Acute insulin resistance mediated by advanced glycation endproducts in severely burned rats.

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Zhang, Xing; Xu, Jie; Cai, Xiaoqing; Ji, Lele; Li, Jia; Cao, Bing; Li, Jun; Hu, Dahai; Li, Yan; Wang, Haichang; Xiong, Lize; Xiao, Ruiping; Gao, Feng

2014-06-01

Hyperglycemia often occurs in severe burns; however, the underlying mechanisms and importance of managing postburn hyperglycemia are not well recognized. This study was designed to investigate the dynamic changes of postburn hyperglycemia and the underlying mechanisms and to evaluate whether early glycemic control is beneficial in severe burns. Prospective, randomized experimental study. Animal research laboratory. Sprague-Dawley rats. Anesthetized rats were subjected to a full-thickness burn injury comprising 40% of the total body surface area and were randomized to receive vehicle, insulin, and a soluble form of receptor for advanced glycation endproducts treatments. An in vitro study was performed on cultured H9C2 cells subjected to vehicle or carboxymethyllysine treatment. We found that blood glucose change presented a distinct pattern with two occurrences of hyperglycemia at 0.5- and 3-hour postburn, respectively. Acute insulin resistance evidenced by impaired insulin signaling and glucose uptake occurred at 3-hour postburn, which was associated with the second hyperglycemia and positively correlated with mortality. Mechanistically, we found that serum carboxymethyllysine, a dominant species of advanced glycation endproducts, increased within 1-hour postburn, preceding the occurrence of insulin resistance. More importantly, treatment of animals with soluble form of receptor for advanced glycation endproducts, blockade of advanced glycation endproducts signaling, alleviated severe burn-induced insulin resistance. In addition, early hyperglycemic control with insulin not only reduced serum carboxymethyllysine but also blunted postburn insulin resistance and reduced mortality. These findings suggest that severe burn-induced insulin resistance is partly at least mediated by serum advanced glycation endproducts and positively correlated with mortality. Early glycemic control with insulin or inhibition of advanced glycation endproducts with soluble form of receptor

Association of high mobility group BOX-1 and receptor for advanced glycation endproducts with clinicopathological features of haematological malignancies: a systematic review

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Austin H. Nguyen

2017-01-01

Full Text Available High-mobility group box 1 (HMGB1 is a versatile protein with nuclear and extracellular functions. In the extracellular milieu, HMGB1 binds to several receptors, notably the receptor for advanced glycation end-products (RAGE. The expressions of HMGB1 and RAGE have been described in a variety of cancers. However, the clinical values of HMGB1 and RAGE in haematological malignancies have yet to be evaluated. A systematic search through PubMed and the Web of Science for articles discussing the role of HMGB1 and RAGE in haematological malignancies produced 15 articles. Overexpression of HMGB1 was reported to be associated with malignancy and, in certain studies, poor prognosis and tumour aggressiveness. Only one included study investigated the clinical value of RAGE, in which no significant difference was found between expression of RAGE in CLL neoplastic cells and nonmalignant controls. The discussed associations of HMGB1 and RAGE with clinicopathological characteristics of patients with haematological malignancies warrants further investigation into the prognostic and diagnostic value of both of these molecules.

The advanced glycation end-product Nϵ -carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes-associated risk and its prevention.

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Menini, Stefano; Iacobini, Carla; de Latouliere, Luisa; Manni, Isabella; Ionta, Vittoria; Blasetti Fantauzzi, Claudia; Pesce, Carlo; Cappello, Paola; Novelli, Francesco; Piaggio, Giulia; Pugliese, Giuseppe

2018-03-13

Diabetes is an established risk factor for pancreatic cancer (PaC), together with obesity, a Western diet, and tobacco smoking. The common mechanistic link might be the accumulation of advanced glycation end-products (AGEs), which characterizes all of the above disease conditions and unhealthy habits. Surprisingly, however, the role of AGEs in PaC has not been examined yet, despite the evidence of a tumour-promoting role of receptor for advanced glycation end-products (RAGE), the receptor for AGEs. Here, we tested the hypothesis that AGEs promote PaC through RAGE activation. To this end, we investigated the effects of the AGE N ϵ -carboxymethyllysine (CML) in human pancreatic ductal adenocarcinoma (PDA) cell lines and in a mouse model of Kras-driven PaC interbred with a bioluminescent model of proliferation. Tumour growth was monitored in vivo by bioluminescence imaging and confirmed by histology. CML promoted PDA cell growth and RAGE expression, in a concentration-dependent and time-dependent manner, and activated downstream tumourigenic signalling pathways. These effects were counteracted by RAGE antagonist peptide (RAP). Exogenous AGE administration to PaC-prone mice induced RAGE upregulation in pancreatic intraepithelial neoplasias (PanINs) and markedly accelerated progression to invasive PaC. At 11 weeks of age (6 weeks of CML treatment), PaC was observed in eight of 11 (72.7%) CML-treated versus one of 11 (9.1%) vehicle-treated [control (Ctr)] mice. RAP delayed PanIN development in Ctr mice but failed to prevent PaC promotion in CML-treated mice, probably because of competition with soluble RAGE for binding to AGEs and/or compensatory upregulation of the RAGE homologue CD166/ activated leukocyte cell adhesion molecule, which also favoured tumour spread. These findings indicate that AGEs modulate the development and progression of PaC through receptor-mediated mechanisms, and might be responsible for the additional risk conferred by diabetes and other

Evaluation of advanced glycation end-products in diabetic and inherited canine cataracts.

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Bras, I Dineli; Colitz, Carmen M H; Kusewitt, Donna F; Chandler, Heather; Lu, Ping; Gemensky-Metzler, Anne J; Wilkie, David A

2007-02-01

The receptor for advanced glycation end-products (RAGE) increases in the human cataract and should correlate with increased DNA damage and proliferation of lens epithelial cells (LECs). The purpose of this study was to measure and immunolocalize RAGE in normal and cataractous canine LECs, and to determine whether there was a correlation between RAGE and DNA damage (gadd45), cell-cycle regulation (p21), and LEC proliferation (proliferating cell nuclear antigen, PCNA). Thirty-two anterior lens capsules from 22 dogs that underwent cataract surgery and 10 lenses from dogs with normal eyes were evaluated. Eleven of the cataractous lenses were from diabetic patients (n=16), and eleven were from patients with inherited cataracts (n=16). Standard immunohistochemical staining was performed using antibodies against RAGE, gadd45, p21, PCNA, alpha-smooth muscle actin, and TGF-beta. Immunostaining intensity for each antibody was given a score of 0-4+. Standard Western blot analysis on normal and cataractous lens capsules was performed using the same antibodies as in the immunohistochemical staining. Comparisons were also made based on age and sex. Real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for RAGE. There was an increase in RAGE expression with age in normal LECs, but no significant difference was seen when normal adult LECs were compared to cataractous LECs. The stage of the cataract and the presence of LIU were not associated with a significant increase in RAGE expression. There was no age-dependent difference in the normal lenses for gadd45, p21, or PCNA. Significant up-regulation of p21 (P RAGE and PCNA expression did not increase with cataractogenesis, possibly due to overexpression associated with normal aging and constant exposure to oxidative stress from sunlight-related ultraviolet irradiation, respectively. However, p21 and PCNA increased in diabetic cataractogenesis suggesting cell cycle and proliferation dysregulation. This may

Soluble Receptor for Advanced Glycation End-Products Predicts Impaired Alveolar Fluid Clearance in Acute Respiratory Distress Syndrome.

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Jabaudon, Matthieu; Blondonnet, Raiko; Roszyk, Laurence; Bouvier, Damien; Audard, Jules; Clairefond, Gael; Fournier, Mathilde; Marceau, Geoffroy; Déchelotte, Pierre; Pereira, Bruno; Sapin, Vincent; Constantin, Jean-Michel

2015-07-15

Levels of the soluble form of the receptor for advanced glycation end-products (sRAGE) are elevated during acute respiratory distress syndrome (ARDS) and correlate with severity and prognosis. Alveolar fluid clearance (AFC) is necessary for the resolution of lung edema but is impaired in most patients with ARDS. No reliable marker of this process has been investigated to date. To verify whether sRAGE could predict AFC during ARDS. Anesthetized CD-1 mice underwent orotracheal instillation of hydrochloric acid. At specified time points, lung injury was assessed by analysis of blood gases, alveolar permeability, lung histology, AFC, and plasma/bronchoalveolar fluid measurements of proinflammatory cytokines and sRAGE. Plasma sRAGE and AFC rates were also prospectively assessed in 30 patients with ARDS. The rate of AFC was inversely correlated with sRAGE levels in the plasma and the bronchoalveolar fluid of acid-injured mice (Spearman's ρ = -0.73 and -0.69, respectively; P < 10(-3)), and plasma sRAGE correlated with AFC in patients with ARDS (Spearman's ρ = -0.59; P < 10(-3)). Similarly, sRAGE levels were significantly associated with lung injury severity, and decreased over time in mice, whereas AFC was restored and lung injury resolved. Our results indicate that sRAGE levels could be a reliable predictor of impaired AFC during ARDS, and should stimulate further studies on the pathophysiologic implications of RAGE axis in the mechanisms leading to edema resolution. Clinical trial registered with www.clinicaltrials.gov (NCT 00811629).

Neurite regeneration in adult rat retinas exposed to advanced glycation end-products and regenerative effects of neurotrophin-4.

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Bikbova, Guzel; Oshitari, Toshiyuki; Yamamoto, Shuichi

2013-10-09

The purpose of this study was to determine the effect of low concentrations of advanced glycation end-products on neurite regeneration in isolated rat retinas, and to determine the effects of neurotrophin-4 on regeneration in advanced glycation end-products exposed retinas. Retinal explants of 4 adult Sprague-Dawley rats were cultured on collagen gel and were incubated in; (1) serum-free control culture media, (2) glucose-advanced glycation end-products-bovine serum albumin media, (3) glycolaldehyde-advanced glycation end-products-bovine serum albumin media, (4) glyceraldehyde-advanced glycation end-products-bovine serum albumin media, (5) glucose-advanced glycation end-products+neurotrophin-4 media, (6) glycolaldehyde-advanced glycation end-products+neurotrophin-4 media, or (7) glyceraldehyde-advanced glycation end-products+neurotrophin-4 supplemented culture media. After 7 days, the number of regenerating neurites from the explants was counted. Then, explants were fixed, cryosectioned, and stained for TUNEL. The ratio of TUNEL-positive cells to all cells in the ganglion cell layer was determined. Immunohistochemical examinations for the active-form of caspase-9 and apoptosis-inducing factor were performed. In retinas incubated with advanced glycation end-products containing media, the number of regenerating neurites were fewer than in retinas without advanced glycation end-products, and the number of TUNEL-positive cells and caspase-9- and apoptosis-inducing factor-immunopositive cells was significantly higher than in control media. Neurotrophin-4 supplementation increased the numbers of regenerating neuritis, and the number of TUNEL-positives, caspase-9-, and apoptosis-inducing factor-immunopositive cells were significantly fewer than that in advanced glycation end-products without neurotrophin-4 media. Low doses of advanced glycation end-products impede neurite regeneration in the rat retinas. Neurotrophin-4 significantly enhances neurite regeneration in

Skin Autofluorescence Relates to Soluble Receptor for Advanced Glycation End-Products and Albuminuria in Diabetes Mellitus

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J. Škrha

2013-01-01

Full Text Available The aim of this study was to compare skin autofluorescence caused by advanced glycation end-products (AGEs with biochemical markers of endothelial dysfunction and soluble receptor for AGEs (sRAGE in patients with diabetes. Skin autofluorescence (AF assessed by AGE-Reader was evaluated with sRAGE and other biochemical parameters in 88 patients with diabetes (47 Type 1/T1DM/ and 41 Type 2/T2DM/ and 20 controls. Skin AF was significantly higher in T1DM and T2DM in comparison to controls (2.39 ± 0.54, 2.63 ± 0.73 versus 1.96 ± 0.33 AU; P<0.0001. Positive correlation of AF with sRAGE was detected in T1DM and T2DM (r=0.37, P<0.02 and r=0.60, P<0.0001, but not in controls. Significantly higher AF values were found in patients with positive albuminuria as compared to those with normal albuminuria. Similarly, higher AF was detected in patients with endothelial dysfunction expressed by vWF, ICAM-1, and VCAM-1. Multiple regression analysis revealed independent association of skin AF with age, sRAGE, and albumin-creatinine ratio in patients with diabetes (R2=0.38. Our study confirms that AF is elevated in patients with diabetes, especially with positive albuminuria and endothelial dysfunction. The strong and independent relationship between AF and sRAGE supports the idea that AF may reflect AGEs/RAGE interactions. The exact mechanism remains to be established.

The AGE-RAGE axis in an Arab population: The United Arab Emirates Healthy Futures (UAEHFS pilot study

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Claire K. Inman

2017-12-01

Full Text Available Aims: The transformation of the United Arab Emirates (UAE from a semi-nomadic to a high income society has been accompanied by increasing rates of obesity and Type 2 diabetes mellitus. We examined if the AGE-RAGE (receptor for advanced glycation endproducts axis is associated with obesity and diabetes mellitus in the pilot phase of the UAE Healthy Futures Study (UAEHFS. Methods: 517 Emirati subjects were enrolled and plasma/serum levels of AGE, carboxy methyl lysine (CML-AGE, soluble (sRAGE and endogenous secretory (esRAGE were measured along with weight, height, waist and hip circumference (WC/HC, blood pressure, HbA1c, Vitamin D levels and routine chemistries. The relationship between the AGE-RAGE axis and obesity and diabetes mellitus was tested using proportional odds models and linear regression. Results: After covariate adjustment, AGE levels were significantly associated with diabetes status. Levels of sRAGE and esRAGE were associated with BMI and levels of sRAGE were associated with WC/HC. Conclusions: The AGE-RAGE axis is associated with diabetes status and obesity in this Arab population. Prospective serial analysis of this axis may identify predictive biomarkers of obesity and cardiometabolic dysfunction in the UAEHFS. Keywords: Advanced glycation endproducts (AGEs, Receptor for AGE (RAGE, Cohort study, Diabetes mellitus, Obesity

RAGE, receptor of advanced glycation endoproducts, negatively regulates chondrocytes differentiation.

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Tatsuya Kosaka

Full Text Available RAGE, receptor for advanced glycation endoproducts (AGE, has been characterized as an activator of osteoclastgenesis. However, whether RAGE directly regulates chondrocyte proliferation and differentiation is unclear. Here, we show that RAGE has an inhibitory role in chondrocyte differentiation. RAGE expression was observed in chondrocytes from the prehypertrophic to hypertrophic regions. In cultured cells, overexpression of RAGE or dominant-negative-RAGE (DN-RAGE demonstrated that RAGE inhibited cartilaginous matrix production, while DN-RAGE promoted production. Additionally, RAGE regulated Ihh and Col10a1 negatively but upregulated PTHrP receptor. Ihh promoter analysis and real-time PCR analysis suggested that downregulation of Cdxs was the key for RAGE-induced inhibition of chondrocyte differentiation. Overexpression of the NF-κB inhibitor I-κB-SR inhibited RAGE-induced NF-κB activation, but did not influence inhibition of cartilaginous matrix production by RAGE. The inhibitory action of RAGE was restored by the Rho family GTPases inhibitor Toxin B. Furthermore, inhibitory action on Ihh, Col10a1 and Cdxs was reproduced by constitutively active forms, L63RhoA, L61Rac, and L61Cdc42, but not by I-κB-SR. Cdx1 induced Ihh and Col10a1 expressions and directly interacted with Ihh promoter. Retinoic acid (RA partially rescued the inhibitory action of RAGE. These data combined suggests that RAGE negatively regulates chondrocyte differentiation at the prehypertrophic stage by modulating NF-κB-independent and Rho family GTPases-dependent mechanisms.

Dietary advanced glycation endproducts

DEFF Research Database (Denmark)

Poulsen, Malene Wibe

High heat cooking induces flavor, aroma, and color of food, but leads to formation of advanced glycation endproducts (AGEs) by the Maillard reaction. In addition to the formation in food, AGEs are also formed in vivo, and increased endogenous formation of AGEs has been linked to diabetic...... on postprandial subjective appetite sensations, appetite hormones, and markers of inflammation of two cooking methods that respectively induce or limit AGE formation were investigated in healthy overweight individuals. It was concluded that the meals affected subjective appetite sensations similarly, but the high...... sensitivity of cooking methods that induce or limit AGE formation were investigated in healthy overweight women. It was concluded that insulin sensitivity was improved with use of low heat cooking methods, compared with high heat cooking methods. In a rat study, effects on expression of AGE receptors, insulin...

In vitro anticancer effects of a RAGE inhibitor discovered using a structure-based drug design system

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El-Far, Ali Hafez Ali Mohammed; Munesue, Seiichi; Harashima, Ai; Sato, Akira; Shindo, Mika; Nakajima, Shingo; Inada, Mana; Tanaka, Mariko; Takeuchi, Akihiko; Tsuchiya, Hiroyuki; Yamamoto, Hiroshi; Shaheen, Hazem M.E.; El-Sayed, Yasser S.; Kawano, Shuhei; Tanuma, Sei-Ichi; Yamamoto, Yasuhiko

2018-01-01

Receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in the pathogenesis of certain types of cancer. In the present study, papaverine was identified as a RAGE inhibitor using the conversion to small molecules through optimized-peptide strategy drug design system. Papaverine significantly inhibited RAGE-dependent nuclear factor κ-B activation driven by high mobility group box-1, a RAGE ligand. Using RAGE- or dominant-negative RAGE-expressing HT1080 human fibrosarcoma cells, the present study revealed that papaverine suppressed RAGE-dependent cell proliferation and migration dose-dependently. Furthermore, papaverine significantly inhibited cell invasion. The results of the present study suggested that papaverine could inhibit RAGE, and provided novel insights into the field of RAGE biology, particularly anticancer therapies. PMID:29541234

The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes

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Meerwaldt, Robbert; Links, Thera; Zeebregts, Clark; Tio, Rene; Hillebrands, Jan-Luuk; Smit, Andries

2008-01-01

Cardiovascular disease is the major cause of morbidity and mortality associated with diabetes. There is increasing evidence that advanced glycation endproducts (AGEs) play a pivotal role in atherosclerosis, in particular in diabetes. AGE accumulation is a measure of cumulative metabolic and

Effects of alagebrium, an advanced glycation endproduct breaker, on exercise tolerance and cardiac function in patients with chronic heart failure

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Hartog, Jasper W. L.; Willemsen, Suzan; van Veldhuisen, Dirk J.; Posma, Jan L.; van Wijk, Leen M.; Hummel, Yoran M.; Hillege, Hans L.; Voors, Adriaan A.

Aims Advanced glycation endproducts (AGEs) have been associated with the development and progression of chronic heart failure (CHF). Advanced glycation endproducts-crosslink breakers might be of benefit in HF, but only small-scale and uncontrolled data are available. Our aim was to conduct a

Accumulation of advanced glycation endproducts reduces chondrocyte-mediated extracellular matrix turnover in human articular cartilage

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Degroot, J.; Verzijl, N.; Jacobs, K. M.; Budde, M.; Bank, R. A.; Bijlsma, J. W.; TeKoppele, J. M.; Lafeber, F. P.

2001-01-01

The prevalence of osteoarthritis (OAs) increases with age and coincides with the accumulation of advanced glycation endproducts (AGEs) in articular cartilage, suggesting that accumulation of glycation products may be involved in the development of OA. This study was designed to examine the effects

The receptor for advanced glycation end products (RAGE) and the lung.

LENUS (Irish Health Repository)

Buckley, Stephen T

2010-01-01

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules. As a pattern-recognition receptor capable of binding a diverse range of ligands, it is typically expressed at low levels under normal physiological conditions in the majority of tissues. In contrast, the lung exhibits high basal level expression of RAGE localised primarily in alveolar type I (ATI) cells, suggesting a potentially important role for the receptor in maintaining lung homeostasis. Indeed, disruption of RAGE levels has been implicated in the pathogenesis of a variety of pulmonary disorders including cancer and fibrosis. Furthermore, its soluble isoforms, sRAGE, which act as decoy receptors, have been shown to be a useful marker of ATI cell injury. Whilst RAGE undoubtedly plays an important role in the biology of the lung, it remains unclear as to the exact nature of this contribution under both physiological and pathological conditions.

Genetics of Plasma Soluble Receptor for Advanced Glycation End-Products and Cardiovascular Outcomes in a Community-based Population: Results from the Atherosclerosis Risk in Communities Study.

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Nisa M Maruthur

Full Text Available Plasma soluble Receptor for Advanced Glycation End-products (sRAGE is a strong marker of vascular outcomes although evidence on the direction of association is mixed. Compared to whites, blacks have lower levels of sRAGE. We hypothesized that genetic determinants of sRAGE would help clarify the causal role of sRAGE and the black-white difference in sRAGE levels. We conducted a genome-wide analysis of sRAGE in whites and blacks from the Atherosclerosis Risk in Communities Study. Median plasma sRAGE levels were lower in blacks than whites (728 vs. 1067 pg/ml; P<0.0001. The T (vs. C allele of rs2070600, a missense variant in AGER, the gene encoding RAGE, was associated with approximately 50% lower sRAGE levels in both whites (N = 1,737; P = 7.26x10-16; minor allele frequency (MAF = 0.04 and blacks (N = 581; P = 0.02; MAF = 0.01. In blacks, the T (vs. C allele of rs2071288, intronic to AGER, was associated with 43% lower sRAGE levels (P = 2.22x10-8; MAF = 0.10 and was nearly absent in whites. These AGER SNPs explained 21.5% and 26% of the variation in sRAGE in blacks and whites, respectively, but did not explain the black-white difference in sRAGE. These SNPs were not significantly associated with incident death, coronary heart disease, diabetes, heart failure, or chronic kidney disease in whites (N = 8,130-9,017 or blacks (N = 2,293-2,871 (median follow up ~20 years. We identified strong genetic determinants of sRAGE that did not explain the large black-white difference in sRAGE levels or clearly influence risk of clinical outcomes, suggesting that sRAGE may not be a causal factor in development of these outcomes.

Skin autofluorescence as a measure of advanced glycation endproduct deposition: a novel risk marker in chronic kidney disease.

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Smit, Andries J; Gerrits, Esther G

2010-11-01

Skin autofluorescence (SAF) is a new method to noninvasively assess accumulation of advanced glycation endproducts (AGEs) in a tissue with low turnover. Recent progress in the clinical application of SAF as a risk marker for diabetic nephropathy as well as cardiovascular disease in nondiabetic end-stage kidney disease, less advanced chronic kidney disease, and renal transplant recipients is reviewed. Experimental studies highlight the fundamental role of the interaction of AGEs with the receptor for AGEs (RAGEs), also called the AGE-RAGE axis, in the pathogenesis of vascular and chronic kidney disease. SAF predicts (cardiovascular) mortality in renal failure and also chronic renal transplant dysfunction. Long-term follow-up results from the Diabetes Control and Complications Trial and UK Prospective Diabetes Study suggest that AGE accumulation is a key carrier of metabolic memory and oxidative stress. Short-term intervention studies in diabetic nephropathy with thiamine, benfotiamine and angiotensin-receptor blockers aimed at reducing AGE formation have reported mixed results. SAF is a noninvasive marker of AGE accumulation in a tissue with low turnover, and thereby of metabolic memory and oxidative stress. SAF independently predicts cardiovascular and renal risk in diabetes, as well as in chronic kidney disease. Further long-term studies are required to assess the potential benefits of interventions to reduce AGE accumulation.

Advanced glycation end-products (AGES) and heart failure : Pathophysiology and clinical implications

NARCIS (Netherlands)

Hartog, Jasper W. L.; Voors, Adriaan A.; Bakker, Stephan J. L.; Smit, Andries J.; van Veldhuisen, Dirk J.

2007-01-01

Advanced glycation end-products (AGEs) are molecules formed during a non-enzymatic reaction between proteins and sugar residues, called the Maillard reaction. AGEs accumulate in the human body with age, and accumulation is accelerated in the presence of diabetes mellitus. In patients with diabetes,

The false alarm hypothesis: Food allergy is associated with high dietary advanced glycation end-products and proglycating dietary sugars that mimic alarmins.

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Smith, Peter K; Masilamani, Madhan; Li, Xiu-Min; Sampson, Hugh A

2017-02-01

The incidence of food allergy has increased dramatically in the last few decades in westernized developed countries. We propose that the Western lifestyle and diet promote innate danger signals and immune responses through production of "alarmins." Alarmins are endogenous molecules secreted from cells undergoing nonprogrammed cell death that signal tissue and cell damage. High molecular group S (HMGB1) is a major alarmin that binds to the receptor for advanced glycation end-products (RAGE). Advanced glycation end-products (AGEs) are also present in foods. We propose the "false alarm" hypothesis, in which AGEs that are present in or formed from the food in our diet are predisposing to food allergy. The Western diet is high in AGEs, which are derived from cooked meat, oils, and cheese. AGEs are also formed in the presence of a high concentration of sugars. We propose that a diet high in AGEs and AGE-forming sugars results in misinterpretation of a threat from dietary allergens, promoting the development of food allergy. AGEs and other alarmins inadvertently prime innate signaling through multiple mechanisms, resulting in the development of allergic phenotypes. Current hypotheses and models of food allergy do not adequately explain the dramatic increase in food allergy in Western countries. Dietary AGEs and AGE-forming sugars might be the missing link, a hypothesis supported by a number of convincing epidemiologic and experimental observations, as discussed in this article. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS).

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Diamanti-Kandarakis, Evanthia; Katsikis, Ilias; Piperi, Christina; Kandaraki, Eleni; Piouka, Athanasia; Papavassiliou, Athanasios G; Panidis, Dimitrios

2008-10-01

Nonenzymatic advanced glycation and oxidation end-products, advanced glycation end-products (AGEs), impart a potent impact on vessels and other tissues in diabetic state and in euglycaemic conditions with increased oxidative stress. Insulin resistant (IR) polycystic ovary syndrome (PCOS) women, have elevated serum AGEs, increased receptor (RAGE) expression, and increased deposition with differential localization in the polycystic ovarian tissue (theca and granulosa) compared to normal. To determine whether the raised AGE levels in noninsulin resistant women with PCOS is a distinct finding compared with those presenting the isolated components of the syndrome and among PCOS subphenotypes. Noninsulin resistant women were selected in order to show that serum AGEs are elevated in PCOS independently of the presence of IR. Clinical trial. One hundred and ninety-three age- and BMI-matched young lean noninsulin resistant women were studied. Among them, 100 women were diagnosed with PCOS according to Rotterdam criteria, and divided to subphenotypes (hyperandrogenaemia with or without PCO morphology and with or without anovulation). Sixty-eight women with the isolated components of the PCOS phenotype were also studied along with 25 healthy women. Serum AGE levels, metabolic, hormonal profiles and intravaginal ultrasound were determined in all subjects. The studied population did not differ in BMI, fasting insulin concentration, waist : hip and glucose : insulin ratios. PCOS women exhibited statistically higher AGEs levels (7.96 +/- 1.87 U/ml, P PCOS, serum AGEs are distinctly elevated compared with women having the isolated characteristics of the syndrome. No difference was observed between PCOS subphenotypes. As chronic inflammation and increased oxidant stress have been incriminated in the pathophysiology of PCOS, the role of AGEs as inflammatory and oxidant mediators, may be linked with the metabolic and reproductive abnormalities of the syndrome.

Microalbuminuria and sRAGE in High-Risk Hypertensive Patients Treated with Nifedipine/Telmisartan Combination Treatment: A Substudy of TALENT

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Colomba Falcone

2012-01-01

Full Text Available Some antihypertensive drugs have also renoprotective and anti-inflammatory properties that go beyond their effect on blood pressure. It has been suggested that microalbuminuria and glomerular filtration rate (GFR are associated with circulating levels of the soluble form of the receptor, sRAGE (soluble receptor for advanced glycation ends-products. In the present analysis, we used data from the TALENT study to evaluate soluble receptor for advanced glycation end-products (sRAGE plasma levels in patients with hypertension and high-cardiovascular risk-treated nifedipine and telmisartan in combination. Treatment with nifedipine-telmisartan significantly decreased mean systolic and diastolic ambulatory blood pressure and resulted in a significant increase in sRAGE plasma concentrations after 24 weeks of therapy. We concluded that in hypertensive patients with early-stage renal disease, sRAGE concentrations are not influenced by either microalbuminuria or GFR. Long-term treatment with a combination of nifedipine-telmisartan may have a beneficial effect increasing sRAGE plasma levels, thus exerting an atheroprotective and anti-inflammatory activity.

Kaempferol modulates pro-inflammatory NF-κB activation by suppressing advanced glycation endproducts-induced NADPH oxidase

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Kim, Ji Min; Lee, Eun Kyeong; Kim, Dae Hyun; Yu, Byung Pal

2010-01-01

Advanced glycation endproducts (AGE) are oxidative products formed from the reaction between carbohydrates and a free amino group of proteins that are provoked by reactive species (RS). It is also known that AGE enhance the generation of RS and that the binding of AGE to a specific AGE receptor (RAGE) induces the activation of the redox-sensitive, pro-inflammatory transcription factor, nuclear factor-kappa B (NF-ĸB). In this current study, we investigated the anti-oxidative effects of short-term kaempferol supplementation on the age-related formation of AGE and the binding activity of RAGE in aged rat kidney. We further investigated the suppressive action of kaempferol against AGE's ability to stimulate activation of pro-inflammatory NF-ĸB and its molecular mechanisms. For this study, we utilized young (6 months old), old (24 months old), and kaempferol-fed (2 and 4 mg/kg/day for 10 days) old rats. In addition, for the molecular work, the rat endothelial cell line, YPEN-1 was used. The results show that AGE and RAGE were increased during aging and that these increases were blunted by kaempferol. In addition, dietary kaempferol reduced age-related increases in NF-κB activity and NF-ĸB-dependant pro-inflammatory gene activity. The most significant new finding from this study is that kaempferol supplementation prevented age-related NF-κB activation by suppressing AGE-induced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase). Taken together, our results demonstrated that dietary kaempferol exerts its anti-oxidative and anti-inflammatory actions by modulating the age-related NF-κB signaling cascade and its pro-inflammatory genes by suppressing AGE-induced NADPH oxidase activation. Based on these data, dietary kaempferol is proposed as a possible anti-AGE agent that may have the potential for use in anti-inflammation therapies. PMID:20431987

Clinical Value of High Mobility Group Box 1 and the Receptor for Advanced Glycation End-products in Head and Neck Cancer: A Systematic Review

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Nguyen, Austin

2016-04-01

Full Text Available Introduction High mobility group box 1 is a versatile protein involved in gene transcription, extracellular signaling, and response to inflammation. Extracellularly, high mobility group box 1 binds to several receptors, notably the receptor for advanced glycation end-products. Expression of high mobility group box 1 and the receptor for advanced glycation end-products has been described in many cancers. Objectives To systematically review the available literature using PubMed and Web of Science to evaluate the clinical value of high mobility group box 1 and the receptor for advanced glycation end-products in head and neck squamous cell carcinomas. Data synthesis A total of eleven studies were included in this review. High mobility group box 1 overexpression is associated with poor prognosis and many clinical and pathological characteristics of head and neck squamous cell carcinomas patients. Additionally, the receptor for advanced glycation end-products demonstrates potential value as a clinical indicator of tumor angiogenesis and advanced staging. In diagnosis, high mobility group box 1 demonstrates low sensitivity. Conclusion High mobility group box 1 and the receptor for advanced glycation end-products are associated with clinical and pathological characteristics of head and neck squamous cell carcinomas. Further investigation of the prognostic and diagnostic value of these molecules is warranted.

Hyperoside Downregulates the Receptor for Advanced Glycation End Products (RAGE and Promotes Proliferation in ECV304 Cells via the c-Jun N-Terminal Kinases (JNK Pathway Following Stimulation by Advanced Glycation End-Products In Vitro

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Zhengyu Zhang

2013-11-01

Full Text Available Hyperoside is a major active constituent in many medicinal plants which are traditionally used in Chinese medicines for their neuroprotective, anti-inflammatory and antioxidative effects. The molecular mechanisms underlying these effects are unknown. In this study, quiescent ECV304 cells were treated in vitro with advanced glycation end products (AGEs in the presence or absence of hyperoside. The results demonstrated that AGEs induced c-Jun N-terminal kinases (JNK activation and apoptosis in ECV304 cells. Hyperoside inhibited these effects and promoted ECV304 cell proliferation. Furthermore, hyperoside significantly inhibited RAGE expression in AGE-stimulated ECV304 cells, whereas knockdown of RAGE inhibited AGE-induced JNK activation. These results suggested that AGEs may promote JNK activation, leading to viability inhibition of ECV304 cells via the RAGE signaling pathway. These effects could be inhibited by hyperoside. Our findings suggest a novel role for hyperoside in the treatment and prevention of diabetes.

Extracellular matrix glycation and receptor for advanced glycation end-products activation: a missing piece in the puzzle of the association between diabetes and cancer.

Science.gov (United States)

Rojas, Armando; Añazco, Carolina; González, Ileana; Araya, Paulina

2018-04-05

A growing body of epidemiologic evidence suggests that people with diabetes are at a significantly higher risk of many forms of cancer. However, the molecular mechanisms underlying this association are not fully understood. Cancer cells are surrounded by a complex milieu, also known as tumor microenvironment, which contributes to the development and metastasis of tumors. Of note, one of the major components of this niche is the extracellular matrix (ECM), which becomes highly disorganized during neoplastic progression, thereby stimulating cancer cell transformation, growth and spread. One of the consequences of chronic hyperglycemia, the most frequently observed sign of diabetes and the etiological source of diabetes complications, is the irreversible glycation and oxidation of proteins and lipids leading to the formation of the advanced glycation end-products (AGEs). These compounds may covalently crosslink and biochemically modify structure and functions of many proteins, and AGEs accumulation is particularly high in long-living proteins with low biological turnover, features that are shared by most, if not all, ECM proteins. AGEs-modified proteins are recognized by AGE-binding proteins, and thus glycated ECM components have the potential to trigger Receptor for advanced glycation end-products-dependent mechanisms. The biological consequence of receptor for advanced glycation end-products activation mechanisms seems to be connected, in different ways, to drive some hallmarks of cancer onset and tumor growth. The present review intends to highlight the potential impact of ECM glycation on tumor progression by triggering receptor for advanced glycation end-products-mediated mechanisms.

N(epsilon)-carboxymethyllysine-modified proteins are unable to bind to RAGE and activate an inflammatory response.

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Buetler, Timo M; Leclerc, Estelle; Baumeyer, Alexandra; Latado, Helia; Newell, John; Adolfsson, Oskar; Parisod, Véronique; Richoz, Janique; Maurer, Sarah; Foata, Francis; Piguet, Dominique; Junod, Sylviane; Heizmann, Claus W; Delatour, Thierry

2008-03-01

Advanced glycation endproducts (AGEs) containing carboxymethyllysine (CML) modifications are generally thought to be ligands of the receptor for AGEs, RAGEs. It has been argued that this results in the activation of pro-inflammatory pathways and diseases. However, it has not been shown conclusively that a CML-modified protein can interact directly with RAGE. Here, we have analyzed whether beta-lactoglobulin (bLG) or human serum albumin (HSA) modified chemically to contain only CML (10-40% lysine modification) can (i) interact with RAGE in vitro and (ii) interact with and activate RAGE in lung epithelial cells. Our results show that CML-modified bLG or HSA are unable to bind to RAGE in a cell-free assay system (Biacore). Furthermore, they are unable to activate pro-inflammatory signaling in the cellular system. Thus, CML probably does not form the necessary structure(s) to interact with RAGE and activate an inflammatory signaling cascade in RAGE-expressing cells.

Receptor for Advanced Glycation End Products (RAGE and Its Ligands: Focus on Spinal Cord Injury

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Juhyun Song

2014-07-01

Full Text Available Spinal cord injury (SCI results in neuronal and glial death and the loss of axons at the injury site. Inflammation after SCI leads to the inhibition of tissue regeneration and reduced neuronal survival. In addition, the loss of axons after SCI results in functional loss below the site of injury accompanied by neuronal cell body’s damage. Consequently, reducing inflammation and promoting axonal regeneration after SCI is a worthy therapeutic goal. The receptor for advanced glycation end products (RAGE is a transmembrane protein and receptor of the immunoglobulin superfamily. RAGE is implicated in inflammation and neurodegeneration. Several recent studies demonstrated an association between RAGE and central nervous system disorders through various mechanisms. However, the relationship between RAGE and SCI has not been shown. It is imperative to elucidate the association between RAGE and SCI, considering that RAGE relates to inflammation and axonal degeneration following SCI. Hence, the present review highlights recent research regarding RAGE as a compelling target for the treatment of SCI.

Edaravone Protected Human Brain Microvascular Endothelial Cells from Methylglyoxal-Induced Injury by Inhibiting AGEs/RAGE/Oxidative Stress

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Li, Wenlu; Xu, Hongjiao; Hu, Yangmin; He, Ping; Ni, Zhenzhen; Xu, Huimin; Zhang, Zhongmiao; Dai, Haibin

2013-01-01

Subjects with diabetes experience an increased risk of cerebrovascular disease and stroke compared with nondiabetic age-matched individuals. Increased formation of reactive physiological dicarbonyl compound methylglyoxal (MGO) seems to be implicated in the development of diabetic vascular complication due to its protein glycation and oxidative stress effect. Edaravone, a novel radical scavenger, has been reported to display the advantageous effects on ischemic stroke both in animals and clinical trials; however, little is known about whether edaravone has protective effects on diabetic cerebrovascular injury. Using cultured human brain microvascular endothelial cells (HBMEC), protective effects of edaravone on MGO and MGO enhancing oxygen-glucose deprivation (OGD) induced injury were investigated. Cell injury was measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formation, cell account, lactate dehydrogenase (LDH) release and Rhodamine 123 staining. Advanced glycation end-products (AGEs) formation and receptor for advanced glycation end-products (RAGE) expression were measured by western blotting. Cellular oxidative stress was measured by reactive oxygen species (ROS) release. Treatment of MGO for 24 h significantly induced HBMEC injury, which was inhibited by pretreatment of edaravone from 10–100 µmol/l. What’s more, treatment of MGO enhanced AGEs accumulation, RAGE expression and ROS release in the cultured HBMEC, which were inhibited by 100 µmol/l edaravone. Finally, treatment of MGO for 24 h and then followed by 3 h OGD insult significantly enhanced cell injury when compared with OGD insult only, which was also protected by 100 µmol/l edaravone. Thus, edaravone protected HBMEC from MGO and MGO enhancing OGD-induced injury by inhibiting AGEs/RAGE/oxidative stress. PMID:24098758

Edaravone protected human brain microvascular endothelial cells from methylglyoxal-induced injury by inhibiting AGEs/RAGE/oxidative stress.

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Wenlu Li

Full Text Available Subjects with diabetes experience an increased risk of cerebrovascular disease and stroke compared with nondiabetic age-matched individuals. Increased formation of reactive physiological dicarbonyl compound methylglyoxal (MGO seems to be implicated in the development of diabetic vascular complication due to its protein glycation and oxidative stress effect. Edaravone, a novel radical scavenger, has been reported to display the advantageous effects on ischemic stroke both in animals and clinical trials; however, little is known about whether edaravone has protective effects on diabetic cerebrovascular injury. Using cultured human brain microvascular endothelial cells (HBMEC, protective effects of edaravone on MGO and MGO enhancing oxygen-glucose deprivation (OGD induced injury were investigated. Cell injury was measured by 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT formation, cell account, lactate dehydrogenase (LDH release and Rhodamine 123 staining. Advanced glycation end-products (AGEs formation and receptor for advanced glycation end-products (RAGE expression were measured by western blotting. Cellular oxidative stress was measured by reactive oxygen species (ROS release. Treatment of MGO for 24 h significantly induced HBMEC injury, which was inhibited by pretreatment of edaravone from 10-100 µmol/l. What's more, treatment of MGO enhanced AGEs accumulation, RAGE expression and ROS release in the cultured HBMEC, which were inhibited by 100 µmol/l edaravone. Finally, treatment of MGO for 24 h and then followed by 3 h OGD insult significantly enhanced cell injury when compared with OGD insult only, which was also protected by 100 µmol/l edaravone. Thus, edaravone protected HBMEC from MGO and MGO enhancing OGD-induced injury by inhibiting AGEs/RAGE/oxidative stress.

Implication of advanced glycation end products (Ages) and their receptor (Rage) on myocardial contractile and mitochondrial functions.

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Neviere, Remi; Yu, Yichi; Wang, Lei; Tessier, Frederic; Boulanger, Eric

2016-08-01

Advanced glycation end products (AGEs) play an important role for the development and/or progression of cardiovascular diseases, mainly through induction of oxidative stress and inflammation. AGEs are a heterogeneous group of molecules formed by non-enzymatic reaction of reducing sugars with amino acids of proteins, lipids and nucleic acids. AGEs are mainly formed endogenously, while recent studies suggest that diet constitutes an important exogenous source of AGEs. The presence and accumulation of AGEs in various cardiac cell types affect extracellular and intracellular structure and function. AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE). Activation of RAGE by AGEs causes up regulation of the transcription factor nuclear factor-κB and its target genes. of the RAGE engagement stimulates oxidative stress, evokes inflammatory and fibrotic reactions, which all contribute to the development and progression of devastating cardiovascular disorders. This review discusses potential targets of glycation in cardiac cells, and underlying mechanisms that lead to heart failure with special interest on AGE-induced mitochondrial dysfunction in the myocardium.

Advanced glycation endproducts form during ovalbumin digestion in the presence of fructose: Inhibition by chlorogenic acid.

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Bains, Yasmin; Gugliucci, Alejandro; Caccavello, Russell

2017-07-01

One mechanism by which fructose could exert deleterious effects is through intestinal formation and absorption of pro-inflammatory advanced glycation endproducts via the Maillard reaction. We employed simulated stomach and duodenum digestion of ovalbumin (OVA) to test the hypothesis that advanced glycation endproducts (AGEs) are formed by fructose during simulated digestion of a ubiquitous food protein under model physiological conditions. OVA was subjected to simulated gastric and intestinal digestion using standard models, in presence of fructose or glucose (0-100mM). Peptide fractions were analyzed by fluorescence spectroscopy and intensity at Excitation: λ370nm, Emission: λ 440nm. AGE adducts formed between fructose and OVA, evidenced by the peptide fractions (fructose-AGE formation on a ubiquitous dietary protein under model physiological conditions. Our study also suggests ways to decrease the damage: enteral fructose-AGE formation may be partially inhibited by co-intake of beverages, fruits and vegetables with concentrations of phenolics high enough to serve as anti-glycation agents. Copyright © 2017 Elsevier B.V. All rights reserved.

The AGE-RAGE Axis: Implications for Age-Associated Arterial Diseases

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Laura M. Senatus

2017-12-01

Full Text Available The process of advanced glycation leads to the generation and accumulation of an heterogeneous class of molecules called advanced glycation endproducts, or AGEs. AGEs are produced to accelerated degrees in disorders such as diabetes, renal failure, inflammation, neurodegeneration, and in aging. Further, AGEs are present in foods and in tobacco products. Hence, through both endogenous production and exogenous consumption, AGEs perturb vascular homeostasis by a number of means; in the first case, AGEs can cause cross-linking of long-lived molecules in the basement membranes such as collagens, thereby leading to “vascular stiffening” and processes that lead to hyperpermeability and loss of structural integrity. Second, AGEs interaction with their major cell surface signal transduction receptor for AGE or RAGE sets off a cascade of events leading to modulation of gene expression and loss of vascular and tissue homeostasis, processes that contribute to cardiovascular disease. In addition, it has been shown that an enzyme, which plays key roles in the detoxification of pre-AGE species, glyoxalase 1 (GLO1, is reduced in aged and diabetic tissues. In the diabetic kidney devoid of Ager (gene encoding RAGE, higher levels of Glo1 mRNA and GLO1 protein and activity were observed, suggesting that in conditions of high AGE accumulation, natural defenses may be mitigated, at least in part through RAGE. AGEs are a marker of arterial aging and may be detected by both biochemical means, as well as measurement of “skin autofluorescence.” In this review, we will detail the pathobiology of the AGE-RAGE axis and the consequences of its activation in the vasculature and conclude with potential avenues for therapeutic interruption of the AGE-RAGE ligand-RAGE pathways as means to forestall the deleterious consequences of AGE accumulation and signaling via RAGE.

Acute secondhand smoke-induced pulmonary inflammation is diminished in RAGE knockout mice.

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Wood, Tyler T; Winden, Duane R; Marlor, Derek R; Wright, Alex J; Jones, Cameron M; Chavarria, Michael; Rogers, Geraldine D; Reynolds, Paul R

2014-11-15

The receptor for advanced glycation end-products (RAGE) has increasingly been demonstrated to be an important modulator of inflammation in cases of pulmonary disease. Published reports involving tobacco smoke exposure have demonstrated increased expression of RAGE, its participation in proinflammatory signaling, and its role in irreversible pulmonary remodeling. The current research evaluated the in vivo effects of short-term secondhand smoke (SHS) exposure in RAGE knockout and control mice compared with identical animals exposed to room air only. Quantitative PCR, immunoblotting, and immunohistochemistry revealed elevated RAGE expression in controls after 4 wk of SHS exposure and an anticipated absence of RAGE expression in RAGE knockout mice regardless of smoke exposure. Ras activation, NF-κB activity, and cytokine elaboration were assessed to characterize the molecular basis of SHS-induced inflammation in the mouse lung. Furthermore, bronchoalveolar lavage fluid was procured from RAGE knockout and control animals for the assessment of inflammatory cells and molecules. As a general theme, inflammation coincident with leukocyte recruitment was induced by SHS exposure and significantly influenced by the availability of RAGE. These data reveal captivating information suggesting a role for RAGE signaling in lungs exposed to SHS. However, ongoing research is still warranted to fully explain roles for RAGE and other receptors in cells coping with involuntary smoke exposure for prolonged periods of time. Copyright © 2014 the American Physiological Society.

Glucagon-like peptide-1 counteracts the detrimental effects of Advanced Glycation End-Products in the pancreatic beta cell line HIT-T 15

International Nuclear Information System (INIS)

Puddu, A.; Storace, D.; Durante, A.; Odetti, P.; Viviani, G.L.

2010-01-01

Research highlights: → GLP-1 prevents AGEs-induced cell death. → GLP-1 prevents AGEs-induced oxidative stress. → GLP-1 ameliorated AGEs-induced cell dysfunction. → GLP-1 attenuates AGEs-induced RAGE increment. → GLP-1 counteracts AGEs-induced pancreatic cell death and dysfunction. -- Abstract: Advanced Glycation End-Products (AGEs), a group of compounds resulting from the non-enzymatic reaction of reducing sugars with the free amino group of proteins, are implicated in diabetic complications. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T 15 to high concentrations of AGEs significantly decreases cell proliferation and insulin secretion, and affects transcription factors regulating insulin gene transcription. The glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases proinsulin biosynthesis, stimulates insulin secretion, and improves pancreatic beta-cell viability. The aim of this work was to investigate the effects of GLP-1 on the function and viability of HIT-T 15 cells cultured with AGEs. HIT-T 15 cells were cultured for 5 days in presence of AGEs alone, or supplemented with 10 nmol/l GLP-1. Cell viability, insulin secretion, redox balance, and expression of the AGEs receptor (RAGE) were then determined. The results showed that GLP-1 protected beta cell against AGEs-induced cell death preventing both apoptosis and necrosis. Moreover, addition of GLP-1 to the AGEs culture medium restored the redox balance, improved the responsiveness to glucose, and attenuated AGEs-induced RAGE expression. These findings provide evidence that GLP-1 protects beta cells from the dangerous effects of AGEs.

The receptor for advanced glycation end products (RAGE contributes to the progression of emphysema in mice.

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Nisha Sambamurthy

Full Text Available Several recent clinical studies have implied a role for the receptor for advanced glycation end products (RAGE and its variants in chronic obstructive pulmonary disease (COPD. In this study we have defined a role for RAGE in the pathogenesis of emphysema in mice. RAGE deficient mice (RAGE-/- exposed to chronic cigarette smoke were significantly protected from smoke induced emphysema as determined by airspace enlargement and had no significant reduction in lung tissue elastance when compared to their air exposed controls contrary to their wild type littermates. The progression of emphysema has been largely attributed to an increased inflammatory cell-mediated elastolysis. Acute cigarette smoke exposure in RAGE-/- mice revealed an impaired early recruitment of neutrophils, approximately a 6-fold decrease compared to wild type mice. Hence, impaired neutrophil recruitment with continued cigarette smoke exposure reduces elastolysis and consequent emphysema.

Effect of Benfotiamine on Advanced Glycation Endproducts and Markers of Endothelial Dysfunction and Inflammation in Diabetic Nephropathy

NARCIS (Netherlands)

Alkhalaf, Alaa; Kleefstra, Nanne; Groenier, Klaas H.; Bilo, Henk J. G.; Gans, Reinold O. B.; Heeringa, Peter; Scheijen, Jean L.; Schalkwijk, Casper G.; Navis, Gerjan J.; Bakker, Stephan J. L.

2012-01-01

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

Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure.

Science.gov (United States)

Caraher, Erin J; Kwon, Sophia; Haider, Syed H; Crowley, George; Lee, Audrey; Ebrahim, Minah; Zhang, Liqun; Chen, Lung-Chi; Gordon, Terry; Liu, Mengling; Prezant, David J; Schmidt, Ann Marie; Nolan, Anna

2017-01-01

World Trade Center-particulate matter(WTC-PM) exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI). The receptor for advanced glycation end-products (RAGE) is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV). Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE)≥97pg/mL, CRP≥2.4mg/L, and MMP-9≤397ng/mL, respectively, assessed in a multivariate logistic regression model (ROCAUC of 0.72). Wild type(WT) and RAGE-deficient(Ager-/-) mice were exposed to PM or PBS-control by oropharyngeal aspiration. Lung function, airway hyperreactivity, bronchoalveolar lavage, histology, transcription factors and plasma/BAL cytokines were quantified. WT-PM mice had decreased FEV and compliance, and increased airway resistance and methacholine reactivity after 24-hours. Decreased IFN-γ and increased LPA were observed in WT-PM mice; similar findings have been reported for firefighters who eventually develop WTC-LI. In the murine model, lack of RAGE was protective from loss of lung function and airway hyperreactivity and was associated with modulation of MAP kinases. We conclude that in a multivariate adjusted model increased sRAGE is

An advanced glycation endproduct (AGE)-rich diet promotes accumulation of AGEs in Achilles tendon

DEFF Research Database (Denmark)

Skovgaard, Dorthe; Svensson, Rene B; Scheijen, Jean

2017-01-01

Advanced Glycation Endproducts (AGEs) accumulate in long-lived tissue proteins like collagen in bone and tendon causing modification of the biomechanical properties. This has been hypothesized to raise the risk of orthopedic injury such as bone fractures and tendon ruptures. We evaluated the rela......Advanced Glycation Endproducts (AGEs) accumulate in long-lived tissue proteins like collagen in bone and tendon causing modification of the biomechanical properties. This has been hypothesized to raise the risk of orthopedic injury such as bone fractures and tendon ruptures. We evaluated...... the relationship between AGE content in the diet and accumulation of AGEs in weight-bearing animal Achilles tendon. Two groups of mice (C57BL/6Ntac) were fed with either high-fat diet low in AGEs high-fat diet (HFD) (n = 14) or normal diet high in AGEs (ND) (n = 11). AGE content in ND was six to 50-fold higher...... than HFD The mice were sacrificed at week 40 and Achilles and tail tendons were carefully excised to compare weight and nonweight-bearing tendons. The amount of the AGEs carboxymethyllysine (CML), methylglyoxal-derived hydroimidazolone (MG-H1) and carboxyethyllysine (CEL) in Achilles and tail tendon...

The AGE-RAGE axis in an Arab population: The United Arab Emirates Healthy Futures (UAEHFS) pilot study.

