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Purpose of review: Sepsis is still associated with excess morbidity and mortality worldwide, despite significant advances in critical care medicine. A novel approach is needed in the treatment of sepsis, one that will aim to correct the specific immunologic imbalance that is detrimental to the septic host. Recent findings: As receptor for advanced glycation end products (RAGE) is involved in diverse cellular mechanisms that to a lesser or greater extent participate in the septic process, modulating its function could favorably affect outcome. Altering RAGE may result in regulating the release of proinflammatory cytokines, controlling apoptosis or modifying endothelial architecture. In that regard, several strategies have been used to study RAGE deficiency in experimental models of sepsis including antibodies against RAGE, genetically deleted RAGE knockouts, siRNA to silence RAGE, soluble forms of RAGE, and antibodies and inhibitors directed toward RAGE ligands, such as HMGB1 and S100 proteins. Summary: These studies thus far have yielded inconsistent results as to whether RAGE is beneficial or not to the host response during bacterial infection and sepsis. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. 25 3 304 311

Objectives Levels of soluble receptor for advanced glycation endproducts (sRAGE) have been linked to several components of the metabolic syndrome. We tested the hypothesis that plasma levels of sRAGE may be associated with non-alcoholic fatty liver disease. Design and methods We enrolled subjects with definite nonalcoholic steatohepatitis (NASH, n = 40), borderline NASH (n = 8), simple fatty liver (n = 9) and healthy controls (n = 14). Plasma levels of sRAGE were measured by ELISA. Results Concentrations of sRAGE were significantly lower in patients with definite NASH (1080 ± 392 pg/mL, P

Altered vascular reactivity due to endothelial dysfunction, consequent to vascular damage, is observed in rheumatoid arthritis. We investigated the effect of angiotensin (Ang)-(1-7) on vasculature changes in arthritis induced by complete Freund's adjuvant in male Wistar rats. Arthritis decreased soluble receptor for advanced glycation end products (sRAGE) whereas elevated aortic RAGE expression, increased interleukin-1ß (IL-1ß) and tumor necrosis factor-? (TNF-?), systolic blood pressure and the contractility induced by phenylephrine and KCl. Moreover, arthritis decreased the relaxing effect of acetylcholine. Neither arthritis nor Ang-(1-7) altered sodium nitroprusside relaxation. Ang-(1-7) reversed the effect of arthritis on TNF-?, sRAGE and RAGE expression without any effect on the IL-1ß. Ang-(1-7) decreased phenylephrine and KCl contractility, especially in the endothelial-denuded aorta, whereas increased acetylcholine relaxation in the endothelial-intact aorta. Ang-(1-7) could find its place in the treatment protocol of arthritis and vascular diseases. © 2016 S. Karger AG, Basel.

Accumulation of advanced glycation endproducts (AGEs) plays a crucial part in the development of age-related diseases and diabetic complications. AGEs are formed in vivo via the so-called Maillard reaction: a reducing sugar reacts with a protein to form a labile Amadori product that is subsequently stabilized, producing an irreversible, non-enzymatic post-translational modification of the protein involved. Recently, it has become clear that, in addition to sugars, lipids play an important role in the initiation of AGE formation, and that genetic factors contribute to an individual's AGE levels. The highest AGE levels are found in tissues with slow turnover, such as tendon, skin, bone, amyloid plaques and cartilage. AGEs exert their effects by adversely affecting the mechanical properties of the matrix and by modulating tissue turnover. In cartilage, these detrimental effects result in tissue that is more prone to the development of osteoarthritis. As such, the accumulation of AGEs provides the first molecular mechanism explaining the age-related increase in the incidence of osteoarthritis. Ongoing research into anti-AGE-ing therapies, such as pyrodoxamine and thiazolium compounds, which are often developed to prevent AGE-induced diabetic complications, might also prove beneficial for the prevention of osteoarthritis. © Elsevier Ltd. All rights reserved. Chemicals / CAS: advanced glycation end product receptor, 198785-73-8, 247590-69-8; alagebrium, 341028-37-3; glucosamine, 3416-24-8, 4607-22-1; lipid, 66455-18-3; pyridoxamine, 13876-70-5, 5103-96-8, 524-36-7, 85-87-0; Glycosylation End Products, Advanced

Ligands for the receptor for advanced glycation endproducts (RAGE) are increased in RA synovial fluid (SF), serum and synovium. Since RAGE is present on fibroblast-like synoviocytes (FLS), the present study investigates whether the RAGE ligands HMGB-1 and AGEs are able to stimulate the characteristic, pathological invasive behaviour of these cells. FLS were obtained during joint replacement surgery. FLS were seeded in serum free medium with HMGB-1 or glycated albumin (BSA-AGE) on transwell filters coated with Matrigel. The lower compartment contained medium with serum as a chemoattractant. After three days, the percentage of invading cells was determined and compared to the control invasion. Stimulation with HMGB-1 increased invasiveness to 125% compared to the control (p = 0.001). Addition of anti-RAGE antibody reduced this back to baseline (98%, p = 0.002). Stimulation with BSA-AGE, another RAGE ligand, increased invasiveness to 150% compared to the control (p = 0.003). Addition of anti RAGE was again able to reduce the increased invasiveness back to baseline (95%, p = 0.008). HMGB-1 and BSA-AGE stimulated the invasiveness of RA-FLS by activation of RAGE. As such, RAGE may be an interesting target for therapy directed at the inhibition of synoviocyte activation. © Copyright Clinical and Experimental Rheumatology 2007.

Diabetes represents an independent risk factor for coronary artery disease (CAD), and the prognosis in terms of survival rates is worse for diabetic patients who have CAD with respect to those with CAD but no diabetes. An acute coronary event represents a cause of death in more than 30% of diabetics. Experimental studies suggested that the increased incidence of myocardial infarction in diabetics is due to an increased risk of developing atherosclerotic plaque with subsequent ulceration and intracoronary thrombus formation. Structural abnormalities of the coronary vessel wall were associated with an abnormal pattern of coronary flow and of coagulation abnormalities: all these abnormalities explain the epidemiological evidence of widespread and severe vascular atherosclerotic disease in diabetics. Due to the extreme complexity of ischemic vascular disease in patients with diabetes, an optimal therapeutic strategy is based on the correction of elevated blood glucose and lipid levels, of blood pressure, of platelet and coagulation abnormalities and of any other risk factor. Both percutaneous and surgical myocardial revascularization have been proved equally effective for CAD treatment in diabetes, even though a recent randomized trial has shown a significantly improved outcome after surgical revascularization. More recently the characterization of the advanced glycation end-product receptor opened new perspectives in the treatment of the complications of diabetes, and gave a new impact to the need of further investigations, through new randomized trials, of the best therapeutic options for diabetic patients.