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Mechanical ventilation during experimental sepsis increases deposition of advanced glycation end products and myocardial inflammation
Martin CJ Kneyber, Roel P Gazendam, Hans WM Niessen, Jan-Willem Kuiper, Claudia C Dos Santos, Arthur S Slutsky, Frans B Pl?tz
Critical Care , 2009, DOI: 10.1186/cc7911
Abstract: Sepsis was induced using a modified cecal ligation and perforation (CLP) technique in 36 male adult Sprague Dawley rats. Rats were randomized to four hours of MV with low tidal volume (LTV: 6 ml/kg, PEEP 5 cmH2O, n = 10) or high tidal volume (HTV: 15 ml/kg, PEEP 3 cmH2O, n = 10) 24 hours after the induction of sepsis. Eight rats served as septic, non-ventilated controls and eight as non-septic, non-ventilated controls. After 28 hours all rats were killed. The number of extravascular polymorphonuclear (PMN) leucocytes, macrophages, and lymphocytes was measured as the number of positive cells/mm2. The number of CML positive endothelial cells were semi-quantified based upon an intensity score. The CML intensity score was correlated with the number of inflammatory cells to study the association between CML depositions and inflammation.Gas exchange was comparable between the ventilated groups. Sepsis induced a significant increase in CML deposition in both ventricles that was significantly augmented by MV compared with non-ventilated septic controls (left ventricle 1.1 ± 1.0 vs 0.7 ± 0.1, P = 0.030; right ventricle 2.5 ± 0.5 vs 0.6 ± 0.1, P = 0.037), irrespective of ventilatory strategy. In the right ventricle there was a non-significant tendency towards increased CML deposition in the HTV group compared with septic, non-ventilated controls (1.0 ± 0.1 vs 0.7 ± 0.09, P = 0.07). Sepsis induced a significant increase in the number of macrophages and PMNs compared with non-ventilated septic controls that was augmented by MV, irrespective of ventilatory strategy. CML deposition was significantly correlated with the number of macrophages and PMNs in the heart.Sepsis induces CML deposition in the heart with a predominant right ventricular inflammation that is significantly augmented by MV, irrespective of the ventilatory strategy.Sepsis-induced cardiac dysfunction occurs in approximately 40 to 50% of patients with prolonged septic shock and is associated with increased mortalit
The role of receptor for advanced glycation endproducts (RAGE) in infection
Marieke AD van Zoelen, Ahmed Achouiti, Tom van der Poll
Critical Care , 2011, DOI: 10.1186/cc9990
Abstract: Known PAMPs include lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria, peptidoglycan (present in most bacteria), lipoteichoic acid (in many Gram-positive bacteria), bacterial DNA, viral DNA/RNA and mannans in the yeast cell wall. PAMPs are recognized by pattern recognition receptors (PRRs), in particular Toll-like receptors (TLRs) and Nod-like receptors (NLRs), leading to an inflammatory response via several signaling pathways, including nuclear factor-kappa B (NF-κB) activation and subsequent tumor necrosis factor (TNF)-α production.Examples of putative DAMPs, the endogenous equivalents of PAMPs, are high-mobility group box 1 (HMGB1), some S100 proteins (S100A8/A9, S100A12), interleukins such as IL-1α, heat-shock proteins (HSPs), and nucleosomes [3]. DAMPs can be secreted either actively or passively following necrosis but are not released by apoptotic cells [4] and have activating effects on receptor-expressing cells engaged in host defense. DAMPs can also be detected by TLRs and NLRs and their engagement induces NF-κB activation as well, suggesting that DAMPs and PAMPs use, at least partially, the same receptors and signaling pathways. Liu et al. [5] however, propose that the immune system treats DAMPs and PAMPs differently; they suggest that DAMPs - but not PAMPs - bring CD24-Siglec G/10 into the proximity of TLRs/NLRs, resulting in repressed DAMP-induced TLR/NLR signaling.When invaded by pathogens, host defense systems encounter PAMPs from microorganisms and DAMPs that are released from tissues, which are recognized by TLRs and NLRs to warn the host of imminent danger. In addition, the multiligand receptor for advanced glycation endproducts (RAGE) is regarded as a prototypic DAMP receptor that can bind several DAMPs, including HMGB1 and S100A12 [6]. Other known RAGE ligands include amyloid, β-sheet fibrils, S100B and S100P [7]; furthermore, β2 integrins can interact with RAGE [8]. RAGE is expressed at high levels in the lungs and at low