Science.gov (United States)

Inman, Claire K; Aljunaibi, Abdullah; Koh, Hyunwook; Abdulle, Abdishakur; Ali, Raghib; Alnaeemi, Abdullah; Al Zaabi, Eiman; Oumeziane, Naima; Al Bastaki, Marina; Al-Houqani, Mohammed; Al-Maskari, Fatma; Al Dhaheri, Ayesha; Shah, Syed M; Abdel Wareth, Laila; Al Mahmeed, Wael; Alsafar, Habiba; Al Anouti, Fatme; Al Hosani, Ayesha; Haji, Muna; Galani, Divya; O'Connor, Matthew J; Ahn, Jiyoung; Kirchhoff, Tomas; Sherman, Scott; Hayes, Richard B; Li, Huilin; Ramasamy, Ravichandran; Schmidt, Ann Marie

2017-12-01

The transformation of the United Arab Emirates (UAE) from a semi-nomadic to a high income society has been accompanied by increasing rates of obesity and Type 2 diabetes mellitus. We examined if the AGE-RAGE (receptor for advanced glycation endproducts) axis is associated with obesity and diabetes mellitus in the pilot phase of the UAE Healthy Futures Study (UAEHFS). 517 Emirati subjects were enrolled and plasma/serum levels of AGE, carboxy methyl lysine (CML)-AGE, soluble (s)RAGE and endogenous secretory (es)RAGE were measured along with weight, height, waist and hip circumference (WC/HC), blood pressure, HbA1c, Vitamin D levels and routine chemistries. The relationship between the AGE-RAGE axis and obesity and diabetes mellitus was tested using proportional odds models and linear regression. After covariate adjustment, AGE levels were significantly associated with diabetes status. Levels of sRAGE and esRAGE were associated with BMI and levels of sRAGE were associated with WC/HC. The AGE-RAGE axis is associated with diabetes status and obesity in this Arab population. Prospective serial analysis of this axis may identify predictive biomarkers of obesity and cardiometabolic dysfunction in the UAEHFS.

Advanced glycation end-products: a biological consequence of lifestyle contributing to cancer disparity

OpenAIRE

Turner, David P.

2015-01-01

Low income, poor diet, obesity and a lack of exercise are inter-related lifestyle factors that can profoundly alter our biological make-up to increase cancer risk, growth and development. We recently reported a potential mechanistic link between carbohydrate derived metabolites and cancer which may provide a biological consequence of lifestyle that can directly impact tumor biology. Advanced glycation end-products (AGEs) are reactive metabolites produced as a by-product of sugar metabolism. F...

AGE-RAGE Stress, Stressors, and Antistressors in Health and Disease.

Science.gov (United States)

Prasad, Kailash; Mishra, Manish

2018-03-01

Adverse effects of advanced glycation end-products (AGEs) on the tissues are through nonreceptor- and receptor-mediated mechanisms. In the receptor-mediated mechanism, interaction of AGEs with its cell-bound receptor of AGE (RAGE) increases generation of oxygen radicals, activates nuclear factor-kappa B, and increases expression and release of pro-inflammatory cytokines resulting in the cellular damage. The deleterious effects of AGE and AGE-RAGE interaction are coined as "AGE-RAGE stress." The body is equipped with defense mechanisms to counteract the adverse effects of AGE and RAGE through endogenous enzymatic (glyoxalase 1, glyoxalase 2) and AGE receptor-mediated (AGER1, AGER2) degradation of AGE, and through elevation of soluble receptor of AGE (sRAGE). Exogenous defense mechanisms include reduction in consumption of AGE, prevention of AGE formation, and downregulation of RAGE expression. We have coined AGE and RAGE as "stressors" and the defense mechanisms as "anti-stressors." AGE-RAGE stress is defined as a shift in the balance between stressors and antistressors in the favor of stressors. Measurements of stressors or antistressors alone would not assess AGE-RAGE stress. For true assessment of AGE-RAGE stress, the equation should include all the stressors and antistressors. The equation for AGE-RAGE stress, therefore, would be the ratio of AGE + RAGE/sRAGE + glyoxalase1 + glyoxalase 2 + AGER1 +AGER2. This is, however, not practical in patients. AGE-RAGE stress may be assessed simply by the ratio of AGE/sRAGE. A high ratio of AGE/sRAGE indicates a relative shift in stressors from antistressors, suggesting the presence of AGE-RAGE stress, resulting in tissue damage, initiation, and progression of the diseases and their complications.

Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure.

Directory of Open Access Journals (Sweden)

Erin J Caraher

Full Text Available World Trade Center-particulate matter(WTC-PM exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI. The receptor for advanced glycation end-products (RAGE is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV. Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE≥97pg/mL, CRP≥2.4mg/L, and MMP-9≤397ng/mL, respectively, assessed in a multivariate logistic regression model (ROCAUC of 0.72. Wild type(WT and RAGE-deficient(Ager-/- mice were exposed to PM or PBS-control by oropharyngeal aspiration. Lung function, airway hyperreactivity, bronchoalveolar lavage, histology, transcription factors and plasma/BAL cytokines were quantified. WT-PM mice had decreased FEV and compliance, and increased airway resistance and methacholine reactivity after 24-hours. Decreased IFN-γ and increased LPA were observed in WT-PM mice; similar findings have been reported for firefighters who eventually develop WTC-LI. In the murine model, lack of RAGE was protective from loss of lung function and airway hyperreactivity and was associated with modulation of MAP kinases. We conclude that in a multivariate adjusted model increased sRAGE

High-mobility group B1 (HMGB1) and receptor for advanced glycation end-products (RAGE) expression in canine lymphoma.

Science.gov (United States)

Sterenczak, Katharina A; Joetzke, Alexa E; Willenbrock, Saskia; Eberle, Nina; Lange, Sandra; Junghanss, Christian; Nolte, Ingo; Bullerdiek, Jörn; Simon, Daniela; Murua Escobar, Hugo

2010-12-01

Canine lymphoma is a commonly occurring, spontaneously developing neoplasia similar to human non-Hodgkin's lymphoma and, thus, is used as a valuable model for human malignancy. HMGB1 and RAGE are strongly associated with tumour progression and vascularisation. Consequently, deregulated RAGE and HMGB1 may play an important role in the mechanisms involved in lymphoma progression. Expression patterns of HMGB1 and RAGE were analysed in 22 canine lymphoma and three canine non-neoplastic control samples via real time PCR and canine beta-glucuronidase gene (GUSB) as endogenous control. HMGB1 was up-regulated in the neoplastic samples, while RAGE expression remained inconspicuous. This study demonstrated similar mechanisms in lymphoma progression in humans and dogs due to overexpression of HMGB1, which was described in human lymphomas. RAGE remained stable in terms of expression indicating that the extracellular HMGB1-induced effects are regulated by HMGB1 itself.

The S100P/RAGE signaling pathway regulates expression of microRNA-21 in colon cancer cells.

Science.gov (United States)

Mercado-Pimentel, Melania E; Onyeagucha, Benjamin C; Li, Qing; Pimentel, Angel C; Jandova, Jana; Nelson, Mark A

2015-08-19

S100P signaling through the receptor for advanced glycation end-products (RAGE) contributes to colon cancer invasion and metastasis, but the mechanistic features of this process are obscure. Here, we investigate whether activation of S100P/RAGE signaling regulates oncogenic microRNA-21 (miR-21). We show that exogenous S100P up-regulates miR-21 levels in human colon cancer cells, whereas knockdown of S100P results in a decrease of miR-21. Furthermore, blockage of RAGE with anti-RAGE antibody suppresses S100P induction of miR-21. In addition, we found that S100P induction of miR-21 expression involves ERK and is suppressed by the MEK inhibitor U0126. Also, S100P treatment stimulates the enrichment of c-Fos, and AP-1 family members, at the miR-21 gene promoter. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Low-molecular weight fractions of Japanese soy sauce act as a RAGE antagonist via inhibition of RAGE trafficking to lipid rafts.

Science.gov (United States)

Munesue, Seiichi; Yamamoto, Yasuhiko; Urushihara, Ryouta; Inomata, Kouhei; Saito, Hidehito; Motoyoshi, So; Watanabe, Takuo; Yonekura, Hideto; Yamamoto, Hiroshi

2013-12-01

Advanced glycation end-products (AGE) have been implicated in aging and the pathogenesis of diabetic complications, inflammation, Alzheimer's disease, and cancer. AGE engage the cell surface receptor for AGE (RAGE), which in turn elicits intracellular signaling, leading to activation of NF-κB to cause deterioration of tissue homeostasis. AGE are not only formed within our bodies but are also derived from foods, endowing them with flavor. In the present study, we assessed the agonistic/antagonistic effects of food-derived AGE on RAGE signaling in a reporter assay system and found that low-molecular weight AGE can antagonize the action of AGE-BSA. Foods tested were Japanese soy sauce, coffee, cola, and red wine, all of which showed fluorescence characteristics of AGE. Soy sauce and coffee contained N(ε)-carboxymethyl-lysine (CML). Soy sauce, coffee, and red wine inhibited the RAGE ligand-induced activation of NF-κB, whereas cola had no effect on the ligand induction of NF-κB. The liquids were then fractionated into high-molecular weight (HMW) fractions and low-molecular weight (LMW) fractions. Soy sauce-, coffee-, and red wine-derived LMW fractions consistently inhibited the RAGE ligand induction of NF-κB, whereas the HMW fractions of these foods activated RAGE signaling. Using the LMW fraction of soy sauce as a model food-derived RAGE antagonist, we performed a plate-binding assay and found that the soy sauce LMW fractions competitively inhibited AGE-RAGE association. Further, this fraction significantly reduced AGE-dependent monocyte chemoattractant protein-1 (MCP-1) secretion from murine peritoneal macrophages. The LMF from soy sauce suppressed the AGE-induced RAGE trafficking to lipid rafts. These results indicate that small components in some, if not all, foods antagonize RAGE signaling and could exhibit beneficial effects on RAGE-related diseases.

The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes

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Hillebrands Jan-Luuk

2008-10-01

Full Text Available Abstract Cardiovascular disease is the major cause of morbidity and mortality associated with diabetes. There is increasing evidence that advanced glycation endproducts (AGEs play a pivotal role in atherosclerosis, in particular in diabetes. AGE accumulation is a measure of cumulative metabolic and oxidative stress, and may so represent the "metabolic memory". Furthermore, increased AGE accumulation is closely related to the development of cardiovascular complications in diabetes. This review article will focus on the clinical relevance of measuring AGE accumulation in diabetic patients by focusing on AGE formation, AGEs as predictors of long-term complications, and interventions against AGEs.

Role of protein-bound carbonyl groups in the formation of advanced glycation endproducts.

Science.gov (United States)

Liggins, J; Furth, A J

1997-08-22

Several mechanisms have been postulated for the formation of advanced glycation endproducts (AGEs) from glycated proteins; they all feature protein-bound carbonyl intermediates. Using 2,4-dinitrophenylhydrazine (DNPH), we have detected these intermediates on bovine serum albumin, lysozyme and beta-lactoglobulin after in vitro glycation by glucose or fructose. Carbonyls were formed in parallel with AGE-fluorophores, via oxidative Maillard reactions. Neither Amadori nor Heyns products contributed to the DNPH reaction. Fluorophore and carbonyl yields were much enhanced in lipid-associated proteins, but both groups could also be detected in lipid-free proteins. When pre-glycated proteins were incubated in the absence of free sugar, carbonyl groups were rapidly lost in a first-order reaction, while fluorescence continued to develop beyond the 21 days of incubation. Another unexpected finding was that not all carbonyl groups were blocked by aminoguanidine, although there was complete inhibition of reactions leading to AGE-fluorescence. It is suggested that carbonyls acting as fluorophore precursors react readily with aminoguanidine, while others are resistant to this hydrazine, possibly because they are involved in ring closure. Factors influencing the relative rates of acyclisation and hydrazone formation are discussed, together with possible implications for antiglycation therapy.

Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate tumor growth

International Nuclear Information System (INIS)

Elangovan, Indira; Thirugnanam, Sivasakthivel; Chen, Aoshuang; Zheng, Guoxing; Bosland, Maarten C.; Kajdacsy-Balla, André; Gnanasekar, Munirathinam

2012-01-01

Highlights: ► Targeting RAGE by RNAi induces apoptosis in prostate cancer cells. ► Silencing RAGE expression abrogates rHMGB1 mediated cell proliferation. ► Down regulation of RAGE by RNAi inhibits PSA secretion of prostate cancer cells. ► Knock down of RAGE abrogates prostate tumor growth in vivo. ► Disruption of RAGE expression in prostate tumor activates death receptors. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer.

Morphological Changes and Immunohistochemical Expression of RAGE and its Ligands in the Sciatic Nerve of Hyperglycemic Pig (Sus Scrofa

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Judyta K. Juranek

2010-09-01

Full Text Available The aim of our project was to study the effect of streptozotocin (STZ—induced hyperglycemia on sciatic nerve morphology, blood plasma markers and immunohistochemical expression of RAGE (the Receptor for Advanced Glycation End-products, and its ligands—S100B and Carboxymethyl Lysine (CML-advanced glycation endproduct (AGE in the laboratory pig. Six months after STZ—injections, blood plasma measurements, morphometric analysis of sciatic nerve fiber density, immunofluorescent distribution of potential molecular neuropathy contributors, ELISA measurement of plasma AGE level and HPLC analysis of sciatic nerve levels of one of the pre-AGE and the glycolysis intermediate products—methyl-glyoxal (MG were performed. The results of our study revealed that STZ—injected animals displayed elevated levels of plasma glucose, gamma glutamyl transferase (GGT and triglycerides. The sciatic nerve of STZ-injected pigs revealed significantly lower numbers of small-diameter myelinated fibers, higher immunoreactivity for RAGE and S100B and increased levels of MG as compared to control animals. Our results correspond to clinical findings in human patients with hyperglycemia/diabetes-evoked peripheral neuropathy and suggest that the domestic pig may be a suitable large animal model for the study of mechanisms underlying hyperglycemia-induced neurological complications in the peripheral nerve and may serve as a relevant model for the pre-clinical assessment of candidate drugs in neuropathy.

Morphological Changes and Immunohistochemical Expression of RAGE and its Ligands in the Sciatic Nerve of Hyperglycemic Pig (Sus Scrofa

Directory of Open Access Journals (Sweden)

Judyta K. Juranek

2010-01-01

Full Text Available The aim of our project was to study the effect of streptozotocin (STZ–-induced hyperglycemia on sciatic nerve morphology, blood plasma markers and immunohistochemical expression of RAGE (the Receptor for Advanced Glycation End-products, and its ligands–-S100B and Carboxymethyl Lysine (CML-advanced glycation endproduct (AGE in the laboratory pig. Six months after STZ–-injections, blood plasma measurements, morphometric analysis of sciatic nerve fiber density, immunofluorescent distribution of potential molecular neuropathy contributors, ELISA measurement of plasma AGE level and HPLC analysis of sciatic nerve levels of one of the pre-AGE and the glycolysis intermediate products–-methylglyoxal (MG were performed. The results of our study revealed that STZ–-injected animals displayed elevated levels of plasma glucose, gamma glutamyl transferase (GGT and triglycerides. The sciatic nerve of STZ-injected pigs revealed significantly lower numbers of small-diameter myelinated fibers, higher immunoreactivity for RAGE and S100B and increased levels of MG as compared to control animals. Our results correspond to clinical findings in human patients with hyperglycemia/diabetes-evoked peripheral neuropathy and suggest that the domestic pig may be a suitable large animal model for the study of mechanisms underlying hyperglycemia-induced neurological complications in the peripheral nerve and may serve as a relevant model for the pre-clinical assessment of candidate drugs in neuropathy.

Differential impact of glucose levels and advanced glycation end-products on tubular cell viability and pro-inflammatory/profibrotic functions.

Science.gov (United States)

Franko, Benoit; Brault, Julie; Jouve, Thomas; Beaumel, Sylvain; Benhamou, Pierre-Yves; Zaoui, Philippe; Stasia, Marie José

2014-09-05

High glucose (HG) or synthetic advanced glycation end-products (AGE) conditions are generally used to mimic diabetes in cellular models. Both models have shown an increase of apoptosis, oxidative stress and pro-inflammatory cytokine production in tubular cells. However, the impact of the two conditions combined has rarely been studied. In addition, the impact of glucose level variation due to cellular consumption is not clearly characterized in such experiments. Therefore, the aim of this study was to compare the effect of HG and AGE separately and of both on tubular cell phenotype changes in the HK2 cell line. Moreover, glucose consumption was monitored every hour to maintain the glucose level by supplementation throughout the experiments. We thus observed a significant decrease of apoptosis and H2O2 production in the HK2 cell. HG or AGE treatment induced an increase of total and mitochondrial apoptosis as well as TGF-β release compared to control conditions; however, AGE or HG led to apoptosis preferentially involving the mitochondria pathway. No cumulative effect of HG and AGE treatment was observed on apoptosis. However, a pretreatment with RAGE antibodies partially abolished the apoptotic effect of HG and completely abolished the apoptotic effect of AGE. In conclusion, tubular cells are sensitive to the lack of glucose as well as to the HG and AGE treatments, the AGE effect being more deleterious than the HG effect. Absence of a potential synergistic effect of HG and AGE could indicate that they act through a common pathway, possibly via the activation of the RAGE receptors. Copyright © 2014 Elsevier Inc. All rights reserved.

Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond

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Radha Ananthakrishnan

2013-10-01

Full Text Available Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS and consequent downstream signal transduction and regulation of gene expression. The primary mechanism by which RAGE generates oxidative stress is via activation of NADPH oxidase; amplification mechanisms in the mitochondria may further drive ROS production. Recent studies indicating that the cytoplasmic domain of RAGE binds to the formin mDia1 provide further support for the critical roles of this pathway in oxidative stress; mDia1 was required for activation of rac1 and NADPH oxidase in primary murine aortic smooth muscle cells treated with RAGE ligand S100B. In vivo, in multiple distinct disease models in animals, RAGE action generates oxidative stress and modulates cellular/tissue fate in range of disorders, such as in myocardial ischemia, atherosclerosis, and aneurysm formation. Blockade or genetic deletion of RAGE was shown to be protective in these settings. Indeed, beyond cardiovascular disease, evidence is accruing in human subjects linking levels of RAGE ligands and soluble RAGE to oxidative stress in disorders such as doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, diabetes, preeclampsia, rheumatoid arthritis and pulmonary fibrosis. Blockade of RAGE signal transduction may be a key strategy for the prevention of the deleterious consequences of oxidative stress, particularly in chronic disease.

Skin autofluorescence as a measure of advanced glycation endproduct deposition : a novel risk marker in chronic kidney disease

NARCIS (Netherlands)

Smit, Andries J.; Gerrits, Esther G.

2010-01-01

Purpose of review Skin autofluorescence (SAF) is a new method to noninvasively assess accumulation of advanced glycation endproducts (AGEs) in a tissue with low turnover. Recent progress in the clinical application of SAF as a risk marker for diabetic nephropathy as well as cardiovascular disease in

Association between Fluorescent Advanced Glycation End-Products and Vascular Complications in Type 2 Diabetic Patients

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Alexis Guerin-Dubourg

2017-01-01

Full Text Available Objectives. Diabetes is a major health problem associated with hyperglycemia and chronically increased oxidative stress and enhanced formation of advanced glycation end-products (AGEs. The aim of this study was to determine whether oxidative plasma biomarkers in diabetic patients could be evidenced and associated with vascular complications. Methods. Oxidative stress biomarkers such as thiols, ischemia-modified albumin (IMA, glycated albumin (GA, fructosamine, and AGEs were measured in 75 patients with poorly controlled type 2 diabetes (HbA1c > 7.5% with (44 or without (31 vascular disease and in 31 nondiabetic controls. Results. Most biomarkers of oxidation and glycation were significantly increased in diabetic patients in comparison with nondiabetics. Fructosamines, GA, IMA, and AGEs were positively correlated and levels of fluorescent AGEs were significantly increased in the plasma from patients presenting vascular complication. Conclusions. These results bring new evidence for the potential interest of glycated albumin, oxidative stress, and glycoxidation parameters in the monitoring of type 2 diabetic patients. Furthermore, it emphasizes fluorescent AGEs as a putative indicator for vascular event prediction in diabetic patients.

Advanced glycation End-products (AGEs): an emerging concern for processed food industries.

Science.gov (United States)

Sharma, Chetan; Kaur, Amarjeet; Thind, S S; Singh, Baljit; Raina, Shiveta

2015-12-01

The global food industry is expected to increase more than US $ 7 trillion by 2014. This rise in processed food sector shows that more and more people are diverging towards modern processed foods. As modern diets are largely heat processed, they are more prone to contain high levels of advanced glycation end products (AGEs). AGEs are a group of complex and heterogeneous compounds which are known as brown and fluorescent cross-linking substances such as pentosidine, non-fluorescent cross-linking products such as methylglyoxal-lysine dimers (MOLD), or non-fluorescent, non-cross linking adducts such as carboxymethyllysine (CML) and pyrraline (a pyrrole aldehyde). The chemistry of the AGEs formation, absorption and bioavailability and their patho-biochemistry particularly in relation to different complications like diabetes and ageing discussed. The concept of AGEs receptor - RAGE is mentioned. AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE). Different methods of detection and quantification along with types of agents used for the treatment of AGEs are reviewed. Generally, ELISA or LC-MS methods are used for analysis of foods and body fluids, however lack of universally established method highlighted. The inhibitory effect of bioactive components on AGEs by trapping variety of chemical moieties discussed. The emerging evidence about the adverse effects of AGEs makes it necessary to investigate the different therapies to inhibit AGEs.

Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation.

Science.gov (United States)

Ramasamy, Ravichandran; Vannucci, Susan J; Yan, Shirley Shi Du; Herold, Kevan; Yan, Shi Fang; Schmidt, Ann Marie

2005-07-01

The products of nonenzymatic glycation and oxidation of proteins and lipids, the advanced glycation end products (AGEs), accumulate in a wide variety of environments. AGEs may be generated rapidly or over long times stimulated by a range of distinct triggering mechanisms, thereby accounting for their roles in multiple settings and disease states. A critical property of AGEs is their ability to activate receptor for advanced glycation end products (RAGE), a signal transduction receptor of the immunoglobulin superfamily. It is our hypothesis that due to such interaction, AGEs impart a potent impact in tissues, stimulating processes linked to inflammation and its consequences. We hypothesize that AGEs cause perturbation in a diverse group of diseases, such as diabetes, inflammation, neurodegeneration, and aging. Thus, we propose that targeting this pathway may represent a logical step in the prevention/treatment of the sequelae of these disorders.

Plausible Roles for RAGE in Conditions Exacerbated by Direct and Indirect (Secondhand) Smoke Exposure.

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Lewis, Joshua B; Hirschi, Kelsey M; Arroyo, Juan A; Bikman, Benjamin T; Kooyman, David L; Reynolds, Paul R

2017-03-17

Approximately 1 billion people smoke worldwide, and the burden placed on society by primary and secondhand smokers is expected to increase. Smoking is the leading risk factor for myriad health complications stemming from diverse pathogenic programs. First- and second-hand cigarette smoke contains thousands of constituents, including several carcinogens and cytotoxic chemicals that orchestrate chronic inflammatory responses and destructive remodeling events. In the current review, we outline details related to compromised pulmonary and systemic conditions related to smoke exposure. Specifically, data are discussed relative to impaired lung physiology, cancer mechanisms, maternal-fetal complications, cardiometabolic, and joint disorders in the context of smoke exposure exacerbations. As a general unifying mechanism, the receptor for advanced glycation end-products (RAGE) and its signaling axis is increasingly considered central to smoke-related pathogenesis. RAGE is a multi-ligand cell surface receptor whose expression increases following cigarette smoke exposure. RAGE signaling participates in the underpinning of inflammatory mechanisms mediated by requisite cytokines, chemokines, and remodeling enzymes. Understanding the biological contributions of RAGE during cigarette smoke-induced inflammation may provide critically important insight into the pathology of lung disease and systemic complications that combine during the demise of those exposed.

Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner.

Science.gov (United States)

Nelson, Michael B; Swensen, Adam C; Winden, Duane R; Bodine, Jared S; Bikman, Benjamin T; Reynolds, Paul R

2015-07-01

Cigarette smoke exposure is associated with an increased risk of cardiovascular complications. The role of advanced glycation end products (AGEs) is already well established in numerous comorbidities, including cardiomyopathy. Given the role of AGEs and their receptor, RAGE, in activating inflammatory pathways, we sought to determine whether ceramides could be a mediator of RAGE-induced altered heart mitochondrial function. Using an in vitro model, we treated H9C2 cardiomyocytes with the AGE carboxy-methyllysine before mitochondrial respiration assessment. We discovered that mitochondrial respiration was significantly impaired in AGE-treated cells, but not when cotreated with myriocin, an inhibitor of de novo ceramide biosynthesis. Moreover, we exposed wild-type and RAGE knockout mice to secondhand cigarette smoke and found reduced mitochondrial respiration in the left ventricular myocardium from wild-type mice, but RAGE knockout mice were protected from this effect. Finally, conditional overexpression of RAGE in the lungs of transgenic mice elicited a robust increase in left ventricular ceramides in the absence of smoke exposure. Taken together, these findings suggest a RAGE-ceramide axis as an important contributor to AGE-mediated disrupted cardiomyocyte mitochondrial function. Copyright © 2015 the American Physiological Society.

Determination of advanced glycation endproducts in cooked meat products.

Science.gov (United States)

Chen, Gengjun; Smith, J Scott

2015-02-01

Advanced glycation endproducts (AGEs), a pathogenic factor implicated in diabetes and other chronic diseases, are produced in cooked meat products. The objective of this study was to determine the AGE content, as measured by Nε-carboxymethyllysine (CML) levels, in cooked chicken, pork, beef and fish (salmon and tilapia) prepared by three common cooking methods used by U.S. consumers: frying, baking, and broiling. The CML was detected in all the cooked samples, but the levels were dependent on types of meat, cooking conditions, and the final internal temperature. Broiling and frying at higher cooking temperature produced higher levels of CML, and broiled beef contained the highest CML content (21.8μg/g). Baked salmon (8.6μg/g) and baked tilapia (9.7μg/g) contained less CML as compared to the other muscle food samples. Copyright © 2014 Elsevier Ltd. All rights reserved.

Advanced glycation end products (AGEs) and their receptor (RAGE) induce apoptosis of periodontal ligament fibroblasts

International Nuclear Information System (INIS)

Li, D.X.; Deng, T.Z.; Lv, J.; Ke, J.

2014-01-01

Diabetics have an increased prevalence of periodontitis, and diabetes is one of the causative factors of severe periodontitis. Apoptosis is thought to be involved in this pathogenic relationship. The aim of this study was to investigate apoptosis in human periodontal ligament (PDL) fibroblasts induced by advanced glycation end products (AGEs) and their receptor (RAGE). We examined the roles of apoptosis, AGEs, and RAGE during periodontitis in diabetes mellitus using cultured PDL fibroblasts that were treated by AGE-modified bovine serum albumin (AGE-BSA), bovine serum albumin (BSA) alone, or given no treatment (control). Microscopy and real-time quantitative PCR indicated that PDL fibroblasts treated with AGE-BSA were deformed and expressed higher levels of RAGE and caspase 3. Cell viability assays and flow cytometry indicated that AGE-BSA reduced cell viability (69.80±5.50%, P<0.01) and increased apoptosis (11.31±1.73%, P<0.05). Hoechst 33258 staining and terminal-deoxynucleotidyl transferase-mediated nick-end labeling revealed that AGE-BSA significantly increased apoptosis of PDL fibroblasts. The results showed that the changes in PDL fibroblasts induced by AGE-BSA may explain how AGE-RAGE participates in and exacerbates periodontium destruction

Advanced glycation end products (AGEs) and their receptor (RAGE) induce apoptosis of periodontal ligament fibroblasts

Energy Technology Data Exchange (ETDEWEB)

Li, D.X.; Deng, T.Z.; Lv, J.; Ke, J. [Department of Stomatology, Air Force General Hospital PLA, Haidian District, Beijing (China)

2014-09-19

Diabetics have an increased prevalence of periodontitis, and diabetes is one of the causative factors of severe periodontitis. Apoptosis is thought to be involved in this pathogenic relationship. The aim of this study was to investigate apoptosis in human periodontal ligament (PDL) fibroblasts induced by advanced glycation end products (AGEs) and their receptor (RAGE). We examined the roles of apoptosis, AGEs, and RAGE during periodontitis in diabetes mellitus using cultured PDL fibroblasts that were treated by AGE-modified bovine serum albumin (AGE-BSA), bovine serum albumin (BSA) alone, or given no treatment (control). Microscopy and real-time quantitative PCR indicated that PDL fibroblasts treated with AGE-BSA were deformed and expressed higher levels of RAGE and caspase 3. Cell viability assays and flow cytometry indicated that AGE-BSA reduced cell viability (69.80±5.50%, P<0.01) and increased apoptosis (11.31±1.73%, P<0.05). Hoechst 33258 staining and terminal-deoxynucleotidyl transferase-mediated nick-end labeling revealed that AGE-BSA significantly increased apoptosis of PDL fibroblasts. The results showed that the changes in PDL fibroblasts induced by AGE-BSA may explain how AGE-RAGE participates in and exacerbates periodontium destruction.

Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology.

Science.gov (United States)

Moser, Bernhard; Janik, Stefan; Schiefer, Ana-Iris; Müllauer, Leonhard; Bekos, Christine; Scharrer, Anke; Mildner, Michael; Rényi-Vámos, Ferenc; Klepetko, Walter; Ankersmit, Hendrik Jan

2014-01-01

Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (pB3>thymic carcinoma (pepithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

Advanced glycation endproducts in food and their effects on health

DEFF Research Database (Denmark)

Poulsen, Malene Wibe; Hedegaard, Rikke Susanne Vingborg; Andersen, Jeanette Marker

2013-01-01

of AGEs. Some AGEs interact with specific pro- or anti-inflammatory receptors. Most studies on the biological effects of AGEs have been carried out by administering heated foods. The pro-inflammatory and deteriorating biological effects of AGEs in these studies, therefore, need further confirmation......Advanced glycation endproducts (AGEs) form by Maillard-reactions after initial binding of aldehydes with amines or amides in heated foods or in living organisms. The mechanisms of formation may include ionic as well as oxidative and radical pathways. The reactions may proceed within proteins...... to form high-molecular weight (HMW) AGEs or among small molecules to form low-molecular weight (LMW) AGEs. All free amino acids form AGEs, but lysine or arginine side chains dominate AGE formation within proteins. The analysis of AGEs in foods and body fluids is most often performed by ELISA or LC...

Higher plasma soluble Receptor for Advanced Glycation End Products (sRAGE) levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes

DEFF Research Database (Denmark)

Nin, Johanna W M; Jorsal, Anders; Ferreira, Isabel

2010-01-01

To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunct......To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal...

Vitreous advanced glycation endproducts and alpha-dicarbonyls in retinal detachment patients with type 2 diabetes mellitus and non-diabetic controls

NARCIS (Netherlands)

Fokkens, Bernardina T.; Mulder, Douwe J.; Schalkwijk, Casper G.; Scheijen, Jean L.; Smit, Andries J.; Los, Leonoor I.

2017-01-01

Purpose Advanced glycation endproducts (AGEs) and their precursors alpha-dicarbonyls are implicated in the progression of diabetic retinopathy. The purpose of this study was to assess AGEs and a-dicarbonyls in the vitreous of patients with type 2 diabetes mellitus (T2DM) with early stages or absence

Risk factors for chronic transplant dysfunction and cardiovascular disease are related to accumulation of advanced glycation end-products in renal transplant recipients

NARCIS (Netherlands)

Hartog, Jasper W. L.; de Vries, Aiko P. J.; Bakker, Stephan J. L.; Graaff, Reindert; van Son, Willem J.; van der Heide, Jaap J. Homan; Gans, Reinold O. B.; Wolffenbuttel, Bruce H. R.; de Jong, Paul E.; Smit, Andries J.

Background. Accumulation of advanced glycation end-products (AGEs) has been implicated in the pathogenesis of chronic transplant dysfunction and cardiovascular disease in renal transplant recipients. We aimed to investigate which factors are associated with tissue AGE accumulation in renal

Risk factors for chronic transplant dysfunction and cardiovascular disease are related to accumulation of advanced glycation end-products in renal transplant recipients

NARCIS (Netherlands)

Hartog, Jasper W. L.; de Vries, Aiko P. J.; Bakker, Stephan J. L.; Graaff, Reindert; van Son, Willem J.; Homan van der Heide, Jaap J.; Gans, Reinold O. B.; Wolffenbuttel, Bruce H. R.; de Jong, Paul E.; Smit, Andries J.

2006-01-01

Accumulation of advanced glycation end-products (AGEs) has been implicated in the pathogenesis of chronic transplant dysfunction and cardiovascular disease in renal transplant recipients. We aimed to investigate which factors are associated with tissue AGE accumulation in renal transplant

Advanced glycation end-product expression is upregulated in the gastrointestinal tract of type 2 diabetic rats

DEFF Research Database (Denmark)

Chen, Peng-Min; Gregersen, Hans; Zhao, Jingbo

2015-01-01

AIM: To investigate changes in advanced glycation end products (AGEs) and their receptor (RAGE) expression in the gastrointestinal (GI) tract in type 2 diabetic rats. METHODS: Eight inherited type 2 diabetic rats Goto-Kakizak (GK) and ten age-matched normal rats were used in the study. From 18 wk...... and five micron sections were cut. The layer thickness was measured in Hematoxylin and Eosin-stained slides. AGE [N epsilon-(carboxymethyl) lysine and N epsilon-(carboxyethyl)lysine] and RAGE were detected by immunohistochemistry staining and image analysis was done using Sigmascan Pro 4.0 image analysis...... strongest in the diabetes group. Significant difference for AGE was found in the epithelial cells of villi and crypt in duodenum (immuno-positive area/total measuring area %: 13.37 ± 3.51 vs 37.48 ± 8.43, P

Skin autofluorescence, a novel marker for glycemic and oxidative stress-derived advanced glycation endproducts : An overview of current clinical studies, evidence, and limitations

NARCIS (Netherlands)

Mulder, Douwe J.; Van de Water, Tara; Lutgers, Helen L.; Graaff, Reindert; Gans, Rijk O.; Zijlstra, Felix; Smit, Andries J.

2006-01-01

Background: Advanced glycation endproducts (AGES) predict long-term complications in age-related diseases. However, there are no clinically applicable markers for measuring AGES in vivo. Methods: We have recently introduced the AGE-Reader (DiagnOptics B.V., Groningen, The Netherlands) to

Activation of the HMGB1-RAGE axis upregulates TH expression in dopaminergic neurons via JNK phosphorylation.

Science.gov (United States)

Kim, Soo Jeong; Ryu, Min Jeong; Han, Jeongsu; Jang, Yunseon; Kim, Jungim; Lee, Min Joung; Ryu, Ilhwan; Ju, Xianshu; Oh, Eungseok; Chung, Woosuk; Kweon, Gi Ryang; Heo, Jun Young

2017-11-04

The derangement of tyrosine hydroxylase (TH) activity reduces dopamine synthesis and is implicated in the pathogenesis of Parkinson's disease. However, the extracellular modulator and intracellular regulatory mechanisms of TH have yet to be identified. Recently, high-mobility group box 1 (HMGB1) was reported to be actively secreted from glial cells and is regarded as a mediator of dopaminergic neuronal loss. However, the mechanism for how HMGB1 affects TH expression, particularly through the receptor for advanced glycation endproducts (RAGE), has not yet been investigated. We found that recombinant HMGB1 (rHMGB1) upregulates TH mRNA expression via simultaneous activation of JNK phosphorylation, and this induction of TH expression is blocked by inhibitors of RAGE and JNK. To investigate how TH expression levels change through the HMGB1-RAGE axis as a result of MPP + toxicity, we co-treated SN4741 dopaminergic cells with MPP + and rHMGB1. rHMGB1 blocked the reduction of TH mRNA following MPP + treatment without altering cell survival rates. Our results suggest that HMGB1 upregulates TH expression to maintain dopaminergic neuronal function via activating RAGE, which is dependent on JNK phosphorylation. Copyright © 2017 Elsevier Inc. All rights reserved.

The effect of an advanced glycation end-product crosslink breaker and exercise training on vascular function in older individuals: a randomized factorial design trial.

NARCIS (Netherlands)

Oudegeest-Sander, M.H.; Olde Rikkert, M.G.M.; Smits, P.; Thijssen, D.H.J.; Dijk, A.P.J. van; Levine, B.D.; Hopman, M.T.E.

2013-01-01

Aging leads to accumulation of irreversible advanced glycation end-products (AGEs), contributing to vascular stiffening and endothelial dysfunction. When combined with the AGE-crosslink breaker Alagebrium, exercise training reverses cardiovascular aging in experimental animals. This study is the

Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

Energy Technology Data Exchange (ETDEWEB)

Zhang, Liang, E-mail: countryspring@sina.com; Ji, Yunxia, E-mail: 413499057@qq.com; Kang, Zechun, E-mail: davidjiangwl@163.com; Lv, Changjun, E-mail: Lucky_lcj@sina.com; Jiang, Wanglin, E-mail: jwl518@163.com

2015-02-15

An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

International Nuclear Information System (INIS)

Zhang, Liang; Ji, Yunxia; Kang, Zechun; Lv, Changjun; Jiang, Wanglin

2015-01-01

An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway

Local and systemic RAGE axis changes in pulmonary hypertension: CTEPH and iPAH.

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Bernhard Moser

Full Text Available OBJECTIVE: The molecular determinants of chronic thromboembolic pulmonary hypertension (CTEPH and idiopathic pulmonary arterial hypertension (iPAH remain poorly understood. The receptor for advanced glycation endproducts (RAGE and its ligands: HMGB1 and S100A9 are involved in inflammatory disorders. We sought to investigate the role of the RAGE axis in patients with CTEPH undergoing pulmonary endarterectomy (PEA, iPAH undergoing lung transplantation (LuTX. The high pulmonary vascular resistance in CTEPH/iPAH results in pressure overload of the right ventricle. We compared sRAGE measurements to that of patients with aortic valve stenosis (AVS - pressure overload of the left ventricle. METHODS: We enrolled patients with CTEPH(26, iPAH(15, AVS(15 and volunteers(33. Immunohistochemistry with antibodies to RAGE and HMGB1 was performed on PEA specimens and lung tissues. We employed enzyme-linked immunosorbent assays to determine the concentrations of sRAGE, esRAGE, HMGB1 and S100A9 in serum of volunteers and patients with CTEPH, iPAH, AVS before and after PEA, LuTX and aortic valve replacement (AVR. RESULTS: In endarterectomised tissues from patients with CTEPH RAGE and HMGB1 were identified in myofibroblasts (α-SMA+vimentin+CD34-, recanalizing vessel-like structures of distal myofibrotic tissues and endothelium of neointima. RAGE was differentially expressed in prototypical Heath Edwards lesions in iPAH. We found significantly increased serum concentrations of sRAGE, esRAGE and HMGB1 in CTEPH. In iPAH, sRAGE and esRAGE were significantly higher than in controls. Serum concentrations of sRAGE were significantly elevated in iPAH(p<0.001 and CTEPH(p = 0.001 compared to AVS. Serum sRAGE was significantly higher in iPAH compared to CTEPH(p = 0.042 and significantly reduced in AVS compared to controls(p = 0.001. There were no significant differences in sRAGE serum concentrations before and after surgical therapy for CTEPH, iPAH or AVS. CONCLUSIONS: Our

Soluble Receptor for Advanced Glycation End Products (sRAGE is Up-Regulated in Multiple Sclerosis Patients Treated with Interferon β-1a

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Mahnoosh Rahimi

2018-03-01

Full Text Available Background/Aims: Multiple sclerosis (MS is a chronic inflammatory disorder of the central nervous system. Considering the role of immune system in its pathogenesis, researchers have focused on evaluation of the expression of immune-related genes or proteins in MS patients. Among proteins whose participation in inflammatory process has been documented is the receptor for advanced glycation end products (RAGE. Methods: In the present study, we compared RAGE transcript levels by means of quantitative real-time PCR as well as the serum level of soluble RAGE (sRAGE by means of enzyme- linked immunosorbent assay (ELISA in 50 IFNβ-1a responsive relapsing-remitting MS patients when compared with age and sex-matched healthy subjects. Results: Elevated expression of RAGE as well as higher levels of sRAGE were detected in IFN-β responsive MS patients compared with the controls. A significant inverse correlation between sRAGE plasma concentrations and the expanded disability status scale (EDSS was also detected in which each unit of increase in sRAGE level resulted in a 0.308 unit decrease in EDSS. Conclusion: Considering the stable clinical state of the MS patients in this study and their response to IFNβ-1a, the elevated levels of sRAGE in patients compared with healthy subjects could be related to the effects of this kind of treatment.

Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology.

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Bernhard Moser

Full Text Available Recently, a role of the receptor for advanced glycation endproducts (RAGE in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1 play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (pB3>thymic carcinoma (p<0.001. Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none, B1 (strong, B2 (moderate, B3 and thymic carcinoma (weak; (p<0.001. Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay: serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008; and in invasive tumors (p = 0.008. Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003, HMGB1 was only elevated in malignancies (p = 0.036. Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

Higher plasma soluble Receptor for Advanced Glycation End Products (sRAGE) levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12-year follow-up study

DEFF Research Database (Denmark)

Nin, Johanna W M; Jorsal, Anders; Merces Ferreira, Isabel Maria

2010-01-01

To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunct......To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal...

The specific localization of advanced glycation end-products (AGEs) in rat pancreatic islets.

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Morioka, Yuta; Teshigawara, Kiyoshi; Tomono, Yasuko; Wang, Dengli; Izushi, Yasuhisa; Wake, Hidenori; Liu, Keyue; Takahashi, Hideo Kohka; Mori, Shuji; Nishibori, Masahiro

2017-08-01

Advanced glycation end-products (AGEs) are produced by non-enzymatic glycation between protein and reducing sugar such as glucose. Although glyceraldehyde-derived AGEs (Glycer-AGEs), one of the AGEs subspecies, have been reported to be involved in the pathogenesis of various age-relating diseases such as diabetes mellitus or arteriosclerosis, little is known about the pathological and physiological mechanism of AGEs in vivo. In present study, we produced 4 kinds of polyclonal antibodies against AGEs subspecies and investigated the localization of AGEs-modified proteins in rat peripheral tissues, making use of these antibodies. We found that Glycer-AGEs and methylglyoxal-derived AGEs (MGO-AGEs) were present in pancreatic islets of healthy rats, distinguished clearly into the pancreatic α and β cells, respectively. Although streptozotocin-induced diabetic rats suffered from remarkable impairment of pancreatic islets, the localization and deposit levels of the Glycer- and MGO-AGEs were not altered in the remaining α and β cells. Remarkably, the MGO-AGEs in pancreatic β cells were localized into the insulin-secretory granules. These results suggest that the cell-specific localization of AGEs-modified proteins are presence generally in healthy peripheral tissues, involved in physiological intracellular roles, such as a post-translational modulator contributing to the secretory and/or maturational functions of insulin. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Soluble Receptor for Advanced Glycation End Product: A Biomarker for Acute Coronary Syndrome

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Louise J. N. Jensen

2015-01-01

Full Text Available The receptor of advanced glycation end products (RAGE and its ligands are linked to the pathogenesis of coronary artery disease (CAD, and circulating soluble receptor of advanced glycation end products (sRAGE, reflecting the RAGE activity, is suggested as a potential biomarker. Elevated sRAGE levels are reported in relation to acute ischemia and this review focuses on the role of sRAGE as a biomarker for the acute coronary syndrome (ACS. The current studies demonstrated that sRAGE levels are elevated in relation to ACS, however during a very narrow time period, indicating that the time of sampling needs attention. Interestingly, activation of RAGE may influence the pathogenesis and reflection in sRAGE levels in acute and stable CAD differently.

Receptor for advanced glycation end products (RAGE) functions as receptor for specific sulfated glycosaminoglycans, and anti-RAGE antibody or sulfated glycosaminoglycans delivered in vivo inhibit pulmonary metastasis of tumor cells.

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Mizumoto, Shuji; Takahashi, Jun; Sugahara, Kazuyuki

2012-06-01

Altered expression of chondroitin sulfate (CS) and heparan sulfate (HS) at the surfaces of tumor cells plays a key role in malignant transformation and tumor metastasis. Previously we demonstrated that a Lewis lung carcinoma (LLC)-derived tumor cell line with high metastatic potential had a higher proportion of E-disaccharide units, GlcUA-GalNAc(4,6-O-disulfate), in CS chains than low metastatic LLC cells and that such CS chains are involved in the metastatic process. The metastasis was markedly inhibited by the pre-administration of CS-E from squid cartilage rich in E units or by preincubation with a phage display antibody specific for CS-E. However, the molecular mechanism of the inhibition remains to be investigated. In this study the receptor molecule for CS chains containing E-disaccharides expressed on LLC cells was revealed to be receptor for advanced glycation end products (RAGE), which is a member of the immunoglobulin superfamily predominantly expressed in the lung. Interestingly, RAGE bound strongly to not only E-disaccharide, but also HS-expressing LLC cells. Furthermore, the colonization of the lungs by LLC cells was effectively inhibited by the blocking of CS or HS chains at the tumor cell surface with an anti-RAGE antibody through intravenous injections in a dose-dependent manner. These results provide the clear evidence that RAGE is at least one of the critical receptors for CS and HS chains expressed at the tumor cell surface and involved in experimental lung metastasis and that CS/HS and RAGE are potential molecular targets in the treatment of pulmonary metastasis.

An advanced glycation endproduct (AGE)-rich diet promotes accumulation of AGEs in Achilles tendon

DEFF Research Database (Denmark)

Skovgaard, Dorthe; Svensson, Rene B; Scheijen, Jean

2017-01-01

the relationship between AGE content in the diet and accumulation of AGEs in weight-bearing animal Achilles tendon. Two groups of mice (C57BL/6Ntac) were fed with either high-fat diet low in AGEs high-fat diet (HFD) (n = 14) or normal diet high in AGEs (ND) (n = 11). AGE content in ND was six to 50-fold higher......Advanced Glycation Endproducts (AGEs) accumulate in long-lived tissue proteins like collagen in bone and tendon causing modification of the biomechanical properties. This has been hypothesized to raise the risk of orthopedic injury such as bone fractures and tendon ruptures. We evaluated...... was measured using ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and pentosidine with high-pressure liquid chromatography (HPLC) with fluorescent detection. AGEs in Achilles tendon were higher than in tail tendon for CML (P

Glycated Lysine Residues: A Marker for Non-Enzymatic Protein Glycation in Age-Related Diseases

OpenAIRE

Ansari, Nadeem A.; Moinuddin,; Ali, Rashid

2011-01-01

Nonenzymatic glycosylation or glycation of macromolecules, especially proteins leading to their oxidation, play an important role in diseases. Glycation of proteins primarily results in the formation of an early stage and stable Amadori-lysine product which undergo further irreversible chemical reactions to form advanced glycation endproducts (AGEs). This review focuses these products in lysine rich proteins such as collagen and human serum albumin for their role in aging and age-related dise...

RAGE splicing variants in mammals.

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Sterenczak, Katharina Anna; Nolte, Ingo; Murua Escobar, Hugo

2013-01-01

The receptor for advanced glycation end products (RAGE) is a multiligand receptor of environmental stressors which plays key roles in pathophysiological processes, including immune/inflammatory disorders, Alzheimer's disease, diabetic arteriosclerosis, tumorigenesis, and metastasis. Besides the full-length RAGE protein in humans nearly 20 natural occurring RAGE splicing variants were described on mRNA and protein level. These naturally occurring isoforms are characterized by either N-terminally or C-terminally truncations and are discussed as possible regulators of the full-length RAGE receptor either by competitive ligand binding or by displacing the full-length protein in the membrane. Accordingly, expression deregulations of the naturally occurring isoforms were supposed to have significant effect on RAGE-mediated disorders. Thereby the soluble C-truncated RAGE isoforms present in plasma and tissues are the mostly focused isoforms in research and clinics. Deregulations of the circulating levels of soluble RAGE forms were reported in several RAGE-associated pathological disorders including for example atherosclerosis, diabetes, renal failure, Alzheimer's disease, and several cancer types. Regarding other mammalian species, the canine RAGE gene showed high similarities to the corresponding human structures indicating RAGE to be evolutionary highly conserved between both species. Similar to humans the canine RAGE showed a complex and extensive splicing activity leading to a manifold pattern of RAGE isoforms. Due to the similarities seen in several canine and human diseases-including cancer-comparative structural and functional analyses allow the development of RAGE and ligand-specific therapeutic approaches beneficial for human and veterinary medicine.

Ligature-associated bacterial profiles are linked to type 2 diabetes mellitus in a rat model and influenced by antibody treatment against TNF-α or RAGE

DEFF Research Database (Denmark)

Grauballe, M B; Belstrøm, D; Østergaard, J A

2017-01-01

on oral bacterial profiles. Therefore, we aimed to evaluate the influence of T2D on the ligature-associated bacterial profile in a diabetic rat model with PD and investigated the impact of blocking inflammatory pathways with antibodies targeting either Tumor Necrosis Factor α (TNF-α) or the receptor......There is a bidirectional relationship between periodontal disease (PD) and type 2 diabetes mellitus (T2D). T2D may lead to ecological perturbations in the oral environment, which may facilitate an altered microbiota. However, previous studies have been inconclusive in determining the effect of T2D...... of advanced glycation end-products (RAGE). A total of 62 Zucker obese rats (45 T2D) and 17 lean (non-T2D) were divided into 4 treatment groups; lean with PD, obese with PD, obese with PD and anti-TNF-α treatment, and obese with PD with anti-RAGE treatment. Periodontal disease was ligature induced. Ligature...

Evaluation of In Vitro Inhibitory Activity of Rye-Buckwheat Ginger Cakes with Rutin on the Formation of Advanced Glycation End-Products (AGEs)

OpenAIRE

Przygodzka Małgorzata; Zieliński Henryk

2015-01-01

In this study, the relationship between the inhibitory effects of extracts from rye-buckwheat ginger cakes supplemented with low and high rutin dosage baked without or with dough fermentation step on the formation of fluorescent advanced glycation end-products (AGEs), and phenolic compounds, rutin, D-chiro-inositol and antioxidant capacity were addressed. The cakes were based on rye flour substituted by light buckwheat flour or flour from roasted buckwheat groats at 30% level, and were produc...

Caffeic acid attenuates the inflammatory stress induced by glycated LDL in human endothelial cells by mechanisms involving inhibition of AGE-receptor, oxidative, and endoplasmic reticulum stress.

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Toma, Laura; Sanda, Gabriela M; Niculescu, Loredan S; Deleanu, Mariana; Stancu, Camelia S; Sima, Anca V

2017-09-10

Type 2 diabetes mellitus is a worldwide epidemic and its atherosclerotic complications determine the high morbidity and mortality of diabetic patients. Caffeic acid (CAF), a phenolic acid present in normal diets, is known for its antioxidant properties. The aim of this study was to investigate CAF's anti-inflammatory properties and its mechanism of action, using cultured human endothelial cells (HEC) incubated with glycated low-density lipoproteins (gLDL). Levels of the receptor for advanced glycation end-products (RAGE), inflammatory stress markers (C reactive protein, CRP; vascular cell adhesion molecule-1, VCAM-1; monocyte chemoattractant protein-1, MCP-1), and oxidative stress and endoplasmic reticulum stress (ERS) markers were evaluated in gLDL-exposed HEC, in the presence/absence of CAF. RAGE silencing or blocking, specific inhibitors for oxidative stress (apocynin, N-acetyl-cysteine), and ERS (salubrinal) were used. The results showed that: (i) gLDL induced CRP synthesis and secretion through mechanisms involving NADPH oxidase-dependent oxidative stress and ERS in HEC; (ii) gLDL-RAGE interaction, oxidative stress, and ERS stimulated the secretion of VCAM-1 and MCP-1 in HEC; and (iii) CAF reduced the secretion of CRP, VCAM-1, and MCP-1 in gLDL-exposed HEC by inhibiting RAGE expression, oxidative stress, and ERS. In conclusion, CAF might be a promising alternative to ameliorate a wide spectrum of disorders due to its complex mechanisms of action resulting in anti-inflammatory and antioxidative properties. © 2017 BioFactors, 43(5):685-697, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

The association of low muscle mass with soluble receptor for advanced glycation end products (sRAGE): The Korean Sarcopenic Obesity Study (KSOS).

