls. Levels of sRAGE, EN‐RAGE, and HMGB1 (but not CML) were significantly greater (P < 0.001) in ALF patients versus normal controls. The levels of sRAGE, HMGB1, and EN‐RAGE were significantly higher (P = 0.03, P < 0.01, and P = 0.03) in patients with a systemic inflammatory response syndrome (SIRS) score > 2 versus patients with a SIRS score ≤ 2. Nevertheless, only sRAGE levels were significantly higher in patients who underwent transplantation and/or died versus spontaneous survivors (P < 0.001), and they were positively associated with conventional markers of liver disease severity. Multivariate logistic regression identified an encephalopathy grade > 2 as an independent predictor of an adverse outcome on admission (odds ratio, 13; 95% confidence interval, 2.3‐73; P < 0.001). The RAGE‐ligand axis may interfere with liver regeneration and should be a promising objective for further research. Liver Transpl 21:847‐854, 2015.

Procoagulant activity of circulating microparticles is associated with the presence of moderate calcified plaque burden detected by multislice computed tomography

Background Circulating microparticles (MPs) have been reported to be associated with coronary artery disease (CAD). In this study, we explored the relationship between MPs procoagulant activity and characteristics of atherosclerotic plaque detected by 64-slice computed tomography angiography (CTA). Methods In 127 consecutive patients with CAD but without acute coronary syndrome and who underwent 64-slice CTA, MPs procoagulant activity in plasma (by a thrombin generation test), soluble form of lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) and N(epsilon)-(carboxymethyl) lysine (CML) circulating levels (by ELISA) were measured. A quantitative volumetric analysis of the lumen and plaque burden of the vessel wall (soft and calcific components), for the three major coronary vessels, was performed. The patients were classified in three groups according to the presence of calcium volume: non-calcified plaque (NCP) group (calcium volume (%) = 0), moderate calcified plaque (MCP) group (0 < calcium volume (%) < 1), and calcified plaque (CP) group (calcium volume (%) ≥ 1). Results MPs procoagulant activity and CML levels were higher in MCP group than in CP or NCP group (P = 0.009 and P = 0.027, respectively). MPs procoagulant activity was positively associated with CML (r = 0.317, P < 0.0001) and sLOX-1 levels (r = 0.216, P = 0.0025). Conclusions MPs procoagulant activity was higher in the MCP patient group and correlated positively with sLOX-1 and CML levels, suggesting that it may characterize a state of blood vulnerability that may locally precipitate plaque instability and increase the risk of subsequent major cardiovascular events.

A New Natural Antioxidant Mixture Protects against Oxidative and DNA Damage in Endothelial Cell Exposed to Low-Dose Irradiation

Exposure to ionizing radiation during diagnostic procedures increases systemic oxidative stress and predisposes to higher risk of cancer and cardiovascular disease development. Many studies indicated that antioxidants protect against radiation-induced damage and have high efficacy and lack of toxicity in preventing radiation exposure damages. The purpose of this study was to investigate the in vitro protective effect of a new antioxidant mixture, named RiduROS, on oxidative stress generation and DNA double-strand breaks (DSBs) induced by low doses of X-rays in endothelial cells. Human umbilical vein endothelial cells (HUVEC) were treated with RiduROS mixture 24 h before a single exposure to X-rays at an absorbed dose of 0.25 Gy. The production of reactive oxygen species (ROS) was evaluated by fluorescent dye staining and nitric oxide (NO) by the Griess reaction, and DSBs were evaluated as number of γ-H2AX foci. We demonstrated that antioxidant mixture reduced oxidative stress induced by low dose of X-ray irradiation and that RiduROS pretreatment is more effective in protecting against radiation-induced oxidative stress than single antioxidants. Moreover, RiduROS mixture is able to reduce γ-H2AX foci formation after low-dose X-ray exposure. The texted mixture of antioxidants significantly reduced oxidative stress and γ-H2AX foci formation in endothelial cells exposed to low-dose irradiation. These results suggest that RiduROS could have a role as an effective radioprotectant against low-dose damaging effects.

Circulating levels of soluble receptor for advanced glycation end products and ligands of the receptor for advanced glycation end products in patients with acute liver failure: sRAGE, RAGE LIGANDS, AND ALF

Animal studies suggest that receptor for advanced glycation end products (RAGE)–dependent mechanisms contribute to acetaminophen‐induced liver damage. We examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) or RAGE ligands, including extracellular newly identified receptor for advanced glycation end products binding protein (EN‐RAGE), high‐mobility group box 1 (HMGB1), and Nε‐(Carboxymethyl)lysine adducts (CML), could aid in prognostication after an acetaminophen overdose. Sixty well‐characterized acetaminophen‐related acute liver failure (ALF) patients (30 spontaneous survivors and 30 patients who underwent transplantation and/or died) who were enrolled in the National Institutes of Health–sponsored Acute Liver Failure Study Group, were matched by age, met standard criteria for encephalopathy, and had an international normalized ratio > 1.5 were retrospectively studied. HMGB1, EN‐RAGE, CML, and sRAGE were detected by enzyme‐linked immunosorbent assay methods in sera from ALF patients and 30 healthy controls. Levels of sRAGE, EN‐RAGE, and HMGB1 (but not CML) were significantly greater (P < 0.001) in ALF patients versus normal controls. The levels of sRAGE, HMGB1, and EN‐RAGE were significantly higher (P = 0.03, P < 0.01, and P = 0.03) in patients with a systemic inflammatory response syndrome (SIRS) score > 2 versus patients with a SIRS score ≤ 2. Nevertheless, only sRAGE levels were significantly higher in patients who underwent transplantation and/or died versus spontaneous survivors (P < 0.001), and they were positively associated with conventional markers of liver disease severity. Multivariate logistic regression identified an encephalopathy grade > 2 as an independent predictor of an adverse outcome on admission (odds ratio, 13; 95% confidence interval, 2.3‐73; P < 0.001). The RAGE‐ligand axis may interfere with liver regeneration and should be a promising objective for further research. Liver Transpl 21:847‐854, 2015.