Inhibitory Effects of Several Spices on Inflammation Caused by Advanced Glycation Endproducts  [PDF]
Su-Chen Ho, Pei-Wen Chang
American Journal of Plant Sciences (AJPS) , 2012, DOI: 10.4236/ajps.2012.327118
Abstract: Advanced glycation endproducts (AGEs) is implicated in the pathogenesis of diabetic complications. Inhibiting the formation of AGEs and interfering with AGEs-mediated inflammation are two practicable strategies for developing a dietary adjuvant against diabetic complications. This study evaluated the protective capacities against diabetic complications of several spices based on their inhibition of the formation of AGEs in an in vitro BSA/glucose system and on the AGEs-induced production of proinflammatory cytokine in RAW 264.7 macrophages. Among the tested spices, cinnamon exhibited most strongly inhibited both the formation of AGEs and the AGEs-induced production of nitric oxide, interleukin-6 and tumor necrosis factor-α. Additionally, correlative results revealed that the capacity of spices to inhibit the formation of AGEs is attributable to phenolic compounds and, in contrast, the capacity to inhibit AGEs-induced inflammation is attributable to condensed tannin. This investigation demonstrates the potential of cinnamon to serve as a dietary adjuvant against diabetic complications.
RAGE (Receptor for Advanced Glycation Endproducts), RAGE Ligands, and their role in Cancer and Inflammation
Louis J Sparvero, Denise Asafu-Adjei, Rui Kang, Daolin Tang, Neilay Amin, Jaehyun Im, Ronnye Rutledge, Brenda Lin, Andrew A Amoscato, Herbert J Zeh, Michael T Lotze
Journal of Translational Medicine , 2009, DOI: 10.1186/1479-5876-7-17
Abstract: The Receptor for Advanced Glycation Endproducts [RAGE] is a member of the immunoglobulin superfamily, encoded in the Class III region of the major histocompatability complex [1-4]. This multiligand receptor has one V type domain, two C type domains, a transmembrane domain, and a cytoplasmic tail. The V domain has two N-glycosylation sites and is responsible for most (but not all) extracellular ligand binding [5]. The cytoplasmic tail is believed to be essential for intracellular signaling, possibly binding to diaphanous-1 to mediate cellular migration [6]. Originally advanced glycation endproducts (AGEs) were indeed thought to be its main activating ligands, but since then many other ligands of RAGE including damage-associated molecular patterns (DAMP's) have been identified [1,7,8]. RAGE is thus considered a pattern-recognition receptor (PRR), having a wide variety of ligands [9-11].RAGE is expressed as both full-length, membrane-bound forms (fl-RAGE or mRAGE, not to be confused with mouse RAGE) and various soluble forms lacking the transmembrane domain. Soluble RAGE is produced by both proteolytic cleavage of fl-RAGE and alternative mRNA splicing. The soluble isoforms include the extracellular domains but lack the transmembrane and cytoplasmic domains [12-15]. Soluble RAGE derived specifically from proteolytic cleavage is sRAGE, although this terminology is not consistent in the literature – sRAGE sometimes refers to soluble RAGE in general. RAGE is expressed at low levels in a wide range of differentiated adult cells in a regulated manner but in mature lung type-I pneumocytes it is expressed at substantially higher levels than in other resting cell types. It is highly expressed in readily detectable amounts in embryonic cells [16]. RAGE is also highly expressed and associated with many inflammation-related pathological states such as vascular disease, cancer, neurodegeneration and diabetes (Figure 1) [17,18]. The exceptions are lung tumors and idiopathic pulmonar