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Kim, Tae Nyun; Park, Man Sik; Lee, Eun Joo; Chung, Hye Soo; Yoo, Hye Jin; Kang, Hyun Joo; Song, Wook; Baik, Sei Hyun; Choi, Kyung Mook

2018-03-01

Advanced glycation end products (AGEs) are accumulated with aging in various tissues of humans. The soluble receptor for AGEs (sRAGE) exerts a protective role against the development of aging-related chronic disorders by neutralizing the action of AGEs. We investigated the implication of sRAGE on low muscle mass in Asian men and women. This cross-sectional study included a 390-participant, nondiabetic subcohort recruited within the framework of the Korean Sarcopenic Obesity Study, an ongoing prospective cohort study. Low muscle mass was defined based on the distribution of appendicular skeletal muscle mass divided by body mass index, as proposed by the Foundation for the National Institutes Sarcopenia Project. Serum sRAGE levels were significantly lower in participants with low muscle mass than in participants without low muscle mass (0.76 [0.60-1.00] ng/mL vs 0.87 [0.67-1.15] ng/mL, P = .005). In age- and sex-adjusted correlation analyses, appendicular skeletal muscle mass divided by body mass index was associated with sRAGE (r = 0.109, P = .037). Furthermore, decreased circulating levels of sRAGE are independently associated with low muscle mass (odds ratio = 0.254, P = .002) after adjusting for confounding factors, including insulin resistance and inflammatory markers. The present study shows that a low circulating level of sRAGE may be an independent risk factor for the presence of low muscle mass. Copyright © 2017 John Wiley & Sons, Ltd.

Glycated Lysine Residues: A Marker for Non-Enzymatic Protein Glycation in Age-Related Diseases

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Nadeem A. Ansari

2011-01-01

Full Text Available Nonenzymatic glycosylation or glycation of macromolecules, especially proteins leading to their oxidation, play an important role in diseases. Glycation of proteins primarily results in the formation of an early stage and stable Amadori-lysine product which undergo further irreversible chemical reactions to form advanced glycation endproducts (AGEs. This review focuses these products in lysine rich proteins such as collagen and human serum albumin for their role in aging and age-related diseases. Antigenic characteristics of glycated lysine residues in proteins together with the presence of serum autoantibodies to the glycated lysine products and lysine-rich proteins in diabetes and arthritis patients indicates that these modified lysine residues may be a novel biomarker for protein glycation in aging and age-related diseases.

Advanced glycation endproducts in 35 types of seafood products consumed in eastern China

Science.gov (United States)

Wang, Jing; Li, Zhenxing; Pavase, Ramesh Tushar; Lin, Hong; Zou, Long; Wen, Jie; Lv, Liangtao

2016-08-01

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 Nɛ-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.

Methylglyoxal and carboxyethyllysine reduce glutamate uptake and S100B secretion in the hippocampus independently of RAGE activation.

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Hansen, Fernanda; Battú, Cíntia Eickhoff; Dutra, Márcio Ferreira; Galland, Fabiana; Lirio, Franciane; Broetto, Núbia; Nardin, Patrícia; Gonçalves, Carlos-Alberto

2016-02-01

Diabetes is a metabolic disease characterized by high fasting-glucose levels. Diabetic complications have been associated with hyperglycemia and high levels of reactive compounds, such as methylglyoxal (MG) and advanced glycation endproducts (AGEs) formation derived from glucose. Diabetic patients have a higher risk of developing neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. Herein, we examined the effect of high glucose, MG and carboxyethyllysine (CEL), a MG-derived AGE of lysine, on oxidative, metabolic and astrocyte-specific parameters in acute hippocampal slices, and investigated some of the mechanisms that could mediate these effects. Glucose, MG and CEL did not alter reactive oxygen species (ROS) formation, glucose uptake or glutamine synthetase activity. However, glutamate uptake and S100B secretion were decreased after MG and CEL exposure. RAGE activation and glycation reactions, examined by aminoguanidine and L-lysine co-incubation, did not mediate these changes. Acute MG and CEL exposure, but not glucose, were able to induce similar effects on hippocampal slices, suggesting that conditions of high glucose concentrations are primarily toxic by elevating the rates of these glycation compounds, such as MG, and by generation of protein cross-links. Alterations in the secretion of S100B and the glutamatergic activity mediated by MG and AGEs can contribute to the brain dysfunction observed in diabetic patients.

The receptor RAGE: Bridging inflammation and cancer

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Hess Jochen

2009-05-01

Full Text Available Abstract The receptor for advanced glycation end products (RAGE is a single transmembrane receptor of the immunoglobulin superfamily that is mainly expressed on immune cells, neurons, activated endothelial and vascular smooth muscle cells, bone forming cells, and a variety of cancer cells. RAGE is a multifunctional receptor that binds a broad repertoire of ligands and mediates responses to cell damage and stress conditions. It activates programs responsible for acute and chronic inflammation, and is implicated in a number of pathological diseases, including diabetic complications, stroke, atheriosclerosis, arthritis, and neurodegenerative disorders. The availability of Rage knockout mice has not only advanced our knowledge on signalling pathways within these pathophysiological conditions, but also on the functional importance of the receptor in processes of cancer. Here, we will summarize molecular mechanisms through which RAGE signalling contributes to the establishment of a pro-tumourigenic microenvironment. Moreover, we will review recent findings that provide genetic evidence for an important role of RAGE in bridging inflammation and cancer.

Advanced glycation end-products: a biological consequence of lifestyle contributing to cancer disparity.

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Turner, David P

2015-05-15

Low income, poor diet, obesity, and a lack of exercise are interrelated lifestyle factors that can profoundly alter our biologic make up to increase cancer risk, growth, and development. We recently reported a potential mechanistic link between carbohydrate-derived metabolites and cancer, which may provide a biologic consequence of lifestyle that can directly affect tumor biology. Advanced glycation end-products (AGE) are reactive metabolites produced as a by-product of sugar metabolism. Failure to remove these highly reactive metabolites can lead to protein damage, aberrant cell signaling, increased stress responses, and decreased genetic fidelity. Critically, AGE accumulation is also directly affected by our lifestyle choices and shows a race-specific, tumor-dependent pattern of accumulation in cancer patients. This review will discuss the contribution of AGEs to the cancer phenotype, with a particular emphasis on their biologic links with the socioeconomic and environmental risk factors that drive cancer disparity. Given the potential benefits of lifestyle changes and the potential biologic role of AGEs in promoting cancer, opportunities exist for collaborations affecting basic, translational, epidemiologic, and cancer prevention initiatives. ©2015 American Association for Cancer Research.

Receptor for advanced glycation end product polymorphisms and type 2 diabetes: the CODAM study

NARCIS (Netherlands)

Gaens, K.H.; Kallen, C.J.; Greevenboek, van M.M.; Feskens, E.J.M.; Stehouwer, C.D.; Schalkwijk, C.G.

2008-01-01

Genetic variation in the receptor for advanced glycation end products (RAGE) gene may alter the expression and function of RAGE and affect disease development and outcome. We investigated whether single nucleotide polymorphisms (SNPs) in RAGE were associated with diabetes and parameters of glucose

Associations between advanced glycation endproducts and matrix metalloproteinases and its inhibitor in individuals with type 1 diabetes

DEFF Research Database (Denmark)

Peeters, S A; Engelen, L; Buijs, J

2018-01-01

the production of MMPs and/or TIMP-1. Therefore, we investigated associations between specific AGEs and MMP-1, -2, -3, -9, and -10, and TIMP-1 in individuals with type 1 diabetes. METHODS: In 670 type 1 diabetic individuals we determined serum levels of protein-bound AGEs Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine......AIMS: Advanced glycation endproducts (AGEs) and altered extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) are associated with vascular complications in type 1 diabetes. Experimental studies have shown that AGEs regulate...... (CEL), 5-hydro-5-methylimidazolone (MG-H1) and pentosidine, and MMP-1, -2, -3, -9, and -10, and TIMP-1. We performed linear regression analyses to investigate associations between AGEs and markers of the MMP-TIMP system. Analyses were adjusted for age, sex, HbA1c and duration of diabetes...

Protection against RAGE-mediated neuronal cell death by sRAGE-secreting human mesenchymal stem cells in 5xFAD transgenic mouse model.

Science.gov (United States)

Son, Myeongjoo; Oh, Seyeon; Park, Hyunjin; Ahn, Hyosang; Choi, Junwon; Kim, Hyungho; Lee, Hye Sun; Lee, Sojung; Park, Hye-Jeong; Kim, Seung U; Lee, Bonghee; Byun, Kyunghee

2017-11-01

Alzheimer's disease (AD), which is the most commonly encountered neurodegenerative disease, causes synaptic dysfunction and neuronal loss due to various pathological processes that include tau abnormality and amyloid beta (Aβ) accumulation. Aβ stimulates the secretion and the synthesis of Receptor for Advanced Glycation End products (RAGE) ligand by activating microglial cells, and has been reported to cause neuronal cell death in Aβ 1-42 treated rats and in mice with neurotoxin-induced Parkinson's disease. The soluble form of RAGE (sRAGE) is known to reduce inflammation, and to decrease microglial cell activation and Aβ deposition, and thus, it protects from neuronal cell death in AD. However, sRAGE protein has too a short half-life for therapeutic purposes. We developed sRAGE-secreting umbilical cord derived mesenchymal stem cells (sRAGE-MSCs) to enhance the inhibitory effects of sRAGE on Aβ deposition and to reduce the secretion and synthesis of RAGE ligands in 5xFAD mice. In addition, these cells improved the viability of injected MSCs, and enhanced the protective effects of sRAGE by inhibiting the binding of RAGE and RAGE ligands in 5xFAD mice. These findings suggest sRAGE protein from sRAGE-MSCs has better protection against neuronal cell death than sRAGE protein or single MSC treatment by inhibiting the RAGE cell death cascade and RAGE-induce inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

Receptor for Advanced Glycation End Products Facilitates Host Defense during Escherichia coli-Induced Abdominal Sepsis in Mice

NARCIS (Netherlands)

van Zoelen, Marieke A. D.; Schmidt, Ann-Marie; Florquin, Sandrine; Meijers, Joost C.; de Beer, Regina; de Vos, Alex F.; Nawroth, Peter P.; Bierhaus, Angelika; van der Poll, Tom

2009-01-01

Background. The receptor for advanced glycation end products (RAGE) mediates a variety of inflammatory responses. Methods. To determine the role of RAGE in the innate immune response to abdominal sepsis caused by Escherichia coli, RAGE-deficient (RAGE(-/-)) and normal wild-type mice were

Advanced Glycation End-Products affect transcription factors regulating insulin gene expression

International Nuclear Information System (INIS)

Puddu, A.; Storace, D.; Odetti, P.; Viviani, G.L.

2010-01-01

Advanced Glycation End-Products (AGEs) are generated by the covalent interaction of reducing sugars with proteins, lipids or nucleic acids. AGEs are implicated in diabetic complications and pancreatic β-cell dysfunction. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T15 to high concentrations of AGEs leads to a significant decrease of insulin secretion and content. Insulin gene transcription is positively regulated by the beta cell specific transcription factor PDX-1 (Pancreatic and Duodenal Homeobox-1). On the contrary, the forkhead transcription factor FoxO1 inhibits PDX-1 gene transcription. Activity of FoxO1 is regulated by post-translational modifications: phosphorylation deactivates FoxO1, and acetylation prevents FoxO1 ubiquitination. In this work we investigated whether AGEs affect expression and subcellular localization of PDX-1 and FoxO1. HIT-T15 cells were cultured for 5 days in presence of AGEs. Cells were then lysed and processed for subcellular fractionation. We determined intracellular insulin content, then we assessed the expression and subcellular localization of PDX-1, FoxO1, phosphoFoxO1 and acetylFoxO1. As expected intracellular insulin content was lower in HIT-T15 cells cultured with AGEs. The results showed that AGEs decreased expression and nuclear localization of PDX-1, reduced phosphorylation of FoxO1, and increased expression and acetylation of FoxO1. These results suggest that AGEs decrease insulin content unbalancing transcription factors regulating insulin gene expression.

The distribution of advanced glycation end products and their receptor in the gastrointestinal tract in the rats

DEFF Research Database (Denmark)

Chen, Pengmin; Zhao, Jingbo; Gregersen, Hans

2012-01-01

To investigate the distribution of advanced glycation end products (AGEs) and their receptor (RAGE) in the gastrointestinal (GI) tract to provide a basis for further study of the association between AGE/RAGE and diabetic GI dysfunction. METHODS: The distribution of AGEs [N epsilon-(carboxymethyl)......To investigate the distribution of advanced glycation end products (AGEs) and their receptor (RAGE) in the gastrointestinal (GI) tract to provide a basis for further study of the association between AGE/RAGE and diabetic GI dysfunction. METHODS: The distribution of AGEs [N epsilon......-(carboxymethyl) lysine and N epsilon-(carboxyethyl) lysine] and RAGE were detected in the esopha-geal, gastric, duodenal, jejunal, ileal, colonic and rectal tissues of normal adult Wistar rats using immunohistochemistry. RESULTS: In the esophagus, AGEs and RAGE were mainly distributed in striated muscle cells...

Determination of advanced glycation endproducts by LC-MS/MS in raw and roasted almonds (Prunus dulcis).

Science.gov (United States)

Zhang, Gong; Huang, Guangwei; Xiao, Lu; Mitchell, Alyson E

2011-11-23

A sensitive and reliable LC-(ESI)MS/MS method was developed and validated for the simultaneous analysis of five common advanced glycation endproducts (AGEs) after enzymatic digestion in raw and roasted almonds. AGEs included carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL), pyralline (Pyr), argpyrimidine (Arg-p), and pentosidine (Pento-s). This method allows accurate quantitation of free and AGE-protein adducts of target AGEs. Results indicate that CML and CEL are found in both raw and roasted almonds. Pyr was identified for the first time in roasted almonds and accounted for 64.4% of free plus bound measured AGEs. Arg-p and Pento-s were below the limit of detection in all almond samples tested. Free AGEs accounted for 1.3-26.8% of free plus bound measured AGEs, indicating that protein-bound forms predominate. The roasting process significantly increased CML, CEL, and Pyr formation, but no significant correlation was observed between these AGEs and roasting temperature.

Advanced glycation end-product (AGE)-albumin from activated macrophage is critical in human mesenchymal stem cells survival and post-ischemic reperfusion injury.

Science.gov (United States)

Son, Myeongjoo; Kang, Woong Chol; Oh, Seyeon; Bayarsaikhan, Delger; Ahn, Hyosang; Lee, Jaesuk; Park, Hyunjin; Lee, Sojung; Choi, Junwon; Lee, Hye Sun; Yang, Phillip C; Byun, Kyunghee; Lee, Bonghee

2017-09-14

Post-ischemic reperfusion injury (PIRI) triggers an intense inflammatory response which is essential for repair but is also implicated in pathogenesis of post-ischemic remodeling in several organs in human. Stem cell therapy has recently emerged as a promising method for treatment of PIRI in human. However, satisfactory results have not been reported due to severe loss of injected stem cells in PIRI including critical limb ischemia (CLI). For investigating the advanced glycation end-product-albumin (AGE-albumin) from activated macrophages is critical in both muscle cell and stem cell death, we evaluated the recovery of PIRI-CLI by injection of human bone marrow derived mesenchymal stem cells (hBD-MSCs) with or without soluble receptor for AGEs (sRAGE). Our results showed that activated M1 macrophages synthesize and secrete AGE-albumin, which induced the skeletal muscle cell death and injected hBD-MSCs in PIRI-CLI through RAGE increase. Combined injection of sRAGE and hBD-MSCs resulted in enhanced survival of hBD-MSCs and angiogenesis in PIRI-CLI mice. Taken together, AGE-albumin from activated macrophages is critical for both skeletal muscle cell and hBD-MSCs death in PIRI-CLI. Therefore, the inhibition of AGE-albumin from activated macrophages could be a successful therapeutic strategy for treatment of PIRI including CLI with or without stem cell therapy.

Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation

Energy Technology Data Exchange (ETDEWEB)

Matsui, Takanori [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Yamagishi, Sho-ichi, E-mail: shoichi@med.kurume-u.ac.jp [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Takeuchi, Masayoshi [Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa (Japan); Ueda, Seiji; Fukami, Kei; Okuda, Seiya [Department of Medicine, Kurume University School of Medicine, Kurume (Japan)

2010-07-23

Research highlights: {yields} Nifedipine inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma}. {yields} GW9662 treatment alone increased RAGE mRNA levels in tubular cells. {yields} Nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-{beta} gene expression in tubular cells, all of which were blocked by GW9662. -- Abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenic reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE expression

Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation

International Nuclear Information System (INIS)

Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

2010-01-01

Research highlights: → Nifedipine inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ. → GW9662 treatment alone increased RAGE mRNA levels in tubular cells. → Nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-κB activation and increases in intercellular adhesion molecule-1 and transforming growth factor-β gene expression in tubular cells, all of which were blocked by GW9662. -- Abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenic reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPARγ). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-κB activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE expression via PPARγ activation.

Systemic levels of the anti-inflammatory decoy receptor soluble RAGE (receptor for advanced glycation end products) are decreased in dogs with inflammatory bowel disease.

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Heilmann, Romy M; Otoni, Cristiane C; Jergens, Albert E; Grützner, Niels; Suchodolski, Jan S; Steiner, Jörg M

2014-10-15

Inflammatory bowel disease (IBD) is a common condition in dogs, and a dysregulated innate immunity is believed to play a major role in its pathogenesis. S100A12 is an endogenous damage-associated molecular pattern molecule, which is involved in phagocyte activation and is increased in serum/fecal samples from dogs with IBD. S100A12 binds to the receptor of advanced glycation end products (RAGE), a pattern-recognition receptor, and results of studies in human patients with IBD and other conditions suggest a role of RAGE in chronic inflammation. Soluble RAGE (sRAGE), a decoy receptor for inflammatory proteins (e.g., S100A12) that appears to function as an anti-inflammatory molecule, was shown to be decreased in human IBD patients. This study aimed to evaluate serum sRAGE and serum/fecal S100A12 concentrations in dogs with IBD. Serum and fecal samples were collected from 20 dogs with IBD before and after initiation of medical treatment and from 15 healthy control dogs. Serum sRAGE and serum and fecal S100A12 concentrations were measured by ELISA, and were compared between dogs with IBD and healthy controls, and between dogs with a positive outcome (i.e., clinical remission, n=13) and those that were euthanized (n=6). The relationship of serum sRAGE concentrations with clinical disease activity (using the CIBDAI scoring system), serum and fecal S100A12 concentrations, and histologic disease severity (using a 4-point semi-quantitative grading system) was tested. Serum sRAGE concentrations were significantly lower in dogs with IBD than in healthy controls (p=0.0003), but were not correlated with the severity of histologic lesions (p=0.4241), the CIBDAI score before (p=0.0967) or after treatment (p=0.1067), the serum S100A12 concentration before (p=0.9214) and after treatment (p=0.4411), or with the individual outcome (p=0.4066). Clinical remission and the change in serum sRAGE concentration after treatment were not significantly associated (p=0.5727); however, serum sRAGE

The Course of Skin and Serum Biomarkers of Advanced Glycation Endproducts and Its Association with Oxidative Stress, Inflammation, Disease Severity, and Mortality during ICU Admission in Critically Ill Patients : Results from a Prospective Pilot Study

NARCIS (Netherlands)

Meertens, John H.; Nienhuis, Hans L; Lefrandt, Joop D; Schalkwijk, Casper G; Nyyssönen, Kristiina; Ligtenberg, Jack J M; Smit, Andries J; Zijlstra, Jan G; Mulder, Douwe J.

2016-01-01

Background Advanced glycation end products (AGEs) have been implicated in multiple organ failure, predominantly via their cellular receptor (RAGE) in preclinical studies. Little is known about the time course and prognostic relevance of AGEs in critically ill human patients, including those with

Ethyl pyruvate inhibits proliferation and induces apoptosis of hepatocellular carcinoma via regulation of the HMGB1–RAGE and AKT pathways

Energy Technology Data Exchange (ETDEWEB)

Cheng, Ping; Dai, Weiqi; Wang, Fan; Lu, Jie; Shen, Miao; Chen, Kan; Li, Jingjing; Zhang, Yan; Wang, Chengfen; Yang, Jing; Zhu, Rong; Zhang, Huawei; Zheng, Yuanyuan; Guo, Chuan-Yong, E-mail: guochuanyong@hotmail.com; Xu, Ling, E-mail: xuling606@sina.com

2014-01-24

Highlights: • Ethyl pyruvate inhibits liver cancer. • Promotes apoptosis. • Decreased the expression of HMGB1, p-Akt. - Abstract: Ethyl pyruvate (EP) was recently identified as a stable lipophilic derivative of pyruvic acid with significant antineoplastic activities. The high mobility group box-B1 (HMGB1)–receptor for advanced glycation end-products (RAGE) and the protein kinase B (Akt) pathways play a crucial role in tumorigenesis and development of many malignant tumors. We tried to observe the effects of ethyl pyruvate on liver cancer growth and explored its effects in hepatocellular carcinoma model. In this study, three hepatocellular carcinoma cell lines were treated with ethyl pyruvate. An MTT colorimetric assay was used to assess the effects of EP on cell proliferation. Flow cytometry and TUNEL assays were used to analyze apoptosis. Real-time PCR, Western blotting and immunofluorescence demonstrated ethyl pyruvate reduced the HMGB1–RAGE and AKT pathways. The results of hepatoma orthotopic tumor model verified the antitumor effects of ethyl pyruvate in vivo. EP could induce apoptosis and slow the growth of liver cancer. Moreover, EP decreased the expression of HMGB1, RAGE, p-AKT and matrix metallopeptidase-9 (MMP9) and increased the Bax/Bcl-2 ratio. In conclusion, this study demonstrates that ethyl pyruvate induces apoptosis and cell-cycle arrest in G phase in hepatocellular carcinoma cells, plays a critical role in the treatment of cancer.

The Receptor for Advanced Glycation End Products Impairs Host Defense in Pneumococcal Pneumonia

NARCIS (Netherlands)

van Zoelen, Marieke A. D.; Schouten, Marcel; de Vos, Alex F.; Florquin, Sandrine; Meijers, Joost C. M.; Nawroth, Peter P.; Bierhaus, Angelika; van der Poll, Tom

2009-01-01

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that is expressed ubiquitously in the lungs. Engagement of RAGE leads to activation of multiple intracellular signaling pathways,

High mobility group box 1 levels are not associated with subclinical carotid atherosclerosis in patients with granulomatosis with polyangiitis but are reduced by glucocorticoids and statins

NARCIS (Netherlands)

Silva de Souza, Alexandre; De Leeuw, Karina; Westra, Johanna; Smit, Andries J.; Van Der Graaf, Anne Marijn; Nienhuis, Hans L.A.; Bijzet, Johan; Limburg, Pieter C.; Stegeman, Coen A.; Bijl, Marc; Kallenberg, Cees G.M.

2012-01-01

Background/Purpose: High mobility group box 1 (HMGB1) is a non-histone DNA binding protein that is passively released by dying cells or actively secreted by immunocompetent cells and the receptor for advanced glycation end-products (RAGE) is one of its receptors. Higher levels of HMGB1 have been

A ternary-complex of a suicide gene, a RAGE-binding peptide, and polyethylenimine as a gene delivery system with anti-tumor and anti-angiogenic dual effects in glioblastoma.

Science.gov (United States)

Choi, Eunji; Oh, Jungju; Lee, Dahee; Lee, Jaewon; Tan, Xiaonan; Kim, Minkyung; Kim, Gyeungyun; Piao, Chunxian; Lee, Minhyung

2018-04-13

The receptor for advanced glycation end-products (RAGE) is involved in tumor angiogenesis. Inhibition of RAGE might be an effective anti-angiogenic therapy for cancer. In this study, a cationic RAGE-binding peptide (RBP) was produced as an antagonist of RAGE, and a ternary-complex consisting of RBP, polyethylenimine (2 kDa, PEI2k), and a suicide gene (pHSVtk) was developed as a gene delivery system with dual functions: the anti-tumor effect of pHSVtk and anti-angiogenic effect of RBP. As an antagonist of RAGE, RBP decreased the secretion of vascular-endothelial growth factor (VEGF) in activated macrophages and reduced the tube-formation of endothelial cells in vitro. In in vitro transfection assays, the RBP/PEI2k/plasmid DNA (pDNA) ternary-complex had higher transfection efficiency than the PEI2k/pDNA binary-complex. In an intracranial glioblastoma animal model, the RBP/PEI2k/pHSVtk ternary-complex reduced α-smooth muscle actin expression, suggesting that the complex has an anti-angiogenic effect. In addition, the ternary-complex had higher pHSVtk delivery efficiency than the PEI2k/pHSVtk and PEI25k/pHSVtk binary-complexes in an animal model. As a result, the ternary-complex induced apoptosis and reduced tumor volume more effectively than the PEI2k/pHSVtk and PEI25k/pHSVtk binary-complexes. In conclusion, due to its dual anti-tumor and anti-angiogenesis effects, the RBP/PEI2k/pHSVtk ternary-complex might be an efficient gene delivery system for the treatment of glioblastoma. Copyright © 2018 Elsevier B.V. All rights reserved.

Dietary intake of advanced glycation endproducts is associated with higher levels of advanced glycation endproducts in plasma and urine: The CODAM study.

Science.gov (United States)

Scheijen, Jean L J M; Hanssen, Nordin M J; van Greevenbroek, Marleen M; Van der Kallen, Carla J; Feskens, Edith J M; Stehouwer, Coen D A; Schalkwijk, Casper G

2018-06-01

Advanced glycation endproducts (AGEs) are formed by the reaction between reducing sugars and proteins. AGEs in the body have been associated with several age-related diseases. High-heat treated and most processed foods are rich in AGEs. The aim of our study was to investigate whether dietary AGEs, are associated with plasma and urinary AGE levels. In 450 participants of the Cohort on Diabetes and Atherosclerosis Maastricht study (CODAM study) we measured plasma and urine concentrations of the AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) using UPLC-MS/MS. We also estimated dietary intake of CML, CEL and MG-H1 with the use of a dietary AGE database and a food frequency questionnaire (FFQ). We used linear regression to investigate the association between standardized dietary AGE intake and standardized plasma or urinary AGE levels, after adjustment for age, sex, glucose metabolism status, waist circumference, kidney function, energy- and macro-nutrient intake, smoking status, physical activity, alcohol intake, LDL-cholesterol and markers of oxidative stress. We found that higher intake of dietary CML, CEL and MG-H1 was associated with significantly higher levels of free plasma and urinary CML, CEL and MG-H1 (βCML = 0.253 (95% CI 0.086; 0.415), βCEL = 0.194 (95% CI 0.040; 0.339), βMG-H1 = 0.223 (95% CI 0.069; 0.373) for plasma and βCML = 0.223 (95% CI 0.049; 0.393), βCEL = 0.180 (95% CI 0.019; 0.332), βMG-H1 = 0.196 (95% CI 0.037; 0.349) for urine, respectively). In addition, we observed non-significant associations of dietary AGEs with their corresponding protein bound plasma AGEs. We demonstrate that higher intake of dietary AGEs is associated with higher levels of AGEs in plasma and urine. Our findings may have important implications for those who ingest a diet rich in AGEs. Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and

RAGE: a new frontier in chronic airways disease

Science.gov (United States)

Sukkar, Maria B; Ullah, Md Ashik; Gan, Wan Jun; Wark, Peter AB; Chung, Kian Fan; Hughes, J Margaret; Armour, Carol L; Phipps, Simon

2012-01-01

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand–RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions. PMID:22506507

Oligomerization interface of RAGE receptor revealed by MS-monitored hydrogen deuterium exchange.

Directory of Open Access Journals (Sweden)

Ewa Sitkiewicz

Full Text Available Activation of the receptor for advanced glycation end products (RAGE leads to a chronic proinflammatory signal, affecting patients with a variety of diseases. Potentially beneficial modification of RAGE activity requires understanding the signal transduction mechanism at the molecular level. The ligand binding domain is structurally uncoupled from the cytoplasmic domain, suggesting receptor oligomerization is a requirement for receptor activation. In this study, we used hydrogen-deuterium exchange and mass spectrometry to map structural differences between the monomeric and oligomeric forms of RAGE. Our results indicated the presence of a region shielded from exchange in the oligomeric form of RAGE and led to the identification of a new oligomerization interface localized at the linker region between domains C1 and C2. Based on this finding, a model of a RAGE dimer and higher oligomeric state was constructed.

RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose.

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Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P; Campanucci, Verónica A

2018-01-01

Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes.

Hepatic microvascular dysfunction and increased advanced glycation end products are components of non-alcoholic fatty liver disease.

Science.gov (United States)

Pereira, Evelyn Nunes Goulart da Silva; Silvares, Raquel Rangel; Flores, Edgar Eduardo Ilaquita; Rodrigues, Karine Lino; Ramos, Isalira Peroba; da Silva, Igor José; Machado, Marcelo Pelajo; Miranda, Rosiane Aparecida; Pazos-Moura, Carmen Cabanelas; Gonçalves-de-Albuquerque, Cassiano F; Faria-Neto, Hugo Caire de Castro; Tibiriça, Eduardo; Daliry, Anissa

2017-01-01

This study aimed to investigate the pathophysiology of hepatic microcirculatory dysfunction in non-alcoholic fatty liver disease (NAFLD). In Wistar rats, NAFLD model was induced by 20 weeks of high-fat diet (HFD) feeding. Rolling and adhesion of leukocytes and tissue perfusion in hepatic microcirculation were examined using in vivo microscopic and laser speckle contrast imaging (LSCI), respectively. Oxidative stress and inflamatory parameters were analysed by TBARs, catalase enzyme activity, RT-PCR and ELISA. The participation of advanced glycation end-products (AGE) and its receptor RAGE was evaluated by the measurement of gene and protein expression of RAGE by RT-PCR and Western-blot, respectively and by liver and serum quantification of fluorescent AGEs. Wistar rats fed high-fat diet (HFD) showed increase in epididymal and abdominal fat content, systolic arterial blood pressure, fasting blood glucose levels, hepatic triglycerides and cholesterol, and impairment of glucose and insulin metabolisms. Liver histology confirmed the presence of steatosis and ultrasound analysis revealed increased liver size and parenchymal echogenicity in HFD-fed rats. HFD causes significant increases in leukocyte rolling and adhesion on hepatic microcirculation and decrease in liver microvascular blood flow. Liver tissue presented increase in oxidative stress and inflammtion. At 20 weeks, there was a significantly increase in AGE content in the liver and serum of HFD-fed rats and an increase in RAGE gene expression in the liver. The increase in liver AGE levels and microcirculatory disturbances could play a role in the pathogenesis of liver injury and are key components of NAFLD.

Benazepril, an angiotensin-converting enzyme inhibitor, alleviates renal injury in spontaneously hypertensive rats by inhibiting advanced glycation end-product-mediated pathways.

Science.gov (United States)

Liu, Xue-Ping; Pang, Yue-Jiu; Zhu, Wei-Wei; Zhao, Ting-Ting; Zheng, Min; Wang, Yi-Bing; Sun, Zhi-Jian; Sun, Siao-Jing

2009-03-01

1. Advanced glycation end-products (AGE) and their receptors (RAGE) have been implicated in renal damage in diabetes. The aim of the present study was to investigate the effects of benazepril, an angiotensin-converting enzyme inhibitor (ACEI), on the formation of AGE, the expression RAGE and other associated components in the oxidative stress pathway in spontaneously hypertensive rats (SHR). 2. Groups of SHR were treated with or without 10 mg/kg per day benazepril for 12 weeks. Systolic blood pressure (SBP) and angiotensin (Ang) II levels were evaluated in SHR and control Wistar-Kyoto (WKY) rats. Renal function was investigated by determining levels of proteinuria and glomerulosclerosis. Furthermore, reactive oxygen species (ROS) in the rat renal cortex were analysed using an H(2)O(2)-based hydroxyl radical-detection assay and the renal content of AGE, RAGE, NADPH oxidase p47phox, nuclear factor (NF)-kappaB p65, phosphorylated (p-) NF-kappaB p65, vascular cell adhesion molecule (VCAM)-1 and transforming growth factor (TGF)-beta1 was determined by immunohistochemistry, quantitative real-time polymerase chain reaction and western blot analysis. 3. Treatment with benazepril inhibited the formation of AngII, reduced SBP and alleviated renal lesions in SHR compared with both untreated SHR and control WKY rats. Benazepril treatment significantly suppressed the accumulation of AGE and expression of RAGE in the kidney of SHR. In addition, benazepril treatment reduced the upregulation of NADPH oxidase p47phox, ROS generation and NF-kappaB p65, p-NF-kappaB p65, VCAM-1 and TGF-beta1 expression in the kidney of SHR compared with both untreated SHR and control WKY rats. 4. The results of the present study provide new insights into the regulation by the renin-angiotensin system of AGE-RAGE, oxidative stress and nephropathy, increasing our understanding of the role of the RAS in nephropathy.

RAGE and TLRs: relatives, friends or neighbours?

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Ibrahim, Zaridatul Aini; Armour, Carol L; Phipps, Simon; Sukkar, Maria B

2013-12-01

The innate immune system forms the first line of protection against infectious and non-infectious tissue injury. Cells of the innate immune system detect pathogen-associated molecular patterns or endogenous molecules released as a result of tissue injury or inflammation through various innate immune receptors, collectively termed pattern-recognition receptors. Members of the Toll-like receptor (TLR) family of pattern-recognition receptors have well established roles in the host immune response to infection, while the receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor predominantly involved in the recognition of endogenous molecules released in the context of infection, physiological stress or chronic inflammation. RAGE and TLRs share common ligands and signaling pathways, and accumulating evidence points towards their co-operative interaction in the host immune response. At present however, little is known about the mechanisms that result in TLR versus RAGE signalling or RAGE-TLR cross-talk in response to their shared ligands. Here we review what is known in relation to the physicochemical basis of ligand interactions between TLRs and RAGE, focusing on three shared ligands of these receptors: HMGB1, S100A8/A9 and LPS. Our aim is to discuss what is known about differential ligand interactions with RAGE and TLRs and to highlight important areas for further investigation so that we may better understand the role of these receptors and their relationship in host defense. Copyright © 2013 Elsevier Ltd. All rights reserved.

RAGE: a new frontier in chronic airways disease.

Science.gov (United States)

Sukkar, Maria B; Ullah, Md Ashik; Gan, Wan Jun; Wark, Peter A B; Chung, Kian Fan; Hughes, J Margaret; Armour, Carol L; Phipps, Simon

2012-11-01

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand-RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Comprehensive analyses of how tubule occlusion and advanced glycation end-products diminish strength of aged dentin

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Shinno, Yuko; Ishimoto, Takuya; Saito, Mitsuru; Uemura, Reo; Arino, Masumi; Marumo, Keishi; Nakano, Takayoshi; Hayashi, Mikako

2016-01-01

In clinical dentistry, since fracture is a major cause of tooth loss, better understanding of mechanical properties of teeth structures is important. Dentin, the major hard tissue of teeth, has similar composition to bone. In this study, we investigated the mechanical properties of human dentin not only in terms of mineral density but also using structural and quality parameters as recently accepted in evaluating bone strength. Aged crown and root dentin (age ≥ 40) exhibited significantly lower flexural strength and toughness than young dentin (age mineral density; but showed significantly lower flexural strength than young dentin. Dentin with strong alignment of the c-axis in hydroxyapatite exhibited high fracture strength, possibly because the aligned apatite along the collagen fibrils may reinforce the intertubular dentin. Aged dentin, showing a high advanced glycation end-products (AGEs) level in its collagen, recorded low flexural strength. We first comprehensively identified significant factors, which affected the inferior mechanical properties of aged dentin. The low mechanical strength of aged dentin is caused by the high mineral density resulting from occlusion of dentinal tubules and accumulation of AGEs in dentin collagen.

Advanced glycation end-products produced systemically and by macrophages: A common contributor to inflammation and degenerative diseases.

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Byun, Kyunghee; Yoo, YongCheol; Son, Myeongjoo; Lee, Jaesuk; Jeong, Goo-Bo; Park, Young Mok; Salekdeh, Ghasem Hosseini; Lee, Bonghee

2017-09-01

Advanced glycation end products (AGEs) and their receptor have been implicated in the progressions of many intractable diseases, such as diabetes and atherosclerosis, and are also critical for pathologic changes in chronic degenerative diseases, such as Alzheimer's disease, Parkinson's disease, and alcoholic brain damage. Recently activated macrophages were found to be a source of AGEs, and the most abundant form of AGEs, AGE-albumin excreted by macrophages has been implicated in these diseases and to act through common pathways. AGEs inhibition has been shown to prevent the pathogenesis of AGEs-related diseases in human, and therapeutic advances have resulted in several agents that prevent their adverse effects. Recently, anti-inflammatory molecules that inhibit AGEs have been shown to be good candidates for ameliorating diabetic complications as well as degenerative diseases. This review was undertaken to present, discuss, and clarify current understanding regarding AGEs formation in association with macrophages, different diseases, therapeutic and diagnostic strategy and links with RAGE inhibition. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

N-Acetyl Cysteine Attenuated the Deleterious Effects of Advanced Glycation End-Products on the Kidney of Non-Diabetic Rats

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Karina Thieme

2016-11-01

Full Text Available Aim: To assess the renal effects of chronic exposure to advanced glycation end-products (AGEs in the absence of diabetes and the potential impact of concomitant treatment with the antioxidant N-acetyl cysteine (NAC. Methods: Wistar rats received intraperitoneally 20 mg/kg/day of albumin modified (AlbAGE or not (AlbC by advanced glycation for 12 weeks and oral NAC (600mg/L; AlbAGE+NAC and AlbC+NAC, respectively. Biochemical, urinary and renal morphological analyses; carboxymethyl-lysine (CML, an AGE, CD68 (macrophage infiltration, and 4-hydroxynonenal (4-HNE, marker of oxidative stress immunostaining; intrarenal mRNA expression of genes belonging to pathways related to AGEs (Ager, Ddost, Nfkb1, renin-angiotensin system (Agt, Ren, Ace, fibrosis (Tgfb1, Col4a1, oxidative stress (Nox4, Txnip, and apoptosis (Bax, Bcl2; and reactive oxidative species (ROS content were performed. Results: AlbAGE significantly increased urine protein-to-creatinine ratio; glomerular area; renal CML content and macrophage infiltration; expression of Ager, Nfkb1, Agt, Ren, Tgfb1, Col4a1, Txnip, Bax/Bcl2 ratio; and 4-HNE and ROS contents. Some of these effects were attenuated by NAC concomitant treatment. Conclusion: Because AGEs are highly consumed in modern diets and implicated in the progression of different kidney diseases, NAC could be a therapeutic intervention to decrease renal damage, considering that long-term restriction of dietary AGEs is difficult to achieve in practice.

Advanced Glycation Endproducts and Bone Material Properties in Type 1 Diabetic Mice.

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Mishaela R Rubin

Full Text Available Fractures, particularly at the lower extremities and hip, are a complication of diabetes. In both type 1 (T1D and type 2 diabetes (T2D, fracture risk is disproportionately worse than that predicted from the measurement of bone mineral density. Although an explanation for this discrepancy is the presence of organic matrix abnormalities, it has not been fully elucidated how advanced glycation endproducts (AGEs relate to bone deterioration at both the macroscopic and microscopic levels. We hypothesized that there would be a relationship between skeletal AGE levels (determined by Raman microspectroscopy at specific anatomical locations and bone macroscopic and microscopic properties, as demonstrated by the biomechanical measures of crack growth and microindentation respectively. We found that in OVE26 mice, a transgenic model of severe early onset T1D, AGEs were increased by Raman (carboxymethyl-lysine [CML] wildtype (WT: 0.0143 ±0.0005 vs T1D: 0.0175 ±0.0002, p = 0.003 at the periosteal surface. These differences were associated with less tough bone in T1D by fracture mechanics (propagation toughness WT: 4.73 ± 0.32 vs T1D: 3.39 ± 0.24 NM/m1/2, p = 0.010 and by reference point indentation (indentation distance increase WT: 6.85 ± 0.44 vs T1D: 9.04 ± 0.77 μm; p = 0.043. Within T1D, higher AGEs by Raman correlated inversely with macroscopic bone toughness. These data add to the existing body of knowledge regarding AGEs and the relationship between skeletal AGEs with biomechanical indices.

Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes

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Miranda, Edwin R; Somal, Vikram S; Mey, Jacob T

2017-01-01

The soluble receptor for advanced glycation end products (sRAGE) may be protective against inflammation associated with obesity and type 2 diabetes (T2DM). The aim of this study was to determine the distribution of sRAGE isoforms and whether sRAGE isoforms are associated with risk of T2DM...... development in subjects spanning the glucose tolerance continuum. In this retrospective analysis, circulating total sRAGE and endogenous secretory RAGE (esRAGE) were quantified via ELISA, and cleaved RAGE (cRAGE) was calculated in 274 individuals stratified by glucose tolerance status (GTS) and obesity. Group......RAGE, and esRAGE were all lower with IGT and T2DM, while the ratio of cRAGE to esRAGE (cRAGE:esRAGE) was only lower (P obesity, cRAGE:esRAGE was higher with obesity and lower with IGT (P

Pentamidine blocks the interaction between mutant S100A5 and RAGE V domain and inhibits the RAGE signaling pathway

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Cho, Ching Chang, E-mail: ccjwo@yahoo.com.tw [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China); Chou, Ruey Hwang, E-mail: rhchou@mail.cmu.edu.tw [Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan (China); Yu, Chin, E-mail: cyu.nthu@gmail.com [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China)

2016-08-19

The human S100 protein family contains small, dimeric and acidic proteins that contain two EF-hand motifs and bind calcium. When S100A5 binds calcium, its conformation changes and promotes interaction with the target protein. The extracellular domain of RAGE (Receptor of Advanced Glycation End products) contain three domains: C1, C2 and V. The RAGE V domain is the target protein of S100A5 that promotes cell survival, growth and differentiation by activating several signaling pathways. Pentamidine is an apoptotic and antiparasitic drug that is used to treat or prevent pneumonia. Here, we found that pentamidine interacts with S100A5 using HSQC titration. We elucidated the interactions of S100A5 with RAGE V domain and pentamidine using fluorescence and NMR spectroscopy. We generated two binary models—the S100A5-RAGE V domain and S100A5-Pentamidine complex—and then observed that the pentamidine and RAGE V domain share a similar binding region in mS100A5. We also used the WST-1 assay to investigate the bioactivity of S100A5, RAGE V domain and pentamidine. These results indicated that pentamidine blocks the binding between S100A5 and RAGE V domain. This finding is useful for the development of new anti-proliferation drugs. - Highlights: • The interaction between mS100A5–RAGE V was investigated by fluorescence spectroscopy. • The interfacial residues on mS100A5–RAGE V and mS100A5–pentamidine contact surface were mapped by {sup 1}H-{sup 15}N HSQC experiments. • mS100A5–RAGE V and mS100A5–pentamidine complex models were generated from NMR restraints using HADDOCK program. • The bioactivity of the mS100A5–RAGE V and mS100A5–pentamidine complex was studied using WST-1 assay.

Advanced glycation end products impair the functions of saphenous vein but not thoracic artery smooth muscle cells through RAGE/MAPK signalling pathway in diabetes.

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Sun, Yongxin; Kang, Le; Li, Jun; Liu, Huan; Wang, Yulin; Wang, Chunsheng; Zou, Yunzeng

2016-10-01

Saphenous vein (SV) and internal thoracic artery (ITA) are commonly used bypass conduits. However, graft failure occurs in SV rather than in ITA, especially in diabetes (DM). The mechanism for this difference has not been fully understood. Accumulation of advanced glycation end products (AGEs) and activation of AGEs receptor (RAGE) could accelerate smooth muscle cells (SMC) proliferation in DM, we thus asked whether AGEs-RAGE could mediate the differences between SMC from SV (SMCV ) and from ITA (SMCA ). Twenty-five patients with DM and other 25 patients without DM were enclosed in DM and control group, respectively. AGEs (100 μg/ml) were added to cultured SMCA and SMCV obtained at coronary artery bypass graft (CABG) and proliferative rates were determined. Transcript expression, phosphorylation or protein expression levels of MAP kinase family (ERK, p38 and JNK), matrix metalloproteinases (MMP)-2 and MMP-9 were analysed by real-time PCR, Western-blot or immunofluorescence staining, respectively. Compared with paired SMCA , SMCV showed significantly increased proliferation rate, MAP kinase family phosphorylation, and MMP-2/9 expression in both groups, especially in DM group. The responses of SMCV induced by AGEs were significantly larger in DM than in control group, which could be suppressed by inhibition of RAGE and ERK. However, all the cellular events of SMCV were not found in paired SMCA . This study suggests that AGEs-RAGE could induce the proliferation of SMCV but not SMCA via MAP kinase pathway in DM. It is the intrinsic 'inactive' tendency of SMCA that contributes to the different rates of graft disease between SV and ITA after CABG. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Soluble receptor for advanced glycation end products (sRAGE) and ...

African Journals Online (AJOL)

Egyptian Journal of Medical Human Genetics ... Patients with disease duration less than 5 years, connective tissue disease, liver dysfunction, or apparent cardiovascular disease and those on lipid lowering ... Laboratory investigations included; HbA1c%, urinary albumin excretion (UAE), fasting lipid profile and sRAGE.

Effect of benfotiamine on advanced glycation endproducts and markers of endothelial dysfunction and inflammation in diabetic nephropathy.

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Alaa Alkhalaf

Full Text Available 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.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 (N(ε-(carboxymethyl lysine [CML], N(ε-(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.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.Benfotiamine for 12 weeks did not significantly affect intermediate pathways of hyperglycemia-induced vascular complications. TRIAL REGRISTRATION: ClinicalTrials.gov NCT00565318.

Effect of benfotiamine on advanced glycation endproducts and markers of endothelial dysfunction and inflammation in diabetic nephropathy.

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Alkhalaf, Alaa; Kleefstra, Nanne; Groenier, Klaas H; Bilo, Henk J G; Gans, Reinold O B; Heeringa, Peter; Scheijen, Jean L; Schalkwijk, Casper G; Navis, Gerjan J; Bakker, Stephan J L

2012-01-01

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. 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 (N(ε)-(carboxymethyl) lysine [CML], N(ε)-(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. 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. Benfotiamine for 12 weeks did not significantly affect intermediate pathways of hyperglycemia-induced vascular complications. TRIAL REGRISTRATION: ClinicalTrials.gov NCT00565318.

Clearance kinetics and matrix binding partners of the receptor for advanced glycation end products.

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Pavle S Milutinovic

Full Text Available Elucidating the sites and mechanisms of sRAGE action in the healthy state is vital to better understand the biological importance of the receptor for advanced glycation end products (RAGE. Previous studies in animal models of disease have demonstrated that exogenous sRAGE has an anti-inflammatory effect, which has been reasoned to arise from sequestration of pro-inflammatory ligands away from membrane-bound RAGE isoforms. We show here that sRAGE exhibits in vitro binding with high affinity and reversibly to extracellular matrix components collagen I, collagen IV, and laminin. Soluble RAGE administered intratracheally, intravenously, or intraperitoneally, does not distribute in a specific fashion to any healthy mouse tissue, suggesting against the existence of accessible sRAGE sinks and receptors in the healthy mouse. Intratracheal administration is the only effective means of delivering exogenous sRAGE to the lung, the organ in which RAGE is most highly expressed; clearance of sRAGE from lung does not differ appreciably from that of albumin.

Hydrogen Sulfide Prevents Advanced Glycation End-Products Induced Activation of the Epithelial Sodium Channel

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Qiushi Wang

2015-01-01

Full Text Available Advanced glycation end-products (AGEs are complex and heterogeneous compounds implicated in diabetes. Sodium reabsorption through the epithelial sodium channel (ENaC at the distal nephron plays an important role in diabetic hypertension. Here, we report that H2S antagonizes AGEs-induced ENaC activation in A6 cells. ENaC open probability (PO in A6 cells was significantly increased by exogenous AGEs and that this AGEs-induced ENaC activity was abolished by NaHS (a donor of H2S and TEMPOL. Incubating A6 cells with the catalase inhibitor 3-aminotriazole (3-AT mimicked the effects of AGEs on ENaC activity, but did not induce any additive effect. We found that the expression levels of catalase were significantly reduced by AGEs and both AGEs and 3-AT facilitated ROS uptake in A6 cells, which were significantly inhibited by NaHS. The specific PTEN and PI3K inhibitors, BPV(pic  and LY294002, influence ENaC activity in AGEs-pretreated A6 cells. Moreover, after removal of AGEs from AGEs-pretreated A6 cells for 72 hours, ENaC PO remained at a high level, suggesting that an AGEs-related “metabolic memory” may be involved in sodium homeostasis. Our data, for the first time, show that H2S prevents AGEs-induced ENaC activation by targeting the ROS/PI3K/PTEN pathway.

Advanced glycation endproducts link inflammatory cues to upregulation of galectin-1 in diabetic retinopathy.

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Kanda, Atsuhiro; Dong, Yoko; Noda, Kousuke; Saito, Wataru; Ishida, Susumu

2017-11-23

Diabetic retinopathy (DR) is an inflammatory and progressive vaso-occlusive disease resulting in angiogenesis. Galectin-1 is a hypoxia-induced angiogenic factor associated with cancer and proliferative DR. Here we reveal a significant upregulation of galectin-1 in eyes of DR patients along with progression of clinical stages beginning from the pre-ischemic, inflammatory stage with diabetic macular edema, but not in eyes with non-diabetic retinal vascular occlusions. As for its regulatory mechanism unrelated to hypoxia but selective to DR, in vitro galectin-1/LGALS1 expression was shown to increase after application to Müller glial cells with interleukin (IL)-1β, which was induced in monocyte-derived macrophages and microglial cells via toll-like receptor (TLR) 4 signaling stimulated by advanced glycation endproducts (AGE). In vivo inhibition of AGE generation with aminoguanidine, macrophage depletion with clodronate liposomes, and antibody-based blockade of Il-1β and Tlr4 attenuated diabetes-induced retinal Lgals1 expression in mice. Fibrovascular tissues from proliferative DR eyes were immunoreactive for AGE, TRL4 and IL-1β in macrophages, and IL-1β receptor-positive glial cells expressed galectin-1. Therefore, diabetes-induced retinal AGE accumulation was suggested to activate IL-1β-related inflammatory cues in macrophages followed by Müller cells, linking to galectin-1 upregulation in human DR with time. Our data highlight AGE-triggered inflammation as the DR-selective inducer of galectin-1.

Soluble receptor for advanced glycation end products (sRAGE) and ...

African Journals Online (AJOL)

Eman M. Sherif

2014-07-10

Jul 10, 2014 ... other metabolites such as methylglyoxal. AGEs formation in ... Patients were further subdivided into two groups according to the presence of microvascular complications; Group I: ... variables using independent t-test in cases of two independent .... between sRAGE and SBP were only detected in controls.

Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gamma activation

International Nuclear Information System (INIS)

Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

2009-01-01

The interaction between advanced glycation end products (AGE) and their receptor RAGE mediates the progressive alteration in renal architecture and loss of renal function in diabetic nephropathy. Oxidative stress generation and inflammation also play a central role in diabetic nephropathy. This study investigated whether and how nifedipine, a calcium channel blocker (CCB), blocked the AGE-elicited mesangial cell damage in vitro. Nifedipine, but not amlodipine, a control CCB, down-regulated RAGE mRNA levels and subsequently reduced reactive oxygen species (ROS) generation in AGE-exposed mesangial cells. AGE increased mRNA levels of vascular cell adhesion molecule-1 (VCAM-1) and induced monocyte chemoattractant protein-1 (MCP-1) production in mesangial cells, both of which were prevented by the treatment with nifedipine, but not amlodipine. The beneficial effects of nifedipine on AGE-exposed mesangial cells were blocked by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPAR-γ). Although nifedipine did not affect expression levels of PPAR-γ, it increased the PPAR-γ transcriptional activity in mesangial cells. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-inflammatory agent against AGE by suppressing RAGE expression in cultured mesangial cells via PPAR-γ activation.

A Molecular Dynamics Study on RAGE-Aβ42 Interaction and the Influence of G82S RAGE Polymorphism on Aβ Interaction

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Sreeram Krishnan

2015-12-01

Full Text Available Interaction of amyloid peptides (Aβ with receptor for advanced glycation end products (RAGE elicits an inflammatory response and augments Alzheimer's disease (AD pathology. The present study was aimed to analyse the interactions of different forms of Aβ42 peptide with ligand binding domain of normal and G82S RAGE and their possible consequences in AD pathology. The structures of RAGE ectodomain (3CJJ, monomeric forms of Aβ42 - 1IYT (apolar and 1Z0Q (polar and fibrillar (2BEG were obtained from PDB. The structure of G82 and S82 RAGE was generated using SWISS MODEL. SIFT and PolyPhen analysis was performed to predict the phenotypic and functional effect of the amino acid substitution. The G82 and S82 variant structures were simulated in GROMACS and the 10 lowest energy structures were docked with different forms of Aβ42 using CLUSPRO in antibody mode. The lowest energy docked structure was further simulated for 5 ns. The structures corresponding to 0-5 ns were taken and the amino acid interactions were generated using PDBSUM. SIFT analysis indicated that G82S SNP had a tolerating effect on the structure of protein but polyphen predicted a probable damaging effect. Highest binding score was obtained with 2BEG docked with both G82 RAGE (-375.84 ± 7.425 Kcal/mol and G82S variant (-391.09 ± 13.391 Kcal/mol indicating that the fibrillar form showed better interaction. Compared to G82 RAGE, the S82 variant showed better interaction to all three forms of Aβ42. The results of study indicate that RAGE interacted better with fibrillar form of Aβ42 peptide and G82S mutation enhanced the binding affinity of RAGE towards amyloid peptides leading to enhanced inflammatory response.

Inhibition of Nonenzymatic Protein Glycation by Pomegranate and Other Fruit Juices

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Dorsey, Pamela Garner; Greenspan, Phillip

2014-01-01

Abstract The nonenzymatic glycation of proteins and the formation of advanced glycation endproducts in diabetes leads to the crosslinking of proteins and disease complications. Our study sought to demonstrate the effect of commonly consumed juices (pomegranate, cranberry, black cherry, pineapple, apple, and Concord grape) on the fructose-mediated glycation of albumin. Albumin glycation decreased by 98% in the presence of 10 μL of pomegranate juice/mL; other juices inhibited glycation by only 20%. Pomegranate juice produced the greatest inhibition on protein glycation when incubated at both the same phenolic concentration and the same antioxidant potential. Both punicalagin and ellagic acid significantly inhibited the glycation of albumin by ∼90% at 5 μg/mL. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis revealed that pomegranate, but not apple juice, protected albumin from modification. These results demonstrate that pomegranate juice and two of its major constituents are potent inhibitors of fructose-mediated protein glycation. PMID:24433074

Cloning, characterisation, and comparative quantitative expression analyses of receptor for advanced glycation end products (RAGE) transcript forms.

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Sterenczak, Katharina A; Willenbrock, Saskia; Barann, Matthias; Klemke, Markus; Soller, Jan T; Eberle, Nina; Nolte, Ingo; Bullerdiek, Jörn; Murua Escobar, Hugo

2009-04-01

RAGE is a member of the immunoglobulin superfamily of cell surface molecules playing key roles in pathophysiological processes, e.g. immune/inflammatory disorders, Alzheimer's disease, diabetic arteriosclerosis and tumourigenesis. In humans 19 naturally occurring RAGE splicing variants resulting in either N-terminally or C-terminally truncated proteins were identified and are lately discussed as mechanisms for receptor regulation. Accordingly, deregulation of sRAGE levels has been associated with several diseases e.g. Alzheimer's disease, Type 1 diabetes, and rheumatoid arthritis. Administration of recombinant sRAGE to animal models of cancer blocked tumour growth successfully. In spite of its obvious relationship to cancer and metastasis data focusing sRAGE deregulation and tumours is rare. In this study we screened a set of tumours, healthy tissues and various cancer cell lines for RAGE splicing variants and analysed their structure. Additionally, we analysed the ratio of the mainly found transcript variants using quantitative Real-Time PCR. In total we characterised 24 previously not described canine and 4 human RAGE splicing variants, analysed their structure, classified their characteristics, and derived their respective protein forms. Interestingly, the healthy and the neoplastic tissue samples showed in majority RAGE transcripts coding for the complete receptor and transcripts showing insertions of intron 1.

Novel α-Oxoamide Advanced-Glycation Endproducts within the N6-Carboxymethyl Lysine and N6-Carboxyethyl Lysine Reaction Cascades.

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Baldensperger, Tim; Jost, Tobias; Zipprich, Alexander; Glomb, Marcus A

2018-02-28

The highly reactive α-dicarbonyl compounds glyoxal and methylglyoxal are major precursors of posttranslational protein modifications in vivo. Model incubations of N 2 -t-Boc-lysine and either glyoxal or methylglyoxal were used to further elucidate the underlying mechanisms of the N 6 -carboxymethyl lysine and N 6 -carboxyethyl lysine reaction cascades. After independent synthesis of the authentic reference standards, we were able to detect N 6 -glyoxylyl lysine and N 6 -pyruvoyl lysine for the first time by HPLC-MS 2 analyses. These two novel amide advanced-glycation endproducts were exclusively formed under aerated conditions, suggesting that they were potent markers for oxidative stress. Analogous to the well-known Strecker degradation pathway, leading from amino acids to Strecker acids, the oxidation of an enaminol intermediate is suggested to be the key mechanistic step. A highly sensitive workup for the determination of AGEs in tissues was developed. In support of our hypothesis, the levels of N 6 -glyoxylyl lysine and N 6 -pyruvoyl lysine in rat livers indeed correlated with liver cirrhosis and aging.

Relationship between advanced glycation end-products with the severity of chronic heart failure in 85 patients

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Amir Farhang Zand Parsa

2013-12-01

Full Text Available Background: Advanced glycation end-products (AGEs came up with the recent researches regarding new biomarkers for the diagnosis of heart failure. AGEs are the end products of non-enzymatic glycation and oxidation of proteins, lipids and nucleotides during Maillard biochemical reaction. Although it has been known that AGEs have a role in the pathogenesis of chronic heart failure (CHF, information regarding its role and its pathogenetic mechanism is very limited. The aim of this study was to find any relationship between AGEs with the etiology and severity of chronic heart failure.Methods: This study is a prospective cross sectional study that enrolled 85 patients with chronic heart failure. Measurement of left ventricle ejection fraction (LVEF was done by echocardiography. Blood samples were collected for measuring AGEs just before or after echocardiography assessment (in the same session. Measurement of AGEs was done by the enzyme-linked immunosorbent assay (ELISA method. The relationship between AGEs with the severity of CHF and as well as the etiology of CHF were evaluated via SPSS-15.Results: Of 85 patients 48 (56.5% patients were male and 37 (43.5% were female; Mean±SD of their ages was 55.8±13.4 years old (ranges from 27 to 84 years. Correlation coefficient between LVEF and AGEs was 0.269 (P=0.013. Mean of AGEs in patients with and without ischemic etiology of their heart failure were 16.8±9.8µg/ml and 11.6±7.3 µg/ml, respectively. Although trend was in favor of ischemic heart failure, the difference between two groups was not statistically significant (P= 0.141.Conclusion: According to this study the rate of AGES could be helpful in the diagnosis and assessment of severity of CHF. Based on our findings, higher blood levels of AGEs in the ischemic CHF cases, also it could be concluded that in the future this marker may be used for etiologic differentiation of heart failure syndrome.

Reduction of serum advanced glycation end-products with a low calorie Mediterranean diet.

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Rodríguez, Juan Manuel; Leiva Balich, Laura; Concha, M J; Mizón, C; Bunout Barnett, Daniel; Barrera Acevedo, Gladys; Hirsch Birn, Sandra; Jiménez Jaime, Teresa; Henríquez, Sandra; Uribarri, Jaime; de la Maza Cave, María Pía

2015-06-01

Dietary intake of advanced glycation end-products (AGEs) increases circulating and tissue levels of these substances, contributing to a state of increased oxidative stress and inflammation. A low dietary AGE intervention has been shown to reduce body AGE content. Mediterranean diets (MD) are theoretically considered low in AGEs, but the specific effects of a MD on AGEs serum levels has not been tested. Forty-seven overweight and obese premenopausal women underwent a three-month calorie restriction treatment (20 kcal/kg initial weight) with a Mediterranean-type diet that excluded wine intake. The adherence to the MD was assessed before and at the end of treatment using an on-line questionnaire, which scores from 0 to 14 (minimal to maximal adherence). Body composition, insulin resistance, lipoproteins and carboxymethyl-lisine (CML) serum levels were measured at both time periods. Serum CML was assessed through ELISA (enzyme-linked immunosorbent assay). Compliance to calorie restriction was assessed according to weight loss ( 5% initial weight). Mean body weight, body fat, waist circumference, total cholesterol, triglycerides and serum CML fell significantly, together with an increase in the Mediterranean score, although none of the patients reached the highest score. Significant changes in CML and insulin resistance were observed in 17 women classified as compliant to caloric restriction, but not in the 27 participants who were considered adherent to the MD (according to improvement of the Mediterranean Score). CML serum levels can be reduced through calorie restricted-Mediterranean-type diet. We could not reach a high enough MD score, so we cannot conclude whether the MD itself has an additive effect to caloric restriction. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Benfotiamine alleviates diabetes-induced cerebral oxidative damage independent of advanced glycation end-product, tissue factor and TNF-alpha.

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Wu, Shan; Ren, Jun

2006-02-13

Diabetes mellitus leads to thiamine deficiency and multiple organ damage including diabetic neuropathy. This study was designed to examine the effect of benfotiamine, a lipophilic derivative of thiamine, on streptozotocin (STZ)-induced cerebral oxidative stress. Adult male FVB mice were made diabetic with a single injection of STZ (200 mg/kg, i.p.). Fourteen days later, control and diabetic (fasting blood glucose >13.9 mM) mice received benfotiamine (100 mg/kg/day, i.p.) for 14 days. Oxidative stress and protein damage were evaluated by glutathione/glutathione disulfide (GSH/GSSG) assay and protein carbonyl formation, respectively. Pro-oxidative or pro-inflammatory factors including advanced glycation end-product (AGE), tissue factor and tumor necrosis factor-alpha (TNF-alpha) were evaluated by immunoblot analysis. Four weeks STZ treatment led to hyperglycemia, enhanced cerebral oxidative stress (reduced GSH/GSSG ratio), elevated TNF-alpha and AGE levels without changes in protein carbonyl or tissue factor. Benfotiamine alleviated diabetes-induced cerebral oxidative stress without affecting levels of AGE, protein carbonyl, tissue factor and TNF-alpha. Collectively, our results indicated benfotiamine may antagonize diabetes-induced cerebral oxidative stress through a mechanism unrelated to AGE, tissue factor and TNF-alpha.

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

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Rahul Jandial

2018-01-01

Full Text Available Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1 to detoxify the toxic glycolytic byproduct methylglyoxal (MG and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs. Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM, the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA approaches. Inhibition of GLO1 with S-(p-bromobenzyl glutathione dicyclopentyl ester (p-BrBzGSH(Cp2 increased levels of the DNA-AGE N2-1-(carboxyethyl-2′-deoxyguanosine (CEdG, a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE; and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models.

Science.gov (United States)

Jandial, Rahul; Neman, Josh; Lim, Punnajit P; Tamae, Daniel; Kowolik, Claudia M; Wuenschell, Gerald E; Shuck, Sarah C; Ciminera, Alexandra K; De Jesus, Luis R; Ouyang, Ching; Chen, Mike Y; Termini, John

2018-01-30

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S -( p -bromobenzyl) glutathione dicyclopentyl ester ( p- BrBzGSH(Cp)₂) increased levels of the DNA-AGE N ²-1-(carboxyethyl)-2'-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p -BrBzGSH(Cp)₂ exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

Signal Diversity of Receptor for Advanced Glycation End Products.

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Sakaguchi, Masakiyo; Kinoshita, Rie; Putranto, Endy Widya; Ruma, I Made Winarsa; Sumardika, I Wayan; Youyi, Chen; Tomonobu, Naoko; Yamamoto, Ken-Ichi; Murata, Hitoshi

2017-12-01

The receptor for advanced glycation end products (RAGE) is involved in inflammatory pathogenesis. It functions as a receptor to multiple ligands such as AGEs, HMGB1 and S100 proteins, activating multiple intracellular signaling pathways with each ligand binding. The molecular events by which ligand-activated RAGE controls diverse signaling are not well understood, but some progress was made recently. Accumulating evidence revealed that RAGE has multiple binding partners within the cytoplasm and on the plasma membrane. It was first pointed out in 2008 that RAGE's cytoplasmic tail is able to recruit Diaphanous-1 (Dia-1), resulting in the acquisition of increased cellular motility through Rac1/Cdc42 activation. We also observed that within the cytosol, RAGE's cytoplasmic tail behaves similarly to a Toll-like receptor (TLR4)-TIR domain, interacting with TIRAP and MyD88 adaptor molecules that in turn activate multiple downstream signals. Subsequent studies demonstrated the presence of an alternative adaptor molecule, DAP10, on the plasma membrane. The coupling of RAGE with DAP10 is critical for enhancing the RAGE-mediated survival signal. Interestingly, RAGE interaction on the membrane was not restricted to DAP10 alone. The chemotactic G-protein-coupled receptors (GPCRs) formyl peptide receptors1 and 2 (FPR1 and FPR2) also interacted with RAGE on the plasma membrane. Binding interaction between leukotriene B4 receptor 1 (BLT1) and RAGE was also demonstrated. All of the interactions affected the RAGE signal polarity. These findings indicate that functional interactions between RAGE and various molecules within the cytoplasmic area or on the membrane area coordinately regulate multiple ligand-mediated RAGE responses, leading to typical cellular phenotypes in several pathological settings. Here we review RAGE's signaling diversity, to contribute to the understanding of the elaborate functions of RAGE in physiological and pathological contexts.

Association between advanced glycation end-products and functional performance in Alzheimer's disease and mixed dementia.

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Drenth, Hans; Zuidema, Sytse U; Krijnen, Wim P; Bautmans, Ivan; van der Schans, Cees; Hobbelen, Hans

2017-09-01

People with Alzheimer's disease (AD) experience, in addition to the progressive loss of cognitive functions, a decline in functional performance such as mobility impairment and disability in activities of daily living (ADL). Functional decline in dementia is mainly linked to the progressive brain pathology. Peripheral biomechanical changes by advanced glycation end-products (AGEs) have been suggested but have yet to be thoroughly studied. A multi-center, longitudinal, one-year follow-up cohort study was conducted in 144 people with early stage AD or mixed Alzheimer's/Vascular dementia. Linear mixed model analyses was used to study associations between AGE-levels (AGE reader) and mobility (Timed Up and Go), and ADL (Groningen Activity Restriction Scale and Barthel index), respectively. A significant association between AGE levels and mobility (β = 3.57, 95%CI: 1.43-5.73) was revealed; however, no significant association between AGE levels and ADL was found. Over a one-year time span, mean AGE levels significantly increased, and mobility and ADL performance decreased. Change in AGE levels was not significantly correlated with change in mobility. This study indicates that high AGE levels could be a contributing factor to impaired mobility but lacks evidence for an association with ADL decline in people with early stage AD or mixed dementia. Future research is necessary on the reduction of functional decline in dementia regarding the effectiveness of interventions such as physical activity programs and dietary advice possibly in combination with pharmacologic strategies targeting AGE accumulation.

Protein Glycation in Diabetes as Determined by Mass Spectrometry

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Annunziata Lapolla

2013-01-01

Full Text Available Diabetes is a common endocrine disorder characterized by hyperglycemia leading to nonenzymatic glycation of proteins, responsible for chronic complications. The development of mass spectrometric techniques able to give highly specific and reliable results in proteome field is of wide interest for physicians, giving them new tools to monitor the disease progression and the possible complications related to diabetes, as well as the effectiveness of therapeutic treatments. This paper reports and discusses some of the data pertaining protein glycation in diabetic subjects obtained by matrix-assisted laser desorption ionization (MALDI mass spectrometry (MS. The preliminary studies carried out by in vitro protein glycation experiments show clear differences in molecular weight of glycated and unglycated proteins. Then, the attention was focused on plasma proteins human serum albumin (HSA and immunoglobulin G (IgG. Enzymatic degradation products of in vitro glycated HSA were studied in order to simulate the in vivo enzymatic digestion of glycated species by the immunological system leading to the highly reactive advanced glycation end-products (AGEs peptides. Further studies led to the evaluation of glycated Apo A-I and glycated haemoglobin levels. A different MALDI approach was employed for the identification of markers of disease in urine samples of healthy, diabetic, nephropathic, and diabetic-nephropathic subjects.

Advanced Glycation Endproducts Are Increased in the Animal Model of Multiple Sclerosis but Cannot Be Reduced by Pyridoxamine Treatment or Glyoxalase 1 Overexpression

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Suzan Wetzels

2018-04-01

Full Text Available Multiple sclerosis (MS is a demyelinating autoimmune disease of the central nervous system (CNS. The immune response in MS patients leads to the infiltration of immune cells in the CNS and their subsequent activation. Immune cell activation induces a switch towards glycolysis. During glycolysis, the dicarbonyl product methylglyoxal (MGO is produced. MGO is a glycating agent that can rapidly form advanced glycation endproducts (AGEs. In turn, AGEs are able to induce inflammatory responses. The glyoxalase system is the endogenous defense system of the body to reduce the burden of MGO thereby reducing AGE formation. This system consists of glyoxalase-1 and glyoxalase-2 which are able to detoxify MGO to D-lactate. We investigated whether AGE levels are induced in experimental autoimmune encephalitis (EAE, an inflammatory animal model of MS. Twenty seven days post EAE induction, MGO and AGE (Nε-(carboxymethyllysine (CML, Nε-(carboxyethyllysine (CEL, 5-hydro-5-methylimidazolone (MG-H1 levels were significantly increased in the spinal cord of mice subjected to EAE. Yet, pyridoxamine treatment and glyoxalase-1 overexpression were unable to counteract AGE production during EAE and did not influence the clinical course of EAE. In conclusion, AGEs levels increase during EAE in the spinal cord, but AGE-modifying treatments do not inhibit EAE-induced AGE production and do not affect disease progression.

Protective mechanisms against oxidative stress and angiopathy in young patients with diabetes type 1 (DM1).

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Koutroumani, Nikolitsa; Partsalaki, Ioanna; Lamari, Fotini; Dettoraki, Athina; Gil, Andrea Paola Rojas; Karvela, Alexia; Kostopoulou, Eirini; Spiliotis, Bessie E

2013-01-01

Advanced glycation end-products (AGEs) via their receptor, RAGE, are involved in diabetic angiopathy. Soluble RAGE, an inhibitor of this axis, is formed by enzymatic catalysis (sRAGE) or alternative splicing (esRAGE). Malondialdehyde (MDA) is an oxidative stress marker, and ferric reducing ability of plasma (FRAP) is an anti-oxidant capacity marker. In isolated mononuclear blood cells from 110 DM1-patients (P) and 124 controls (C) (4-29 years) RAGE mRNA (g) and protein expression (pe) were measured by RT-PCR and Western immunoblotting, respectively. Plasma levels of CML (AGEs) and sRAGE were measured by ELISA, MDA by flurometry and FRAP according to 'Benzie and Strain'. P showed: (i) higher g of RAGE, especially in p>13 years of age and >5 years DM1, (ii) increased pe of esRAGE in DM1>5 years and (iii) increased FRAP and MDA. The increased esRAGE and FRAP with increased levels of CML and MDA possibly reflects a protective response against the formation of diabetic complications in these young diabetic patients.

Age-related accumulation of advanced glycation end-products-albumin, S100β, and the expressions of advanced glycation end product receptor differ in visceral and subcutaneous fat

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Son, Kuk Hui [Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon (Korea, Republic of); Son, Myeongjoo [Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon (Korea, Republic of); Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon (Korea, Republic of); Ahn, Hyosang; Oh, Seyeon; Yum, Yoonji [Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon (Korea, Republic of); Choi, Chang Hu [Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon (Korea, Republic of); Park, Kook Yang, E-mail: kkyypark@ghil.com [Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon (Korea, Republic of); Byun, Kyunghee, E-mail: khbyun1@gachon.ac.kr [Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon (Korea, Republic of); Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon (Korea, Republic of)

2016-08-19

Visceral fat induces more inflammation by activating macrophages than subcutaneous fat, and inflammation is an underlying feature of the pathogeneses of various diseases, including cardiovascular disease and diabetes. Advanced glycation end products (AGEs), S100β, and their receptors, the receptor for advanced glycation end products (RAGE), lead to macrophage activation. However, little information is available regarding the differential accumulations of AGE-albumin (serum albumin modified by AGEs), S100β, or expressions of RAGE in different adipocyte types in fat tissues. In this study, the authors investigated whether age-related AGE-albumin accumulations S100β level, and RAGE expressions differ in subcutaneous and visceral fat tissues. Subcutaneous and visceral fat were harvested from 3- and 28-week-old rats. Macrophage activation was confirmed by Iba1 staining, and AGE-albumin accumulations and RAGE expressions were assessed by confocal microscopy. S100β were analyzed by immunoblotting. It was found that activated macrophage infiltration, AGE-albumin accumulation, and S100β in visceral fat was significantly greater in 28-week-old rats than in 3-week-old rats, but similar in subcutaneous fat. The expression of RAGE in visceral fat was much greater in 28-week-old rats, but its expression in subcutaneous fat was similar in 3- and 28-week-old rats. Furthermore, inflammatory signal pathways (NFκB, TNF-α) and proliferation pathways (FAK) in visceral fat were more activated in 28-week-old rats. These results imply that age-related AGE-albumin accumulation, S100β, and RAGE expression are more prominent in visceral than in subcutaneous fat, suggesting that visceral fat is involved in the pathogenesis of inflammation-induced diseases in the elderly. - Highlights: • The age-related AGE-albumin accumulation and S100β were more prominent in visceral than subcutaneous fat. • The age-related RAGE expression were more prominent in visceral than subcutaneous fat. �

Age-related accumulation of advanced glycation end-products-albumin, S100β, and the expressions of advanced glycation end product receptor differ in visceral and subcutaneous fat

International Nuclear Information System (INIS)

Son, Kuk Hui; Son, Myeongjoo; Ahn, Hyosang; Oh, Seyeon; Yum, Yoonji; Choi, Chang Hu; Park, Kook Yang; Byun, Kyunghee

2016-01-01

Visceral fat induces more inflammation by activating macrophages than subcutaneous fat, and inflammation is an underlying feature of the pathogeneses of various diseases, including cardiovascular disease and diabetes. Advanced glycation end products (AGEs), S100β, and their receptors, the receptor for advanced glycation end products (RAGE), lead to macrophage activation. However, little information is available regarding the differential accumulations of AGE-albumin (serum albumin modified by AGEs), S100β, or expressions of RAGE in different adipocyte types in fat tissues. In this study, the authors investigated whether age-related AGE-albumin accumulations S100β level, and RAGE expressions differ in subcutaneous and visceral fat tissues. Subcutaneous and visceral fat were harvested from 3- and 28-week-old rats. Macrophage activation was confirmed by Iba1 staining, and AGE-albumin accumulations and RAGE expressions were assessed by confocal microscopy. S100β were analyzed by immunoblotting. It was found that activated macrophage infiltration, AGE-albumin accumulation, and S100β in visceral fat was significantly greater in 28-week-old rats than in 3-week-old rats, but similar in subcutaneous fat. The expression of RAGE in visceral fat was much greater in 28-week-old rats, but its expression in subcutaneous fat was similar in 3- and 28-week-old rats. Furthermore, inflammatory signal pathways (NFκB, TNF-α) and proliferation pathways (FAK) in visceral fat were more activated in 28-week-old rats. These results imply that age-related AGE-albumin accumulation, S100β, and RAGE expression are more prominent in visceral than in subcutaneous fat, suggesting that visceral fat is involved in the pathogenesis of inflammation-induced diseases in the elderly. - Highlights: • The age-related AGE-albumin accumulation and S100β were more prominent in visceral than subcutaneous fat. • The age-related RAGE expression were more prominent in visceral than subcutaneous fat. �

Advanced glycation end products (AGEs) and its receptors in the pathogenesis of hyperthyroidism.

Science.gov (United States)

Caspar-Bell, Gudrun; Dhar, Indu; Prasad, Kailash

2016-03-01

Oxidative stress has been implicated in the pathogenesis of hyperthyroidism and its complications. Interaction of advanced glycation end products (AGEs) with receptor RAGE (receptor for AGEs) generates reactive oxygen species. Soluble receptor for AGEs (sRAGE) competes with RAGE for binding with AGEs and attenuates the generation of ROS. Low levels sRAGE and high levels AGEs would generate more ROS leading to hyperthyroidism and its complications. The objectives are to determine if levels of serum sRAGE are low and the levels of AGEs and AGEs/sRAGE are high in patients with hyperthyroidism. The study subjects comprised of 33 patients with hyperthyroidism and 20 controls. Levels of serum sRAGE were lower, while that of AGEs and AGEs/sRAGE were higher in patients compared to controls, being significant only for sRAGE and AGEs/sRAGE. When the levels of sRAGE, AGEs, and AGEs/sRAGE were assessed for hyperthyroidism associated with different diseases, the levels of sRAGE were lower in Hashimoto disease, and levels of AGEs were higher in patients with Graves' disease compared to control. The levels of AGEs/sRAGE were elevated in an all except patients with Hashimoto disease. The levels of AGEs, sRAGE, or AGEs/RAGE were not correlated with age, weight, and blood pressures except systolic pressure which was inversely correlated with sRAGE. The levels of sRAGE were negatively correlated with AGEs and AGEs/sRAGE. The levels of AGEs/sRAGE were positively correlated with AGEs. In conclusion, low levels of sRAGE, and high levels of AGEs and AGEs/sRAGE are risk biomarkers in the pathogenesis hyperthyroidism and its complications.

Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature.

Science.gov (United States)

Carnevale, Daniela; Mascio, Giada; D'Andrea, Ivana; Fardella, Valentina; Bell, Robert D; Branchi, Igor; Pallante, Fabio; Zlokovic, Berislav; Yan, Shirley Shidu; Lembo, Giuseppe

2012-07-01

Although epidemiological data associate hypertension with a strong predisposition to develop Alzheimer disease, no mechanistic explanation exists so far. We developed a model of hypertension, obtained by transverse aortic constriction, leading to alterations typical of Alzheimer disease, such as amyloid plaques, neuroinflammation, blood-brain barrier dysfunction, and cognitive impairment, shown here for the first time. The aim of this work was to investigate the mechanisms involved in Alzheimer disease of hypertensive mice. We focused on receptor for advanced glycation end products (RAGE) that critically regulates Aβ transport at the blood-brain barrier and could be influenced by vascular factors. The hypertensive challenge had an early and sustained effect on RAGE upregulation in brain vessels of the cortex and hippocampus. Interestingly, RAGE inhibition protected from hypertension-induced Alzheimer pathology, as showed by rescue from cognitive impairment and parenchymal Aβ deposition. The increased RAGE expression in transverse aortic coarctation mice was induced by increased circulating advanced glycation end products and sustained by their later deposition in brain vessels. Interestingly, a daily treatment with an advanced glycation end product inhibitor or antioxidant prevented the development of Alzheimer traits. So far, Alzheimer pathology in experimental animal models has been recognized using only transgenic mice overexpressing amyloid precursor. This is the first study demonstrating that a chronic vascular insult can activate brain vascular RAGE, favoring parenchymal Aβ deposition and the onset of cognitive deterioration. Overall we demonstrate that RAGE activation in brain vessels is a crucial pathogenetic event in hypertension-induced Alzheimer disease, suggesting that inhibiting this target can limit the onset of vascular-related Alzheimer disease.

Decreased Neointimal Extracellular Matrix Formation in RAGE-Knockout Mice After Microvascular Denudation

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Groezinger, Gerd, E-mail: gerd.groezinger@med.uni-tuebingen.de; Schmehl, Joerg, E-mail: joerg.schmehl@med.uni-tuebingen.de; Bantleon, Ruediger, E-mail: ruediger.bantleon@med.uni-tuebingen.de; Kehlbach, Rainer, E-mail: rainer.kehlbach@uni-tuebingen.de [University of Tuebingen, Department of Diagnostic and Interventional Radiology (Germany); Mehra, Tarun, E-mail: tarun.mehra@med.uni-tuebingen.de [University of Tuebingen, Department of Dermatology (Germany); Claussen, Claus, E-mail: gerd.groezinger@med.uni-tuebingen.de; Wiesinger, Benjamin, E-mail: benjamin.wiesinger@med.uni-tuebingen.de [University of Tuebingen, Department of Diagnostic and Interventional Radiology (Germany)

2012-12-15

Purpose: To evaluate in vivo the role of RAGE (receptor for advanced glycated end products) in the development of restenosis and neointimal proliferation in RAGE-deficient knockout (KO) mice compared with wild-type (WT) mice in an animal model. Materials and Methods: Sixteen WT and 15 RAGE-deficient mice underwent microvascular denudation of the common femoral artery under general anaesthesia. Contralateral arteries underwent a sham operation and served as controls. Four weeks after the intervention, all animals were killed, and paraformaldehyde-fixed specimens of the femoral artery were analysed with different stains (hematoxylin and eosin and Elastica van Gieson) and several different types of immunostaining (proliferating cell nuclear antigen, {alpha}-actin, collagen, von Willebrand factor, RAGE). Luminal area, area of the neointima, and area of the media were measured in all specimens. In addition, colony-formation assays were performed, and collagen production by WT smooth muscle cells (SMCs) and RAGE-KO SMCs was determined. For statistical analysis, P < 0.05 was considered statistically significant. Results: Four weeks after denudation, WT mice showed a 49.6% loss of luminal area compared with 14.9% loss of luminal area in RAGE-deficient mice (sham = 0% loss) (P < 0.001). The neointima was 18.2 (*1000 {mu}m{sup 2} [n = 15) in the WT group compared with only 8.4 (*1000 {mu}m{sup 2} [n = 16]) in the RAGE-KO group. RAGE-KO SMCs showed significantly decreased proliferation activity and production of extracellular matrix protein. Conclusion: RAGE may be shown to play a considerable role in the formation of neointima leading to restenosis after vascular injury.

Decreased levels of sRAGE in follicular fluid from patients with PCOS.

Science.gov (United States)

Wang, BiJun; Li, Jing; Yang, QingLing; Zhang, FuLi; Hao, MengMeng; Guo, YiHong

2017-03-01

This study aimed to explore the association between soluble receptor for advanced glycation end products (sRAGE) levels in follicular fluid and the number of oocytes retrieved and to evaluate the effect of sRAGE on vascular endothelial growth factor (VEGF) in granulosa cells in patients with polycystic ovarian syndrome (PCOS). Two sets of experiments were performed in this study. In part one, sRAGE and VEGF protein levels in follicular fluid samples from 39 patients with PCOS and 35 non-PCOS patients were measured by ELISA. In part two, ovarian granulosa cells were isolated from an additional 10 patients with PCOS and cultured. VEGF and SP1 mRNA and protein levels, as well as pAKT levels, were detected by real-time PCR and Western blotting after cultured cells were treated with different concentrations of sRAGE. Compared with the non-PCOS patients, patients with PCOS had lower sRAGE levels in follicular fluid. Multi-adjusted regression analysis showed that high sRAGE levels in follicular fluid predicted a lower Gn dose, more oocytes retrieved, and a better IVF outcome in the non-PCOS group. Logistic regression analysis showed that higher sRAGE levels predicted favorably IVF outcomes in the non-PCOS group. Multi-adjusted regression analysis also showed that high sRAGE levels in follicular fluid predicted a lower Gn dose in the PCOS group. Treating granulosa cells isolated from patients with PCOS with recombinant sRAGE decreased VEGF and SP1 mRNA and protein expression and pAKT levels in a dose-dependent manner. © 2017 Society for Reproduction and Fertility.

Evaluation of Asteraceae herbal extracts in the management of diabetes and obesity. Contribution of caffeoylquinic acids on the inhibition of digestive enzymes activity and formation of advanced glycation end-products (in vitro).

Science.gov (United States)

Spínola, Vítor; Castilho, Paula C

2017-11-01

The study was performed to assess, for the first time, the in vitro anti-diabetic potential of ten Asteraceae plant extracts to inhibit the activity of digestive enzymes (α-amylase, α-, β-glucosidases and lipase) responsible for hydrolysis/digestion of sugar and lipids. Prevention of advanced glycation end-products (AGEs) formation was evaluated in bovine serum albumin/ribose glycation reaction model. The phytochemical profiles and caffeoylquinic acids (CQAs) contents were determined for the methanolic extract of each plant. Analyzed plant extracts exhibited significant inhibitory activity against key digestive enzymes linked to type II diabetes and obesity. A strong inhibition was observed for glucosidases and mild activity towards amylase and lipase (compared to reference compounds). Moreover, some extracts exhibited potent ability to prevent formation of AGEs, implicated in some diabetic complications. Caffeoylquinic acids were dominant in all plant extracts and findings demonstrate that these compounds are the most relevant hypoglycemic and anti-glycation agents. From the obtained results, Argyranthemum pinnatifidum, Helichrysum melaleucum, and Phagnalon lowei are good candidates for further development of phyto-pharmaceutical preparations as complementary therapy for diabetes and obesity control. Copyright © 2017 Elsevier Ltd. All rights reserved.

糖基化终末产物及其受体在糖尿病大鼠胃组织中的分布 (Distribution of advanced glycation end products and their receptor in the stomach of diabetic rats)

DEFF Research Database (Denmark)

Tian, Jia Xing; Zhao, Jingbo; Li, Min

2015-01-01

AIM: To observe the distribution of advanced glycation end products (AGEs) and their receptor (RAGE) in the stomach of diabetic rats. METHODS: Diabetes mellitus (DM) and control (CON) rats were reared for eight weeks. Fasting plasma glucose (FPG), glycated serum protein (GSP) and gastric layer...... with the CON group (P stomach was significantly higher in the DM group than in the CON group (P ...: The expression of AGEs and RAGE is up-regulated in the stomach of diabetic rats. The increased levels of AGE and RAGE in gastric tissue may contribute to diabetic gastrointestinal dysfunction. © 2015 Baishideng Publishing Group Inc. All rights reserved. Key Words: Diabetes mellitus; Stomach; Advanced glycation...

RAGE mediates the inactivation of nAChRs in sympathetic neurons under high glucose conditions.

Science.gov (United States)

Chandna, Andrew R; Nair, Manoj; Chang, Christine; Pennington, Paul R; Yamamoto, Yasuhiko; Mousseau, Darrell D; Campanucci, Verónica A

2015-02-01

Autonomic dysfunction is a serious complication of diabetes and can lead to cardiovascular abnormalities and premature death. It was recently proposed that autonomic dysfunction is triggered by oxidation-mediated inactivation of neuronal nicotinic acetylcholine receptors (nAChRs), impairing synaptic transmission in sympathetic ganglia and resulting in autonomic failure. We investigated whether the receptor for advanced glycation end products (RAGE) and its role in the generation of reactive oxygen species (ROS) could be contributing to the events that initiate sympathetic malfunction under high glucose conditions. Using biochemical, live imaging and electrophysiological tools we demonstrated that exposure of sympathetic neurons to high glucose increases RAGE expression and oxidative markers, and that incubation with RAGE ligands (e.g. AGEs, S100 and HMGB1) mimics both ROS elevation and nAChR inactivation. In contrast, co-treatment with either antioxidants or an anti-RAGE IgG prevented the inactivation of nAChRs. Lastly, a role for RAGE in this context was corroborated by the lack of sensitivity of sympathetic neurons from RAGE knock-out mice to high glucose. These data define a pivotal role for RAGE in initiating the events associated with exposure of sympathetic neurons to high glucose, and strongly support RAGE signaling as a potential therapeutic target in the autonomic complications associated with diabetes. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

RAGE polymorphisms and oxidative stress levels in Hashimoto's thyroiditis.

Science.gov (United States)

Giannakou, Maria; Saltiki, Katerina; Mantzou, Emily; Loukari, Eleni; Philippou, Georgios; Terzidis, Konstantinos; Lili, Kiriaki; Stavrianos, Charalampos; Kyprianou, Miltiades; Alevizaki, Maria

2017-05-01

Polymorphisms of the receptor for advanced glycation end products (RAGE) gene have been studied in various autoimmune disorders, but not in Hashimoto's thyroiditis. Also, increased oxidative stress has been described in patients with Hashimoto's thyroiditis. The aim of this study was to investigate the possible role of two common RAGE polymorphisms (-429T>C, -374T>A) in Hashimoto's thyroiditis; in parallel, we studied oxidative stress levels. A total of 300 consecutive euthyroid women were examined and classified into three groups: Hashimoto's thyroiditis with treatment (n = 96), Hashimoto's thyroiditis without treatment (n = 109) and controls (n = 95). For a rough evaluation of oxidative stress, total lipid peroxide levels in serum were measured. The -429T>C AluI and -374T>A MfeI polymorphisms of RAGE were studied in genomic DNA. Significant association of the RAGE system with Hashimoto's thyroiditis was found only with regard to the prevalence of the -429T>C, but not with -374T>A polymorphism. The levels of oxidative stress were significantly elevated in Hashimoto's thyroiditis patients under treatment. Further analysis demonstrated that an oxidative stress cut-off value of 590 μmol/L is associated with an increased risk of progression of Hashimoto's thyroiditis from euthyroidism to hypothyroidism; this risk is further increased in carriers of the RAGE -429T>C polymorphism. Our findings indicate that both examined risk factors may be implicated in the occurrence of Hashimoto's thyroiditis, but this covers only a fraction of the pathophysiology of the disease. © 2017 Stichting European Society for Clinical Investigation Journal Foundation.

Differential Receptor for Advanced Glycation End Products Expression in Preeclamptic, Intrauterine Growth Restricted, and Gestational Diabetic Placentas.

Science.gov (United States)

Alexander, Kristen L; Mejia, Camilo A; Jordan, Clinton; Nelson, Michael B; Howell, Brian M; Jones, Cameron M; Reynolds, Paul R; Arroyo, Juan A

2016-02-01

Receptor for advanced glycation end products (RAGE) is a receptor implicated in the modulation of inflammation. Inflammation has been associated with pregnancy pathologies including preeclampsia (PE), intrauterine growth restriction (IUGR), and gestational diabetes mellitus (GDM). Our objective was to examine placental RAGE expression in PE, IUGR, and GDM complications. Human placental tissues were obtained for RAGE determination using Q-PCR, immunohistochemistry, and Western blot. Invasive trophoblast cells were cultured and treated with AGES for RAGE activation studies. Compared to control placenta, we observed: (i) decreased RAGE gene expression during GDM, (ii) increased RAGE protein in the PE placenta, and (iii) decreased RAGE protein in the IUGR placenta. In trophoblast cells exposed AGEs, we observed: (i) decreased trophoblast invasion, (ii) increased c-Jun N-terminal kinases (JNK) and Extracellular signal-regulated kinases (ERK), and (iii) increased TNF-α and IL-1β secretion. We conclude that placental RAGE is activated during PE and that RAGE-mediated inflammation in the trophoblast involves increased pro-inflammatory cytokine secretion. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Accumulation of methylglyoxal increases the advanced glycation end-product levels in DRG and contributes to lumbar disk herniation-induced persistent pain.

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Liu, Cui-Cui; Zhang, Xin-Sheng; Ruan, Yu-Ting; Huang, Zhu-Xi; Zhang, Su-Bo; Liu, Meng; Luo, Hai-Jie; Wu, Shao-Ling; Ma, Chao

2017-08-01

Lumbar disk herniation (LDH) with discogenic low back pain and sciatica is a common and complicated musculoskeletal disorder. The underlying mechanisms are poorly understood, and there are no effective therapies for LDH-induced pain. In the present study, we found that the patients who suffered from LDH-induced pain had elevated plasma methylglyoxal (MG) levels. In rats, implantation of autologous nucleus pulposus (NP) to the left lumbar 5 spinal nerve root, which mimicked LDH, induced mechanical allodynia, increased MG level in plasma and dorsal root ganglion (DRG), and enhanced the excitability of small DRG neurons (DRG neurons ex vivo increased the number of action potentials evoked by depolarizing current pulses. Furthermore, inhibition of MG accumulation by aminoguanidine attenuated the enhanced excitability of small DRG neurons and the mechanical allodynia induced by NP implantation. In addition, NP implantation increased levels of advanced glycation end products (AGEs) in DRG, and intrathecal injection of MG-derived AGEs induced the mechanical allodynia and DRG neuronal hyperactivity. Intrathecal injection of MG also significantly increased the expression of AGEs in DRG. Importantly, scavenging of MG by aminoguanidine also attenuated the increase in AGEs induced by NP implantation. These results suggested that LDH-induced MG accumulation contributed to persistent pain by increasing AGE levels. Thus generation of AGEs from MG may represent a target for treatment of LDH-induced pain. NEW & NOTEWORTHY Our study demonstrates that methylglyoxal accumulation via increasing advanced glycation end-product levels in dorsal root ganglion contributes to the persistent pain induced by lumbar disk herniation, which proposed potential targets for the treatment of lumbar disk herniation-induced persistent pain. Copyright © 2017 the American Physiological Society.

Oncocalyxone A functions as an anti-glycation agent in vitro.

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Ingrid Sofia Vieira de Melo

Full Text Available Advanced glycation endproducts (AGE are the result of post-translational changes to proteins, which ultimately compromise their structure and/or function. The identification of methods to prevent the formation of these compounds holds great promise in the development of alternative therapies for diseases such as diabetes. Plants used in traditional medicine are often rich sources of anti-glycation agents. Therefore, in this study, we investigated the anti-glycation activity of one such compound, Oncocalyxone A (Onco A. Using spectrofluorimetric techniques, we determined that Onco A inhibits AGE formation in a concentration-dependent manner. Its IC50 value (87.88 ± 3.08 μM was almost two times lower than the standard anti-glycation compound aminoguanidine (184.68 ± 4.85 μM. The excellent anti-glycation activity of Onco A makes it an exciting candidate for the treatment of diseases associated with excessive accumulation of AGE. However, additional studies are necessary to identify its mechanism of action, as well as the in vivo response in suitable model organisms.

Correlation between follicular fluid levels of sRAGE and vitamin D in women with PCOS.

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Garg, Deepika; Grazi, Richard; Lambert-Messerlian, Geralyn M; Merhi, Zaher

2017-11-01

The pro-inflammatory advanced glycation end products (AGEs) and their anti-inflammatory soluble receptors, sRAGE, play a role in the pathogenesis of PCOS. There is a correlation between vitamin D (vit D) and sRAGE in the serum, whereby vit D replacement increases serum sRAGE levels in women with PCOS, thus incurring a protective anti-inflammatory role. This study aims to compare levels of sRAGE, N-carboxymethyl-lysine (CML; one of the AGEs), and 25-hydroxy-vit D in the follicular fluid (FF) of women with or without PCOS, and to evaluate the correlation between sRAGE and 25-hydroxy-vit D in the FF. Women with (n = 12) or without (n = 13) PCOS who underwent IVF were prospectively enrolled. Women with PCOS had significantly higher anti-Mullerian hormone levels, higher number of total retrieved and mature oocytes, and higher number of day 3 and day 5 embryos formed. Compared to women without PCOS, women with PCOS had significantly lower FF sRAGE levels. In women with PCOS, in women without PCOS, and in all participants together, there was a significant positive correlation between sRAGE and 25-hydroxy-vit D. sRAGE positively correlated with CML in women without PCOS but not in women with PCOS. In women with PCOS, the low ovarian levels of the anti-inflammatory sRAGE suggest that sRAGE could represent a biomarker and a potential therapeutic target for ovarian dysfunction in PCOS. Whether there is a direct causal relationship between sRAGE and vit D in the ovaries remains to be determined.

Sputum–plasma ratio of soluble receptor for advanced glycation end-products in patients with chronic obstructive pulmonary disease

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Essam Gouda Hassanein

2016-07-01

Conclusions: sRAGE level either in induced sputum, plasma or sputum plasma ratio is not significantly different between stable COPD patients, smokers and healthy controls. Thus, sRAGE cannot be considered as a marker of either diagnosis or severity of COPD.

Effect of Amaranthus on Advanced Glycation End-Products Induced Cytotoxicity and Proinflammatory Cytokine Gene Expression in SH-SY5Y Cells

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Warisa Amornrit

2015-09-01

Full Text Available Amaranthus plants, or spinach, are used extensively as a vegetable and are known to possess medicinal properties. Neuroinflammation and oxidative stress play a major role in the pathogenesis of many neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Advanced glycation end-products (AGEs cause cell toxicity in the human neuronal cell line, SH-SY5Y, through an increase in oxidative stress, as shown by reducing cell viability and increasing cell toxicity in a dose-dependent manner. We found that preincubation of SH-SY5Y cells with either petroleum ether, dichloromethane or methanol extracts of A. lividus and A. tricolor dose-dependently attenuated the neuron toxicity caused by AGEs treatment. Moreover, the results showed that A. lividus and A. tricolor extracts significantly downregulated the gene expression of the pro-inflammatory cytokines, TNF-α, IL-1 and IL-6 genes in AGEs-induced cells. We concluded that A. lividus and A. tricolor extracts not only have a neuroprotective effect against AGEs toxicity, but also have anti-inflammatory activity by reducing pro-inflammatory cytokine gene expression. This suggests that Amaranthus may be useful for treating chronic inflammation associated with neurodegenerative disorders.

Glucagon-like peptide 1: A potential anti-inflammatory pathway in obesity-related asthma.

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Nguyen, Dan-Vinh; Linderholm, Angela; Haczku, Angela; Kenyon, Nicholas

2017-12-01

Alterations in arginine metabolism and accelerated formation of advanced glycation end-products (AGEs), crucial mechanisms in obesity-related asthma, can be modulated by glucagon-like peptide 1 (GLP-1). l-arginine dysregulation in obesity promotes inflammation and bronchoconstriction. Prolonged hyperglycemia, dyslipidemia, and oxidative stress leads to production of AGEs, that bind to their receptor (RAGE) further potentiating inflammation. By binding to its widely distributed receptor, GLP-1 blunts the effects of RAGE activation and arginine dysregulation. The GLP-1 pathway, while comprehensively studied in the endocrine and cardiovascular literature, is under-recognized in pulmonary research. Insights into GLP-1 and the lung may lead to novel treatments for obesity-related asthma. Published by Elsevier Inc.

Structural insights into calcium-bound S100P and the V domain of the RAGE complex.

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Srinivasa R Penumutchu

Full Text Available The S100P protein is a member of the S100 family of calcium-binding proteins and possesses both intracellular and extracellular functions. Extracellular S100P binds to the cell surface receptor for advanced glycation end products (RAGE and activates its downstream signaling cascade to meditate tumor growth, drug resistance and metastasis. Preventing the formation of this S100P-RAGE complex is an effective strategy to treat various disease conditions. Despite its importance, the detailed structural characterization of the S100P-RAGE complex has not yet been reported. In this study, we report that S100P preferentially binds to the V domain of RAGE. Furthermore, we characterized the interactions between the RAGE V domain and Ca(2+-bound S100P using various biophysical techniques, including isothermal titration calorimetry (ITC, fluorescence spectroscopy, multidimensional NMR spectroscopy, functional assays and site-directed mutagenesis. The entropy-driven binding between the V domain of RAGE and Ca(+2-bound S100P was found to lie in the micromolar range (Kd of ∼ 6 µM. NMR data-driven HADDOCK modeling revealed the putative sites that interact to yield a proposed heterotetrameric model of the S100P-RAGE V domain complex. Our study on the spatial structural information of the proposed protein-protein complex has pharmaceutical relevance and will significantly contribute toward drug development for the prevention of RAGE-related multifarious diseases.

Serum Levels of sRAGE Are Associated with Body Measurements, but Not Glycemic Parameters in Patients with Prediabetes.

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Guclu, Metin; Ali, Asuman; Eroglu, Derya Ustun; Büyükuysal, Sema Oral; Cander, Soner; Ocak, Nihal

2016-02-01

Our aim was to assess serum levels of the soluble receptor for advanced glycation end products (sRAGE) and to examine their association with anthropometric and metabolic parameters in patients with prediabetes and obese controls. The two study groups were composed of 42 patients with prediabetes and diabetic neuropathy and 42 age-, gender-, body weight (BW)-, and body mass index (BMI)-matched obese adults as the control group. Prediabetes was diagnosed by the following criteria issued by the American Diabetes Association: impaired fasting glucose [fasting plasma glucose (FPG) level of 100-125 mg/dL], impaired glucose tolerance (2 hr plasma glucose level of 140-199 mg/dL after a 75 grams oral glucose challenge), or a glycated hemoglobin (HbA1C) level of 5.7%-6.4%. There were no differences between the groups in terms of age, gender distribution, BW, or BMI. Despite these similarities, patients with prediabetes had higher FPG, HbA1c, and 2-hr postchallenge glucose levels, higher systolic and diastolic blood pressure, and larger waist and hip circumferences compared with the obese controls. Lipid measurements, complete blood counts, kidney and liver function tests, high-sensitivity C-reactive protein, and sRAGE levels were similar between the two groups. We found significant negative correlations between sRAGE levels and BW, BMI, waist and hip circumferences, waist-to-hip ratios, and low-density lipoprotein (LDL) cholesterol levels. There were no significant correlations with other parameters, including demographic, metabolic, and blood pressure measurements. In contrast to glycemic parameters, serum levels of sRAGE were negatively correlated with body measurements indicative of obesity in the prediabetic state. In addition, the negative correlation with LDL cholesterol levels suggests that sRAGE has a more robust association with metabolic syndrome than with prediabetes.

Nutritional supplements modulate fluorescent protein-bound advanced glycation endproducts and digestive enzymes related to type 2 diabetes mellitus.

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Koch, Emily R; Deo, Permal

2016-09-01

Chronic hyperglycemia enhances the formation of advanced glycation endproducts (AGEs) and reactive oxygen species (ROS), contributing to diabetic complications. Thus, controlling blood glucose levels, inhibiting the formation of AGEs and reducing ROS are key therapeutic targets in early stage type 2 diabetes. The inhibitory effects of seven commercial liquid nutritional supplements against carbohydrate hydrolysing enzymes, α-amylase and α-glucosidase, was determined by dinitrosalicylic (DNS) reagent and p-nitrophenyl-α-D-glucopyranoside solution, respectively. Antiglycation activity was determined using the formation of fluorescent protein-bound AGEs. Total phenolic and flavonoid content and antioxidant properties (1,1-diphenyl-2-picrylhydrazyl antioxidant activity (DPPH) and ferric reducing antioxidant power (FRAP)) were determined for correlation among these components and inhibitory activities. Samoan noni juice showed the greatest inhibitory effects against α-amylase, whereas chlorophyll extracts showed the greatest inhibitory effect against α-glucosidase. Inhibition of α-glucosidase correlated with TFC (r(2) = 0.766; p 1) and FRAP (r(2) = 0.750; p 1) whereas no correlation was observed for α-amylase inhibition. All supplements inhibited fluorescent protein-bound AGEs, with the greatest effect exerted by Olive Leaf Extract, Blood Sugar Support (IC50 = 0.5 mg/ml). The IC50 values negatively correlated with TPC (r(2) = -0.707; p 1) and DPPH scavenging activities (r(2) = 0.515; p nutritional supplements in managing and treating type 2 diabetes mellitus.