The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes
Robbert Meerwaldt, Thera Links, Clark Zeebregts, Rene Tio, Jan-Luuk Hillebrands, Andries Smit
Cardiovascular Diabetology , 2008, DOI: 10.1186/1475-2840-7-29
Abstract: Patients with diabetes have a mortality rate from cardiovascular disease (CVD) that is over twice compared to that in the general population [1]. The Adult Treatment Panel III regards diabetes as a coronary heart disease risk equivalent. A number of hemodynamic and metabolic factors co-operate in diabetes [2]. Both the Diabetes Control and Complications Trial (DCCT) in type 1 diabetes mellitus and the UK Prospective Diabetes Study (UKPDS) in type 2 diabetes mellitus established a causal relationship between chronic hyperglycemia and long-term diabetic complications [3,4]. There is increasing evidence that advanced glycation endproducts (AGEs) play a pivotal role in atherosclerosis, in particular in diabetes. AGE accumulation is not just a measure of hyperglycemia, but represents cumulative metabolic burden (both hyperglycemia and hyperlipidemia), oxidative stress and inflammation [5]. Interaction between AGEs and AGE-specific receptors induce inflammatory reactions and endothelial dysfunction [6]. This review will focus on the clinical merits of assessing AGE accumulation in diabetic patients, outlining the evidence for the role of AGEs in the pathogenesis of CVD and the possibilities for AGE-intervention. Finally, we will discuss the clinical relevance for assessing AGE accumulation.The original Maillard hypothesis on the formation of AGEs proposed that chemical modification of proteins by reducing sugars (glycation of proteins) in diabetes alters the structure and function of tissue proteins, precipitating the development of diabetic complications (Fig. 1) [7]. Glycation involves the formation of chemically reversible early glycosylation products with proteins, so called Schiff bases and Amadori adducts (e.g. glycated hemoglobin; HbA1C). With time, it became clear that these early adducts undergo slow and complex rearrangements to form advanced glycation end-products (AGEs). Baynes and colleagues noted the importance of oxidizing conditions and reactive oxygen spe
Advanced Glycation Endproducts in 35 Types of Seafood Products Consumed in Eastern China Advanced Glycation Endproducts in 35 Types of Seafood Products Consumed in Eastern China  [PDF]
WANG Jing,LI Zhenxing,PAVASE Ramesh Tushar,LIN Hong,ZOU Long,WEN Jie,LV Liangtao
- , 2016,
Abstract: Advanced glycation endproducts(AGEs) have been recognized as hazards in processed foods that can induce chronic diseases such as cardiovascular disease, diabetes, and diabetic nephropathy. In this study, we investigated the AGEs contents of 35 types of industrial seafood products that are consumed frequently in eastern China. Total fluorescent AGEs level and Nε-carboxymethyl-lysine(CML) content were evaluated by fluorescence spectrophotometry and gas chromatography-mass spectrometry(GC-MS), respectively. The level of total fluorescent AGEs in seafood samples ranged from 39.37 to 1178.3 AU, and was higher in canned and packaged instant aquatic products that were processed at high temperatures. The CML content in seafood samples ranged from 44.8 to 439.1 mg per kg dried sample, and was higher in roasted seafood samples. The total fluorescent AGEs and CML content increased when seafood underwent high-temperature processing, but did not show an obvious correlation. The present study suggested that commonly consumed seafood contains different levels of AGEs, and the seafood processed at high temperatures always displays a high level of either AGEs or CML
Protective Effects of Corni Fructus against Advanced Glycation Endproducts and Radical Scavenging
Chan Hum Park,Takashi Tanaka,Hyun Young Kim,Jong Cheol Park,Takako Yokozawa
Evidence-Based Complementary and Alternative Medicine , 2012, DOI: 10.1155/2012/418953