Nuclear DAMP complex-mediated RAGE-dependent macrophage cell death

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Chen, Ruochan [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Fu, Sha; Fan, Xue-Gong [Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Lotze, Michael T.; Zeh, Herbert J. [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Tang, Daolin, E-mail: tangd2@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Kang, Rui, E-mail: kangr@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States)

2015-03-13

High mobility group box 1 (HMGB1), histone, and DNA are essential nuclear components involved in the regulation of chromosome structure and function. In addition to their nuclear function, these molecules act as damage-associated molecular patterns (DAMPs) alone or together when released extracellularly. The synergistic effect of these nuclear DNA-HMGB1-histone complexes as DAMP complexes (nDCs) on immune cells remains largely unexplored. Here, we demonstrate that nDCs limit survival of macrophages (e.g., RAW264.7 and peritoneal macrophages) but not cancer cells (e.g., HCT116, HepG2 and Hepa1-6). nDCs promote production of inflammatory tumor necrosis factor α (TNFα) release, triggering reactive oxygen species-dependent apoptosis and necrosis. Moreover, the receptor for advanced glycation end products (RAGE), but not toll-like receptor (TLR)-4 and TLR-2, was required for Akt-dependent TNFα release and subsequent cell death following treatment with nDCs. Genetic depletion of RAGE by RNAi, antioxidant N-Acetyl-L-cysteine, and TNFα neutralizing antibody significantly attenuated nDC-induced cell death. These findings provide evidence supporting novel signaling mechanisms linking nDCs and inflammation in macrophage cell death. - Highlights: • Nuclear DAMP complexes (nDCs) selectively induce cell death in macrophages, but not cancer cells. • TNFα-mediated oxidative stress is required for nDC-induced death. • RAGE-mediated Akt activation is required for nDC-induced TNFα release. • Blocking RAGE and TNFα inhibits nDC-induced macrophage cell death.

Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling

International Nuclear Information System (INIS)

Li, Guofeng; Xu, Jingren; Li, Zengchun

2012-01-01

Highlights: ► RAGE overexpression suppresses cell proliferation in MC3T3-E1 cells. ► RAGE overexpression decreases Wnt/β-catenin signaling. ► RAGE overexpression decreases ERK and PI3K signaling. ► Inhibition of Wnt signaling abolishes PI3K signaling restored by RAGE blockade. ► Inhibition of Wnt signaling abolishes ERK signaling restored by RAGE blockade. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a crucial role in bone metabolism. However, the role of RAGE in the control of osteoblast proliferation is not yet evaluated. In the present study, we demonstrate that RAGE overexpression inhibits osteoblast proliferation in vitro. The negative regulation of RAGE on cell proliferation results from suppression of Wnt, PI3K and ERK signaling, and is restored by RAGE neutralizing antibody. Prevention of Wnt signaling using Sfrp1 or DKK1 rescues RAGE-decreased PI3K and ERK signaling and cell proliferation, indicating that the altered cell growth in RAGE overexpressing cells is in part secondary to alterations in Wnt signaling. Consistently, RAGE overexpression inhibits the expression of Wnt targets cyclin D1 and c-myc, which is partially reversed by RAGE blockade. Overall, these results suggest that RAGE inhibits osteoblast proliferation via suppression of Wnt, PI3K and ERK signaling, which provides novel mechanisms by which RAGE regulates osteoblast growth.

A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

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Deane, Rashid; Singh, Itender; Sagare, Abhay P.; Bell, Robert D.; Ross, Nathan T.; LaRue, Barbra; Love, Rachal; Perry, Sheldon; Paquette, Nicole; Deane, Richard J.; Thiyagarajan, Meenakshisundaram; Zarcone, Troy; Fritz, Gunter; Friedman, Alan E.; Miller, Benjamin L.; Zlokovic, Berislav V.

2012-01-01

In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD. PMID:22406537

Advanced Glycation End-Products Induce Apoptosis of Vascular Smooth Muscle Cells: A Mechanism for Vascular Calcification

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Sayo Koike

2016-09-01

Full Text Available Vascular calcification, especially medial artery calcification, is associated with cardiovascular death in patients with diabetes mellitus and chronic kidney disease (CKD. To determine the underlying mechanism of vascular calcification, we have demonstrated in our previous report that advanced glycation end-products (AGEs stimulated calcium deposition in vascular smooth muscle cells (VSMCs through excessive oxidative stress and phenotypic transition into osteoblastic cells. Since AGEs can induce apoptosis, in this study we investigated its role on VSMC apoptosis, focusing mainly on the underlying mechanisms. A rat VSMC line (A7r5 was cultured, and treated with glycolaldehyde-derived AGE-bovine serum albumin (AGE3-BSA. Apoptotic cells were identified by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL staining. To quantify apoptosis, an enzyme-linked immunosorbent assay (ELISA for histone-complexed DNA fragments was employed. Real-time PCR was performed to determine the mRNA levels. Treatment of A7r5 cells with AGE3-BSA from 100 µg/mL concentration markedly increased apoptosis, which was suppressed by Nox inhibitors. AGE3-BSA significantly increased the mRNA expression of NAD(PH oxidase components including Nox4 and p22phox, and these findings were confirmed by protein levels using immunofluorescence. Dihydroethidisum assay showed that compared with cBSA, AGE3-BSA increased reactive oxygen species level in A7r5 cells. Furthermore, AGE3-induced apoptosis was significantly inhibited by siRNA-mediated knockdown of Nox4 or p22phox. Double knockdown of Nox4 and p22phox showed a similar inhibitory effect on apoptosis as single gene silencing. Thus, our results demonstrated that NAD(PH oxidase-derived oxidative stress are involved in AGEs-induced apoptosis of VSMCs. These findings might be important to understand the pathogenesis of vascular calcification in diabetes and CKD.

Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling

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Li, Guofeng [Department of Emergency Surgery, East Hospital, Tongji University School of Medicine, Shanghai 200120 (China); Xu, Jingren [Department of Traditional Chinese Orthopaedics, East Hospital, Tongji University School of Medicine, Shanghai 200120 (China); Li, Zengchun, E-mail: lizc.2007@yahoo.com.cn [Department of Emergency Surgery, East Hospital, Tongji University School of Medicine, Shanghai 200120 (China)

2012-07-13

Highlights: Black-Right-Pointing-Pointer RAGE overexpression suppresses cell proliferation in MC3T3-E1 cells. Black-Right-Pointing-Pointer RAGE overexpression decreases Wnt/{beta}-catenin signaling. Black-Right-Pointing-Pointer RAGE overexpression decreases ERK and PI3K signaling. Black-Right-Pointing-Pointer Inhibition of Wnt signaling abolishes PI3K signaling restored by RAGE blockade. Black-Right-Pointing-Pointer Inhibition of Wnt signaling abolishes ERK signaling restored by RAGE blockade. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a crucial role in bone metabolism. However, the role of RAGE in the control of osteoblast proliferation is not yet evaluated. In the present study, we demonstrate that RAGE overexpression inhibits osteoblast proliferation in vitro. The negative regulation of RAGE on cell proliferation results from suppression of Wnt, PI3K and ERK signaling, and is restored by RAGE neutralizing antibody. Prevention of Wnt signaling using Sfrp1 or DKK1 rescues RAGE-decreased PI3K and ERK signaling and cell proliferation, indicating that the altered cell growth in RAGE overexpressing cells is in part secondary to alterations in Wnt signaling. Consistently, RAGE overexpression inhibits the expression of Wnt targets cyclin D1 and c-myc, which is partially reversed by RAGE blockade. Overall, these results suggest that RAGE inhibits osteoblast proliferation via suppression of Wnt, PI3K and ERK signaling, which provides novel mechanisms by which RAGE regulates osteoblast growth.

Association of peripheral neuropathy with circulating advanced glycation end products, soluble receptor for advanced glycation end products and other risk factors in patients with type 2 diabetes.

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Aubert, C E; Michel, P-L; Gillery, P; Jaisson, S; Fonfrede, M; Morel, F; Hartemann, A; Bourron, O

2014-11-01

The pathogenesis of diabetic peripheral neuropathy remains uncertain and nonenzymatic glycoxidation is one of the contributing mechanisms. The aim of this study was to assess the respective relationship of diabetic peripheral neuropathy with glycoxidation, compared with other identified risk factors, in patients with type 2 diabetes. We included 198 patients with type 2 diabetes and high risk for vascular complications. Circulating concentrations of three advanced glycation end products (carboxymethyllysine, methyl-glyoxal-hydroimidazolone-1, pentosidine) and of their soluble receptor (sRAGE) were measured. Peripheral neuropathy was assessed by the neuropathy disability score and by the monofilament test and defined as either an abnormal monofilament test and/or a neuropathy disability score ≥6. Multivariate regression analyses were performed adjusting for potential confounding factors for neuropathy: age, gender, diabetes duration, current smoking, systolic blood pressure, waist circumference, height, peripheral arterial occlusive disease, glycated haemoglobin, estimated glomerular filtration rate and lipid profile. Prevalence of peripheral neuropathy was 20.7%. sRAGE and carboxymethyllysine were independently and positively associated with the presence of peripheral neuropathy. No significant association was found between peripheral neuropathy and methyl-glyoxal-hydroimidazolone-1 or pentosidine. Waist circumference, height and peripheral arterial occlusive disease were independently associated with peripheral neuropathy. Carboxymethyllysine and sRAGE were independently associated with peripheral neuropathy in patients with type 2 diabetes. Although the conclusions are limited by the absence of a healthy control population, this study confirms the relationship between advanced glycoxidation and diabetic peripheral neuropathy, independently of other risk factors. Copyright © 2014 John Wiley & Sons, Ltd.

Skin Autofluorescence, as Marker of Accumulation of Advanced Glycation Endproducts and of Cumulative Metabolic Stress, Is Not Increased in Patients with Systemic Sclerosis

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M. E. Hettema

2011-01-01

Full Text Available 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 (1.68±0.58 a.u. versus 1.63±0.41 a.u., P=0.684. Skin AF-EEMS in SSc patients was associated with levels of CRP (r=0.44, P=0.004, Medsger's severity scale (r=0.45, P=0.006, and use of agents intervening in the renin-angiotensin system (r=0.33, P=0.027. 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.

A Perspective on the Maillard Reaction and the Analysis of Protein Glycation by Mass Spectrometry: Probing the Pathogenesis of Chronic Disease

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Zhang, Qibin; Ames, Jennifer M.; Smith, Richard D.; Baynes, John W.; Metz, Thomas O.

2009-01-01

The Maillard reaction, starting from the glycation of protein and progressing to the formation of advanced glycation end-products (AGEs), is implicated in the development of complications of diabetes mellitus, as well as in the pathogenesis of cardiovascular, renal, and neurodegenerative diseases. In this perspective review, we provide an overview on the relevance of the Maillard reaction in the pathogenesis of chronic disease and discuss traditional approaches and recent developments in the ...

Accumulation of advanced glycation end-products and activation of the SCAP/SREBP Lipogenetic pathway occur in diet-induced obese mouse skeletal muscle.

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Raffaella Mastrocola

Full Text Available Aim of this study was to investigate whether advanced glycation end-products (AGEs accumulate in skeletal myofibers of two different animal models of diabesity and whether this accumulation could be associated to myosteatosis. Male C57Bl/6j mice and leptin-deficient ob/ob mice were divided into three groups and underwent 15 weeks of dietary manipulation: standard diet-fed C57 group (C57, n = 10, high-fat high-sugar diet-fed C57 group (HFHS, n = 10, and standard diet-fed ob/ob group (OB/OB, n = 8. HFHS mice and OB/OB mice developed glycometabolic abnormalities in association with decreased mass of the gastrocnemius muscle, fast-to-slow transition of muscle fibers, and lipid accumulation (that occurred preferentially in slow compared to fast fibers. Moreover, we found in muscle fibers of HFHS and OB/OB mice accumulation of AGEs that was preferential for the lipid-accumulating cells, increased expression of the lipogenic pathway SCAP/SREBP, and co-localisation between AGEs and SCAP-(hyperexpressing cells (suggestive for SCAP glycosylation. The increased expression of the SCAP/SREBP lipogenic pathway in muscle fibers is a possible mechanism underlying lipid accumulation and linking myosteatosis to muscle fiber atrophy and fast-to-slow transition that occur in response to diabesity.

Persistent Increase in Microglial RAGE Contributes to Chronic Stress-Induced Priming of Depressive-like Behavior.

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Franklin, Tina C; Wohleb, Eric S; Zhang, Yi; Fogaça, Manoela; Hare, Brendan; Duman, Ronald S

2018-01-01

Chronic stress-induced inflammatory responses occur in part via danger-associated molecular pattern (DAMP) molecules, such as high mobility group box 1 protein (HMGB1), but the receptor(s) underlying DAMP signaling have not been identified. Microglia morphology and DAMP signaling in enriched rat hippocampal microglia were examined during the development and expression of chronic unpredictable stress (CUS)-induced behavioral deficits, including long-term, persistent changes after CUS. The results show that CUS promotes significant morphological changes and causes robust upregulation of HMGB1 messenger RNA in enriched hippocampal microglia, an effect that persists for up to 6 weeks after CUS exposure. This coincides with robust and persistent upregulation of receptor for advanced glycation end products (RAGE) messenger RNA, but not toll-like receptor 4 in hippocampal microglia. CUS also increased surface expression of RAGE protein on hippocampal microglia as determined by flow cytometry and returned to basal levels 5 weeks after CUS. Importantly, exposure to short-term stress was sufficient to increase RAGE surface expression as well as anhedonic behavior, reflecting a primed state that results from a persistent increase in RAGE messenger RNA expression. Further evidence for DAMP signaling in behavioral responses is provided by evidence that HMGB1 infusion into the hippocampus was sufficient to cause anhedonic behavior and by evidence that RAGE knockout mice were resilient to stress-induced anhedonia. Together, the results provide evidence of persistent microglial HMGB1-RAGE expression that increases vulnerability to depressive-like behaviors long after chronic stress exposure. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Quantitative PCR and immunohistochemical analyses of HMGB1 and RAGE expression in canine disseminated histiocytic sarcoma (malignant histiocytosis).

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Sterenczak, Katharina A; Kleinschmidt, Sven; Wefstaedt, Patrick; Eberle, Nina; Hewicker-Trautwein, Marion; Bullerdiek, Jörn; Nolte, Ingo; Murua Escobar, Hugo

2011-05-01

Disorders of histiocytic origin affecting humans and dogs share various similarities. Canine disseminated histiocytic sarcoma (DHS) (formerly known as malignant histiocytosis) is an aggressive neoplasm of interstitial dendritic cells (DCs). The receptor for glycation end products (RAGE) and the high mobility group box1 protein (HMGB1) have been shown to be required for the maturation and migration of DCs. Thus, deregulation of the expression of these genes could have a major effect on the progression of histiocytic disorders. Neoplastic canine DHS samples and non-neoplastic control samples were analysed immunohistochemically and via real-time PCR. Significant down-regulation of RAGE in the lung tumour samples and down-regulation of HMGB1 in the lung, lymph node and spleen tumour samples were detected compared to their non-neoplastic counterparts. RAGE and HMGB1 expression down-regulation in canine DHS points to a role in the progression of histiocytic disorders.

RAGE-Specific Inhibitor FPS-ZM1 Attenuates AGEs-Induced Neuroinflammation and Oxidative Stress in Rat Primary Microglia.

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Shen, Chao; Ma, Yingjuan; Zeng, Ziling; Yin, Qingqing; Hong, Yan; Hou, Xunyao; Liu, Xueping

2017-10-01

Advanced glycation end products (AGEs) enhance microglial activation and intensify the inflammatory response and oxidative stress in the brain. This process may occur due to direct cytotoxicity or interacting with AGEs receptors (RAGE), which are expressed on the surface of microglia. FPS-ZM1 is a high-affinity but nontoxic RAGE-specific inhibitor that has been recently shown to attenuate the Aβ-induced inflammatory response by blocking the ligation of Aβ to RAGE. In this study, we further investigated the effect of FPS-ZM1 on the AGEs/RAGE interaction and downstream elevation of neuroinflammation and oxidative stress in primary microglia cells. The results suggested that FPS-ZM1 significantly suppressed AGEs-induced RAGE overexpression, RAGE-dependent microglial activation, nuclear translocation of nuclear factor kappaB p65 (NF-κB p65), and the expression of downstream inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) and inducible nitric oxide synthase (iNOS)/nitric oxide (NO). Furthermore, FPS-ZM1 attenuated AGEs-stimulated NADPH oxidase (NOX) activation and reactive oxygen species (ROS) expression. Finally, FPS-ZM1 elevated the levels of transcription factors nuclear-factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1), as well as decreased antioxidant capacity and increased production of oxidative species. Our results suggest that FPS-ZM1 may be neuroprotective through attenuating microglial activation, oxidative stress and inflammation by blocking RAGE.

Receptor for advanced glycation end products - membrane type1 matrix metalloproteinase axis regulates tissue factor expression via RhoA and Rac1 activation in high-mobility group box-1 stimulated endothelial cells.

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Koichi Sugimoto

Full Text Available BACKGROUND: Atherosclerosis is understood to be a blood vessel inflammation. High-mobility group box-1 (HMGB-1 plays a key role in the systemic inflammation. Tissue factor (TF is known to lead to inflammation which promotes thrombus formation. Membrane type1 matrix metalloprotease (MT1-MMP associates with advanced glycation endproducts (AGE triggered-TF protein expression and phosphorylation of NF-κB. However, it is still unclear about the correlation of MT1-MMP and HMBG-1-mediated TF expression. In this study, we investigated the molecular mechanisms of TF expression in response to HMGB-1 stimulation and the involvement of MT1-MMP in endothelial cells. METHODS AND RESULTS: Pull-down assays and Western blotting revealed that HMGB-1 induced RhoA/Rac1 activation and NF-kB phosphorylation in cultured human aortic endothelial cells. HMGB-1 increased the activity of MT1-MMP, and inhibition of RAGE or MT1-MMP by siRNA suppressed HMGB-1-induced TF upregulation as well as HMGB-1-triggered RhoA/Rac1 activation and NF-kB phosphorylation. CONCLUSIONS: The present study showed that RAGE/MT1-MMP axis modified HMBG-1-mediated TF expression through RhoA and Rac1 activation and NF-κB phosphorylation in endothelial cells. These results suggested that MT1-MMP was involved in vascular inflammation and might be a good target for treating atherosclerosis.

Targeted reduction of advanced glycation improves renal function in obesity

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Harcourt, Brooke E; Sourris, Karly C; Coughlan, Melinda T

2011-01-01

-lowering pharmaceutical, alagebrium, and mice in which the receptor for AGE (RAGE) was deleted. Obesity, resulting from a diet high in both fat and AGE, caused renal impairment; however, treatment of the RAGE knockout mice with alagebrium improved urinary albumin excretion, creatinine clearance, the inflammatory profile...... if treatments that lower tissue AGE burden in patients and mice would improve obesity-related renal dysfunction. Overweight and obese individuals (body mass index (BMI) 26-39¿kg/m(2)) were recruited to a randomized, crossover clinical trial involving 2 weeks each on a low- and a high-AGE-containing diet. Renal......, and renal oxidative stress. Alagebrium treatment, however, resulted in decreased weight gain and improved glycemic control compared with wild-type mice on a high-fat Western diet. Thus, targeted reduction of the advanced glycation pathway improved renal function in obesity....

Inhibition of advanced glycation endproduct (AGE) rescues against streptozotocin-induced diabetic cardiomyopathy: Role of autophagy and ER stress.

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Pei, Zhaohui; Deng, Qinqin; Babcock, Sara A; He, Emily Y; Ren, Jun; Zhang, Yingmei

2018-03-01

Diabetes mellitus leads to oxidative stress and contractile dysfunction in the heart. Although several rationales have been speculated, the precise mechanism behind diabetic cardiomyopathy remains elusive. This study was designed to assess the role of inhibition of advanced glycation endproducts (AGE) in streptozotocin (STZ)-induced diabetic cardiac dysfunction. Cardiac contractile function was assessed in normal C57BL/6 and STZ (200mg/kg, single injection and maintained for 2 wks)-induced diabetic mice treated with or without the AGE inhibitor aminoguanidine (50mg/kg/d in drinking water) for 2 weeks using echocardiography and IonOptix MyoCam techniques. Diabetes compromised cardiac contractile function shown as reduced fractional shortening and ejection fraction, enlarged left ventricular end systolic/diastolic diameters, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged shortening and relengthening duration as well as impaired intracellular Ca 2+ homeostasis, the effects of which were alleviated or reversed by aminoguanidine treatment. Diabetes also inhibited autophagy, increased ER stress and phosphorylation of pro-hypertrophic signaling molecules Akt and mTOR, the effect of which was reversed by aminoguanidine. In vitro study revealed that methylglyoxal-derived AGE (MG-AGE) incubation in isolated cardiomyocytes promoted oxidation of sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA2a) and production of superoxide, the effects of which were negated by the autophagy inducer rapamycin, the ER stress chaperone TUDCA or the antioxidant N-acetylcysteine. Taken together, these data revealed that inhibition of AGE formation rescues against experimental diabetes-induced cardiac remodeling and contractile dysfunction possible through regulation of autophagy and ER stress. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of glycation on α-crystallin structure and chaperone-like function

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Kumar, P. Anil; Kumar, M. Satish; Reddy, G. Bhanuprakash

2007-01-01

The chaperone-like activity of α-crystallin is considered to play an important role in the maintenance of the transparency of the eye lens. However, in the case of aging and in diabetes, the chaperone function of α-crystallin is compromized, resulting in cataract formation. Several post-translational modifications, including non-enzymatic glycation, have been shown to affect the chaperone function of α-crystallin in aging and in diabetes. A variety of agents have been identified as the predominant sources for the formation of AGEs (advanced glycation end-products) in various tissues, including the lens. Nevertheless, glycation of α-crystallin with various sugars has resulted in divergent results. In the present in vitro study, we have investigated the effect of glucose, fructose, G6P (glucose 6-phosphate) and MGO (methylglyoxal), which represent the major classes of glycating agents, on the structure and chaperone function of α-crystallin. Modification of α-crystallin with all four agents resulted in the formation of glycated protein, increased AGE fluorescence, protein cross-linking and HMM (high-molecular-mass) aggregation. Interestingly, these glycation-related profiles were found to vary with different glycating agents. For instance, CML [Nϵ-(carboxymethyl)lysine] was the predominant AGE formed upon glycation of α-crystallin with these agents. Although fructose and MGO caused significant conformational changes, there were no significant structural perturbations with glucose and G6P. With the exception of MGO modification, glycation with other sugars resulted in decreased chaperone activity in aggregation assays. However, modification with all four sugars led to the loss of chaperone activity as assessed using an enzyme inactivation assay. Glycation-induced loss of α-crystallin chaperone activity was associated with decreased hydrophobicity. Furthermore, α-crystallin isolated from glycated TSP (total lens soluble protein) had also increased AGE

Soluble Receptor for Advanced Glycation End Product Ameliorates Chronic Intermittent Hypoxia Induced Renal Injury, Inflammation, and Apoptosis via P38/JNK Signaling Pathways

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Xu Wu

2016-01-01

Full Text Available Obstructive sleep apnea (OSA associated chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH triggered tissue damage. Receptor for advanced glycation end product (RAGE and its ligand high mobility group box 1 (HMGB1 are expressed on renal cells and mediate inflammatory responses in OSA-related diseases. To determine their roles in CIH-induced renal injury, soluble RAGE (sRAGE, the RAGE neutralizing antibody, was intravenously administered in a CIH model. We also evaluated the effect of sRAGE on inflammation and apoptosis. Rats were divided into four groups: (1 normal air (NA, (2 CIH, (3 CIH+sRAGE, and (4 NA+sRAGE. Our results showed that CIH accelerated renal histological injury and upregulated RAGE-HMGB1 levels involving inflammatory (NF-κB, TNF-α, and IL-6, apoptotic (Bcl-2/Bax, and mitogen-activated protein kinases (phosphorylation of P38, ERK, and JNK signal transduction pathways, which were abolished by sRAGE but p-ERK. Furthermore, sRAGE ameliorated renal dysfunction by attenuating tubular endothelial apoptosis determined by immunofluorescence staining of CD31 and TUNEL. These findings suggested that RAGE-HMGB1 activated chronic inflammatory transduction cascades that contributed to the pathogenesis of the CIH-induced renal injury. Inhibition of RAGE ligand interaction by sRAGE provided a therapeutic potential for CIH-induced renal injury, inflammation, and apoptosis through P38 and JNK pathways.

A Perspective on the Maillard Reaction and the Analysis of Protein Glycation by Mass Spectrometry: Probing the Pathogenesis of Chronic Disease

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Zhang, Qibin; Ames, Jennifer M.; Smith, Richard D.; Baynes, John; Metz, Thomas O.

2008-12-18

The Maillard reaction, starting from the glycation of protein and progressing to the formation of advanced glycation end-products (AGEs), is implicated in the development of complications of diabetes mellitus, as well as in the pathogenesis of cardiovascular, renal, and neurodegenerative diseases. In this perspective review, we provide on overview on the relevance of the Maillard reaction in the pathogenesis of chronic disease and discuss traditional approaches and recent developments in the analysis of glycated proteins by mass spectrometry. We propose that proteomics approaches, particularly bottom-up proteomics, will play a significant role in analyses of clinical samples leading to the identification of new markers of disease development and progression.

A perspective on the Maillard reaction and the analysis of protein glycation by mass spectrometry: probing the pathogenesis of chronic disease.

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Zhang, Qibin; Ames, Jennifer M; Smith, Richard D; Baynes, John W; Metz, Thomas O

2009-02-01

The Maillard reaction, starting from the glycation of protein and progressing to the formation of advanced glycation end-products (AGEs), is implicated in the development of complications of diabetes mellitus, as well as in the pathogenesis of cardiovascular, renal, and neurodegenerative diseases. In this perspective review, we provide an overview on the relevance of the Maillard reaction in the pathogenesis of chronic disease and discuss traditional approaches and recent developments in the analysis of glycated proteins by mass spectrometry. We propose that proteomics approaches, particularly bottom-up proteomics, will play a significant role in analyses of clinical samples leading to the identification of new markers of disease development and progression.

Clinical and Biological Predictors of Plasma Levels of Soluble RAGE in Critically Ill Patients: Secondary Analysis of a Prospective Multicenter Observational Study

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Thibaut Pranal

2018-01-01

Full Text Available Rationale. Although soluble forms of the receptor for advanced glycation end products (RAGE have been recently proposed as biomarkers in multiple acute or chronic diseases, few studies evaluated the influence of usual clinical and biological parameters, or of patient characteristics and comorbidities, on circulating levels of soluble RAGE in the intensive care unit (ICU setting. Objectives. To determine, among clinical and biological parameters that are usually recorded upon ICU admission, which variables, if any, could be associated with plasma levels of soluble RAGE. Methods. Data for this ancillary study were prospectively obtained from adult patients with at least one ARDS risk factor upon ICU admission enrolled in a large multicenter observational study. At ICU admission, plasma levels of total soluble RAGE (sRAGE and endogenous secretory (esRAGE were measured by duplicate ELISA and baseline patient characteristics, comorbidities, and usual clinical and biological indices were recorded. After univariate analyses, significant variables were used in multivariate, multidimensional analyses. Measurements and Main Results. 294 patients were included in this ancillary study, among whom 62% were admitted for medical reasons, including septic shock (11%, coma (11%, and pneumonia (6%. Although some variables were associated with plasma levels of RAGE soluble forms in univariate analysis, multidimensional analyses showed no significant association between admission parameters and baseline plasma sRAGE or esRAGE. Conclusions. We found no obvious association between circulating levels of soluble RAGE and clinical and biological indices that are usually recorded upon ICU admission. This trial is registered with NCT02070536.

Glycation of extracellular matrix proteins and its role in atherosclerosis 

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Aleksandra Kuzan

2012-10-01

Full Text Available Glycation consists in formation of advanced glycation end-products (AGE during non-enzymatic reaction between reducing sugars and proteins, lipids or nucleic acids. This review is focused mainly on glycation of collagen and its role in acceleration of vascular disease. Collagen is an extracellular matrix protein characterized by unique structure forming fibrils with great anti-tensile and anti-breaking strength. The protein builds the connective tissue and is responsible for biomechanical properties of blood vessels. It is reported that higher content of glycated collagen correlates with lower elasticity and greater toughness of the vessel walls and, as a consequence, a faster rate of atherosclerosis development. Numerous mechanisms connected with AGE formation are involved in atherogenesis, among others: receptor-mediated production of free radicals, triggering an inflammatory process, activation of leukocytes and thrombocytes, facilitation of LDL binding, change in level of growth factors, adhesion molecules, MMP and some other proteins’ expression. The coverages allow the development of therapeutic strategies to prevent or slow down the pathological processes connected with glycation of collagen and other proteins in the artery wall. The main strategies are based on limitation of exogenous AGE, consumption of products which contain rutin, treatment with drugs which inhibit AGE formation, such aspyridoxamine, and chemicals which are able to cleave already formed AGE protein-protein crosslinks, such as ALT-711.

Discovering Small Molecule Inhibitors Targeted to Ligand-Stimulated RAGE-DIAPH1 Signaling Transduction

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Pan, Jinhong

The receptor of advanced glycation end product (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules, which plays an important role in immune responses. Full-length RAGE includes three extracellular immunoglobulin domains, a transmembrane domain and an intracellular domain. It is a pattern recognition receptor that can bind diverse ligands. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. It is found that calgranulin binding to the C1C2 domain or AGEs binding to the V domain activates extracellular signaling, which triggers interactions of the RAGE cytoplasmic tail (ctRAGE) with intracellular effector, such as diaphanous 1 (DIAPH1), to initiate signal transduction cascades. ctRAGE is essential for RAGE-ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE is over-expressed in diseased tissues of most RAGE-associated pathogenic conditions, such as complications of Alzheimer's diseases, diabetes, vascular diseases, inflammation, cancers and neurodegeneration. They are the major diseases affecting a large population worldwide. RAGE can function as a biomarker or drug target for these diseases. The cytoplasmic tail of RAGE can be used as a drug target to inhibit RAGE-induced intracellular signaling by small molecule inhibitors to treat RAGE-associated diseases. We developed a high throughput screening assay with which we probed a small molecule library of 58,000 compounds to find that 777 small molecules displayed 50% inhibition and 97 compounds demonstrated dose-dependent inhibition of the binding of ctRAGE-DIAPH1. Eventually, there were 13 compounds which displayed dose-dependent inhibition of ctRAGE binding to DIAPH1 and direct binding to ctRAGE analyzed by 15N HSQC-NMR and native tryptophan fluorescence titration experiments; thus, they were

Beneficial effects of banana (Musa sp. var. elakki bale) flower and pseudostem on hyperglycemia and advanced glycation end-products (AGEs) in streptozotocin-induced diabetic rats.

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Bhaskar, Jamuna J; Shobha, Mysore S; Sambaiah, Kari; Salimath, Paramahans V

2011-09-01

Diabetes is a chronic health problem and major cause of death in most of the countries. Diet management plays an important role in controlling diabetes and its complications along with insulin and drugs. We have examined the effect of banana (Musa sp. var. elakki bale) flower and pseudostem on hyperglycemia and advanced glycation end-products (AGEs) in streptozotocin-induced diabetic rats. Our results indicated that banana flower and pseudostem have low glycemic index and have a high content of dietary fiber and antioxidants. Diabetic symptoms like hyperglycemia, polyuria, polyphagia, polydipsia, urine sugar, and body weight were ameliorated in banana flower- and pseudostem-treated rats. Increased glomerular filtration rate in the diabetic group (5.1 ± 0.22 ml/min) was decreased in banana flower-fed (2.5 ± 0.37 ml/min) and pseudostem-fed (3.0 ± 0.45 ml/min) groups and were significant at P banana flower- and pseudostem-fed groups, it was reduced to 9.21 ± 0.32 and 9.29 ± 0.24 μg/mg protein, respectively, and were significant at P banana flower and pseudostem have anti-diabetic and anti-AGEs properties and are beneficial as food supplements for diabetics.

A high throughput screening assay for identifying glycation inhibitors on MALDI-TOF target.

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Zhang, Qiuting; Tu, Zongcai; Wang, Hui; Fan, Liangliang; Huang, Xiaoqin; Xiao, Hui

2015-03-01

The Maillard reaction plays an important role in the food industry, however, the deleterious effects generated by the advanced glycation end-products (AGEs) have been well recognized. Many efforts have been made to seek new AGE inhibitors, in particular those natural ones without adverse effect. We have developed a rapid, mass spectrometry based, on-plate screening assay for novel AGE inhibitors. The glycation reaction, inhibition feedback as well as the subsequent MALDI mass spectrometric analysis occurred on one single MALDI plate. At 1:10 M ratio of peptide to sugar, as little as 4h incubation time allowed the screening test to be ready for analysis. DSP, inhibition and IC50 were calculated to evaluate selected inhibitors and resulting inhibition efficiencies were consistent with available references. We demonstrated that this method provide a potential high throughput screening assay to analyze and identify the anti-glycation agents. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of RAGE-Specific Inhibitor FPS-ZM1 on Amyloid-β Metabolism and AGEs-Induced Inflammation and Oxidative Stress in Rat Hippocampus.

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Hong, Yan; Shen, Chao; Yin, Qingqing; Sun, Menghan; Ma, Yingjuan; Liu, Xueping

2016-05-01

An increased level of advanced glycation end products (AGEs) is observed in brains of patients with Alzheimer's disease (AD). AGEs and receptor for AGEs (RAGE) play important roles in the pathogenesis of AD. FPS-ZM1 is a high-affinity RAGE-specific blocker that inhibits amyloid-β binding to RAGE, neurological damage and inflammation in the APP(sw/0) transgenic mouse model of AD. FPS-ZM1 is not toxic to mice and can easily cross the blood-brain barrier. In this study, an AGEs-RAGE-activated rat model were established by intrahippocampal injection of AGEs, then these rats were treated with intraperitoneal administration of FPS-ZM1 and the possible neuroprotective effects were investigated. We found that AGEs administration induced an-regulation of Abeta production, inflammation, and oxidative stress, and an increased escape latency of rats in the Morris water maze test, all of these are significantly reduced by FPS-ZM1 treatment. Our results suggest that the AGEs-RAGE pathway is responsible for cognitive deficits, and therefore may be a potential treatment target. FPS-ZM1 might be a novel therapeutic agent to treat AD patients.

RAGE-dependent activation of gene expression of superoxide dismutase and vanins by AGE-rich extracts in mice cardiac tissue and murine cardiac fibroblasts.

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Leuner, Beatrice; Ruhs, Stefanie; Brömme, Hans-Jürgen; Bierhaus, Angelika; Sel, Saadettin; Silber, Rolf-Edgar; Somoza, Veronika; Simm, Andreas; Nass, Norbert

2012-10-01

Advanced glycation end products (AGEs) are stable compounds formed from initial Maillard reaction products. They are considered as markers for ageing and often associated with age-related, degenerative diseases. Bread crust represents an established model for nutritional compounds rich in AGEs and is able to induce antioxidative defense genes such as superoxide dismutases and vanins in cardiac cells. The aim of this study was to investigate to what extend the receptor for AGEs (RAGE) contributes to this response. Signal transduction in response to bread crust extract was analysed in cardiac fibroblasts derived from C57/B6-NCrl (RAGE +/+) and the corresponding RAGE-knock out C57/B6-NCrl mouse strain (RAGE -/-). Activation of superoxide dismutases in animals was then analysed upon bread crust feeding in these two mice strains. Cardiac fibroblasts from RAGE -/- mice did not express RAGE, but the expression of AGER-1 and AGER-3 was up-regulated, whereas the expression of SR-B1 was down-regulated. RAGE -/- cells were less sensitive to BCE in terms of MAP-kinase phosphorylation and NF-κB reporter gene activation. Bread crust extract induced mRNA levels of MnSOD and Vnn-1 were also reduced in RAGE -/- cells, whereas Vnn-3 mRNA accumulation seemed to be RAGE receptor independent. In bread crust feeding experiments, RAGE -/- mice did not exhibit an activation of MnSOD-mRNA and -protein accumulation as observed for the RAGE +/+ animals. In conclusion, RAGE was clearly a major factor for the induction of antioxidant defense signals derived from bread crust in cardiac fibroblast and mice. Nevertheless higher doses of bread crust extract could overcome the RAGE dependency in cell cultures, indicating that additional mechanisms are involved in BCE-mediated activation of SOD and vanin expression.

Advanced glycation end products impair function of late endothelial progenitor cells through effects on protein kinase Akt and cyclooxygenase-2

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Chen Qin; Dong Li; Wang Lian; Kang Lina; Xu Biao

2009-01-01

Endothelial progenitor cells (EPCs) exhibit impaired function in the context of diabetes, and advanced glycation end products (AGEs), which accumulate in diabetes, may contribute to this. In the present study, we investigated the mechanism by which AGEs impair late EPC function. EPCs from human umbilical cord blood were isolated, and incubated with AGE-modified albumin (AGE-albumin) at different concentrations found physiologically in plasma. Apoptosis, migration, and tube formation assays were used to evaluate EPC function including capacity for vasculogenesis, and expression of the receptor for AGEs (RAGE), Akt, endothelial nitric oxide synthase (eNOS), and cycloxygenase-2 (COX-2) were determined. Anti-RAGE antibody was used to block RAGE function. AGE-albumin concentration-dependently enhanced apoptosis and depressed migration and tube formation, but did not affect proliferation, of late EPCs. High AGE-albumin increased RAGE mRNA and protein expression, and decreased Akt and COX-2 protein expression, whilst having no effect on eNOS mRNA or protein in these cells. These effects were inhibited by co-incubation with anti-RAGE antibody. These results suggest that RAGE mediates the AGE-induced impairment of late EPC function, through down-regulation of Akt and COX-2 in these cells.

Advanced Glycation End-Products Are Associated With the Presence and Severity of Paratonia in Early Stage Alzheimer Disease.

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Drenth, Hans; Zuidema, Sytse U; Krijnen, Wim P; Bautmans, Ivan; van der Schans, Cees; Hobbelen, Hans

2017-07-01

Paratonia, a distinctive form of hypertonia in patients with dementia, causes loss of functional mobility in early stage dementia to severe contractures and pain in the late stages. The pathogenesis of paratonia is not well understood. Patients in early stage dementia with diabetes mellitus showed a significantly higher risk for the development of paratonia. Both Alzheimer disease and diabetes mellitus are related to higher concentrations of advanced glycation end-products (AGEs). The purpose of this study is to explore the association of AGEs with the prevalence and severity of paratonia in patients with Alzheimer disease. Observational longitudinal, 1-year follow-up cohort study with 3 assessments. Day care centers for patients with dementia. A total of 144 community-dwelling patients with early stage Alzheimer or Alzheimer/vascular disease were recruited from 24 dementia day care centers in The Netherlands. The presence of paratonia (Paratonia Assessment Instrument), the severity of paratonia (Modified Ashworth Scale for paratonia), and AGE levels (AGE-reader). From the 144 participants (56.3% female and 43.7% male, with a mean [standard deviation] age of 80.7 [7.7] years), 118 participants were available for final follow-up. A significant association between AGE levels and the presence of paratonia (odds ratio 3.47, 95% confidence interval [CI] 1.87-6.44, P factor to paratonia and its severity and could be the result of peripheral biomechanical changes reducing elasticity and increasing stiffness. These results provide a new perspective on paratonia and gives rise to further research whether paratonia could be postponed or movement stiffness can be improved by reducing AGE levels. Copyright © 2017 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

Hyperglycemia-related advanced glycation end-products is associated with the altered phosphatidylcholine metabolism in osteoarthritis patients with diabetes.

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Weidong Zhang

Full Text Available To test whether type 2 diabetic patients have an elevated level of advanced glycation end-products (AGEs and responsible for altered phosphatidylcholine metabolism, which we recently found to be associated with osteoarthritis (OA and diabetes mellitus (DM, synovial fluid (SF and plasma samples were collected from OA patients with and without DM. Hyperglycemia-related AGEs including methylglyoxal (MG, free methylglyoxal-derived hydroimidazolone (MG-H1, and protein bound N-(Carboxymethyllysine (CML and N-(Carboxyethyllysine (CEL levels were measured in both SF and plasma samples using liquid chromatography coupled tandem mass spectrometry methodology. The correlation between these AGEs and phosphatidylcholine acyl-alkyl C34:3 (PC ae C34:3 and C36:3 (PC ae C36:3 were examined. Eighty four patients with knee OA, including 46 with DM and 38 without DM, were included in the study. There was no significant difference in plasma levels of MG, MG-H1, CML, and CEL between OA patients with and without DM. However, the levels of MG and MG-H1, but not CML and CEL in SF were significantly higher in OA patients with DM than in those without (all p ≤0.04. This association strengthened after adjustment for age, body mass index (BMI, sex and hexose level (p<0.02. Moreover, the levels of MG-H1 in SF was negatively and significantly correlated with PC ae C34:3 (ρ = -0.34; p = 0.02 and PC ae C36:3 (ρ = -0.39; P = 0.03 after the adjustment of age, BMI, sex and hexose level. Our data indicated that the production of non-protein bound AGEs was increased within the OA-affected joint of DM patients. This is associated with changes in phosphatidylcholine metabolism and might be responsible for the observed epidemiological association between OA and DM.

Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARγ activation in high fructose diet-induced metabolic syndrome.

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Cannizzaro, Luca; Rossoni, Giuseppe; Savi, Federica; Altomare, Alessandra; Marinello, Cristina; Saethang, Thammakorn; Carini, Marina; Payne, D Michael; Pisitkun, Trairak; Aldini, Giancarlo; Leelahavanichkul, Asada

2017-01-01

The AGE-RAGE-oxidative stress (AROS) axis is involved in the onset and progression of metabolic syndrome induced by a high-fructose diet (HFD). PPARγ activation is known to modulate metabolic syndrome; however a systems-level investigation looking at the protective effects of PPARγ activation as related to the AROS axis has not been performed. The aim of this work is to simultaneously characterize multiple molecular parameters within the AROS axis, using samples taken from different body fluids and tissues of a rat model of HFD-induced metabolic syndrome, in the presence or absence of a PPARγ agonist, Rosiglitazone (RGZ). Rats were fed with 60% HFD for the first half of the treatment duration (21 days) then continued with either HFD alone or HFD plus RGZ for the second half. Rats receiving HFD alone showed metabolic syndrome manifestations including hypertension, dyslipidemia, increased glucose levels and insulin resistance, as well as abnormal kidney and inflammatory parameters. Systolic blood pressure, plasma triglyceride and glucose levels, plasma creatinine, and albuminuria were significantly improved in the presence of RGZ. The following molecular parameters of the AROS axis were significantly upregulated in our rat model: carboxymethyl lysine (CML) in urine and liver; carboxyethyl lysine (CEL) in urine; advanced glycation end products (AGEs) in plasma; receptor for advanced glycation end products (RAGE) in liver and kidney; advanced oxidation protein products (AOPP) in plasma; and 4-hydroxynonenal (HNE) in plasma, liver, and kidney. Conversely, with RGZ administration, the upregulation of AOPP and AGEs in plasma, CML and CEL in urine, RAGE in liver as well as HNE in plasma and liver was significantly counteracted/prevented. Our data demonstrate (i) the systems-level regulatory landscape of HFD-induced metabolic syndrome involving multiple molecular parameters, including HNE, AGEs and their receptor RAGE, and (ii) attenuation of metabolic syndrome by

Overexpression of Receptor for Advanced Glycation End Products and High-Mobility Group Box 1 in Human Dental Pulp Inflammation

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Salunya Tancharoen

2014-01-01

Full Text Available High mobility group box 1 (HMGB1, a nonhistone DNA-binding protein, is released into the extracellular space and promotes inflammation. HMGB1 binds to related cell signaling transduction receptors, including receptor for advanced glycation end products (RAGE, which actively participate in vascular and inflammatory diseases. The aim of this study was to examine whether RAGE and HMGB1 are involved in the pathogenesis of pulpitis and investigate the effect of Prevotella intermedia (P. intermedia lipopolysaccharide (LPS on RAGE and HMGB1 expression in odontoblast-like cells (OLC-1. RAGE and HMGB1 expression levels in clinically inflamed dental pulp were higher than those in healthy dental pulp. Upregulated expression of RAGE was observed in odontoblasts, stromal pulp fibroblasts-like cells, and endothelial-like cell lining human pulpitis tissue. Strong cytoplasmic HMGB1 immunoreactivity was noted in odontoblasts, whereas nuclear HMGB1 immunoreactivity was seen in stromal pulp fibroblasts-like cells in human pulpitis tissue. LPS stimulated OLC-1 cells produced HMGB1 in a dose-dependent manner through RAGE. HMGB1 translocation towards the cytoplasm and secretion from OLC-1 in response to LPS was inhibited by TPCA-1, an inhibitor of NF-κB activation. These findings suggest that RAGE and HMGB1 play an important role in the pulpal immune response to oral bacterial infection.

Effects of non-enzymatic glycation in human serum albumin. Spectroscopic analysis

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Szkudlarek, A.; Sułkowska, A.; Maciążek-Jurczyk, M.; Chudzik, M.; Równicka-Zubik, J.

2016-01-01

Human serum albumin (HSA), transporting protein, is exposed during its life to numerous factors that cause its functions become impaired. One of the basic factors - glycation of HSA - occurs in diabetes and may affect HSA-drug binding. Accumulation of advanced glycation end-products (AGEs) leads to diseases e.g. diabetic and non-diabetic cardiovascular diseases, Alzheimer disease, renal disfunction and in normal aging. The aim of the present work was to estimate how non-enzymatic glycation of human serum albumin altered its tertiary structure using fluorescence technique. We compared glycated human serum albumin by glucose (gHSAGLC) with HSA glycated by fructose (gHSAFRC). We focused on presenting the differences between gHSAFRC and nonglycated (HSA) albumin used acrylamide (Ac), potassium iodide (KI) and 2-(p-toluidino)naphthalene-6-sulfonic acid (TNS). Changes of the microenvironment around the tryptophan residue (Trp-214) of non-glycated and glycated proteins was investigated by the red-edge excitation shift method. Effect of glycation on ligand binding was examined by the binding of phenylbutazone (PHB) and ketoprofen (KP), which a primary high affinity binding site in serum albumin is subdomain IIA and IIIA, respectively. At an excitation and an emission wavelength of λex 335 nm and λem 420 nm, respectively the increase of fluorescence intensity and the blue-shift of maximum fluorescence was observed. It indicates that the glycation products decreases the polarity microenvironment around the fluorophores. Analysis of red-edge excitation shift method showed that the red-shift for gHSAFRC is higher than for HSA. Non-enzymatic glycation also caused, that the Trp residue of gHSAFRC becomes less accessible for the negatively charged quencher (I-), KSV value is smaller for gHSAFRC than for HSA. TNS fluorescent measurement demonstrated the decrease of hydrophobicity in the glycated albumin. KSV constants for gHSA-PHB systems are higher than for the unmodified serum

Current therapeutic interventions in the glycation pathway: evidence from clinical studies.

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Engelen, L; Stehouwer, C D A; Schalkwijk, C G

2013-08-01

The increased formation of advanced glycation endproducts (AGEs) constitutes a potential mechanism of hyperglycaemia-induced micro- and macrovascular disease in diabetes. In vitro and animal experiments have shown that various interventions can inhibit formation and/or actions of AGEs, in particular the specific AGE inhibitor aminoguanidine and the AGEs crosslink breaker alagebrium, and the B vitamins pyridoxamine and thiamine, and the latter's synthetic derivative, benfotiamine. The potential clinical value of these interventions, however, remains to be established. The present review provides, from the clinical point of view, an overview of current evidence on interventions in the glycation pathway relating to (i) the clinical benefits of specific AGE inhibitors and AGE breakers and (ii) the potential AGE-inhibiting effects of therapies developed for purposes unrelated to the glycation pathway. We found that safety and/or efficacy in clinical studies with the specific AGE inhibitor, aminoguanidine and the AGE breaker, alagebrium, appeared to be a concern. The clinical evidence on the potential AGE-inhibiting effects of B vitamins is still limited. Finally, current evidence for AGE inhibition by therapies developed for purposes unrelated to glycation is limited due to a large heterogeneity in study designs and/or measurement techniques, which have often been sub-optimal. We conclude that, clinical evidence on interventions to inhibit formation and/or action of AGEs is currently weak and unconvincing. © 2012 Blackwell Publishing Ltd.

Associations of advanced glycation end-products with cognitive functions in individuals with and without type 2 diabetes: the maastricht study.

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Spauwen, P J J; van Eupen, M G A; Köhler, S; Stehouwer, C D A; Verhey, F R J; van der Kallen, C J H; Sep, S J S; Koster, A; Schaper, N C; Dagnelie, P C; Schalkwijk, C G; Schram, M T; van Boxtel, M P J

2015-03-01

Advanced glycation end-products (AGEs) are thought to be involved in the pathogenesis of Alzheimer's disease. AGEs are products resulting from nonenzymatic chemical reactions between reduced sugars and proteins, which accumulate during natural aging, and their accumulation is accelerated in hyperglycemic conditions such as type 2 diabetes mellitus. The objective of the study was to examine associations between AGEs and cognitive functions. This study was performed as part of the Maastricht Study, a population-based cohort study in which, by design, 215 participants (28.1%) had type 2 diabetes mellitus. We examined associations of skin autofluorescence (SAF) (n = 764), an overall estimate of skin AGEs, and specific plasma protein-bound AGEs (n = 781) with performance on tests for global cognitive functioning, information processing speed, verbal memory (immediate and delayed word recall), and response inhibition. After adjustment for demographics, diabetes, smoking, alcohol, waist circumference, total cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, and lipid-lowering medication use, higher SAF was significantly associated with worse delayed word recall (regression coefficient, b = -0.44; P = .04), and response inhibition (b = 0.03; P = .04). After further adjustment for systolic blood pressure, cardiovascular disease, estimated glomerular filtration rate, and depression, associations were attenuated (delayed word recall, b = -0.38, P = .07; response inhibition, b = 0.02, P = .07). Higher pentosidine levels were associated with worse global cognitive functioning (b = -0.61; P = .04) after full adjustment, but other plasma AGEs were not. Associations did not differ between individuals with and without diabetes. We found inverse associations of SAF (a noninvasive marker for tissue AGEs) with cognitive performance, which were attenuated after adjustment for vascular risk factors and depression.

Serum level of soluble receptor for advanced glycation end products in asthmatic children and its correlation to severity and pulmonary functions.

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El-Seify, Magda Y Hussein; Fouda, Eman Mahmoud; Nabih, Enas Samir

2014-01-01

Soluble receptor for advanced glycation end products (sRAGE) acts as a decoy receptor for RAGE which has several distinct pro-inflammatory ligands in the extracellular compartment, and is believed to afford protection against inflammation and cell injury. This study was conducted to measure serum sRAGE in asthmatic children and to assess its correlation with clinical and functional severity and to asthma phenotype according to sputum cytology. The study was conducted on 60 asthmatic children from the Pediatric Chest Clinic, Children's Hospital, Ain Shams University. The patients were divided according to asthma control and severity. sRAGE showed statistically significant lower levels in asthmatic patients (899.1 +/- 399.8 pg/mL) compared to the control group (1406.7 +/- 474.3 pg/mL, p = 0.000), with a cut off value of asthma diagnosis of 1080.4 pg/mL with a sensitivity and specificity of 77% and 75%, respectively. Uncontrolled and severe asthmatic subgroups showed lower levels of sRAGE, cut off value of sRAGE for the severity of asthma was 829 pg/mL with 89% sensitivity and 81% specificity. Asthmatic patients stratified according to sputum cytology revealed that those with > 2% eosinophils and > or = 40% neutrophils showed lower levels of sRAGE (710 +/- 258 pg/mL) compared to those with > 2% eosinophils and functionally. It may be a target of future therapeutic interventions.

Lower serum endogenous secretory receptor for advanced glycation end product level as a risk factor of metabolic syndrome among Japanese adult men: a 2-year longitudinal study.

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Momma, Haruki; Niu, Kaijun; Kobayashi, Yoritoshi; Huang, Cong; Chujo, Masahiko; Otomo, Atsushi; Tadaura, Hiroko; Miyata, Toshio; Nagatomi, Ryoichi

2014-02-01

Receptor for advanced glycation end products (RAGE) activation by its ligands is implicated in obesity-related metabolic disease and accelerated atherothrombosis. Circulating soluble (sRAGE) and/or endogenous secretory RAGE (esRAGE) may counteract the detrimental effects of RAGE. This study aimed at determining the relationship between circulating RAGE and metabolic syndrome (MetS) incidence among Japanese adult men. This 2-year longitudinal study included 426 Japanese men aged 30-83 years who had no MetS at baseline. Serum esRAGE and sRAGE were assayed by ELISA at baseline. Incident metabolic syndrome, defined according to the Asian cutoff based on the 2009 criteria of the American Heart Association Scientific Statements, was evaluated after the 2-year follow-up. During the follow-up period, 55 participants (12.9%) had newly diagnosed MetS. In the multiple logistic models comparing MetS risk in the lowest with that in the highest tertile of baseline esRAGE, a high serum esRAGE level was found to be significantly associated with a low risk of MetS [odds ratios (95% confidence interval), 0.37 (0.14-0.95); P for trend = 0.038] after adjusting for lifestyle and sociodemographic factors, serum high-sensitivity C-reactive protein level, estimated glomerular filtration rate, and MetS components at baseline. Although sRAGE and esRAGE were strongly correlated (r(s) = 0.88), the sRAGE level was not associated with MetS incidence. A high circulating esRAGE level, but not sRAGE level, was associated with a low MetS incidence among Japanese adult men.

Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation.

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Ullah, Md Ashik; Loh, Zhixuan; Gan, Wan Jun; Zhang, Vivian; Yang, Huan; Li, Jian Hua; Yamamoto, Yasuhiko; Schmidt, Ann Marie; Armour, Carol L; Hughes, J Margaret; Phipps, Simon; Sukkar, Maria B

2014-08-01

The receptor for advanced glycation end products (RAGE) shares common ligands and signaling pathways with TLR4, a key mediator of house dust mite (Dermatophagoides pteronyssinus) (HDM) sensitization. We hypothesized that RAGE and its ligand high-mobility group box-1 (HMGB1) cooperate with TLR4 to mediate HDM sensitization. To determine the requirement for HMGB1 and RAGE, and their relationship with TLR4, in airway sensitization. TLR4(-/-), RAGE(-/-), and RAGE-TLR4(-/-) mice were intranasally exposed to HDM or cockroach (Blatella germanica) extracts, and features of allergic inflammation were measured during the sensitization or challenge phase. Anti-HMGB1 antibody and the IL-1 receptor antagonist Anakinra were used to inhibit HMGB1 and the IL-1 receptor, respectively. The magnitude of allergic airway inflammation in response to either HDM or cockroach sensitization and/or challenge was significantly reduced in the absence of RAGE but not further diminished in the absence of both RAGE and TLR4. HDM sensitization induced the release of HMGB1 from the airway epithelium in a biphasic manner, which corresponded to the sequential activation of TLR4 then RAGE. Release of HMGB1 in response to cockroach sensitization also was RAGE dependent. Significantly, HMGB1 release occurred downstream of TLR4-induced IL-1α, and upstream of IL-25 and IL-33 production. Adoptive transfer of HDM-pulsed RAGE(+/+)dendritic cells to RAGE(-/-) mice recapitulated the allergic responses after HDM challenge. Immunoneutralization of HMGB1 attenuated HDM-induced allergic airway inflammation. The HMGB1-RAGE axis mediates allergic airway sensitization and airway inflammation. Activation of this axis in response to different allergens acts to amplify the allergic inflammatory response, which exposes it as an attractive target for therapeutic intervention. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of RAGE-NFκB and Nrf2-antioxidant signaling pathways.

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Abdelsalam, Rania M; Safar, Marwa M

2015-06-01

Gliptins have been recently shown to conquer neuronal degeneration in cell cultures via modulating glucagon-like peptide (GLP)-1. This peptide produced in the gut not only crosses the blood-brain barrier but is also synthesized in the brain and acts on GLP-1R exerting central anti-inflammatory and antiapoptotic effects, thus impeding neuronal damage. This study investigated the antiparkinsonian effect of vildagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor in a rat rotenone model targeting mainly the RAGE-NFκB/Nrf2-signaling pathways, to judge the potential anti-inflammatory/antioxidant effects of the drug. Vildagliptin markedly improved the motor performance in the open field and rotarod tests, effects that were emphasized by the accompanied reduction in striatal dopamine content. It modified the striatal energy level (ADP/ATP) associated with partial antagonism of body weight reduction. This incretin enhancer suppressed nuclear factor (NF)κB and, consequently, the downstream inflammatory mediator tumor necrosis factor-α. Normalization of receptor for advanced glycated end product (RAGE) is a main finding which justifies the anti-inflammatory effects of vildagliptin, together with hampering striatal inducible nitric oxide synthase, intracellular adhesion molecule-1 as well as myeloperoxidase. The antioxidant potential of vildagliptin was depicted as entailing reduction in thiobarbituric acid-reactive substances and the transcriptional factor Nrf-2 level. Vildagliptin guarded against neuronal demise through an antiapoptotic effect as reflected by the reduction in the mitochondrial matrix component cytochrome c and the key downstream executioner caspase-3. In conclusion, vildagliptin is endowed with various neuroprotective effects and thus can be a promising candidate for the management of Parkinson's disease. In the rat rotenone model of Parkinson's disease (PD), striatal RAGE/NFκB signaling was up-regulated associated with elevated levels of inflammatory

Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes.

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Pamela Maher

Full Text Available The elevated glycation of macromolecules by the reactive dicarbonyl and α-oxoaldehyde methylglyoxal (MG has been associated with diabetes and its complications. We have identified a rare flavone, fisetin, which increases the level and activity of glyoxalase 1, the enzyme required for the removal of MG, as well as the synthesis of its essential co-factor, glutathione. It is shown that fisetin reduces two major complications of diabetes in Akita mice, a model of type 1 diabetes. Although fisetin had no effect on the elevation of blood sugar, it reduced kidney hypertrophy and albuminuria and maintained normal levels of locomotion in the open field test. This correlated with a reduction in proteins glycated by MG in the blood, kidney and brain of fisetin-treated animals along with an increase in glyoxalase 1 enzyme activity and an elevation in the expression of the rate-limiting enzyme for the synthesis of glutathione, a co-factor for glyoxalase 1. The expression of the receptor for advanced glycation end products (RAGE, serum amyloid A and serum C-reactive protein, markers of protein oxidation, glycation and inflammation, were also increased in diabetic Akita mice and reduced by fisetin. It is concluded that fisetin lowers the elevation of MG-protein glycation that is associated with diabetes and ameliorates multiple complications of the disease. Therefore, fisetin or a synthetic derivative may have potential therapeutic use for the treatment of diabetic complications.

Fisetin Lowers Methylglyoxal Dependent Protein Glycation and Limits the Complications of Diabetes

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Maher, Pamela; Dargusch, Richard; Ehren, Jennifer L.; Okada, Shinichi; Sharma, Kumar; Schubert, David

2011-01-01

The elevated glycation of macromolecules by the reactive dicarbonyl and α-oxoaldehyde methylglyoxal (MG) has been associated with diabetes and its complications. We have identified a rare flavone, fisetin, which increases the level and activity of glyoxalase 1, the enzyme required for the removal of MG, as well as the synthesis of its essential co-factor, glutathione. It is shown that fisetin reduces two major complications of diabetes in Akita mice, a model of type 1 diabetes. Although fisetin had no effect on the elevation of blood sugar, it reduced kidney hypertrophy and albuminuria and maintained normal levels of locomotion in the open field test. This correlated with a reduction in proteins glycated by MG in the blood, kidney and brain of fisetin-treated animals along with an increase in glyoxalase 1 enzyme activity and an elevation in the expression of the rate-limiting enzyme for the synthesis of glutathione, a co-factor for glyoxalase 1. The expression of the receptor for advanced glycation end products (RAGE), serum amyloid A and serum C-reactive protein, markers of protein oxidation, glycation and inflammation, were also increased in diabetic Akita mice and reduced by fisetin. It is concluded that fisetin lowers the elevation of MG-protein glycation that is associated with diabetes and ameliorates multiple complications of the disease. Therefore, fisetin or a synthetic derivative may have potential therapeutic use for the treatment of diabetic complications. PMID:21738623

Relationship of Soluble RAGE with Insulin Resistance and Beta Cell Function during Development of Type 2 Diabetes Mellitus

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Subrata Kumar Biswas

2015-01-01

Full Text Available This study examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE alter in prediabetes and correlate with insulin resistance (IR and beta cell function in prediabetes and newly diagnosed type 2 diabetes mellitus (T2DM. Subjects without previous history of diabetes were recruited and grouped as control, prediabetes, and newly diagnosed T2DM. The control subjects (n=40 and people with prediabetes (n=52 and diabetes (n=66 were similar in terms of age, sex, BMI, systolic and diastolic BP, and fasting insulin level. HOMA-IR was found significantly higher in people with diabetes than control subjects (p<0.001 and people with prediabetes (p=0.005; and HOMA-%B was found significantly deteriorated in people with diabetes (p<0.001 compared to control subjects and people with prediabetes. However, serum sRAGE levels did not show any significant alteration in people with prediabetes compared to control subjects. Moreover, univariate and multivariate analyses did not identify any significant correlation and statistical association of sRAGE with HOMA-IR and HOMA-%B in people with prediabetes and newly diagnosed T2DM. Our data suggest that serum sRAGE levels do not alter in people with prediabetes compared to control subjects and do not correlate or associate with IR and beta cell function during development of T2DM.

Advanced glycation end-products inhibition improves endothelial dysfunction in rheumatoid arthritis.

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Syngle, Ashit; Vohra, Kanchan; Garg, Nidhi; Kaur, Ladbans; Chand, Prem

2012-02-01

Chronic inflammation in rheumatoid arthritis is associated with vascular endothelial dysfunction. The objective was to study the efficacy and safety of advanced glycation end products (AGEs) inhibitor (benfotiamine 50 mg + pyridoxamine 50 mg + methylcobalamin 500 μg, Vonder(®) (ACME Lifescience, Baddi, Himachal Pradesh, India)) on endothelial function in rheumatoid arthritis (RA). Twenty-four patients with established active RA with high disease activity (Disease Activity Score of 28 joints [DAS28 score] > 5.1) despite treatment with stable doses of conventional disease-modifying antirheumatic drugs were investigated. Inflammatory disease activity (DAS28 and Health Assessment Questionnaire-Disability Index [HAQ-DI] scores, erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), markers of endothelial dysfunction, serum nitrite concentration and endothelium-dependent and -independent vasodilation of the brachial artery were measured before and after 12 weeks therapy with twice a day oral AGEs inhibitor. After treatment, flow-mediated vasodilation improved from 9.64 ± 0.65% to 15.82 ± 1.02% (P < 0.01), whereas there was no significant change in endothelium-independent vasodilation with nitroglycerin and baseline diameter; serum nitrite concentration significantly reduced from 5.6 ± 0.13 to 5.1 ± 0.14 μmol/L (P = 0.004), ESR from 63.00 ± 3.5 to 28.08 ± 1.5 mm in the first h (P < 0.01) and CRP levels from 16.7 ± 4.1 to 10.74 ± 2.9 mg/dL (P < 0.01). DAS28 and HAQ-DI scores were significantly reduced, from 5.9 ± 0.17 to 3.9 ± 0.17 (P < 0.01) and 4.6 ± 0.17 to 1.7 ± 0.22 (P < 0.01), respectively. Advanced glycation end products inhibitor improves endothelial dysfunction and inflammatory disease activity in RA. In RA, endothelial dysfunction is part of the disease process and is mediated by AGEs-induced inflammation. © 2011 The Authors. International Journal of Rheumatic Diseases © 2011 Asia Pacific League of Associations for Rheumatology and

"Uproar, bulk, rage, suffocation, effort unceasing, frenzied and vain": Beckett's Transports of Rage.

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Smith, Russell

2016-06-01

In a 1961 interview, Beckett warded off philosophical interpretations of his work: 'I'm no intellectual. All I am is feeling'. Despite the emotional intensity of Beckett's post-war writing, Beckett criticism has tended to ignore this claim, preferring the kinds of philosophical readings that Beckett here rejects. In particular, Beckett criticism underestimates the element of rage in his work. This paper argues that Beckett's post-war breakthrough is enabled by a radical reconsideration of the nature of feeling and of rage in particular. It involves the rejection of the idea of rage as pathological and the embrace of a positive conception of rage as drive or compulsion, a locus of energy and even pleasure.This paper reads the 'Moran' section of Molloy as a kind of 'rage fable', drawing on the ancient Greek concept of thymos, of anger as a virtue. It draws on Alfred Adler's theory of the 'masculine protest', with which Beckett was familiar from his extensive note-taking on Adler in 1934-5, and Sianne Ngai's discussion of the distinction between irritation and rage. According to this reading, Moran's report charts a narrative of thymotic liberation from the irritations of servitude, prefiguring the Unnamable's abandonment to impersonal affective intensities. It ends by suggesting that the prose of the Trilogy might be better understood, not as a 'syntax of weakness' but as a 'syntax of rage', a stylistic correlative of the imperious drive of thymos. We might then begin to understand the Trilogy as the epic of a heroic, impersonal, implacable and liberated rage.

Evaluation of In Vitro Inhibitory Activity of Rye-Buckwheat Ginger Cakes with Rutin on the Formation of Advanced Glycation End-Products (AGEs

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Przygodzka Małgorzata

2015-09-01

Full Text Available In this study, the relationship between the inhibitory effects of extracts from rye-buckwheat ginger cakes supplemented with low and high rutin dosage baked without or with dough fermentation step on the formation of fluorescent advanced glycation end-products (AGEs, and phenolic compounds, rutin, D-chiro-inositol and antioxidant capacity were addressed. The cakes were based on rye flour substituted by light buckwheat flour or flour from roasted buckwheat groats at 30% level, and were produced with or without dough fermentation step. The inhibitory effect against AGEs formation was studied in bovine serum albumin (BSA-glucose and BSA-methylglyoxal (MGO systems. The antioxidant capacity was measured by 2,2-diphenyl- -1-picrylhydrazyl (DPPH and cyclic voltammetry (CV, rutin and D-chiro-inositol contents by HPLC and total phenolics (TPC by spectrophotometric assays. The study showed the inhibitory effects of extracts from rye-buckwheat ginger cakes supplemented with low and high rutin dosage. The results of the inhibitory activity were highly correlated in two applied model systems. Enrichment of rye-buckwheat ginger cakes with rutin improved their antioxidant properties. The correlation studies showed that the inhibitory effects of rye-buckwheat ginger cakes produced with dough fermentation step and enhanced with rutin against formation of AGEs were highly correlated with TPC, rutin and D-chiro-inositol contents, and antioxidant capacity. Moreover, the effect of rutin enrichment was clearly seen in cakes obtained with dough fermentation step, even the inhibitory activity was slightly lower as compared to the cakes produced without dough fermentation.

Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment.

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Gasparotto, Juciano; Girardi, Carolina S; Somensi, Nauana; Ribeiro, Camila T; Moreira, José C F; Michels, Monique; Sonai, Beatriz; Rocha, Mariane; Steckert, Amanda V; Barichello, Tatiana; Quevedo, João; Dal-Pizzol, Felipe; Gelain, Daniel P

2018-01-05

Patients recovering from sepsis have higher rates of CNS morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases. However, the molecular etiology of these sepsis-induced impairments is unclear. Here, we investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery. Adult Wistar rats underwent cecal ligation and perforation (CLP), and serum and brain (hippocampus and prefrontal cortex) samples were obtained at days 1, 15, and 30 after the CLP. We examined these samples for systemic and brain inflammation; amyloid-β peptide (Aβ) and Ser-202-phosphorylated Tau (p-Tau Ser-202 ) levels; and RAGE, RAGE ligands, and RAGE intracellular signaling. Serum markers associated with the acute proinflammatory phase of sepsis (TNFα, IL-1β, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, N ϵ-[carboxymethyl]lysine, HSP70, and HMGB1). In the brain, levels of RAGE and Toll-like receptor 4, glial fibrillary acidic protein and neuronal nitric-oxide synthase, and Aβ and p-Tau Ser-202 also increased during that time. Of note, intracerebral injection of RAGE antibody into the hippocampus at days 15, 17, and 19 post-CLP reduced Aβ and p-Tau Ser-202 accumulation, Akt/mechanistic target of rapamycin signaling, levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and behavioral deficits associated with cognitive decline. These results indicate that brain RAGE is an essential factor in the pathogenesis of neurological disorders following acute systemic inflammation. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Proteomic characterization of intermediate and advanced glycation end-products in commercial milk samples.

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Renzone, Giovanni; Arena, Simona; Scaloni, Andrea

2015-03-18

The Maillard reaction consists of a number of chemical processes affecting the structure of the proteins present in foods. We previously accomplished the proteomic characterization of the lactosylation targets in commercial milk samples. Although characterizing the early modification derivatives, this analysis did not describe the corresponding advanced glycation end-products (AGEs), which may be formed from the further oxidation of former ones or by reaction of oxidized sugars with proteins, when high temperatures are exploited. To fill this gap, we have used combined proteomic procedures for the systematic characterization of the lactosylated and AGE-containing proteins from the soluble and milk fat globule membrane fraction of various milk products. Besides to confirm all lactulosyl-lysines described previously, 40 novel lactosylation sites were identified. More importantly, 308 additional intermediate and advanced glyco-oxidation derivatives (including cross-linking adducts) were characterized in 31 proteins, providing the widest qualitative inventory of modified species ascertained in commercial milk samples so far. Amadori adducts with glucose/galactose, their dehydration products, carboxymethyllysine and glyoxal-, 3-deoxyglucosone/3-deoxygalactosone- and 3-deoxylactosone-derived dihydroxyimidazolines and/or hemiaminals were the most frequent derivatives observed. Depending on thermal treatment, a variable number of modification sites was identified within each protein; their number increased with harder food processing conditions. Among the modified proteins, species involved in assisting the delivery of nutrients, defense response against pathogens and cellular proliferation/differentiation were highly affected by AGE formation. This may lead to a progressive decrease of the milk nutritional value, as it reduces the protein functional properties, abates the bioavailability of the essential amino acids and eventually affects food digestibility. These aspects

Elevated serum advanced glycation endproducts in obese indicate risk for the metabolic syndrome: a link between healthy and unhealthy obesity?

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Uribarri, Jaime; Cai, Weijing; Woodward, Mark; Tripp, Elizabeth; Goldberg, Laurie; Pyzik, Renata; Yee, Kalle; Tansman, Laurie; Chen, Xue; Mani, Venkatesh; Fayad, Zahi A; Vlassara, Helen

2015-05-01

Although obesity can predispose to the metabolic syndrome (MS), diabetes, and cardiovascular disease, not all obese subjects develop MS, hence the need for new indicators of risk for this syndrome. Advanced glycation end products (AGEs) correlate with factors involved in the MS, including inflammation and insulin resistance (IR). Because AGEs can be derived from food and are modifiable, it is important to determine whether they are a risk factor for MS. The objective of this study was to assess the association of endogenous and exogenous AGEs with MS criteria. The following data were collected in a cross-sectional study of subjects with and without the MS: serum AGEs (sAGEs) and mononuclear cell AGEs, metabolites, pro- and antiinflammatory markers, body fat mass measures, including abdominal magnetic resonance imaging, and caloric and dietary AGE (dAGE) consumption. The study was conducted in the general community. Participants included 130 MS and 139 non-MS subjects of both sexes, older than 50 years. sAGEs ((ϵ)N-carboxymethyllysine, methylglyoxal) were markedly elevated in obese persons with more than one other MS criteria but not in obese without MS criteria. sAGEs directly correlated with markers of IR (HOMA) and inflammation (leptin, TNFα, RAGE) and inversely with innate defenses (SIRT1, AGE receptor 1 [AGER1], glyoxalase-I, adiponectin). sAGEs correlated with dAGEs but not with calories, nutrient consumption, or fat mass measures. Consumption of dAGE, but not of calories, was markedly higher in MS than in non-MS. High sAGEs, a modifiable risk factor for IR, may indicate risk for the MS, type 2 diabetes, and cardiovascular disease. High dietary AGE consumption and serum AGE levels may link healthy obesity to at-risk obesity.

Histone Deacetylase Inhibition Restores Retinal Pigment Epithelium Function in Hyperglycemia.

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Danielle Desjardins

Full Text Available In diabetic individuals, macular edema is a major cause of vision loss. This condition is refractory to insulin therapy and has been attributed to metabolic memory. The retinal pigment epithelium (RPE is central to maintaining fluid balance in the retina, and this function is compromised by the activation of advanced glycation end-product receptors (RAGE. Here we provide evidence that acute administration of the RAGE agonist, glycated-albumin (gAlb or vascular endothelial growth factor (VEGF, increased histone deacetylase (HDAC activity in RPE cells. The administration of the class I/II HDAC inhibitor, trichostatin-A (TSA, suppressed gAlb-induced reductions in RPE transepithelial resistance (in vitro and fluid transport (in vivo. Systemic TSA also restored normal RPE fluid transport in rats with subchronic hyperglycemia. Both gAlb and VEGF increased HDAC activity and reduced acetyl-α-tubulin levels. Tubastatin-A, a relatively specific antagonist of HDAC6, inhibited gAlb-induced changes in RPE cell resistance. These data are consistent with the idea that RPE dysfunction following exposure to gAlb, VEGF, or hyperglycemia is associated with increased HDAC6 activity and decreased acetyl-α-tubulin. Therefore, we propose inhibiting HDAC6 in the RPE as a potential therapy for preserving normal fluid homeostasis in the hyperglycemic retina.

Pharmacologic Approaches Against Advanced Glycation End Products (AGEs) in Diabetic Cardiovascular Disease.

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Nenna, Antonio; Nappi, Francesco; Avtaar Singh, Sanjeet Singh; Sutherland, Fraser W; Di Domenico, Fabio; Chello, Massimo; Spadaccio, Cristiano

2015-05-01

Advanced Glycation End-Products (AGEs) are signaling proteins associated to several vascular and neurological complications in diabetic and non-diabetic patients. AGEs proved to be a marker of negative outcome in both diabetes management and surgical procedures in these patients. The reported role of AGEs prompted the development of pharmacological inhibitors of their effects, giving rise to a number of both preclinical and clinical studies. Clinical trials with anti-AGEs drugs have been gradually developed and this review aimed to summarize most relevant reports. Evidence acquisition process was performed using PubMed and ClinicalTrials.gov with manually checked articles. Pharmacological approaches in humans include aminoguanidine, pyridoxamine, benfotiamine, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statin, ALT-711 (alagebrium) and thiazolidinediones. The most recent promising anti-AGEs agents are statins, alagebrium and thiazolidinediones. The role of AGEs in disease and new compounds interfering with their effects are currently under investigation in preclinical settings and these newer anti-AGEs drugs would undergo clinical evaluation in the next years. Compounds with anti-AGEs activity but still not available for clinical scenarios are ALT-946, OPB-9195, tenilsetam, LR-90, TM2002, sRAGE and PEDF. Despite most studies confirm the efficacy of these pharmacological approaches, other reports produced conflicting evidences; in almost any case, these drugs were well tolerated. At present, AGEs measurement has still not taken a precise role in clinical practice, but its relevance as a marker of disease has been widely shown; therefore, it is important for clinicians to understand the value of new cardiovascular risk factors. Findings from the current and future clinical trials may help in determining the role of AGEs and the benefits of anti-AGEs treatment in cardiovascular disease.

HMGB1/RAGE Signaling and Pro-Inflammatory Cytokine Responses in Non-HIV Adults with Active Pulmonary Tuberculosis.

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Grace Lui

Full Text Available We aimed to study the pathogenic roles of High-Mobility Group Box 1 (HMGB1 / Receptor-for-Advanced-Glycation-End-products (RAGE signaling and pro-inflammatory cytokines in patients with active pulmonary tuberculosis (PTB.A prospective study was conducted among non-HIV adults newly-diagnosed with active PTB at two acute-care hospitals (n = 80; age-and-sex matched asymptomatic individuals (tested for latent TB were used for comparison (n = 45. Plasma concentrations of 8 cytokines/chemokines, HMGB1, soluble-RAGE, and transmembrane-RAGE expressed on monocytes/dendritic cells, were measured. Gene expression (mRNA of HMGB1, RAGE, and inflammasome-NALP3 was quantified. Patients' PBMCs were stimulated with recombinant-HMGB1 and MTB-antigen (lipoarabinomannan for cytokine induction ex vivo.In active PTB, plasma IL-8/CXCL8 [median(IQR, 6.0(3.6-15.1 vs 3.6(3.6-3.6 pg/ml, P<0.001] and IL-6 were elevated, which significantly correlated with mycobacterial load, extent of lung consolidation (rs +0.509, P<0.001, severity-score (rs +0.317, P = 0.004, and fever and hospitalization durations (rs +0.407, P<0.001. IL-18 and sTNFR1 also increased. Plasma IL-8/CXCL8 (adjusted OR 1.12, 95%CI 1.02-1.23 per unit increase, P = 0.021 and HMGB1 (adjusted OR 1.42 per unit increase, 95%CI 1.08-1.87, P = 0.012 concentrations were independent predictors for respiratory failure, as well as for ICU admission/death. Gene expression of HMGB1, RAGE, and inflammasome-NALP3 were upregulated (1.2-2.8 fold. Transmembrane-RAGE was increased, whereas the decoy soluble-RAGE was significantly depleted. RAGE and HMGB1 gene expressions positively correlated with cytokine levels (IL-8/CXCL8, IL-6, sTNFR1 and clinico-/radiographical severity (e.g. extent of consolidation rs +0.240, P = 0.034. Ex vivo, recombinant-HMGB1 potentiated cytokine release (e.g. TNF-α when combined with lipoarabinomannan.In patients with active PTB, HMGB1/RAGE signaling and pro-inflammatory cytokines may play important

Effects of monascin on anti-inflammation mediated by Nrf2 activation in advanced glycation end product-treated THP-1 monocytes and methylglyoxal-treated wistar rats.

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Lee, Bao-Hong; Hsu, Wei-Hsuan; Huang, Tao; Chang, Yu-Ying; Hsu, Ya-Wen; Pan, Tzu-Ming

2013-02-13

Hyperglycemia is associated with advanced glycation end products (AGEs). This study was designed to evaluate the inhibitory effects of monascin on receptor for advanced glycation end product (RAGE) signal and THP-1 monocyte inflammation after treatment with S100b, a specific ligand of RAGE. Monascin inhibited cytokine production by S100b-treated THP-1 monocytes via up-regulation of nuclear factor-erythroid 2-related factor-2 (Nrf2) and alleviated p47phox translocation to the membrane. Methylglyoxal (MG, 600 mg/kg bw) was used to induce diabetes in Wistar rats. Inhibitions of RAGE and p47phox by monascin were confirmed by peripheral blood mononuclear cells (PBMCs) of MG-induced rats. Silymarin (SM) was used as a positive control group. It was found that monascin promoted heme oxygenase-1 (HO-1) expression mediated by Nrf2. Suppressions of AGEs, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-β) in serum of MG-induced rats were attenuated in the monascin administration group treated with retinoic acid (RA). RA treatment resulted in Nrf2 inactivation by increasing RA receptor-α (RARα) activity, suggesting that RA acts as an inhibitor of Nrf2. The results showed that monascin exerted anti-inflammatory and antioxidative effects mediated by Nrf2 to prevent the development of diseases such as type 2 diabetes caused by inflammation.

Cloning and characterization of the canine receptor for advanced glycation end products.

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Murua Escobar, Hugo; Soller, Jan T; Sterenczak, Katharina A; Sperveslage, Jan D; Schlueter, Claudia; Burchardt, Birgit; Eberle, Nina; Fork, Melanie; Nimzyk, Rolf; Winkler, Susanne; Nolte, Ingo; Bullerdiek, Jörn

2006-03-15

Metastasis is one of the major problems when dealing with malignant neoplasias. Accordingly, the finding of molecular targets, which can be addressed to reduce tumour metastasising, will have significant impact on the development of new therapeutic approaches. Recently, the receptor for advanced glycation end products (RAGE)-high mobility group B1 (HMGB1) protein complex has been shown to have significant influence on invasiveness, growth and motility of tumour cells, which are essential characteristics required for metastatic behaviour. A set of in vitro and in vivo approaches showed that blocking of this complex resulted in drastic suppression of tumour cell growth. Due to the similarities of human and canine cancer the dog has joined the common rodent animal model for therapeutic and preclinical studies. However, complete characterisation of the protein complex is a precondition to a therapeutic approach based on the blocking of the RAGE-HMGB1 complex to spontaneously occurring tumours in dogs. We recently characterised the canine HMGB1 gene and protein completely. Here we present the complete characterisation of the canine RAGE gene including its 1384 bp mRNA, the 1215 bp protein coding sequence, the 2835 bp genomic structure, chromosomal localisation, gene expression pattern, and its 404 amino acid protein. Furthermore we compared the CDS of six different canine breeds and screened them for single nucleotide polymorphisms.

Characterizing harmful advanced glycation end-products (AGEs) and ribosylated aggregates of yellow mustard seed phytocystatin: Effects of different monosaccharides

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Ahmed, Azaj; Shamsi, Anas; Bano, Bilqees

2017-01-01

Advanced glycation end products (AGEs) are at the core of variety of diseases ranging from diabetes to renal failure and hence gaining wide consideration. This study was aimed at characterizing the AGEs of phytocystatin isolated from mustard seeds (YMP) when incubated with different monosaccharides (glucose, ribose and mannose) using fluorescence, ultraviolet, circular dichroism (CD) spectroscopy and microscopy. Ribose was found to be the most potent glycating agent as evident by AGEs specific fluorescence and absorbance. YMP exists as a molten globule like structure on day 24 as depicted by high ANS fluorescence and altered intrinsic fluorescence. Glycated YMP as AGEs and ribose induced aggregates were observed at day 28 and 32 respectively. In our study we have also examined the anti-aggregative potential of polyphenol, resveratrol. Our results suggested the anti-aggregative behavior of resveratrol as it prevented the in vitro aggregation of YMP, although further studies are required to decode the mechanism by which resveratrol prevents the aggregation.

Efficacy and tolerability of advanced glycation end-products inhibitor in osteoarthritis: a randomized, double-blind, placebo-controlled study.

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Garg, Shabnam; Syngle, Ashit; Vohra, Kanchan

2013-08-01

Advanced glycation end-products (AGEs) play an important role in pathogenesis of osteoarthritis (OA). The objective of this study was to evaluate the efficacy and tolerability of AGEs inhibitor (benfotiamine [50 mg]+pyridoxamine [50 mg]+methylcobalamin [500 µg]; Vonder [Cosme Farma Laboratories Limited, Goa, India]) in OA patients. A 24-week, double-blind, randomized placebo-controlled study in primary OA patients (n=30 [F/M=26/4; mean age, 57.26±2.16 y]) meeting the classification criteria of American College of Rheumatology, was conducted. Inflammatory disease activity scores on the Western Ontario and McMaster University (WOMAC) Osteoarthritis Index, Lequesne Index, and Pain scores were analyzed. Biomarkers: serum nitrite, AGEs, thiobarbituric acid reactive substances, C-reactive protein, erythrocyte sedimentation rate, were also measured. Time taken to walk 20 m was also recorded. Patients were randomized to either AGEs inhibitor or placebo tablets as thrice-daily regimen. At 24 weeks, net decrease in pain score, -6.64±2.71 versus -8.20±1.28, P=0.003; total WOMAC score, -5.88±0.84 versus -8.26±1.24, P=0.013; Lequesne Index score, -0.60±0.06 versus -0.84±0.09, P=0.05; time taken for 20-m walk test, -5.0±1.39 versus -5.0±0.92 s, P=1.00, were observed in the placebo versus drug group, respectively. Net change in serum nitrite, -0.15±0.01 versus -0.79±0.12 µmol/L, P<0.001; AGEs, -0.12±0.02 versus -0.99±0.09, arbitrary florescence units, P=0.001; thiobarbituric acid reactive substances, -0.69±0.12 versus -1.80±0.12 nmol/L, P<0.01; C-reactive protein, -0.12±0.35 versus -2.45±0.60 mg/L, P<0.01, were observed in the placebo versus drug group, respectively. This study shows the efficacy of an AGE inhibitor on decreasing pain and inflammation, and increasing daily activity and mobility in OA patients.

The in vitro effects of advanced glycation end products on basophil functions.

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Han, Kaiyu; Suzukawa, Maho; Yamaguchi, Masao; Sugimoto, Naoya; Nakase, Yuko; Toda, Takako; Nagase, Hiroyuki; Ohta, Ken

2011-01-01

Basophils are thought to play pivotal roles in the pathogenesis of allergic reactions, but their roles in inflammation associated with systemic abnormalities such as metabolic disorders remain largely unknown. Advanced glycation end products (AGEs) are potentially important substances produced in high-glucose disease conditions. In this in vitro study, we investigated whether the biological functions of human basophils can be influenced by AGEs. We analyzed the effects of AGEs on various functions and markers of human basophils, including CD11b expression, apoptosis, degranulation, and cytokine production. Flow cytometric analysis indicated that the level of the receptor for AGEs (RAGE) on the surface of freshly isolated basophils was very low but was clearly upregulated by IL-3. Apoptosis of basophils was induced by high concentrations of glycated albumin. Although glycated albumin failed to affect the level of surface CD11b expression or to trigger degranulation or production of IL-4 and IL-13 in basophils, it dose-dependently induced IL-6 and IL-8 secretion. AGEs seem to act on human basophils; they suppress the cells' longevity but elicit secretion of inflammatory cytokines. Through these biological changes, basophils might play some roles in inflammatory conditions associated with metabolic disorders presenting elevated levels of AGEs. Copyright © 2011 S. Karger AG, Basel.

Why Do Only Some Women Develop Post Menopausal Osteoporosis

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2016-03-01

ovariectomy, estrogen loss, advanced glycation endproducts, receptor for advanced glycation endproducts, bone remodeling, bone mineral density, high...endproducts, bone remodeling, bone mineral density, high fructose diet...cardiac blood sample X Euthanasia 1 ml cardiac blood sample Euthanasia 1 ml cardiac blood sample X Table 1. Animal study plan . Blood was

Oxidative Stress and Adipocyte Biology: Focus on the Role of AGEs

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Florence Boyer

2015-01-01

Full Text Available Diabetes is a major health problem that is usually associated with obesity, together with hyperglycemia and increased advanced glycation endproducts (AGEs formation. Elevated AGEs elicit severe downstream consequences via their binding to receptors of AGEs (RAGE. This includes oxidative stress and oxidative modifications of biological compounds together with heightened inflammation. For example, albumin (major circulating protein undergoes increased glycoxidation with diabetes and may represent an important biomarker for monitoring diabetic pathophysiology. Despite the central role of adipose tissue in many physiologic/pathologic processes, recognition of the effects of greater AGEs formation in this tissue is quite recent within the obesity/diabetes context. This review provides a brief background of AGEs formation and adipose tissue biology and thereafter discusses the impact of AGEs-adipocyte interactions in pathology progression. Novel data are included showing how AGEs (especially glycated albumin may be involved in hyperglycemia-induced oxidative damage in adipocytes and its potential links to diabetes progression.

A multicenter matched case-control analysis on seven polymorphisms from HMGB1 and RAGE genes in predicting hepatocellular carcinoma risk.

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Wang, Dan; Qi, Xiaoying; Liu, Fang; Yang, Chuanhua; Jiang, Wenguo; Wei, Xiaodan; Li, Xuri; Mi, Jia; Tian, Geng

2017-07-25

Based on 540 hepatocellular carcinoma patients and 540 age- and gender-matched controls, we tested the hypothesis that high mobility group protein box1 (HMGB1) and the receptor for advanced glycation end products (RAGE) genes are two potential candidate susceptibility genes for hepatocellular carcinoma in a multicenter hospital-based case-control analysis. The genotypes of seven widely-studied polymorphisms were determined, and their distributions respected the Hardy-Weinberg equilibrium. The mutant alleles of two polymorphisms, rs1045411 in HMGB1 gene and rs2070600 in RAGE gene, had significantly higher frequencies in patients than in controls (P hepatocellular carcinoma significantly, particularly for rs2070600 under the additive (odds ratio [OR] = 1.77; 95% confidence interval [CI]: 1.34-2.32; P hepatocellular carcinoma compared with the commonest C-C-T haplotype after adjustment. In RAGE gene, the T-T-A-G (rs1800625-rs1800624-rs2070600-rs184003) (adjusted OR; 95% CI; P: 1.75; 1.02-3.03; 0.045) and T-T-A-T (adjusted OR; 95% CI; P: 1.95; 1.01-3.76; 0.048) haplotypes were associated with a marginally increased risk of hepatocellular carcinoma compared with the commonest T-T-G-G haplotype. In summary, we identified two risk-associated polymorphisms (rs1045411 and rs2070600), and more importantly a joint impact of seven polymorphisms from the HMGB1/RAGE axis in susceptibility to hepatocellular carcinoma.

Assessment of the concentrations of various advanced glycation end-products in beverages and foods that are commonly consumed in Japan.

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Masayoshi Takeuchi

Full Text Available Dietary consumption has recently been identified as a major environmental source of pro-inflammatory advanced glycation end-products (AGEs in humans. It is disputed whether dietary AGEs represent a risk to human health. Nε-(carboxymethyllysine (CML, a representative AGE compound found in food, has been suggested to make a significant contribution to circulating CML levels. However, recent studies have found that the dietary intake of AGEs is not associated with plasma CML concentrations. We have shown that the serum levels of glyceraldehyde-derived AGEs (Glycer-AGEs, but not hemoglobin A1c, glucose-derived AGEs (Glu-AGEs, or CML, could be used as biomarkers for predicting the progression of atherosclerosis and future cardiovascular events. We also detected the production/accumulation of Glycer-AGEs in normal rats administered Glu-AGE-rich beverages. Therefore, we assessed the concentrations of various AGEs in a total of 1,650 beverages and foods that are commonly consumed in Japan. The concentrations of four kinds of AGEs (Glu-AGEs, fructose-derived AGEs (Fru-AGEs, CML, and Glycer-AGEs were measured with competitive enzyme-linked immunosorbent assays involving immunoaffinity-purified specific antibodies. The results of the latter assays indicated that Glu-AGEs and Fru-AGEs (especially Glu-AGEs, but not CML or Glycer-AGEs, are present at appreciable levels in beverages and foods that are commonly consumed by Japanese. Glu-AGEs, Fru-AGEs, CML, and Glycer-AGEs exhibited concentrations of ≥85%, 2-12%, <3%, and trace amounts in the examined beverages and ≥82%, 5-15%, <3%, and trace amounts in the tested foods, respectively. The results of the present study indicate that some lactic acid bacteria beverages, carbonated drinks, sugar-sweetened fruit drinks, sports drinks, mixed fruit juices, confectionery (snacks, dried fruits, cakes, cereals, and prepared foods contain markedly higher Glu-AGE levels than other classes of beverages and foods. We

Effects of insulin combined with idebenone on blood-brain barrier permeability in diabetic rats.

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Sun, Yan-Na; Liu, Li-Bo; Xue, Yi-Xue; Wang, Ping

2015-04-01

This study investigates the effect of insulin combined with idebenone on blood-brain barrier (BBB) permeability in experimental streptozotocin-induced diabetic rats as well as the underlying mechanisms. With a diabetic rat model, we show that insulin and idebenone normalize body weight and water intake and restore BBB permeability and that their combination displays a synergistic effect. The results from transmission electron microscopy show that the combination of insulin and idebenone significantly closed the tight junction (TJ) in diabetic rats. The results from Western blotting in diabetic rats show that the upregulation of TJ-associated proteins occludin, and zonula occludens (ZO)-1 caused by the combination of insulin and idebenone is more remarkable than that with either agent alone. In addition, the activations of reactive oxygen species (ROS) and advanced glycation end products (AGEs) and the expression levels of receptors for advanced glycation end-products (RAGE) and nuclear factor-κB (NF-κB) were significantly decreased after treatment with insulin and idebenone in diabetic rats. These results suggest that the combination of insulin and idebenone could decrease the BBB permeability in diabetic rats by upregulating the expression of occludin, claudin-5, and ZO-1 and that the ROS/AGE/RAGE/NF-κB signal pathway might be involved in the process. © 2014 Wiley Periodicals, Inc.

Curcumin and Boswellia serrata Modulate the Glyco-Oxidative Status and Lipo-Oxidation in Master Athletes

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Nino Cristiano Chilelli

2016-11-01

Full Text Available Background: Chronic intensive exercise is associated with a greater induction of oxidative stress and with an excess of endogenous advanced glycation end-products (AGEs. Curcumin can reduce the accumulation of AGEs in vitro and in animal models. We examined whether supplementation with curcumin and Boswellia serrata (BSE gum resin for 3 months could affect plasma levels of markers of oxidative stress, inflammation, and glycation in healthy master cyclists. Methods. Forty-seven healthy male athletes were randomly assigned to Group 1, consisting of 22 subjects given a Mediterranean diet (MD alone (MD group, and Group 2 consisted of 25 subjects given a MD plus curcumin and BSE (curcumin/BSE group. Interleukin-6 (IL-6, tumor necrosis factor-α (TNFα, high-sensitivity c-reactive protein (hs-CRP, total AGE, soluble receptor for AGE (sRAGE, malondialdehyde (MDA, plasma phospholipid fatty acid (PPFA composition, and non-esterified fatty acids (NEFA were tested at baseline and after 12 weeks. Results: sRAGE, NEFA, and MDA decreased significantly in both groups, while only the curcumin/BSE group showed a significant decline in total AGE. Only the changes in total AGE and MDA differed significantly between the curcumin/BSE and MD groups. Conclusions. Our data suggest a positive effect of supplementation with curcumin and BSE on glycoxidation and lipid peroxidation in chronically exercising master athletes.

Inhibition of Advanced Glycation End-Product Formation by Origanum majorana L. In Vitro and in Streptozotocin-Induced Diabetic Rats

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Rosa Martha Perez Gutierrez

2012-01-01

Full Text Available The development of AGE inhibitors is considered to have therapeutic potential in patients with diabetes diseases. The aim of the present study was investigate the effect of methanolic extract of the leaves of Origanum majorana (OM used as spice in many countries on AGEs formation. In vitro studies indicated a significant inhibitory effects on the formation of AGEs. Their antiglycation activities were not only brought about by their antioxidant activities but also related to their trapping abilities of reactive carbonyl species such as methylglyoxal, an intermediate reactive carbonyl of AGE formation. The results demonstrate that OM have significant effects on in vitro AGE formation, and the glycation inhibitory activity was more effectively than those obtained using as standard antiglycation agent aminoguanidine. OM is a potent agent for protecting LDL against oxidation and glycation. Treatment of streptozotocin-diabetic mice with OM and glibenclamide for 28 days had beneficial effects on renal metabolic abnormalities including glucose level and AGEs formation. Diabetic mice showed increase in tail tendon collagen, glycated collagen linked fluorescence and reduction in pepsin digestion. Treatment with OM improved these parameters when compared to diabetic control and glibenclamide.

Pomegranate (Punicagranatum juice decreases lipid peroxidation, but has no effect on plasma advanced glycated end-products in adults with type 2 diabetes: a randomized double-blind clinical trial

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Golbon Sohrab

2015-09-01

Full Text Available Introduction: Diabetes mellitus characterized by hyperglycemia could increase oxidative stress and formation of advanced glycated end-products (AGEs, which contribute to diabetic complications. The purpose of this study was to assess the effect of pomegranate juice (PJ containing natural antioxidant on lipid peroxidation and plasma AGEs in patients with type 2 diabetes (T2D. Materials and methods: In a randomized, double-blind, placebo-controlled trial, 44 patients (age range 56±6.8 years, T2D were randomly assigned to one of two groups: group A (PJ, n=22 and group B (Placebo, n=22. At the baseline and the end of 12-week intervention, biochemical markers including fasting plasma glucose, insulin, oxidative stress, and AGE markers including carboxy methyl lysine (CML and pentosidine were assayed. Results: At baseline, there were no significant differences in plasma total antioxidant capacity (TAC levels between the two groups, but malondialdehyde (MDA decreased levels were significantly different (P<0.001. After 12 weeks of intervention, TAC increased (P<0.05 and MDA decreased (P<0.01 in the PJ group when compared with the placebo group. However, no significant differences were observed in plasma concentration of CML and pentosidine between the two groups. Conclusions: The study showed that PJ decreases lipid peroxidation. Therefore, PJ consumption may delay onset of T2D complications related to oxidative stress.

Receptor for advanced glycation end products involved in lung ischemia reperfusion injury in cardiopulmonary bypass attenuated by controlled oxygen reperfusion in a canine model.

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Rong, Jian; Ye, Sheng; Liang, Meng-ya; Chen, Guang-xian; Liu, Hai; Zhang, Jin-Xin; Wu, Zhong-kai

2013-01-01

Controlled oxygen reperfusion could protect the lung against ischemia-reperfusion injury in cardiopulmonary bypass (CPB) by downregulating high mobility group box 1 (HMGB1), a high affinity receptor of HMGB1. This study investigated the effect of controlled oxygen reperfusion on receptor for advanced glycation end products (RAGE) expression and its downstream effects on lung ischemia-reperfusion injury. Fourteen canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest followed by 90 minutes of reperfusion. Animals were randomized to receive 80% FiO2 during the entire procedure (control group) or to a test group receiving a controlled oxygen reperfusion protocol. Pathologic changes in lung tissues, RAGE expression, serum interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated. The lung pathologic scores after 25 and 90 minutes of reperfusion were significantly lower in the test group compared with the control group (p RAGE expression, TNF-α, and IL-6 were downregulated by controlled oxygen treatment (p RAGE might be involved in the lung ischemia-reperfusion injury in canine model of CPB, which was downregulated by controlled oxygen reperfusion.

Advanced glycation end products delay corneal epithelial wound healing through reactive oxygen species generation.

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Shi, Long; Chen, Hongmei; Yu, Xiaoming; Wu, Xinyi

2013-11-01

Delayed healing of corneal epithelial wounds is a serious complication in diabetes. Advanced glycation end products (AGEs) are intimately associated with the diabetic complications and are deleterious to the wound healing process. However, the effect of AGEs on corneal epithelial wound healing has not yet been evaluated. In the present study, we investigated the effect of AGE-modified bovine serum albumin (BSA) on corneal epithelial wound healing and its underlying mechanisms. Our data showed that AGE-BSA significantly increased the generation of intracellular ROS in telomerase-immortalized human corneal epithelial cells. However, the generation of intracellular ROS was completely inhibited by antioxidant N-acetylcysteine (NAC), anti-receptor of AGEs (RAGE) antibodies, or the inhibitor of NADPH oxidase. Moreover, AGE-BSA increased NADPH oxidase activity and protein expression of NADPH oxidase subunits, p22phox and Nox4, but anti-RAGE antibodies eliminated these effects. Furthermore, prevention of intracellular ROS generation using NAC or anti-RAGE antibodies rescued AGE-BSA-delayed epithelial wound healing in porcine corneal organ culture. In conclusion, our results demonstrated that AGE-BSA impaired corneal epithelial wound healing ex vivo. AGE-BSA increased intracellular ROS generation through NADPH oxidase activation, which accounted for the delayed corneal epithelial wound healing. These results may provide better insights for understanding the mechanism of delayed healing of corneal epithelial wounds in diabetes.

Concentration of Endogenous Secretory Receptor for Advanced Glycation End Products and Matrix Gla Protein in Controlled and Uncontrolled Type 2 Diabetes Mellitus Patients

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Dwi Yuniati Daulay

2013-04-01

Full Text Available BACKGROUND: Advanced glycation end products (AGE and their receptor (RAGE system play an important role in the development of diabetic vascular complications. Recently, an endogenous secretory RAGE (esRAGE has been identified as a novel splice variant, which lacks the transmembrane domain and is secreted in human sera. Interestingly, it was reported that esRAGE binds AGE ligands and neutralizes AGE actions. Many studies have reported that diabetes mellitus correlates with vascular calcification event and increases progressively in uncontrolled diabetes. Matrix Gla Protein (MGP is known to act as an inhibitor in vascular calcification. The aim of this study was to observe progress of vascular calcification in uncontrolled diabetes patient by biochemical markers MGP as inhibitor in vascular calcification, via mechanism of AGEs. METHODS: This study was an observational study with cross sectional design on adult type 2 diabetic male patients who were defined by the 2011 Indonesian diabetes mellitus consensus criteria. RESULTS: The results of this study showed that there was a positive significant correlation between esRAGE and HbA1C (r=0.651, p=0.009, and negative correlation between MGP and HbA1C (r=-0.465, p=0.081 in controlled diabetes group. In uncontrolled diabetes group there was a positive significant correlation between MGP and HbA1C (r=0.350, p=0.023, despite the fact esRAGE showed no significant correlation with HbA1C. There was no significant difference in level of esRAGE and MGP in controlled and uncontrolled diabetes group, but MGP showed lower level in uncontrolled diabetes group, contrary to esRAGE that had higher concentration. CONCLUSIONS: In diabetes condition, complications of vascular calcification are caused by the mechanism of increased AGE formation represented by esRAGE. In diabetes control it is very important to keep the blood vessels from complications caused by vascular calcification. KEYWORDS: type 2 diabetes mellitus

Women's experience of rage: a critical feminist analysis.

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Flemke, Kimberly; Allen, Katherine R

2008-01-01

We conducted in-depth interviews with 37 incarcerated women on their experience of rage towards their intimate partner. Participants used specific criteria to distinguish their experience of rage from anger. Rage is described as an overwhelming experience with particular physiological and cognitive changes that takes control of a woman's emotions and actions. In contrast, anger is described as a controllable emotion with a specific termination point. Motivations for acting violently in rage with an intimate partner are described and discussed. Findings suggest a primary trigger for experiencing rage is feeling threatened and feeling emotionally overwhelmed.

Lower concentrations of receptor for advanced glycation end products and epiregulin in amniotic fluid correlate to chemically induced cleft palate in mice.

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Wang, Xinhuan; Zhu, Jingjing; Fang, Yanjun; Bian, Zhuan; Meng, Liuyan

2017-04-01

This study investigated the correlation between differentially expressed proteins in amniotic fluid (AF) and cleft palate induced by all-trans retinoic acid (atRA), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Seven proteins were differentially expressed at embryonic day (E) 16.5 in atRA and control groups as revealed by label-based mouse antibody array. Enzyme-linked immunosorbent assay was further used to detect the expression levels of these proteins in AF from E13.5 to E16.5 in atRA, TCDD, and control groups. The cleft palate groups showed lower concentrations of receptor for advanced glycation end products (RAGE) and epiregulin at E16.5. RAGE immunostaining obviously decreased in palatal tissue sections obtained from E14.5 to E16.5 in the cleft palate groups as revealed by immunohistochemistry. These findings indicate that reduced levels of RAGE and epiregulin in AF are correlated to chemically induced cleft palate in mice. Copyright © 2017 Elsevier B.V. All rights reserved.