Abstract: We investigated the inhibition of advanced glycation endproduct (AGE) activity using the fluorescence characteristics of fractions and compounds from Corni Fructus. Corni Fructus extract and its iridoid glycoside components showed low inhibitory activities as well as the AGE inhibitor aminoguanidine. However, a low molecular weight polyphenol, 7-O-galloyl-D-sedoheptulose, and an antioxidant, trolox, showed high inhibitory activities compared with aminoguanidine under reactive conditions. The AGE-inhibiting activity of polyphenolic fractions of Corni Fructus ranged from a level comparable to Corni Fructus extract to the higher level of 7-O-galloyl-D-sedoheptulose. As well as the results of AGE-inhibiting activity, Corni Fructus extract and iridoid components showed low or no 1,1-diphenyl-2-pycrylhydrazyl (DPPH) radical-scavenging activities, whereas 7-O-galloyl-D-sedoheptulose showed a level comparable to trolox. Polyphenolic fractions of Corni Fructus quenched DPPH radicals in a concentration-dependent manner. Some fractions exerted a higher DPPH radical-scavenging activity compared with trolox and 7-O-galloyl-D-sedoheptulose. The DPPH radical-scavenging activity was significantly correlated with the AGE-inhibiting activity. These results suggest that polyphenolic fractions of Corni Fructus inhibited AGE formation by antioxidant activity including free radical scavenging. The strong DPPH radical-scavenging and AGE-inhibiting fractions included ellagitannins and polymeric proanthocyanidins.
Skin Autofluorescence, as Marker of Accumulation of Advanced Glycation Endproducts and of Cumulative Metabolic Stress, Is Not Increased in Patients with Systemic Sclerosis  [PDF]
M. E. Hettema,H. Bootsma,R. Graaff,R. de Vries,C. G. M. Kallenberg,A. J. Smit
International Journal of Rheumatology , 2011, DOI: 10.1155/2011/417813
Abstract: Objective. To investigate whether advanced glycation endproducts (AGEs) in the skin are increased in patients with systemic sclerosis (SSc) and are related to the presence of disease-related and traditional cardiovascular risk factors. Methods. Skin autofluorescence, as a measure for the accumulation of AGEs, was assessed by measuring UV-A light excitation-emission matrices (AF-EEMS) in 41 SSc patients and 41 age- and sex-matched controls. Traditional cardiovascular risk factors and disease-related risk factors were recorded. Results. Skin AF-EEMS did not differ between SSc patients and controls ( ?a.u. versus ?a.u., ). Skin AF-EEMS in SSc patients was associated with levels of CRP ( , ), Medsger's severity scale ( , ), and use of agents intervening in the renin-angiotensin system ( , ). When analysing SSc patients and controls together, in multivariate analysis, only age and use of agents intervening in the renin-angiotensin system were independently associated with AF-EEMS. Conclusion. These data demonstrate that skin AGEs are not increased in SSc patients. 1. Introduction Vascular involvement is a key factor in major manifestations of systemic sclerosis (SSc), such as Raynaud’s phenomenon (RP), myocardial dysfunction, pulmonary hypertension, and renal involvement. Microvascular involvement, in which endothelial injury is present, is the main characteristic of SSc [1, 2] Oxidative stress has been suggested as a major player in the process of endothelial dysfunction found in SSc. Endothelial damage may be induced by oxygen free radicals and reactive nitrogen species, generated locally by the inflammatory process and by periods of tissue ischemia followed by postischaemic reperfusion. This so-called ischaemic-reperfusion injury can be seen in RP [3, 4]. Increased levels of antibodies against oxidised low-density lipoproteins (LDL) [4–6] and increased serum levels of 8-isoprostane [7], being markers of oxidative stress, have, indeed, been observed in SSc. Oxidative or carbonyl stress, leading to formation of so-called reactive carbonyl compounds, is an important source for the generation of so-called advanced glycation endproducts (AGEs) [8]. AGE generation as a result of oxidative stress has also been found in inflammatory diseases, such as rheumatoid arthritis and SLE [9–15]. Tissue autofluorescence (AF) is a marker of the accumulation of AGEs, validated in different patient groups and healthy controls [16–18]. Therefore, we assessed AGE accumulation in patients with SSc and hypothesized that AGE accumulation is increased in patients with SSc compared