Clinical significance of AGE-RAGE axis in colorectal cancer: associations with glyoxalase-I, adiponectin receptor expression and prognosis

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Sakellariou, Stratigoula; Fragkou, Paraskevi; Levidou, Georgia; Gargalionis, Antonios N.; Piperi, Christina; Dalagiorgou, Georgia; Adamopoulos, Christos; Saetta, Angelica; Agrogiannis, George; Theohari, Irini; Sougioultzis, Stavros; Tsioli, Panagiota; Karavokyros, Ioannis; Tsavaris, Nikolaos; Kostakis, Ioannis D.; Zizi-Serbetzoglou, Adamantia; Vandoros, Gerasimos P.; Patsouris, Efstratios; Korkolopoulou, Penelope

2016-01-01

Advanced glycation end products (AGEs) and their receptor RAGE emerge as important pathogenic contributors in colorectal carcinogenesis. However, their relationship to the detoxification enzyme Glyoxalase (GLO)-I and Adiponectin receptors (AdipoR1, AdipoR2) in colorectal carcinoma (CRC) is currently understudied. In the present study, we investigated the expression levels of the above molecules in CRC compared to adjacent non-tumoral tissue and their potential correlation with clinicopathological characteristics and patients’ survival. We analyzed the immunohistochemical expression of AGE, RAGE, GLO-1, AdipoR1 and AdipoR2 in 133 primary CRC cases, focusing on GLO-I. The tumour MSI status was further assessed in mucinous carcinomas. Western immunoblotting was employed for validation of immunohistochemical data in normal and tumoral tissues as well in three CRC cell lines. An independent set of 55 patients was also used to validate the results of univariate survival analysis regarding GLO-I. CRC tissue showed higher intensity of both AGE and RAGE expression compared with normal colonic mucosa which was negative for GLO-I in most cases (78 %). Western immunoblotting confirmed AGE, RAGE and GLO-I overexpression in tumoral tissue. GLO-I expression was directly related to RAGE and inversely related to AGE immunolabeling. There was a trend towards higher expression of all markers (except for RAGE) in the subgroup of mucinous carcinomas which, although of borderline significance, seemed to be more prominent for AdipoR1 and AGE. Additionally, AGE, AdipoR1 and Adipo R2 expression was related to tumor grade, whereas GLO-1 and AdipoR1 to T-category. In survival analysis, AdipoR2 and GLO-I overexpression predicted shortened survival in the entire cohort and in early stage cases, an effect which for GLO-I was reproduced in the validation cohort. Moreover, GLO-I emerged as an independent prognosticator of adverse significance in the patients’ cohort. We herein provide novel

The proinflammatory RAGE/NF-κB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia.

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Angelo, Maria Florencia; Aguirre, Alejandra; Avilés Reyes, Rolando X; Villarreal, Alejandro; Lukin, Jerónimo; Melendez, Matías; Vanasco, Virginia; Barker, Phil; Alvarez, Silvia; Epstein, Alberto; Jerusalinsky, Diana; Ramos, Alberto Javier

2014-01-01

Sleep apnea (SA) causes long-lasting changes in neuronal circuitry, which persist even in patients successfully treated for the acute effects of the disease. Evidence obtained from the intermittent hypoxia (IH) experimental model of SA has shown neuronal death, impairment in learning and memory and reactive gliosis that may account for cognitive and structural alterations observed in human patients. However, little is known about the mechanism controlling these deleterious effects that may be useful as therapeutic targets in SA. The Receptor for Advanced Glycation End products (RAGE) and its downstream effector Nuclear Factor Kappa B (NF-κB) have been related to neuronal death and astroglial conversion to the pro-inflammatory neurodegenerative phenotype. RAGE expression and its ligand S100B were shown to be increased in experimental models of SA. We here used dissociated mixed hippocampal cell cultures and male Wistar rats exposed to IH cycles and observed that NF-κB is activated in glial cells and neurons after IH. To disclose the relative contribution of the S100B/RAGE/NF-κB pathway to neuronal damage and reactive gliosis after IH we performed sequential loss of function studies using RAGE or S100B neutralizing antibodies, a herpes simplex virus (HSV)-derived amplicon vector that induces the expression of RAGEΔcyto (dominant negative RAGE) and a chemical blocker of NF-κB. Our results show that NF-κB activation peaks 3 days after IH exposure, and that RAGE or NF-κB blockage during this critical period significantly improves neuronal survival and reduces reactive gliosis. Both in vitro and in vivo, S100B blockage altered reactive gliosis but did not have significant effects on neuronal survival. We conclude that both RAGE and downstream NF-κB signaling are centrally involved in the neuronal alterations found in SA models, and that blockage of these pathways is a tempting strategy for preventing neuronal degeneration and reactive gliosis in SA.

The proinflammatory RAGE/NF-κB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia.

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Maria Florencia Angelo

Full Text Available Sleep apnea (SA causes long-lasting changes in neuronal circuitry, which persist even in patients successfully treated for the acute effects of the disease. Evidence obtained from the intermittent hypoxia (IH experimental model of SA has shown neuronal death, impairment in learning and memory and reactive gliosis that may account for cognitive and structural alterations observed in human patients. However, little is known about the mechanism controlling these deleterious effects that may be useful as therapeutic targets in SA. The Receptor for Advanced Glycation End products (RAGE and its downstream effector Nuclear Factor Kappa B (NF-κB have been related to neuronal death and astroglial conversion to the pro-inflammatory neurodegenerative phenotype. RAGE expression and its ligand S100B were shown to be increased in experimental models of SA. We here used dissociated mixed hippocampal cell cultures and male Wistar rats exposed to IH cycles and observed that NF-κB is activated in glial cells and neurons after IH. To disclose the relative contribution of the S100B/RAGE/NF-κB pathway to neuronal damage and reactive gliosis after IH we performed sequential loss of function studies using RAGE or S100B neutralizing antibodies, a herpes simplex virus (HSV-derived amplicon vector that induces the expression of RAGEΔcyto (dominant negative RAGE and a chemical blocker of NF-κB. Our results show that NF-κB activation peaks 3 days after IH exposure, and that RAGE or NF-κB blockage during this critical period significantly improves neuronal survival and reduces reactive gliosis. Both in vitro and in vivo, S100B blockage altered reactive gliosis but did not have significant effects on neuronal survival. We conclude that both RAGE and downstream NF-κB signaling are centrally involved in the neuronal alterations found in SA models, and that blockage of these pathways is a tempting strategy for preventing neuronal degeneration and reactive gliosis in SA.

Produtos da glicação avançada dietéticos e as complicações crônicas do diabetes Dietetics advanced glycation end-products and chronic complications of diabetes

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Júnia Helena Porto Barbosa

2009-02-01

a conduta terapêutica, concorrendo para a melhoria da qualidade de vida dos portadores dessa enfermidade.The generation of advanced glycation end products is one of the principal mechanisms that lead to the pathologies associated with diabetes mellitus, which include cardiopathy, retinopathy, neuropathy and nephropathy. The objective of this revision is to analyse the role of the advanced glycation end products present in food as intermediaries of diabetic complications, presenting strategies to reduce their ingestion. For this purpose, research was carried out in databases of publications of the area, for the last 15 years, taking into account revision, experimental and clinical studies. Advanced glycation end products are a heterogenous group of molecules coming from non-enzymatic reactions between amino and carbonyl groups, examples being carboxymethyllisine and pentosidine found in food and in vivo. The advanced glycation end products ingested are absorbed and, along with endogenous advanced glycation end-products, promote the progression of the complications of diabetes. There is a direct correlation between advanced glycation end products consumption and blood concentration. Their restriction in food results in the suppression of serum levels of the markers of vascular disease and the intermediaries of inflammation directly involved in the development of diabetic degenerations. The current dietary orientations are concentrated on the proportion of nutrients and on energetic restriction. The risk of ingestion of advanced glycation end products formed during the processing of food should be taken in consideration. It is simply recommended that in the preparation of food, the use of low temperatures for short periods, in the presence of water, has important effects in the prevention of the complications of diabetes. The study of the mechanisms involved in the generation of advanced glycation end products and the antiglycation properties of compounds presented in

Generation of Soluble Advanced Glycation End Products Receptor (sRAGE)-Binding Ligands during Extensive Heat Treatment of Whey Protein/Lactose Mixtures Is Dependent on Glycation and Aggregation

NARCIS (Netherlands)

Liu, Fahui; Teodorowicz, Gosia; Wichers, Harry J.; Boekel, van Tiny; Hettinga, Kasper A.

2016-01-01

Heating of protein- and sugar-containing materials is considered the primary factor affecting the formation of advanced glycation end products (AGEs). This study aimed to investigate the influence of heating conditions, digestion, and aggregation on the binding capacity of AGEs to the soluble AGE

3-Deoxyglucosone: a potential glycating agent accountable for structural alteration in H3 histone protein through generation of different AGEs.

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Jalaluddin M Ashraf

Full Text Available Advanced glycation end-products (AGEs are heterogeneous group of compounds, known to be implicated in diabetic complications. One of the consequences of the Maillard reaction is attributed to the production of reactive intermediate products such as α-oxoaldehydes. 3-deoxyglucosone (3-DG, an α-oxoaldehyde has been found to be involved in accelerating vascular damage during diabetes. In the present study, calf thymus histone H3 was treated with 3-deoxyglucosone to investigate the generation of AGEs (Nε-carboxymethyllysine, pentosidine, by examining the degree of side chain modifications and formation of different intermediates and employing various physicochemical techniques. The results clearly indicate the formation of AGEs and structural changes upon glycation of H3 by 3-deoxyglucosone, which may hamper the normal functioning of H3 histone, that may compromise the veracity of chromatin structures and function in secondary complications of diabetes.

Three-year follow-up comparing metabolic surgery versus medical weight management in patients with type 2 diabetes and BMI 30-35. The role of sRAGE biomarker as predictor of satisfactory outcomes.

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Horwitz, Daniel; Saunders, John K; Ude-Welcome, Aku; Marie Schmidt, Ann; Dunn, Van; Leon Pachter, H; Parikh, Manish

2016-08-01

Patients with type 2 diabetes (T2D) and body mass index (BMI)<35 may benefit from metabolic surgery. The soluble form of the receptor for advanced glycation end products (sRAGE) may identify patients at greater chance for T2D remission. To study long-term outcomes of patients with T2D and BMI 30-35 treated with metabolic surgery or medical weight management (MWM) and search for predictors of T2D remission. University METHODS: Retrospective review of the original cohort, including patients who crossed over from MWM to surgery. Repeated-measures linear models were used to model weight loss (%WL), change in glycated hemoglobin (HbA1C) and association with baseline sRAGE. Fifty-seven patients with T2D and BMI 30-35 were originally randomly assigned to metabolic surgery versus MWM. Mean BMI and HbA1C was 32.6% and 7.8%, respectively. A total of 30 patients underwent surgery (19 sleeves, 8 bypasses, 3 bands). Three-year follow-up in the surgery group and MWM group was 75% and 86%, respectively. Surgery resulted in higher T2D remission (63% versus 0%; P<.001) and lower HbA1C (6.9% versus 8.4%; P<.001) for up to 3 years. There was no difference in %WL in those with versus those without T2D remission (21.7% versus 20.6%, P = .771), suggesting that additional mechanisms other than %WL play an important role for the studied outcome. Higher baseline sRAGE was associated with greater change in HbA1C and greater %WL after surgery (P< .001). Metabolic surgery was effective in promoting remission of T2D in 63% of patients with BMI 30-35; higher baseline sRAGE predicted T2D remission with surgery. Larger-scale randomly assigned trials are needed in this patient population. Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Incidence, clinical correlates and treatment effect of rage in anxious children.

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Johnco, Carly; Salloum, Alison; De Nadai, Alessandro S; McBride, Nicole; Crawford, Erika A; Lewin, Adam B; Storch, Eric A

2015-09-30

Episodic rage represents an important and underappreciated clinical feature in pediatric anxiety. This study examined the incidence and clinical correlates of rage in children with anxiety disorders. Change in rage during treatment for anxiety was also examined. Participants consisted of 107 children diagnosed with an anxiety disorder and their parents. Participants completed structured clinical interviews and questionnaire measures to assess rage, anxiety, functional impairment, family accommodation and caregiver strain, as well as the quality of the child's relationship with family and peers. Rage was a common feature amongst children with anxiety disorders. Rage was associated with a more severe clinical profile, including increased anxiety severity, functional impairment, family accommodation and caregiver strain, as well as poorer relationships with parents, siblings, extended family and peers. Rage was more common in children with separation anxiety, comorbid anxiety, attention deficit/hyperactivity disorder and behavioral disorders, but not depressive symptoms. Rage predicted higher levels of functional impairment, beyond the effect of anxiety severity. Rage severity reduced over treatment in line with changes in anxiety symptoms. Findings suggest that rage is a marker of greater psychopathology in anxious youth. Standard cognitive behavioral treatment for anxiety appears to reduce rage without adjunctive treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease

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Varun Chandrashekaran

2017-10-01

Full Text Available Recent clinical studies found a strong association of colonic inflammation and Inflammatory bowel disease (IBD-like phenotype with NonAlcoholic Fatty liver Disease (NAFLD yet the mechanisms remain unknown. The present study identifies high mobility group box 1 (HMGB1 as a key mediator of intestinal inflammation in NAFLD and outlines a detailed redox signaling mechanism for such a pathway. NAFLD mice showed liver damage and release of elevated HMGB1 in systemic circulation and increased intestinal tyrosine nitration that was dependent on NADPH oxidase. Intestines from NAFLD mice showed higher Toll like receptor 4 (TLR4 activation and proinflammatory cytokine release, an outcome strongly dependent on the existence of NAFLD pathology and NADPH oxidase. Mechanistically intestinal epithelial cells showed the HMGB1 activation of TLR-4 was both NADPH oxidase and peroxynitrite dependent with the latter being formed by the activation of NADPH oxidase. Proinflammatory cytokine production was significantly blocked by the specific peroxynitrite scavenger phenyl boronic acid (FBA, AKT inhibition and NADPH oxidase inhibitor Apocynin suggesting NADPH oxidase-dependent peroxynitrite is a key mediator in TLR-4 activation and cytokine release via an AKT dependent pathway. Studies to ascertain the mechanism of HMGB1-mediated NADPH oxidase activation showed a distinct role of Receptor for advanced glycation end products (RAGE as the use of inhibitors targeted against RAGE or use of deformed HMGB1 protein prevented NADPH oxidase activation, peroxynitrite formation, TLR4 activation and finally cytokine release. Thus, in conclusion the present study identifies a novel role of HMGB1 mediated inflammatory pathway that is RAGE and redox signaling dependent and helps promote ectopic intestinal inflammation in NAFLD.

Circulating levels and dietary intake of the advanced glycation end-product marker carboxymethyl lysine in chronic kidney disease patients on conservative predialysis therapy: a pilot study.

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Piroddi, Marta; Palazzetti, Ingrid; Quintaliani, Giuseppe; Pilolli, Francesca; Montaldi, Massimiliano; Valentina, Viola; Libetta, Carmelo; Galli, Francesco

2011-07-01

Advanced glycation end-products (AGEs) are proposed to influence inflammatory pathways and cardiovascular risk in chronic kidney disease (CKD). Dietary AGEs are believed to sustain circulating levels and toxicity in this condition. We investigated this aspect in a cross-sectional pilot study measuring levels of the AGE marker carboxymethyl lysine (CML) and fluorescent AGEs in the blood of pre-dialysis patients with CKD and hemodialysis (HD) patients (n = 10 each), and in a group of matched healthy controls (Ctr). Plasma CML was measured by immuno-dot blot and fluorescent AGEs were determined by high-performance liquid chromatography (HPLC) analysis measuring the fluorescence of the cross-link pentosidine. The dietary intake of CML was assessed by dietary recall to trace total AGE intake in patients with CKD and the Ctr group. All the subjects included in the study were assessed for dietary intake while maintaining their usual diet. Main exclusion criteria for patients with CKD and HD were severe protein-caloric malnutrition and inflammation (measured by high sensitivity C-reactive protein and interleukin-6 levels). Plasma CML, as well as free and protein-bound fluorescent AGEs, significantly increased in CKD and even more in HD patients than that of the Ctr group. In patients with CKD, the average dietary intake of CML was less than half than that of the Ctr group (6 vs. 13 MU/day) and the lowered protein intake adopted spontaneously by these patients appear to explain this finding. The results show that the intake of CML does not affect circulating levels of this as well as of other AGEs, in well nourished predialysis CKD patients. Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

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Zhang, L.; Ji, Y.X.; Jiang, W.L.; Lv, C.J. [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai (China)

2015-05-08

Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC{sub 50} of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

International Nuclear Information System (INIS)

Zhang, L.; Ji, Y.X.; Jiang, W.L.; Lv, C.J.

2015-01-01

Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC 50 of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway

Soluble receptor for advanced glycation end products as a potential biomarker to predict weight loss and improvement of insulin sensitivity by a very low calorie diet of obese human subjects.

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Hagen, Imke; Schulte, Dominik M; Müller, Nike; Martinsen, Jessica; Türk, Kathrin; Hedderich, Jürgen; Schreiber, Stefan; Laudes, Matthias

2015-06-01

Obesity is associated with low-grade systemic inflammation which is thought to trigger the development of comorbidities such as type 2 diabetes. The soluble receptor for advanced glycation end products (sRAGE) belongs to the innate immune system and has been linked to obesity, recently. The aim of the present study was to examine whether serum sRAGE concentrations are related to the grade of weight loss and improvement of insulin resistance due to a very low calorie diet (VLCD). 22 severe obese subjects (Median Body Mass Index (BMI): 44.5kg/m(2)) were included in a dietary intervention study of 6month, consisting of a very low calorie formula diet phase (VLCD: 800kcal/d) for 12 weeks and a following 12 week weight maintenance phase. Fasting glucose, fasting insulin, adiponectin, leptin and sRAGE were determined from sera. Insulin sensitivity was estimated by Homeostasis Model Assessment (HOMA) index and leptin-to-adiponectin-ratio (LAR). Mean body weight reduction by VLCD accounted to 21.7kg with a significant improvement of insulin resistance. At baseline, sRAGE serum levels were significantly inversely related to BMI (rS=-0.642, p=0.001) and HOMA (rS=-0.419, p=0.041). Of interest, sRAGE serum levels at baseline were significantly lower in study subjects with greater reduction of BMI (p=0.017). In addition, a significantly greater HOMA reduction was observed in subjects with lower sRAGE serum levels at baseline (p=0.006). Finally, correlation analysis revealed, that changes of sRAGE serum levels were significantly correlated to changes of BMI (rS=-0.650, p=0.022) during intervention. Anti-inflammatory sRAGE might be a potential future biomarker to predict weight loss and improvement of insulin resistance by a VLCD whereby lower baseline sRAGE serum levels indicate a better outcome of the dietary intervention. Copyright © 2015 Elsevier Ltd. All rights reserved.

Advanced oxidation protein products induce chondrocyte apoptosis via receptor for advanced glycation end products-mediated, redox-dependent intrinsic apoptosis pathway.

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Wu, Qian; Zhong, Zhao-Ming; Zhu, Si-Yuan; Liao, Cong-Rui; Pan, Ying; Zeng, Ji-Huan; Zheng, Shuai; Ding, Ruo-Ting; Lin, Qing-Song; Ye, Qing; Ye, Wen-Bin; Li, Wei; Chen, Jian-Ting

2016-01-01

Pro-inflammatory cytokine-induced chondrocyte apoptosis is a primary cause of cartilage destruction in the progression of rheumatoid arthritis (RA). Advanced oxidation protein products (AOPPs), a novel pro-inflammatory mediator, have been confirmed to accumulate in patients with RA. However, the effect of AOPPs accumulation on chondrocyte apoptosis and the associated cellular mechanisms remains unclear. The present study demonstrated that the plasma formation of AOPPs was enhanced in RA rats compared with normal. Then, chondrocyte were treated with AOPPs-modified rat serum albumin (AOPPs-RSA) in vitro. Exposure of chondrocyte to AOPPs activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increased expression of NADPH oxidase subunits, which was mediated by receptor for advanced glycation end products (RAGE), but not scavenger receptor CD36. Moreover, AOPPs challenge triggered NADPH oxidase-dependent ROS generation which induced mitochondrial dysfunction and endoplasmic reticulum stress resulted in activation of caspase family that eventually lead to apoptosis. Lastly, blockade of RAGE, instead of CD36, largely attenuated these signals. Our study demonstrated first time that AOPPs induce chondrocyte apoptosis via RAGE-mediated and redox-dependent intrinsic apoptosis pathway in vitro. These data implicates that AOPPs may represent a novel pathogenic factor that contributes to RA progression. Targeting AOPPs-triggered cellular mechanisms might emerge as a promising therapeutic option for patients with RA.

Plasma disappearance of glycated and non-glycated albumin in type 1 (insulin-dependent) diabetes mellitus

DEFF Research Database (Denmark)

Bent-Hansen, L; Feldt-Rasmussen, B; Kverneland, Arne

1993-01-01

transport ratio) was determined from the disappearance data. The index was high in control subjects (1.021 +/- 0.0057 (SEM)). This reflects a mean difference between the two escape rates of 2.1% per hour (for comparison the mean of the fractional escape rate of non-glycated albumin of the normal control......The fractional plasma escape rates of glycated and non-glycated albumin have earlier been measured in groups of Type 1 (insulin-dependent) diabetic patients and control subjects. The escape of non-glycated albumin was similar in control subjects and normoalbuminuric patients, but elevated...... in patients with micro or macroalbuminuria. In all groups the escape rate of glycated albumin was lower than that of non-glycated albumin. Glycation increases the anionic charge of albumin. To assay for charge-dependent alterations of transport a selectivity index (non-glycated albumin/glycated albumin...

Inhibition of Protein Glycation by Tiger Milk Mushroom [Lignosus rhinocerus (Cooke Ryvarden] and Search for Potential Anti-diabetic Activity-Related Metabolic Pathways by Genomic and Transcriptomic Data Mining

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Hui-Yeng Y. Yap

2018-02-01

Full Text Available Naturally occurring anti-glycation compounds have drawn much interest in recent years as they show potential in reducing or preventing the risk of chronic complications for diabetic patients. In this study, annotation of the genome–transcriptome data from tiger milk mushroom (Lignosus rhinocerus, syn. Lignosus rhinocerotis to PlantCyc enzymes database identified transcripts that are related to anti-diabetic properties, and these include genes that are involved in carotenoid and abscisic acid biosynthesis as well as genes that code for glyoxalase I, catalase-peroxidases, and superoxide dismutases. The existence of these genes suggests that L. rhinocerus may contain bioactive compound(s with anti-glycation properties that can be exploited for management of diabetic complications. A medium-molecular-weight (MMW fraction which was obtained from a combination of cold water extraction and Sephadex® G-50 (fine gel filtration chromatography of L. rhinocerus sclerotia powder was demonstrated to exhibit potent anti-glycation activity. The fraction specifically inhibited the formation of N-(carboxymethyllysine, pentosidine, and other advanced glycation end-product (AGE structures in a human serum albumin-glucose system, with an IC50 value of 0.001 mg/ml, almost 520 times lower than that of the positive control, aminoguanidine hydrochloride (IC50 = 0.52 mg/ml. Its ability to suppress protein glycation may be partly associated with its strong superoxide anion radical scavenging activity (10.16 ± 0.12 mmol TE/g. Our results suggest that the MMW fraction of L. rhinocerus shows potential to be developed into a potent glycation inhibitor for preventing AGE-mediated diabetic complications.

Glomerular cell death and inflammation with high-protein diet and diabetes.

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Meek, Rick L; LeBoeuf, Renee C; Saha, Sandeep A; Alpers, Charles E; Hudkins, Kelly L; Cooney, Sheryl K; Anderberg, Robert J; Tuttle, Katherine R

2013-07-01

Overfeeding amino acids (AAs) increases cellular exposure to advanced glycation end-products (AGEs), a mechanism for protein intake to worsen diabetic kidney disease (DKD). This study assessed receptor for AGE (RAGE)-mediated apoptosis and inflammation in glomerular cells exposed to metabolic stressors characteristic of high-protein diets and/or diabetes in vitro with proof-of-concept appraisal in vivo. Mouse podocytes and mesangial cells were cultured under control and metabolic stressor conditions: (i) no addition; (ii) increased AAs (4-6-fold>control); (iii) high glucose (HG, 30.5 mM); (iv) AA/HG combination; (v) AGE-bovine serum albumin (AGE-BSA, 300 µg/mL); (vi) BSA (300 µg/mL). RAGE was inhibited by blocking antibody. Diabetic (streptozotocin) and nondiabetic mice (C57BL/6J) consumed diets with protein calories of 20 or 40% (high) for 20 weeks. People with DKD and controls provided 24-h urine samples. In podocytes and mesangial cells, apoptosis (caspase 3/7 activity and TUNEL) increased in all metabolic stressor conditions. Both inflammatory mediator expression (real-time reverse transcriptase-polymerase chain reaction: serum amyloid A, caspase-4, inducible nitric oxide synthase, and monocyte chemotactic protein-1) and RAGE (immunostaining) also increased. RAGE inhibition prevented apoptosis and inflammation in podocytes. Among mice fed high protein, podocyte number (WT-1 immunostaining) decreased in the diabetic group, and only these diabetic mice developed albuminuria. Protein intake (urea nitrogen) correlated with AGE excretion (carboxymethyllysine) in people with DKD and controls. High-protein diet and/or diabetes-like conditions increased glomerular cell death and inflammation, responses mediated by RAGEs in podocytes. The concept that high-protein diets exacerbate early indicators of DKD is supported by data from mice and people.

The association between the RAGE G82S polymorphism, sRAGE and chronic periodontitis in Taiwanese individuals with and without diabetes.

Science.gov (United States)

Wu, T-L; Tsai, C-C; Wang, Y-Y; Ho, K-Y; Wu, Y-M; Hung, H-C; Lin, Y-C

2015-12-01

The present study investigated the association between the RAGE G82S polymorphism, the plasma levels of sRAGE and chronic periodontitis in subjects with and without diabetes mellitus (DM). A total of 230 patients with DM and 264 non-DM participants were recruited for this study. Genotyping of the RAGE G82S polymorphism was accomplished using polymerase chain reaction-restriction fragment length polymorphism, and associations were analyzed with the chi-squared test and logistic regression analysis. In the non-DM group, the chi-squared test showed that the frequency distributions of the G82S polymorphism were significantly different between chronic periodontitis and non-chronic periodontitis subjects (χ(2) = 8.39, p = 0.02). A multivariate logistic regression model showed that the (G82S + S82S) genotypes were associated with a significantly increased risk of chronic periodontitis development compared to the G82G genotype (adjusted odds ratio = 2.06, 95% confidence interval: 1.08-4.07). In the DM group, there was no association between the G82S polymorphism and chronic periodontitis development when a multivariate logistic regression was performed. Plasma levels of sRAGE were significantly higher in subjects with the G82G genotype compared to those with the (G82S + S82S) genotypes in both the non-DM (856.6 ± 332.0 vs. 720.4 ± 311.4 pg/mL, p = 0.003) and DM groups (915.3 ± 497.1 vs. 603.5 ± 298.3 pg/mL, p chronic periodontitis and non-chronic periodontitis subjects in both the DM and non-DM groups. Moreover, when the subjects were further sub-divided by the G82S polymorphism, the difference in plasma levels of sRAGE between chronic periodontitis and non-chronic periodontitis subjects in the DM and non-DM groups remained statistically insignificant. The present study revealed that the RAGE G82S polymorphism was associated with chronic periodontitis in the non-DM group but not in the DM group. Our results also showed that the plasma levels of sRAGE were

Cross-sectional analysis of obesity and serum analytes in males identifies sRAGE as a novel biomarker inversely associated with diverticulosis.

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Sarah S Comstock

Full Text Available Diverticulosis can lead to diverticulitis, a colon condition involving inflammation and other complications. Diverticulosis can result from biological, behavioral, or genetic causes. However, the etiology of diverticulosis is unknown. Although diet is associated with diverticulosis, recent studies suggest other factors influence risk. We sought to identify anthropometric or serum markers that were associated with the presence of diverticulosis. To determine these associations, 126 asymptomatic men (48-65 yr were recruited at the time of preventative screening colonoscopy. Anthropometric measures were taken, and blood was collected for serum protein analysis. Data were analyzed by logistic regression and factor analysis. Obese individuals (BMI >30 were 7.8 (CI: 2.3-26.3 times more likely than normal weight (BMI 45 inches were 8.1 (CI: 2.8-23.8 times more likely to have diverticulosis than those with a waist circumference <38 inches. Leptin was also positively associated with diverticulosis (OR = 5.5, CI: 2.0-14.7. Both low molecular weight adiponectin (LMW, OR = 0.50; CI: 0.3-0.8 and the soluble receptor for advanced glycation end products (sRAGE, OR = 0.4, CI: 0.3-0.7 were inversely related to the presence of diverticulosis. sRAGE levels were not correlated with leptin or C-peptide concentrations. The pattern of high BMI, waist circumference, leptin and C-peptide increased the odds of diverticulosis while the pattern of high levels of sRAGE and LMW adiponectin decreased the odds of diverticulosis. Associations between diverticulosis and anthropometric or serum markers may elucidate the origins of diverticulosis and may enable physicians to identify individuals at risk for diverticulitis.

Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine

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Chun-tao Yang

2017-02-01

Full Text Available Background/Aim: Accumulation of advanced glycation end products (AGEs is a major cause of diabetes mellitus (DM skin complications. Methylglyoxal (MGO, a reactive dicarbonyl compound, is a crucial intermediate of AGEs generation. N-acetyl-L-cysteine (NAC, an active ingredient of some medicines, can induce endogenous GSH and hydrogen sulfide generation, and set off a condensation reaction with MGO. However, there is rare evidence to show NAC can alleviate DM-induced skin injury through inhibition of AGEs generation or toxicity. The present study aimed to observe the effects of NAC on MGO-induced inflammatory injury and investigate the roles of AGEs and its receptor (RAGE in NAC’s dermal protection in human HaCaT keratinocytes. Methods: The cells were exposed to MGO to simulate a high MGO status in diabetic blood or tissues. The content of AGEs in serum or cell medium was measured with ELISA. The protective effects of NAC against MGO-induce injury were evaluated by administration before MGO one hour, in virtue of cell viability, mitochondrial membrane potential, inflammation reaction, nuclear factor (NF-κB activation, matrix metalloproteinase (MMP-9 expression, as well as cellular behavioral function. Results: We found the AGEs levels of patients with DM were elevated comparing with healthy volunteers. The in vitro AGEs generation was also able to be enhanced by the exposure of HaCaT cells to MGO, which reduced dose-dependently cellular viability, damaged mitochondrial function, triggered secretion of interleukin (IL-6 and IL-8, activated NF-κB and upregulated MMP-9 expression. Furthermore, the exposure caused cellular adhesion and migration dysfunction, as well as collagen type I inhibition. Importantly, before the exposure to MGO, the preconditioning with NAC significantly attenuated MGO-induced AGEs generation, improved cellular viability and mitochondrial function, partially reversed the overexpression of proinflammatory factors and MMP-9

MR imaging in epilepsy with use of 3D MP-RAGE

International Nuclear Information System (INIS)

Tanaka, Akio; Ohno, Sigeru; Sei, Tetsuro; Kanazawa, Susumu; Yasui, Koutaro; Kuroda, Masahiro; Hiraki, Yoshio; Oka, Eiji

1996-01-01

The patients were 40 males and 33 females; their ages ranged from 1 month to 39 years (mean: 15.7 years). The patients underwent MR imaging, including spin-echo T 1 -weighted, turbo spin-echo proton density/T 2 -weighted, and 3D magnetization-prepared rapid gradient-echo (3D MP-RAGE) images. These examinations disclosed 39 focal abnormalities. On visual evaluation, the boundary of abnormal gray matter in the neuronal migration disorder (NMD) cases was most clealy shown on 3D MP-RAGE images as compared to the other images. This is considered to be due to the higher spatial resolution and the better contrast of the 3D MP-RAGE images than those of the other techniques. The relative contrast difference between abnormal gray matter and the adjacent white matter was also assessed. The results revealed that the contrast differences on the 3D MP-RAGE images were larger than those on the other images; this was statistically significant. Although the sensitivity of 3D MP-RAGE for NMD was not specifically evaluated in this study, the possibility of this disorder, in cases suspected on other images, could be ruled out. Thus, it appears that the specificity with respect to NMD was at least increased with us of 3D MP-RAGE. 3D MP-RAGE also enabled us to build three-dimensional surface models that were helpful in understanding the three-dimensional anatomy. Furthermore. 3D MP-RAGE was considered to be the best technique for evaluating hippocampus atrophy in patients with MTS. On the other hand, the sensitivity in the signal change of the hippocampus was higher on T 2 -weighted images. In addition, demonstration of cortical tubers of tuberous sclerosis in neurocutaneous syndrome was superior on T 2 -weighted images than on 3D MP-RAGE images. (K.H.)

N-epsilon-(carboxyethyl)lysine, a product of the chemical modification of proteins by methylglyoxal, increases with age in human lens proteins.

OpenAIRE

Ahmed, M U; Brinkmann Frye, E; Degenhardt, T P; Thorpe, S R; Baynes, J W

1997-01-01

Advanced glycation end-products and glycoxidation products, such as Nepsilon-(carboxymethyl)lysine (CML) and pentosidine, accumulate in long-lived tissue proteins with age and are implicated in the aging of tissue proteins and in the development of pathology in diabetes, atherosclerosis and other diseases. In this paper we describe a new advanced glycation end-product, Nepsilon-(carboxyethyl)lysine (CEL), which is formed during the reaction of methylglyoxal with lysine residues in model compo...

Serum Levels of Toxic AGEs (TAGE May Be a Promising Novel Biomarker for the Onset/Progression of Lifestyle-Related Diseases

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Masayoshi Takeuchi

2016-06-01

Full Text Available Advanced glycation end-products (AGEs generated with aging or in the presence of diabetes mellitus, particularly AGEs derived from the glucose/fructose metabolism intermediate glyceraldehyde (Glycer-AGEs; termed toxic AGEs (TAGE, were recently shown to be closely involved in the onset/progression of diabetic vascular complications via the receptor for AGEs (RAGE. TAGE also contribute to various diseases, such as cardiovascular disease; nonalcoholic steatohepatitis; cancer; Alzheimer’s disease, and; infertility. This suggests the necessity of minimizing the influence of the TAGE-RAGE axis in order to prevent the onset/progression of lifestyle-related diseases (LSRD and establish therapeutic strategies. Changes in serum TAGE levels are closely associated with LSRD related to overeating, a lack of exercise, or excessive ingestion of sugars/dietary AGEs. We also showed that serum TAGE levels, but not those of hemoglobin A1c, glucose-derived AGEs, or Nε-(carboxymethyllysine, have potential as a biomarker for predicting the progression of atherosclerosis and future cardiovascular events. We herein introduce the usefulness of serum TAGE levels as a biomarker for the prevention/early diagnosis of LSRD and the evaluation of the efficacy of treatments; we discuss whether dietary AGE/sugar intake restrictions reduce the generation/accumulation of TAGE, thereby preventing the onset/progression of LSRD.

Glycation precedes lens crystallin aggregation

International Nuclear Information System (INIS)

Swamy, M.S.; Perry, R.E.; Abraham, E.C.

1987-01-01

Non-enzymatic glycosylation (glycation) seems to have the potential to alter the structure of crystallins and make them susceptible to thiol oxidation leading to disulfide-linked high molecular weight (HMW) aggregate formation. They used streptozotocin diabetic rats during precataract and cataract stages and long-term cell-free glycation of bovine lens crystallins to study the relationship between glycation and lens crystallin aggregation. HMW aggregates and other protein components of the water-soluble (WS) and urea-soluble (US) fractions were separated by molecular sieve high performance liquid chromatography. Glycation was estimated by both [ 3 H]NaBH 4 reduction and phenylboronate agarose affinity chromatography. Levels of total glycated protein (GP) in the US fractions were about 2-fold higher than in the WS fractions and there was a linear increase in GP in both WS and US fractions. This increase was parallelled by a corresponding increase in HMW aggregates. Total GP extracted by the affinity method from the US fraction showed a predominance of HMW aggregates and vice versa. Cell-free glycation studies with bovine crystallins confirmed the results of the animals studies. Increasing glycation caused a corresponding increase in protein insolubilization and the insoluble fraction thus formed also contained more glycated protein. It appears that lens protein glycation, HMW aggregate formation, and protein insolubilization are interrelated

Comprehensive Identification of Glycated Peptides and Their Glycation Motifs in Plasma and Erythrocytes of Control and Diabetic Subjects

Energy Technology Data Exchange (ETDEWEB)

Zhang, Qibin; Monroe, Matthew E.; Schepmoes, Athena A.; Clauss, Therese RW; Gritsenko, Marina A.; Meng, Da; Petyuk, Vladislav A.; Smith, Richard D.; Metz, Thomas O.

2011-07-01

Non-enzymatic glycation of proteins is implicated in diabetes mellitus and its related complications. In this report, we extend our previous development and refinement of proteomics-based methods for the analysis of non-enzymatically glycated proteins to comprehensively identify glycated proteins in normal and diabetic human plasma and erythrocytes. Using immunodepletion, enrichment, and fractionation strategies, we identified 7749 unique glycated peptides, corresponding to 3742 unique glycated proteins. Semi-quantitative comparisons revealed a number of proteins with glycation levels significantly increased in diabetes relative to control samples and that erythrocyte proteins are more extensively glycated than plasma proteins. A glycation motif analysis revealed amino acids that are favored more than others in the protein primary structures in the vicinity of the glycation sites in both sample types. The glycated peptides and corresponding proteins reported here provide a foundation for the potential identification of novel markers for diabetes, glycemia, or diabetic complications.

The RAGE Game Software Components Repository for Supporting Applied Game Development

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Krassen Stefanov

2017-09-01

Full Text Available This paper presents the architecture of the RAGE repository, which is a unique and dedicated infrastructure that provides access to a wide variety of advanced technology components for applied game development. The RAGE project, which is the principal Horizon2020 research and innovation project on applied gaming, develops up to three dozens of software components (RAGE software assets that are reusable across a wide diversity of game engines, game platforms and programming languages. The RAGE repository provides storage space for assets and their artefacts and is designed as an asset life-cycle management system for defining, publishing, updating, searching and packaging for distribution of these assets. It will be embedded in a social platform for asset developers and other users. A dedicated Asset Repository Manager provides the main functionality of the repository and its integration with other systems. Tools supporting the Asset Manager are presented and discussed. When the RAGE repository is in full operation, applied game developers will be able to easily enhance the quality of their games by including selected advanced game software assets. Making available the RAGE repository system and its variety of software assets aims to enhance the coherence and decisiveness of the applied game industry.

Chronic sustained inflammation links to left ventricular hypertrophy and aortic valve sclerosis: a new link between S100/RAGE and FGF23.

Science.gov (United States)

Yan, Ling; Bowman, Marion A Hofmann

Cardiovascular disease including left ventricular hypertrophy, diastolic dysfunction and ectopic valvular calcification are common in patients with chronic kidney disease (CKD). Both S100A12 and fibroblast growth factor 23 (FGF23) have been identified as biomarkers of cardiovascular morbidity and mortality in patients with CKD. We tested the hypothesis that human S100/calgranulin would accelerate cardiovascular disease in mice subjected to CKD. This review paper focuses on S100 proteins and their receptor for advanced glycation end products (RAGE) and summarizes recent findings obtained in novel developed transgenic hBAC-S100 mice that express S100A12 and S100A8/9 proteins. A bacterial artificial chromosome of the human S100/calgranulin gene cluster containing the genes and regulatory elements for S100A8, S100A9 and S100A12 was expressed in C57BL/6J mice (hBAC-S100). CKD was induced by ureteral ligation, and hBAC-S100 mice and WT mice were studied after 10 weeks of chronic uremia. hBAC-S100 mice with CKD showed increased FGF23 in the heart, left ventricular hypertrophy (LVH), diastolic dysfunction, focal cartilaginous metaplasia and calcification of the mitral and aortic valve annulus together with aortic valve sclerosis. This phenotype was not observed in WT mice with CKD or in hBAC-S100 mice lacking RAGE with CKD, suggesting that the inflammatory milieu mediated by S100/RAGE promotes pathological cardiac hypertrophy in CKD. In vitro, inflammatory stimuli including IL-6, TNFα, LPS, or serum from hBAC-S100 mice up regulated FGF23 mRNA and protein in primary murine neonatal and adult cardiac fibroblasts. Taken together, our study shows that myeloid-derived human S100/calgranulin is associated with the development of cardiac hypertrophy and ectopic cardiac calcification in a RAGE dependent manner in a mouse model of CKD. We speculate that FGF23 produced by cardiac fibroblasts in response to cytokines may act in a paracrine manner to accelerate LVH and diastolic

RAGE Architecture for Reusable Serious Gaming Technology Components

Directory of Open Access Journals (Sweden)

Wim van der Vegt

2016-01-01

Full Text Available For seizing the potential of serious games, the RAGE project—funded by the Horizon-2020 Programme of the European Commission—will make available an interoperable set of advanced technology components (software assets that support game studios at serious game development. This paper describes the overall software architecture and design conditions that are needed for the easy integration and reuse of such software assets in existing game platforms. Based on the component-based software engineering paradigm the RAGE architecture takes into account the portability of assets to different operating systems, different programming languages, and different game engines. It avoids dependencies on external software frameworks and minimises code that may hinder integration with game engine code. Furthermore it relies on a limited set of standard software patterns and well-established coding practices. The RAGE architecture has been successfully validated by implementing and testing basic software assets in four major programming languages (C#, C++, Java, and TypeScript/JavaScript, resp.. Demonstrator implementation of asset integration with an existing game engine was created and validated. The presented RAGE architecture paves the way for large scale development and application of cross-engine reusable software assets for enhancing the quality and diversity of serious gaming.

Histochemical approaches to assess cell-to-cell transmission of misfolded proteins in neurodegenerative diseases

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G. Natale

2013-03-01

Full Text Available Formation, aggregation and transmission of abnormal proteins are common features in neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. The mechanisms underlying protein alterations in neurodegenerative diseases remain controversial. Novel findings highlighted altered protein clearing systems as common biochemical pathways which generate protein misfolding, which in turn causes protein aggregation and protein spreading. In fact, proteinaceous aggregates are prone to cell-to-cell propagation. This is reminiscent of what happens in prion disorders, where the prion protein misfolds thus forming aggregates which spread to neighbouring cells. For this reason, the term prionoids is currently used to emphasize how several misfolded proteins are transmitted in neurodegenerative diseases following this prion-like pattern. Histochemical techniques including the use of specific antibodies covering both light and electron microscopy offer a powerful tool to describe these phenomena and investigate specific molecular steps. These include: prion like protein alterations; glycation of prion-like altered proteins to form advanced glycation end-products (AGEs; mechanisms of extracellular secretion; interaction of AGEs with specific receptors placed on neighbouring cells (RAGEs. The present manuscript comments on these phenomena aimed to provide a consistent scenario of the available histochemical approaches to dissect each specific step.

Involvement of high mobility group box 1 in the development and maintenance of chemotherapy-induced peripheral neuropathy in rats

International Nuclear Information System (INIS)

Nishida, Takeshi; Tsubota, Maho; Kawaishi, Yudai; Yamanishi, Hiroki; Kamitani, Natsuki; Sekiguchi, Fumiko; Ishikura, Hiroyasu; Liu, Keyue; Nishibori, Masahiro; Kawabata, Atsufumi

2016-01-01

Given that high mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, promotes nociception, we asked if inactivation of HMGB1 prevents or reverses chemotherapy-induced painful neuropathy in rats and also examined possible involvement of Toll-like receptor 4 (TLR4) and the receptor for advanced glycation endproduct (RAGE), known as targets for HMGB1. Painful neuropathy was produced by repeated i.p. administration of paclitaxel or vincristine in rats. Nociceptive threshold was determined by the paw pressure method and/or von Frey test in the hindpaw. Tissue protein levels were determined by immunoblotting. Repeated i.p. administration of the anti-HMGB1-neutralizing antibody or recombinant human soluble thrombomodulin (rhsTM), known to inactivate HMGB1, prevented the development of hyperalgesia and/or allodynia induced by paclitaxel or vincristine in rats. A single i.p. or intraplantar (i.pl.) administration of the antibody or rhsTM reversed the chemotherapy-induced neuropathy. A single i.pl. administration of a TLR4 antagonist or low molecular weight heparin, known to inhibit RAGE, attenuated the hyperalgesia caused by i.pl. HMGB1 and also the chemotherapy-induced painful neuropathy. Paclitaxel or vincristine treatment significantly decreased protein levels of HMGB1 in the dorsal root ganglia, but not sciatic nerves. HMGB1 thus participates in both development and maintenance of chemotherapy-induced painful neuropathy, in part through RAGE and TLR4. HMGB1 inactivation is considered useful to prevent and treat the chemotherapy-induced painful neuropathy.

Ex vivo instability of glycated albumin: A role for autoxidative glycation.

Science.gov (United States)

Jeffs, Joshua W; Ferdosi, Shadi; Yassine, Hussein N; Borges, Chad R

2017-09-01

Ex vivo protein modifications occur within plasma and serum (P/S) samples due to prolonged exposure to the thawed state-which includes temperatures above -30 °C. Herein, the ex vivo glycation of human serum albumin from healthy and diabetic subjects was monitored in P/S samples stored for hours to months at -80 °C, -20 °C, and room temperature, as well as in samples subjected to multiple freeze-thaw cycles, incubated at different surface area-to-volume ratios or under different atmospheric compositions. A simple dilute-and-shoot method utilizing trap-and-elute LC-ESI-MS was employed to determine the relative abundances of the glycated forms of albumin-including forms of albumin bearing more than one glucose molecule. Significant increases in glycated albumin were found to occur within hours at room temperature, and within days at -20 °C. These increases continued over a period of 1-2 weeks at room temperature and over 200 days at -20 °C, ultimately resulting in a doubling of glycated albumin in both healthy and diabetic patients. It was also shown that samples stored at lower surface area-to-volume ratios or incubated under a nitrogen atmosphere experienced less rapid glucose adduction of albumin-suggesting a role for oxidative glycation in the ex vivo glycation of albumin. Copyright © 2017 Elsevier Inc. All rights reserved.

Narcissistic rage: The Achilles’ heel of the patient with chronic physical illness

Science.gov (United States)

Hyphantis, Thomas; Almyroudi, Augustina; Paika, Vassiliki; Goulia, Panagiota; Arvanitakis, Konstantinos

2009-01-01

Based on the psychoanalytic reading of Homer’s Iliad whose principal theme is “Achilles’ rage” (the semi-mortal hero invulnerable in all of his body except for his heel, hence “Achilles’ heel” has come to mean a person’s principal weakness), we aimed to assess whether “narcissistic rage” has an impact on several psychosocial variables in patients with severe physical illness across time. In 878 patients with cancer, rheumatological diseases, multiple sclerosis, inflammatory bowel disease, and glaucoma, we assessed psychological distress (SCL-90 and GHQ-28), quality of life (WHOQOL-BREF), interpersonal difficulties (IIP-40), hostility (HDHQ), and defense styles (DSQ). Narcissistic rage comprised DSQ “omnipotence” and HDHQ “extraverted hostility”. Hierarchical multiple regressions analyses were performed. We showed that, in patients with disease duration less than one year, narcissistic rage had a minor impact on psychosocial variables studied, indicating that the rage was rather part of a “normal” mourning process. On the contrary, in patients with longer disease duration, increased rates of narcissistic rage had a great impact on all outcome variables, and the opposite was true for patients with low rates of narcissistic rage, indicating that narcissistic rage constitutes actually an “Achilles’ Heel” for patients with long-term physical illness. These findings may have important clinical implications. PMID:19936167

The RAGE Advanced Game Technologies Repository for Supporting Applied Game Development

NARCIS (Netherlands)

Georgiev, Atanas; Grigorov, Alexander; Bontchev, Boyan; Boytchev, Pavel; Stefanov, Krassen; Westera, Wim; Prada, Rui; Hollins, Paul; Moreno Ger, Pablo

2016-01-01

This paper describes the structural architecture of the RAGE repository, which is a unique and dedicated infrastructure that provides access to a wide variety of advanced technologies (RAGE software assets) for applied game development. These software assets are reusable across a wide diversity of

High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model.

Science.gov (United States)

Lubitz, Irit; Ricny, Jan; Atrakchi-Baranes, Dana; Shemesh, Chen; Kravitz, Efrat; Liraz-Zaltsman, Sigal; Maksin-Matveev, Anna; Cooper, Itzik; Leibowitz, Avshalom; Uribarri, Jaime; Schmeidler, James; Cai, Weijing; Kristofikova, Zdena; Ripova, Daniela; LeRoith, Derek; Schnaider-Beeri, Michal

2016-04-01

There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42 , AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD-like model mice on high-AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its transport across the blood-brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle-linked disease epidemic. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Curcumin ameliorates hepatic fibrosis in type 2 diabetes mellitus – insights into its mechanisms of action

Science.gov (United States)

Stefanska, B

2012-01-01

A wide variety of beneficial effects have been attributed to curcumin, a major polyphenol from the golden spice Curcuma longa known as turmeric, including amelioration of severe complications of type 2 diabetes such as hepatic fibrosis, retinopathy, neuropathy and nephropathy. In the present issue of BJP, Lin and colleagues reveal new mechanisms by which curcumin inhibits the activation of hepatic stellate cells in vitro, a hallmark of non-alcoholic steatohepatitis and hepatic fibrogenesis associated with type 2 diabetes mellitus. They demonstrated that curcumin suppresses the advanced glycation end-products (AGEs)-mediated induction of the receptor for AGEs (RAGE) gene expression by increasing PPARγ activity and stimulating de novo synthesis of glutathione. As a result, downstream elements of RAGE-activated pathways are inhibited, which prevents oxidative stress, inflammation and hepatic stellate cell activation. This report suggests that curcumin may have potential as an anti-fibrotic agent in type 2 diabetes and opens the door to the evaluation of curcumin therapeutic effects in liver conditions of different aetiology and in other disorders linked to the impairment of PPARγ activity, such as obesity and atherosclerosis. LINKED ARTICLE This article is a commentary on Lin et al., pp. 2212–2227 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.01910.x PMID:22452372

Curcumin ameliorates hepatic fibrosis in type 2 diabetes mellitus - insights into its mechanisms of action.

Science.gov (United States)

Stefanska, B

2012-08-01

A wide variety of beneficial effects have been attributed to curcumin, a major polyphenol from the golden spice Curcuma longa known as turmeric, including amelioration of severe complications of type 2 diabetes such as hepatic fibrosis, retinopathy, neuropathy and nephropathy. In the present issue of BJP, Lin and colleagues reveal new mechanisms by which curcumin inhibits the activation of hepatic stellate cells in vitro, a hallmark of non-alcoholic steatohepatitis and hepatic fibrogenesis associated with type 2 diabetes mellitus. They demonstrated that curcumin suppresses the advanced glycation end-products (AGEs)-mediated induction of the receptor for AGEs (RAGE) gene expression by increasing PPARγ activity and stimulating de novo synthesis of glutathione. As a result, downstream elements of RAGE-activated pathways are inhibited, which prevents oxidative stress, inflammation and hepatic stellate cell activation. This report suggests that curcumin may have potential as an anti-fibrotic agent in type 2 diabetes and opens the door to the evaluation of curcumin therapeutic effects in liver conditions of different aetiology and in other disorders linked to the impairment of PPARγ activity, such as obesity and atherosclerosis. This article is a commentary on Lin et al., pp. 2212-2227 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.01910.x. © 2012 The Author. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Expression of advanced glycation end-products on sun-exposed and non-exposed cutaneous sites during the ageing process in humans.