Effect of Benfotiamine on Advanced Glycation Endproducts and Markers of Endothelial Dysfunction and Inflammation in Diabetic Nephropathy  [PDF]
Alaa Alkhalaf, Nanne Kleefstra, Klaas H. Groenier, Henk J. G. Bilo, Reinold O. B. Gans, Peter Heeringa, Jean L. Scheijen, Casper G. Schalkwijk, Gerjan J. Navis, Stephan J. L. Bakker
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040427
Abstract: Background Formation of advanced glycation endproducts (AGEs), endothelial dysfunction, and low-grade inflammation are intermediate pathways of hyperglycemia-induced vascular complications. We investigated the effect of benfotiamine on markers of these pathways in patients with type 2 diabetes and nephropathy. Methods Patients with type 2 diabetes and urinary albumin excretion in the high-normal and microalbuminuric range (15–300 mg/24h) were randomized to receive benfotiamine (n = 39) or placebo (n = 43). Plasma and urinary AGEs (Nε-(carboxymethyl) lysine [CML], Nε-(Carboxyethyl) lysine [CEL], and 5-hydro-5-methylimidazolone [MG-H1]) and plasma markers of endothelial dysfunction (soluble vascular cell adhesion molecule-1 [sVCAM-1], soluble intercellular adhesion molecule-1 [sICAM-1], soluble E-selectin) and low-grade inflammation (high-sensitivity C-reactive protein [hs-CRP], serum amyloid-A [SAA], myeloperoxidase [MPO]) were measured at baseline and after 6 and 12 weeks. Results Compared to placebo, benfotiamine did not result in significant reductions in plasma or urinary AGEs or plasma markers of endothelial dysfunction and low-grade inflammation. Conclusions Benfotiamine for 12 weeks did not significantly affect intermediate pathways of hyperglycemia-induced vascular complications. Trial Regristration ClinicalTrials.gov NCT00565318
The Bioinformatics and Molecular Biology Approaches for Vascular Cell Signaling by Advanced Glycation Endproducts Receptor and Small Ubiquitin-Related Modifier  [cached]
June Hyun Kim
Interdisciplinary Bio Central , 2012,
Abstract: The advanced glycation endproducts receptor (AGE-R) has been established as a signal transduction receptor for multiligand such as S100b and AGEs. These molecules have been demonstrated to activate various cells with important links to atherosclerosis initiation and progression including endothelial cells and smooth muscle cells via AGER, triggering activation of multiple signaling cascades through its cytoplasmic domain. Very Recently, Small Ubiquitin-Related Modifier 1 (SURM-1 also known as SUMO-1) has recently been recognized as a protein that plays a diverse role in cellular post-translational modifications. SURM-1 functions in a manner similar to ubiquitin in that it is bound to target proteins as part of a post-translational modification system. However, unlike ubiquitin, which targets proteins for degradation, this protein is involved in a variety of cellular processes, such as nuclear transport, apoptosis, and protein stability. Computer Database search indicated that AGE-R has the conserved consensus SURMylation motif, defined as yKXE. The five potential SURMylation sites wereidentified in human AGE-R. The presence of the consensus yKXE motif in the AGE-R strongly suggests that AGE-R may be regulated by SURMylation process. Our results suggest that AGE-R is SURMylated in a living vascular and other cell system. Fully utilizing the power of complementary bioinformatics and molecular biological approaches, we determined the interactions of AGE-R and SURM-1 in a living vascular cell system. Whilst SURMylation and AGE-R undoubtedly plays an important role in the cardiovascular biology, it remains unclear as to the exact nature of this contribution under both physiological and pathological conditions.
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