Science.gov (United States)

Crisan, Maria; Taulescu, Marian; Crisan, Diana; Cosgarea, Rodica; Parvu, Alina; Cãtoi, Cornel; Drugan, Tudor

2013-01-01

The glycation process is involved in both the intrinsic (individual, genetic) and extrinsic (ultraviolet light, polution and lifestyle) aging processes, and can be quantified at the epidermal or dermal level by histological, immunohistochemical (IHC), or imagistic methods. Our study is focused on a histological and immunohistological comparison of sun-protected regions versus sun-exposed regions from different age groups of skin phototype III subjects, related to the aging process. Skin samples collected from non-protected and UV protected regions of four experimental groups with different ages, were studied using histology and IHC methods for AGE-CML [N(epsilon)-(carboxymethyl)lysine]. A semi-quantitative assessment of the CML expression in the microvascular endothelium and dermal fibroblasts was performed. The Pearson one-way ANOVA was used to compare data between the groups. In the dermis of sun-exposed skin, the number and the intensity of CML positive cells in both fibroblasts and endothelial cells (p<0.05) was higher compared to sun-protected skin, and was significantly increased in older patients. The sun-exposed areas had a more than 10% higher AGE-CML score than the protected areas. No statistically significant correlation was observed between the histological score and the IHC expression of CML. We concluded that in healthy integument, the accumulation of final glycation products increases with age and is amplified by ultraviolet exposure. The study provides new knowledge on differences of AGE-CML between age groups and protected and unprotected areas and emphasizes that endothelium and perivascular area are most affected, justifying combined topical and systemic therapies.

Expression of advanced glycation end-products on sun-exposed and non-exposed cutaneous sites during the ageing process in humans.

Directory of Open Access Journals (Sweden)

Maria Crisan

Full Text Available The glycation process is involved in both the intrinsic (individual, genetic and extrinsic (ultraviolet light, polution and lifestyle aging processes, and can be quantified at the epidermal or dermal level by histological, immunohistochemical (IHC, or imagistic methods. Our study is focused on a histological and immunohistological comparison of sun-protected regions versus sun-exposed regions from different age groups of skin phototype III subjects, related to the aging process. Skin samples collected from non-protected and UV protected regions of four experimental groups with different ages, were studied using histology and IHC methods for AGE-CML [N(epsilon-(carboxymethyllysine]. A semi-quantitative assessment of the CML expression in the microvascular endothelium and dermal fibroblasts was performed. The Pearson one-way ANOVA was used to compare data between the groups. In the dermis of sun-exposed skin, the number and the intensity of CML positive cells in both fibroblasts and endothelial cells (p<0.05 was higher compared to sun-protected skin, and was significantly increased in older patients. The sun-exposed areas had a more than 10% higher AGE-CML score than the protected areas. No statistically significant correlation was observed between the histological score and the IHC expression of CML. We concluded that in healthy integument, the accumulation of final glycation products increases with age and is amplified by ultraviolet exposure. The study provides new knowledge on differences of AGE-CML between age groups and protected and unprotected areas and emphasizes that endothelium and perivascular area are most affected, justifying combined topical and systemic therapies.

Dynamic changes in sRAGE levels and relationship with cardiac function in STEMI patients

DEFF Research Database (Denmark)

Jensen, Louise J N; Lindberg, Søren; Hoffmann, Søren

2015-01-01

the dynamic changes in sRAGE levels during AMI and relationship with cardiac dysfunction. DESIGN AND METHODS: We prospectively included 80 patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). sRAGE concentrations were measured before p...... in the early phase of AMI; sRAGE levels significantly increased after pPCI compared with sRAGE before pPCI (median ratio: 1.25, 95% CI: 1.15-1.35, P...phase rather than in the days after AMI and pPCI. The increase...

Effect of taurine on advanced glycation end products-induced hypertrophy in renal tubular epithelial cells

International Nuclear Information System (INIS)

Huang, J.-S.; Chuang, L.-Y.; Guh, J.-Y.; Yang, Y.-L.; Hsu, M.-S.

2008-01-01

Mounting evidence indicates that advanced glycation end products (AGE) play a major role in the development of diabetic nephropathy (DN). Taurine is a well documented antioxidant agent. To explore whether taurine was linked to altered AGE-mediated renal tubulointerstitial fibrosis in DN, we examined the molecular mechanisms of taurine responsible for inhibition of AGE-induced hypertrophy in renal tubular epithelial cells. We found that AGE (but not non-glycated BSA) caused inhibition of cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, bcl-2 protein expression, and mitochondrial cytochrome c release in BSA, AGE, or the antioxidant taurine treatments in these cells. AGE-induced the Raf-1/extracellular signal-regulated kinase (ERK) activation was markedly blocked by taurine. Furthermore, taurine, the Raf-1 kinase inhibitor GW5074, and the ERK kinase inhibitor PD98059 may have the ability to induce cellular proliferation and cell cycle progression from AGE-treated cells. The ability of taurine, GW5074, or PD98059 to inhibit AGE-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of RAGE, p27 Kip1 , collagen IV, and fibronectin. The results obtained in this study suggest that taurine may serve as the potential anti-fibrotic activity in DN through mechanism dependent of its Raf-1/ERK inactivation in AGE-induced hypertrophy in renal tubular epithelial cells

Correlation of advanced glycation end products to Alzheimer's disease

Directory of Open Access Journals (Sweden)

Zong-yan MA

2018-04-01

Full Text Available Alzheimer's disease (AD is a common retrograde neurodegenerative disease of the central nervous system, as well as the most common type of dementia in the aged, the main manifestations of AD are progressive decline of cognitive function and daily life ability. AD seriously affects the quality of life and physical and mental health of the aged, and increased the burden of family and society. The etiology and pathogenesis of AD remain unclear nowadays, and there is no objective and specific biological marker to help the early diagnosis and effective treatment. Advanced glycation end products (AGEs are stable end products formed by non enzymatic reaction between the free amino groups of proteins, lipids, nucleic acids macromolecules and the carbonyls of glucose or other reduced sugars. Recent years, more and more studies have focused on the correlation between AGEs and its receptors (RAGE in patients with cognitive impairment, however, the role played by AGEs in the pathogenesis of AD remains unclear. The present paper will give an overview from three aspects: the structure and characteristics of AGEs, the relationship between the occurrence and development of AD and AGEs and the relationship between AGEs and prognosis of cognitive impairment which we've known so far. DOI: 10.11855/j.issn.0577-7402.2018.01.16

HbA1c Identifies Subjects With Prediabetes and Subclinical Left Ventricular Diastolic Dysfunction.

Science.gov (United States)

Di Pino, Antonino; Mangiafico, Sarah; Urbano, Francesca; Scicali, Roberto; Scandura, Salvatore; D'Agate, Veronica; Piro, Salvatore; Tamburino, Corrado; Purrello, Francesco; Rabuazzo, Agata Maria

2017-10-01

Prediabetes is associated with subclinical cardiac changes associated with heart failure development. We investigated diastolic function and its association with markers of glycation and inflammation related to cardiovascular disease in patients with prediabetes. We focused on individuals with prediabetes identified only by glycated hemoglobin A1c [HbA1c; 5.7% to 6.4% and normal fasting glucose (NFG) and normal glucose tolerance (NGT) after an oral glucose tolerance test (OGTT)]. Cross-sectional study. Departments of Clinical and Experimental Medicine and Cardiology, University of Catania, Catania, Italy. HbA1c, OGTT, Doppler echocardiography, soluble receptor for advanced glycation end products (sRAGEs), and endogenous secretory RAGE (esRAGE) were evaluated. We recruited 167 subjects with NFG/NGT who were stratified according to HbA1c level: controls (HbA1c prediabetes (HbA1c 5.7% to 6.4%). Patients with HbA1c prediabetes (n = 106) showed a lower peak mitral inflow in early diastole (E wave) to late diastolic atrial filling velocity (A wave) ratio (E/A ratio) than controls (n = 61) (1.10 ± 0.24 vs 1.18 ± 0.23; P prediabetes exhibited subclinical cardiac alterations associated with sRAGE, esRAGE, and HbA1c. These subjects would not have been classified as having prediabetes on the basis of fasting glycemia or post-OGTT values. Copyright © 2017 Endocrine Society

xRage Equation of State

Energy Technology Data Exchange (ETDEWEB)

Grove, John W. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

2016-08-16

The xRage code supports a variety of hydrodynamic equation of state (EOS) models. In practice these are generally accessed in the executing code via a pressure-temperature based table look up. This document will describe the various models supported by these codes and provide details on the algorithms used to evaluate the equation of state.

PSEUDOAFFINITY CHROMATOGRAPHY ENRICHMENT OF GLYCATED PEPTIDES FOR MONITORING ADVANCED GLYCATION END PRODUCTS (AGES IN METABOLIC DISORDERS

Directory of Open Access Journals (Sweden)

Rajasekar R. Prasanna

2016-09-01

Full Text Available Advanced Glycation End (AGE products are produced due to diabetic progression and they are responsible for many complications in the diabetic disorder. The diabetic progression is measured, particularly following glycated hemoglobin using specific antibodies. However, the most abundant protein in blood, human serum albumin, is also found to be glycated which has a much shorter half life and gives information on short term glycemic control. In addition, glycated albumins are considered as markers of diabetic complications such as nephropathy, peripheral vascular calcification and also in Alzheimer’s disease. The glycation proceeds from the interaction between aldehyde group of sugar and the free amino group of the protein, resulting in the formation of Schiff’s base, which undergoes a series of modifications leading to generation of imidazoyl derivatives of amino acids known as Amadori rearrangement products. The imidazoyl derivatives from arginine and lysine are the most prominent modifications observed in proteins in the presence of reducing sugar and these imidazoyl derivatives have an affinity towards certain transition metal ions. Based on our earlier exhaustive work on trapping the histidine peptides using transition metal ion, Cu(II linked to imino-diacetate complex, we explored Cu(II immobilized metal affinity chromatography (IMAC as a potential tool for specific detection of glycated peptides of human serum albumin. Our results clearly demonstrate that Cu(II IMAC is able to detect glycated peptides very efficiently while the non-glycated forms were not retained on the Cu (II column as confirmed by LC-MS/MS analysis. We further discuss the utility of IMAC technology to enrich the detection of AGE products in plasma. We anticipate that these studies may provide valuable information on understanding disease pathologies and the potential of AGE products as biomarkers of various diseases including neurodegenerative, renal and

Serum levels of advanced glycation endproducts and other markers of protein damage in early diabetic nephropathy in type 1 diabetes.

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Bruce A Perkins

Full Text Available To determine the role of markers of plasma protein damage by glycation, oxidation and nitration in microalbuminuria onset or subsequent decline of glomerular filtration rate (termed "early GFR decline" in patients with type 1 diabetes.From the 1(st Joslin Kidney Study, we selected 30 patients with longstanding normoalbuminuria and 55 patients with new onset microalbuminuria. Patients with microalbuminuria had 8-12 years follow-up during which 33 had stable GFR and 22 early GFR decline. Mean baseline GFR(CYSTATIN C was similar between the three groups. Glycation, oxidation and nitration markers were measured in protein and ultrafiltrate at baseline by liquid chromatography-tandem mass spectrometry using the most reliable methods currently available.Though none were significantly different between patients with microalbuminuria with stable or early GFR decline, levels of 6 protein damage adduct residues of plasma protein and 4 related free adducts of plasma ultrafiltrate were significantly different in patients with microalbuminuria compared to normoalbuminuria controls. Three protein damage adduct residues were decreased and 3 increased in microalbuminuria while 3 free adducts were decreased and one increased in microalbuminuria. The most profound differences were of N-formylkynurenine (NFK protein adduct residue and N(ω-carboxymethylarginine (CMA free adduct in which levels were markedly lower in microalbuminuria (P<0.001 for both.Complex processes influence levels of plasma protein damage and related proteolysis product free adducts in type 1 diabetes and microalbuminuria. The effects observed point to the possibility that patients who have efficient mechanisms of disposal of damaged proteins might be at an increased risk of developing microalbuminuria but not early renal function decline. The findings support the concept that the mechanisms responsible for microalbuminuria may differ from the mechanisms involved in the initiation of early

Role of advanced glycation end products (AGEs) and oxidative stress in diabetic retinopathy.

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Yamagishi, Sho-ichi; Ueda, Seiji; Matsui, Takanori; Nakamura, Kazuo; Okuda, Seiya

2008-01-01

Diabetic retinopathy is a common and potentially devastating microvascular complication in diabetes and is a leading cause of acquired blindness among the people of occupational age. However, current therapeutic options for the treatment of sight-threatening proliferative diabetic retinopathy such as photocoagulation and vitrectomy are limited by considerable side effects and far from satisfactory. Therefore, to develop novel therapeutic strategies that specifically target diabetic retinopathy is actually desired for most of the patients with diabetes. Chronic hyperglycemia is a major initiator of diabetic retinopathy. However, recent clinical study has substantiated the concept of 'hyperglycemic memory' in the pathogenesis of diabetic retinopathy. Indeed, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, has revealed that the reduction in the risk of progressive retinopathy resulting from intensive therapy in patients with type 1 diabetes persisted for at least several years after the DCCT trial, despite increasing hyperglycemia. These findings suggest a long-term beneficial influence of early metabolic control on clinical outcomes in type 1 diabetic patients. Among various biochemical pathways implicated in the pathogenesis of diabetic retinopathy, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory 'hyperglycemic memory'. Further, there is a growing body of evidence that AGEs-RAGE (receptor for AGEs) interaction-mediated oxidative stress generation plays an important role in diabetic retinopathy. This article summarizes the role of AGEs and oxidative stress in the development and progression of diabetic retinopathy and the therapeutic interventions that could prevent this devastating disorder. We also discuss here the pathological crosstalk between the AGEs-RAGE and the renin-angiotensin system in

Differential effects of ethanol on feline rage and predatory attack behavior: an underlying neural mechanism.

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Schubert, K; Shaikh, M B; Han, Y; Poherecky, L; Siegel, A

1996-08-01

Previous studies have shown that, at certain dose levels, ethanol can exert a powerful, facilitatory effect on aggressive behavior in both animals and humans. In the cat, however, it was discovered that ethanol differentially alters two forms of aggression that are common to this species. Defensive rage behavior is significantly enhanced, whereas predatory attack behavior is suppressed by ethanol administration. One possible mechanism governing alcohol's potentiation of defensive rage behavior is that it acts on the descending pathway from the medial hypothalamus to the midbrain periaqueductal gray (PAG)-an essential pathway for the expression of defensive rage behavior that uses excitatory amino acids as a neurotransmitter. This hypothesis is supported by the finding that the excitatory effects of alcohol on defensive rage behavior are blocked by administration of the N-methyl-D-aspartate antagonist alpha-2-amino-7-phosphoheptanoic acid (AP-7) when microinjected into the periaqueductal gray, a primary neuronal target of descending fibers from the medial hypothalamus that mediate the expression of defensive rage behavior. Thus, the present study establishes for the first time a specific component of the neural circuit for defensive rage behavior over which the potentiating effects of ethanol are mediated.

Peripheral and central mediators of lipopolysaccharide induced suppression of defensive rage behavior in the cat.

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Bhatt, S; Bhatt, R S; Zalcman, S S; Siegel, A

2009-11-10

Based upon recent findings in our laboratory that cytokines microinjected into the medial hypothalamus or periaqueductal gray (PAG) powerfully modulate defensive rage behavior in cat, the present study determined the effects of peripherally released cytokines following lipopolysaccharide (LPS) challenge upon defensive rage. The study involved initial identification of the effects of peripheral administration of LPS upon defensive rage by electrical stimulation from PAG and subsequent determination of the peripheral and central mechanisms governing this process. The results revealed significant elevation in response latencies for defensive rage from 60 to 300 min, post LPS injection, with no detectable signs of sickness behavior present at 60 min. In contrast, head turning behavior elicited by stimulation of adjoining midbrain sites was not affected by LPS administration, suggesting a specificity of the effects of LPS upon defensive rage. Direct administration of LPS into the medial hypothalamus had no effect on defensive rage, suggesting that the effects of LPS were mediated by peripheral cytokines rather than by any direct actions upon hypothalamic neurons. Complete blockade of the suppressive effects of LPS by peripheral pretreatment with an Anti-tumor necrosis factor-alpha (TNFalpha) antibody but not with an anti- interleukin-1 (IL-1) antibody demonstrated that the effects of LPS were mediated through TNF-alpha rather than through an IL-1 mechanism. A determination of the central mechanisms governing LPS suppression revealed that pretreatment of the medial hypothalamus with PGE(2) or 5-HT(1A) receptor antagonists each completely blocked the suppressive effects of LPS, while microinjections of a TNF-alpha antibody into the medial hypothalamus were ineffective. Microinjections of -Iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) benzamide monohydrochloride (p-MPPI) into lateral hypothalamus (to test for anatomical specificity) had no effect upon

Uneven batch data alignment with application to the control of batch end-product quality.

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Wan, Jian; Marjanovic, Ognjen; Lennox, Barry

2014-03-01

Batch processes are commonly characterized by uneven trajectories due to the existence of batch-to-batch variations. The batch end-product quality is usually measured at the end of these uneven trajectories. It is necessary to align the time differences for both the measured trajectories and the batch end-product quality in order to implement statistical process monitoring and control schemes. Apart from synchronizing trajectories with variable lengths using an indicator variable or dynamic time warping, this paper proposes a novel approach to align uneven batch data by identifying short-window PCA&PLS models at first and then applying these identified models to extend shorter trajectories and predict future batch end-product quality. Furthermore, uneven batch data can also be aligned to be a specified batch length using moving window estimation. The proposed approach and its application to the control of batch end-product quality are demonstrated with a simulated example of fed-batch fermentation for penicillin production. Copyright © 2013 ISA. Published by Elsevier Ltd. All rights reserved.

Narcissistic rage: The Achilles’ heel of the patient with chronic physical illness

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Thomas Hyphantis

2009-08-01

Full Text Available Thomas Hyphantis1, Augustina Almyroudi1, Vassiliki Paika1, Panagiota Goulia1, Konstantinos Arvanitakis2,31Department of Psychiatry, Medical School, University of Ioannina, Ioannina, Greece; 2Canadian Institute of Psychoanalysis, Mcgill University, Montreal, Canada; 3Departments of Philosophy and Psychiatry, Mcgill University Health Centre, Montreal, CanadaAbstract: Based on the psychoanalytic reading of Homer’s Iliad whose principal theme is “Achilles’ rage” (the semi-mortal hero invulnerable in all of his body except for his heel, hence “Achilles’ heel” has come to mean a person’s principal weakness, we aimed to assess whether “narcissistic rage” has an impact on several psychosocial variables in patients with severe physical illness across time. In 878 patients with cancer, rheumatological diseases, multiple sclerosis, inflammatory bowel disease, and glaucoma, we assessed psychological distress (SCL-90 and GHQ-28, quality of life (WHOQOL-BREF, interpersonal difficulties (IIP-40, hostility (HDHQ, and defense styles (DSQ. Narcissistic rage comprised DSQ “omnipotence” and HDHQ “extraverted hostility”. Hierarchical multiple regressions analyses were performed. We showed that, in patients with disease duration less than one year, narcissistic rage had a minor impact on psychosocial variables studied, indicating that the rage was rather part of a “normal” mourning process. On the contrary, in patients with longer disease duration, increased rates of narcissistic rage had a great impact on all outcome variables, and the opposite was true for patients with low rates of narcissistic rage, indicating that narcissistic rage constitutes actually an “Achilles’ Heel” for patients with long-term physical illness. These findings may have important clinical implications.Keywords: consultation-liaison psychiatry, psychosomatics, narcissism, physical illness, quality of life, psychological distress, personality

Glycation Reactions of Casein Micelles.

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Moeckel, Ulrike; Duerasch, Anja; Weiz, Alexander; Ruck, Michael; Henle, Thomas

2016-04-13

After suspensions of micellar casein or nonmicellar sodium caseinate had been heated, respectively, in the presence and absence of glucose for 0-4 h at 100 °C, glycation compounds were quantitated. The formation of Amadori products as indicators for the "early" Maillard reaction were in the same range for both micellar and nonmicellar caseins, indicating that reactive amino acid side chains within the micelles are accessible for glucose in a comparable way as in nonmicellar casein. Significant differences, however, were observed concerning the formation of the advanced glycation end products (AGEs), namely, N(ε)-carboxymethyllysine (CML), pyrraline, pentosidine, and glyoxal-lysine dimer (GOLD). CML could be observerd in higher amounts in nonmicellar casein, whereas in the micelles the pyrraline formation was increased. Pentosidine and GOLD were formed in comparable amounts. Furthermore, the extent of protein cross-linking was significantly higher in the glycated casein micelles than in the nonmicellar casein samples. Dynamic light scattering and scanning electron microscopy showed that glycation has no influence on the size of the casein micelles, indicating that cross-linking occurs only in the interior of the micelles, but altered the surface morphology. Studies on glycation and nonenzymatic cross-linking can contribute to the understanding of the structure of casein micelles.

Glycation inhibitors extend yeast chronological lifespan by reducing advanced glycation end products and by back regulation of proteins involved in mitochondrial respiration.

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Kazi, Rubina S; Banarjee, Reema M; Deshmukh, Arati B; Patil, Gouri V; Jagadeeshaprasad, Mashanipalya G; Kulkarni, Mahesh J

2017-03-06

Advanced Glycation End products (AGEs) are implicated in aging process. Thus, reducing AGEs by using glycation inhibitors may help in attenuating the aging process. In this study using Saccharomyces cerevisiae yeast system, we show that Aminoguanidine (AMG), a well-known glycation inhibitor, decreases the AGE modification of proteins in non-calorie restriction (NR) (2% glucose) and extends chronological lifespan (CLS) similar to that of calorie restriction (CR) condition (0.5% glucose). Proteomic analysis revealed that AMG back regulates the expression of differentially expressed proteins especially those involved in mitochondrial respiration in NR condition, suggesting that it switches metabolism from fermentation to respiration, mimicking CR. AMG induced back regulation of differentially expressed proteins could be possibly due to its chemical effect or indirectly by glycation inhibition. To delineate this, Metformin (MET), a structural analog of AMG and a mild glycation inhibitor and Hydralazine (HYD), another potent glycation inhibitor but not structural analog of AMG were used. HYD was more effective than MET in mimicking AMG suggesting that glycation inhibition was responsible for restoration of differentially expressed proteins. Thus glycation inhibitors particularly AMG, HYD and MET extend yeast CLS by reducing AGEs, modulating the expression of proteins involved in mitochondrial respiration and possibly by scavenging glucose. This study reports the role of glycation in aging process. In the non-caloric restriction condition, carbohydrates such as glucose promote protein glycation and reduce CLS. While, the inhibitors of glycation such as AMG, HYD, MET mimic the caloric restriction condition by back regulating deregulated proteins involved in mitochondrial respiration which could facilitate shift of metabolism from fermentation to respiration and extend yeast CLS. These findings suggest that glycation inhibitors can be potential molecules that can be used

Phase I clinical studies of the advanced glycation end-product (AGE)-breaker TRC4186: safety, tolerability and pharmacokinetics in healthy subjects.

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Chandra, Kumar P; Shiwalkar, Ajay; Kotecha, Jignesh; Thakkar, Purav; Srivastava, Ambrish; Chauthaiwale, Vijay; Sharma, Sanjay K; Cross, Maurice R; Dutt, Chaitanya

2009-01-01

Advanced glycation end-products (AGEs) have been implicated in the pathogenesis of diabetic complications through a variety of mechanisms including endothelial dysfunction and structural abnormalities in the vasculature and myocardium. Reducing the AGEs burden and their ensuing pro-inflammatory, pro-oxidative and pro-coagulant effect with associated dysfunctional proteins in various target tissues may retard the progression of and even reverse diabetic macro- and microvascular complications. Pyridinium, 3-[[2-(methylsulfonyl) hydrazino] carbonyl]-1-[2-oxo-2-2-thienyl) ethyl]-chloride (TRC4186) has demonstrated AGE-breaking activities in in vitro experiments and improvement in the endothelial and myocardial function in animal models of diabetes mellitus with reduction of AGEs accumulation in tissues over time. The safety of TRC4186 has been established in in vitro and in vivo preclinical studies. Thus, this drug is being developed for the treatment of complications associated with diabetes. This investigation set out to evaluate the safety, tolerability and pharmacokinetics of TRC4186 in healthy human subjects after single and multiple ascending doses, fixed doses in elderly male and female subjects, and with food and different formulations of the compound. Four studies were conducted during phase I clinical development of TRC4186. These were: (i) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in healthy male subjects with doses of TRC4186 ranging from 250 to 2500 mg administered as an oral solution (total six doses); (ii) a randomized, double-blind, placebo-controlled, multiple-dose, dose-ascending study in healthy male subjects with three doses of TRC4186 ranging from 500 to 2000 mg twice daily for 6 days with a final single dose on day 7; (iii) a randomized, open-label, three-way crossover study to assess the effect of food (fasted vs fed) and formulation (solution vs tablet) with TRC4186 500 mg; (iv) a randomized, double

Molecular markers for predicting end-products quality of wheat ...

African Journals Online (AJOL)

Molecular markers for predicting end-products quality of wheat (Triticum aestivum L.) ... African Journal of Biotechnology. Journal Home · ABOUT ... Four new Saudi wheat lines (KSU 102, KSU 103, KSU 105 and KSU 106) and two. American ...

The medical effects of radioactive fall-out: role of stable end-products

International Nuclear Information System (INIS)

Burrows, B.A.; Cardarelli, J.C.; Boling, E.A.; Sinex, F.M.

1980-01-01

To summarize, from preliminary observations on the possible effects of radioactive fall-out, it may be inferred that in addition to the secondary products of ionizing irradiation per se, the stable end-products of the transmutation of certain radionuclides may adversely influence cellular metabolism, including mutagenesis. The discussion of the possible role of intracellular barium as an end-product of 137Cs decay is offered as an example of an unpredictable number of broad ecological, as well as the more limited medical, effects that may be of both clinical and climatological significance

Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease

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Yii Michael

2011-09-01

Full Text Available Abstract Background Type 2 diabetes and the metabolic syndrome are associated with impaired diastolic function and increased heart failure risk. Animal models and autopsy studies of diabetic patients implicate myocardial fibrosis, cardiomyocyte hypertrophy, altered myocardial microvascular structure and advanced glycation end-products (AGEs in the pathogenesis of diabetic cardiomyopathy. We investigated whether type 2 diabetes and the metabolic syndrome are associated with altered myocardial structure, microvasculature, and expression of AGEs and receptor for AGEs (RAGE in men with coronary artery disease. Methods We performed histological analysis of left ventricular biopsies from 13 control, 10 diabetic and 23 metabolic syndrome men undergoing coronary artery bypass graft surgery who did not have heart failure or atrial fibrillation, had not received loop diuretic therapy, and did not have evidence of previous myocardial infarction. Results All three patient groups had similar extent of coronary artery disease and clinical characteristics, apart from differences in metabolic parameters. Diabetic and metabolic syndrome patients had higher pulmonary capillary wedge pressure than controls, and diabetic patients had reduced mitral diastolic peak velocity of the septal mitral annulus (E', consistent with impaired diastolic function. Neither diabetic nor metabolic syndrome patients had increased myocardial interstitial fibrosis (picrosirius red, or increased immunostaining for collagen I and III, the AGE Nε-(carboxymethyllysine, or RAGE. Cardiomyocyte width, capillary length density, diffusion radius, and arteriolar dimensions did not differ between the three patient groups, whereas diabetic and metabolic syndrome patients had reduced perivascular fibrosis. Conclusions Impaired diastolic function of type 2 diabetic and metabolic syndrome patients was not dependent on increased myocardial fibrosis, cardiomyocyte hypertrophy, alteration of the

Stability and anti-glycation properties of intermediate moisture apple products fortified with green tea.

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Lavelli, Vera; Corey, Mark; Kerr, William; Vantaggi, Claudia

2011-07-15

Intermediate moisture products made from blanched apple flesh and green tea extract (about 6mg of monomeric flavan 3-ols added per g of dry apple) or blanched apple flesh (control) were produced, and their quality attributes were investigated over storage for two months at water activity (a(w)) levels of 0.55 and 0.75, at 30°C. Products were evaluated for colour (L(∗), a(∗), and b(∗) Hunter's parameters), phytochemical contents (flavan 3-ols, chlorogenic acid, dihydrochalcones, ascorbic acid and total polyphenols), ferric reducing antioxidant potential, 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl radical-scavenging activity and ability to inhibit formation of fructose-induced advanced glycation end-products. During storage of the fortified and unfortified intermediate moisture apples, water availability was sufficient to support various chemical reactions involving phytochemicals, which degraded at different rates: ascorbic acid>flavan 3-ols>dihydrochalcones and chlorogenic acid. Colour variations occurred at slightly slower rates after green tea addition. In the intermediate moisture apple, antioxidant and anti-glycoxidative properties decreased at similar rates (half-life was about 80d at a(w) of 0.75, 30°C). In the green tea-fortified intermediate moisture apple, the antioxidant activity decreased at a slow rate (half-life was 165d at a(w) of 0.75, 30°C) and the anti-glycoxidative properties did not change, indicating that flavan 3-ol degradation involved the formation of derivatives that retained the properties of their parent compounds. Since these properties are linked to oxidative- and advanced glycation end-product-related diseases, these results suggest that green tea fortification of intermediate moisture apple products could be a valuable means of product innovation, to address consumers' nutritional needs. Copyright © 2011 Elsevier Ltd. All rights reserved.

A study on human serum albumin influence on glycation of fibrinogen

International Nuclear Information System (INIS)

Kielmas, Martyna; Szewczuk, Zbigniew; Stefanowicz, Piotr

2013-01-01

Highlights: •The glycation of fibrinogen was investigated by isotopic labeling method. •The potential glycation sites in fibrinogen were identified. •Human serum albumin (HSA) inhibits the glycation of fibrinogen. •The effect of HSA on fibrinogen glycation is sequence-dependent. -- Abstract: Although in vivo glycation proceeds in complex mixture of proteins, previous studies did not take in consideration the influence of protein–protein interaction on Maillard reaction. The aim of our study was to test the influence of human serum albumin (HSA) on glycation of fibrinogen. The isotopic labeling using [ 13 C 6 ] glucose combined with LC-MS were applied as tool for identification possible glycation sites in fibrinogen and for evaluation the effect of HSA on the glycation level of selected amino acids in fibrinogen. The obtained data indicate that the addition of HSA protects the fibrinogen from glycation. The level of glycation in presence of HSA is reduced by 30–60% and depends on the location of glycated residue in sequence of protein

A study on human serum albumin influence on glycation of fibrinogen

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Kielmas, Martyna; Szewczuk, Zbigniew; Stefanowicz, Piotr, E-mail: Piotr.stefanowicz@chem.uni.wroc.pl

2013-09-13

Highlights: •The glycation of fibrinogen was investigated by isotopic labeling method. •The potential glycation sites in fibrinogen were identified. •Human serum albumin (HSA) inhibits the glycation of fibrinogen. •The effect of HSA on fibrinogen glycation is sequence-dependent. -- Abstract: Although in vivo glycation proceeds in complex mixture of proteins, previous studies did not take in consideration the influence of protein–protein interaction on Maillard reaction. The aim of our study was to test the influence of human serum albumin (HSA) on glycation of fibrinogen. The isotopic labeling using [{sup 13}C{sub 6}] glucose combined with LC-MS were applied as tool for identification possible glycation sites in fibrinogen and for evaluation the effect of HSA on the glycation level of selected amino acids in fibrinogen. The obtained data indicate that the addition of HSA protects the fibrinogen from glycation. The level of glycation in presence of HSA is reduced by 30–60% and depends on the location of glycated residue in sequence of protein.

Glycated albumin: from biochemistry and laboratory medicine to clinical practice.

Science.gov (United States)

Dozio, Elena; Di Gaetano, Nicola; Findeisen, Peter; Corsi Romanelli, Massimiliano Marco

2017-03-01

This review summarizes current knowledge about glycated albumin. We review the changes induced by glycation on the properties of albumin, the pathological implications of high glycated albumin levels, glycated albumin quantification methods, and the use of glycated albumin as a complementary biomarker for diabetes mellitus diagnosis and monitoring and for dealing with long-term complications. The advantages and limits of this biomarker in different clinical settings are also discussed.

An Ultra-High Field Study of Cerebellar Pathology in Early Relapsing-Remitting Multiple Sclerosis Using MP2RAGE.

Science.gov (United States)

Fartaria, Mário João; OʼBrien, Kieran; Şorega, Alexandra; Bonnier, Guillaume; Roche, Alexis; Falkovskiy, Pavel; Krueger, Gunnar; Kober, Tobias; Bach Cuadra, Meritxell; Granziera, Cristina

2017-05-01

The aim of this study was to study focal cerebellar pathology in early stages of multiple sclerosis (MS) using ultra-high-field magnetization-prepared 2 inversion-contrast rapid gradient-echo (7T MP2RAGE). Twenty early-stage relapsing-remitting MS patients underwent an MP2RAGE acquisition at 7 T magnetic resonance imaging (MRI) (images acquired at 2 different resolutions: 0.58 × 0.58 × 0.58 mm, 7T_0.58, and 0.75 × 0.75 × 0.90 mm, 7T_0.75) and 3 T MRI (1.0 × 1.0 × 1.2 mm, 3T_1.0). Total cerebellar lesion load and volume and mean cerebellar lesion volume were compared across images using a Wilcoxon signed-rank test. Mean T1 relaxation times in lesions and normal-appearing tissue as well as contrast-to-noise ratio (CNR) measurements were also compared using a Wilcoxon signed-rank test. A multivariate analysis was applied to assess the contribution of MRI metrics to clinical performance in MS patients. Both 7T_0.58 and 7T_0.75 MP2RAGE showed significantly higher lesion load compared with 3T_1.0 MP2RAGE (P < 0.001). Plaques that were judged as leukocortical in 7T_0.75 and 3T_1.0 MP2RAGEs were instead identified as WM lesions in 7T_0.58 MP2RAGE. Cortical lesion CNR was significantly higher in MP2RAGEs at 7 T than at 3 T. Total lesion load as well as total and mean lesion volume obtained at both 7 T and 3 T MP2RAGE significantly predicted attention (P < 0.05, adjusted R = 0.5), verbal fluency (P < 0.01, adjusted R = 0.6), and motor performance (P = 0.01, adjusted R = 0.7). This study demonstrates the value of 7 T MP2RAGE to study the cerebellum in early MS patients. 7T_0.58 MP2RAGE provides a more accurate anatomical description of white and gray matter pathology compared with 7T_0.75 and 3T_1.0 MP2RAGE, likely due to the improved spatial resolution, lower partial volume effects, and higher CNR.

Characterization and cytological effects of a novel glycated gelatine substrate

International Nuclear Information System (INIS)

Boonkaew, Benjawan; Supaphol, Pitt; Tompkins, Kevin; Manokawinchoke, Jeeranan; Pavasant, Prasit

2014-01-01

Hyperglycemia in diabetes results in the glycation of long-lived proteins. Protein glycation leads to the formation of advanced glycation end products (AGEs), which are implicated in delayed wound healing and other diabetes-associated pathologies, one of which is periodontal disease. Research into the mechanisms by which glycated long-lived proteins such as collagen exert their effects can allow for the understanding of diabetic pathologies and the development of appropriate treatments. However, the high cost of purified protein can be a limitation for many laboratories around the world. The objective of this study was to develop a low-cost in vitro model of glycated gelatine as an alternative to the glycated collagen model. We investigated the glycation of gelatine type A, a denatured form of collagen, which is low-cost and abundantly available. In this study, gelatine was incubated for 7 days with ribose or methylglyoxal (MG). Cross-linking, autofluorescence and UV–Vis spectrophotometry assays were performed and indicated a dose-dependent linear increase in cross-linking and autofluorescence of gelatine by ribose and MG. MG produced more cross-linking compared to ribose at the same concentrations. The UV–Vis spectra of the glycated gelatines confirmed the presence of AGE fluorophores. Because diabetes is a risk factor for periodontal disease, the effect of the glycated substrates on the basic behaviour of human periodontal ligament (HPDL) cells was evaluated. Glycation dose dependently reduced HPDL attachment and cell spreading, indicating that the novel glycated gelatine substrate affects cell behaviour. These results show that gelatine glycated with ribose or MG can be used as low-cost in vitro models to study the effects of protein glycation on cell behaviour in diabetes and ageing. (paper)

RAGE and TGF-β1 Cross-Talk Regulate Extracellular Matrix Turnover and Cytokine Synthesis in AGEs Exposed Fibroblast Cells.

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Andreea Iren Serban

Full Text Available AGEs accumulation in the skin affects extracellular matrix (ECM turnover and triggers diabetes associated skin conditions and accelerated skin aging. The receptor of AGEs (RAGE has an essential contribution to cellular dysfunction driven by chronic inflammatory responses while TGF-β1 is critical in both dermal homeostasis and inflammation. We investigated the contribution of RAGE and TGF-β1 to the modulation of inflammatory response and ECM turnover in AGEs milieu, using a normal fibroblast cell line. RAGE, TGF-β1, collagen I and III gene and protein expression were upregulated after exposure to AGEs-BSA, and MMP-2 was activated. AGEs-RAGE was pivotal in NF-κB dependent collagen I expression and joined with TGF-β1 to stimulate collagen III expression, probably via ERK1/2 signaling. AGEs-RAGE axis induced upregulation of TGF-β1, TNF-α and IL-8 cytokines. TNF-α and IL-8 were subjected to TGF-β1 negative regulation. RAGE's proinflammatory signaling also antagonized AGEs-TGF-β1 induced fibroblast contraction, suggesting the existence of an inhibitory cross-talk mechanism between TGF-β1 and RAGE signaling. RAGE and TGF-β1 stimulated anti-inflammatory cytokines IL-2 and IL-4 expression. GM-CSF and IL-6 expression appeared to be dependent only on TGF-β1 signaling. Our data also indicated that IFN-γ upregulated in AGEs-BSA milieu in a RAGE and TGF-β1 independent mechanism. Our findings raise the possibility that RAGE and TGF-β1 are both involved in fibrosis development in a complex cross-talk mechanism, while also acting on their own individual targets. This study contributes to the understanding of impaired wound healing associated with diabetes complications.

The low-AGE content of low-fat vegan diets could benefit diabetics - though concurrent taurine supplementation may be needed to minimize endogenous AGE production.

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McCarty, Mark F

2005-01-01

Increased endogenous generation of advanced glycation endproducts (AGEs) contributes importantly to the vascular complications of diabetes, in part owing to activation of the pro-inflammatory RAGE receptor. However, AGE-altered oligopeptides with RAGE-activating potential can also be absorbed from the diet, and indeed make a significant contribution to the plasma and tissue pool of AGEs; this contribution is especially prominent when compromised renal function impairs renal clearance of AGEs. Perhaps surprisingly, foods rich in both protein and fat, and cooked at high heat, tend to be the richest dietary sources of AGEs, whereas low-fat carbohydrate-rich foods tend to be relatively low in AGEs. Conceivably, this reflects the fact that the so-called "AGEs" in the diet are generated primarily, not by glycation reactions, but by interactions between oxidized lipids and protein; such reactions are known to give rise to certain prominent AGEs, such as epsilonN-carboxymethyl-lysine and methylglyoxal. Although roasted nuts and fried or broiled tofu are relatively high in AGEs, low-fat plant-derived foods, including boiled or baked beans, typically are low in AGEs. Thus, a low-AGE content may contribute to the many benefits conferred to diabetics by a genuinely low-fat vegan diet. Nonetheless, the plasma AGE content of healthy vegetarians has been reported to be higher than that of omnivores - suggesting that something about vegetarian diets may promote endogenous AGE production. Some researchers have proposed that the relatively high-fructose content of vegetarian diets may explain this phenomenon, but there so far is no clinical evidence that normal intakes of fructose have an important impact on AGE production. An alternative or additional possibility is that the relatively poor taurine status of vegetarians up-regulates the physiological role of myeloperoxidase-derived oxidants in the generation of AGEs - in which case, taurine supplementation might be expected to

Evaluation of the Antioxidant and Anti-glication Effects of the Hexane Extract from Piper auritum Leaves in Vitro and Beneficial Activity on Oxidative Stress and Advanced Glycation End-Product-Mediated Renal Injury in Streptozotocin-Treated Diabetic Rats

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Adriana Maria Neira Gonzalez

2012-10-01

Full Text Available The aim of this study was to investigate the antioxidant activity of hexane extracts from leaves of Piper auritum (HS. Eight complementary in vitro test methods were used, including inhibition of DPPH· radicals, nitric oxide, superoxide anion, ion-chelating, ABTS, oxygen radical absorbance capacity, β-carotene bleaching and peroxy radical scavenging. The results indicated that HS possesses high antioxidant activity. To add to these finding we tested the effect against oxidative stress in liver, pancreas and kidney in diabetic rats. Low levels of SOD, CAT, GPx and GSH in diabetic rats were reverted to near normal values after treatment with HS. These results suggest that P. auritum prevents oxidative stress, acting as a suppressor of liver cell damage. Given the link between glycation and oxidation, we proposed that HS might possess significant in vitro antiglycation activity. Our data confirmed the inhibitory effect of HS on bovine serum albumin, serum glycosylated protein, glycation of LDL, and glycation hemoglobin. The effect of HS on diabetic renal damage was investigated using streptozotocin-induced diabetic rats. The oral administration of HS at a dose of 200 and 400 mg/kg body weight/day for 28 days significantly reduced advanced glycation endproduct (AGE formation, elevated renal glucose and thiobarbituric acid-reactive substance levels in the kidneys of diabetic rats. This implies that HS would alleviate the oxidative stress under diabetes through the inhibition of lipid peroxidation. These findings indicate that oxidative stress is increased in the diabetic rat kidney and that HS can prevent renal damage associated with diabetes by attenuating the oxidative stress.

Glycation inhibits trichloroacetic acid (TCA)-induced whey protein precipitation

Science.gov (United States)

Four different WPI saccharide conjugates were successfully prepared to test whether glycation could inhibit WPI precipitation induced by trichloroacetic acid (TCA). Conjugates molecular weights after glycation were analyzed with SDS-PAGE. No significant secondary structure change due to glycation wa...

Explaining seemingly paradoxical consumer experiences: conjoining weekly road rage and church attendance.

Science.gov (United States)

Gau, Li-Shiue; Woodside, Arch G; Martin, Drew

2015-02-01

The purposes of the current study are threefold: Provide evidence that an extreme paradoxical group exists-people frequently attending church and exhibiting road rage, profile this group, and frame possible explanations for the seemingly paradoxical behaviors. This study employs data from a national (USA) lifestyle survey conducted by Market Facts with 3,350 American respondents. The major questions asked about church participation and road-rage behavior ("giving a finger" and "flashing headlights"). Nomologically, relevant activities include 3 items for church goers and 3 items for road-rage givers. Additionally, 14 items profiled the lifestyles of the unique paradoxical behavior segment. Utilizing cross-tabulation tables, property space analyses identify the double extreme (XX) group (18 people) and other 6 groups with a significant chi-square test, confirming the extreme group exists. Analyses of variance test results show that comparing nomologically relevant activities among the seven groups is all statistically significant, indicating the nomological validity is met. Overall, the XX group tends to have more males, be younger, and have a higher proportion of people working in sales. The profile of lifestyle analyses shows the XX group members have both high ambitions and expectations, might be very frustrated individuals, and equip with the adventurous and masculine traits related to aggression. The XX behavior group's demographic and psychographic characteristics portray similar lifestyles that differ from other groups. Case-based analyses provide further contextual information of nuances to XX segment individuals. The limited energy theory, the Eagleman's theory of unconscious mind, and justification theory help to explain why people conjointly go to church and commit road rage. Addressing chronic paradoxical behaviors provides implications for social de-marketing to reduce aggressive anti-social behavior such as road rage. Frequent church attendance may

Advanced glycation end-products (AGEs acutely impair Ca2+ signalling in bovine aortic endothelial cells

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Nadim eNaser

2013-03-01

Full Text Available Post-translational modification of proteins in diabetes, including formation of advanced glycation end products (AGEs are believed to contribute to vascular dysfunction and disease. Impaired function of the endothelium is an early indicator of vascular dysfunction in diabetes and as many endothelial cell processes are dependent upon intracellular [Ca2+] and Ca2+ signalling, the aim of this study was to examine the acute effects of AGEs on Ca2+ signalling in bovine aortic endothelial cells (BAEC. Ca2+ signalling was studied using the fluorescent indicator dye Fura2-AM. AGEs were generated by incubating bovine serum albumin with 0 - 250 mM glucose or glucose-6-phosphate for 0 to 120 days at 37ºC. Under all conditions, the main AGE species generated was carboxymethyl lysine (CML as assayed using both GC-MS and HPLC. In Ca2+-replete solution, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2+] and attenuated the increase in intracellular [Ca2+] caused by ATP (100 µM. In the absence of extracellular Ca2+, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2+] and attenuated subsequent intracellular Ca2+ release caused by ATP, thapsigargin (0.1 µM and ionomycin (3 µM, but AGEs did not affect extracellular Ca2+ entry induced by the re-addition of Ca2+ to the bathing solution in the presence of any of these agents. The anti-oxidant α-lipoic acid (2 µM and NAD(PH oxidase inhibitors apocynin (500 µM and diphenyleneiodonium (DPI, 1 µM abolished these effects of AGEs on BAECs, as did the IP3 receptor antagonist xestospongin C (1 µM. In summary, AGEs caused an acute depletion of Ca2+ from the intracellular store in BAECs, such that the Ca2+ signal stimulated by the subsequent application other agents acting upon this store is reduced. The mechanism may involve generation of ROS from NAD(PH oxidase and possible activation of the IP3 receptor.

Review: Joschka Philipps, Ambivalent Rage: Youth Gangs and Urban Protest in Conakry, Guinea (2013)

OpenAIRE

Ineke van Kessel; Afrika-Studiecentrum Leiden

2014-01-01

Review of the Monograph:Joschka Philipps, Ambivalent Rage: Youth Gangs and Urban Protest in Conakry, Guinea, Paris: L’Harmattan, 2013, ISBN 978-2-343-01577-4, 238 pp. Besprechung der Monographie:Joschka Philipps, Ambivalent Rage: Youth Gangs and Urban Protest in Conakry, Guinea, Paris: L’Harmattan, 2013, ISBN 978-2-343-01577-4, 238 Seiten

RAGE Architecture for Reusable Serious Gaming Technology Components

NARCIS (Netherlands)

Van der Vegt, Wim; Westera, Wim; Nyamsuren, Enkhbold; Georgiev, Atanas; Martinez Ortiz, Ivan

2016-01-01

For seizing the potential of serious games, the RAGE project - funded by the Horizon-2020 Programme of the European Commission - will make available an interoperable set of advanced technology components (software assets) that support game studios at serious game development. This paper describes

T1 mapping of the mouse brain following fractionated manganese administration using MP2RAGE.

Science.gov (United States)

Driencourt, Luc; Romero, Carola Jacqueline; Lepore, Mario; Eggenschwiler, Florent; Reynaud, Olivier; Just, Nathalie

2017-01-01

With the increasing development of transgenic mouse models of neurodegenerative diseases allowing improved understanding of the underlying mechanisms of these disorders, robust quantitative mapping techniques are also needed in rodents. MP2RAGE has shown great potential for structural imaging in humans at high fields. In the present work, MP2RAGE was successfully implemented at 9.4T and 14.1T. Following fractionated injections of MnCl 2 , MP2RAGE images were acquired allowing simultaneous depiction and T 1 mapping of structures in the mouse brain at both fields. In addition, T 1 maps demonstrated significant T 1 shortenings in different structures of the mouse brain (p < 0.0008 at 9.4T, p < 0.000001 at 14.1T). T 1 values recovered to the levels of saline-injected animals 1 month after the last injection except in the pituitary gland. We believe that MP2RAGE represents an important prospective translational tool for further structural MRI.

Interaction between tumor cell surface receptor RAGE and proteinase 3 mediates prostate cancer metastasis to bone

Science.gov (United States)

Kolonin, Mikhail G.; Sergeeva, Anna; Staquicini, Daniela I.; Smith, Tracey L.; Tarleton, Christy A.; Molldrem, Jeffrey J.; Sidman, Richard L.; Marchiò, Serena; Pasqualini, Renata; Arap, Wadih

2017-01-01

Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a non-proteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short time frame. Our findings demonstrate how RAGE-PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention. PMID:28428279

[The Habit of Rage in a United States Ghetto.

Science.gov (United States)

Bourgois, Philippe; Castrillo, Fernando Montero; Hart, Laurie; Karandinos, George

2013-04-01

For five years, the open air drug sales block where the authors resided and conducted participant-observation fieldwork in the Puerto Rican corner of inner-city Philadelphia was subject to a routinized whirlwind of shootings, stabbings and assaults. The narcotics industry filled the void left by deindustrialization, turning the city's former factory district into an open-air narcotics supermarket staffed at the entry level by young Puerto Ricans serving primarily poor white injectors. A capacity to mobilize rage ensures success in the drug economy, protection in prison, and minimal income for the no-longer-worthy poor who are diagnosed as cognitively disabled. Many residents seek alliances in social networks that oblige them to participate in solidary exchanges of assistive violence. A dynamic of embodied, primitive accumulation kills, maims, disables or incarcerates most of this industry's entry-level employees and customers. Artificially high profit margins depend on violence and coercion. A rage-filled habitus propels street-level sellers into violently defending the micro-monopoly power of their bosses in the underground economy as if it were fun. They rush to enforce commercial transactions in the absence of protective legal sanctions in an environment of scarcity that is flooded by streams of cash, addictive drugs and automatic weapons. With the end of welfare entitlements, the left hand of the state, in the form of social services, attempts to continue subsidies for vulnerable individuals by diagnosing scarred bodies and brains as proof of permanent cognitive disability in need of heavy pharmaceutical medication. Periodic outbursts of interpersonal or of self-inflicted rage-filled violence emerge as the best way to ensure the continuity of that fragile public subsidy. Simultaneously, within the bowels of the right hand of the state, in overcrowded, hostilely-supervised violent prisons, rage becomes a valuable physical self-protection strategy for inmates. In

Inhibition of protein glycation and advanced glycation end products ...

African Journals Online (AJOL)

Advanced glycation end products (AGEs) formation is increased in diabetes mellitus, leading to microvascular and macrovascular complications. Recently, much attention has been focused on natural and synthetic inhibitors to delay the onset or progression of diabetes and its comorbidities. Ascorbic acid (AA) can react with ...

Optimizing the magnetization-prepared rapid gradient-echo (MP-RAGE sequence.

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Jinghua Wang

Full Text Available The three-dimension (3D magnetization-prepared rapid gradient-echo (MP-RAGE sequence is one of the most popular sequences for structural brain imaging in clinical and research settings. The sequence captures high tissue contrast and provides high spatial resolution with whole brain coverage in a short scan time. In this paper, we first computed the optimal k-space sampling by optimizing the contrast of simulated images acquired with the MP-RAGE sequence at 3.0 Tesla using computer simulations. Because the software of our scanner has only limited settings for k-space sampling, we then determined the optimal k-space sampling for settings that can be realized on our scanner. Subsequently we optimized several major imaging parameters to maximize normal brain tissue contrasts under the optimal k-space sampling. The optimal parameters are flip angle of 12°, effective inversion time within 900 to 1100 ms, and delay time of 0 ms. In vivo experiments showed that the quality of images acquired with our optimal protocol was significantly higher than that of images obtained using recommended protocols in prior publications. The optimization of k-spacing sampling and imaging parameters significantly improved the quality and detection sensitivity of brain images acquired with MP-RAGE.

The RAGE Software Asset Model and Metadata Model

NARCIS (Netherlands)

Georgiev, Atanas; Grigorov, Alexander; Bontchev, Boyan; Boytchev, Pavel; Stefanov, Krassen; Bahreini, Kiavash; Nyamsuren, Enkhbold; Van der Vegt, Wim; Westera, Wim; Prada, Rui; Hollins, Paul; Moreno, Pablo

2016-01-01

Software assets are key output of the RAGE project and they can be used by applied game developers to enhance the pedagogical and educational value of their games. These software assets cover a broad spectrum of functionalities – from player analytics including emotion detection to intelligent

French version of the Rating Scale for Aggressive Behaviour in the Elderly (F-RAGE: Psychometric properties and diagnostic accuracy

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Barry Adama

Full Text Available ABSTRACT Aggressive behaviour is the most disturbing and distressing behaviour displayed by elderly people. The prevalence of aggressive behaviour is around 50% among psychogeriatric patients. Objective: This study sought to analyze the psychometric properties and diagnostic accuracy of the French version of the Rating Scale for Aggressive Behaviour in the Elderly (F-RAGE. Methods: The F-RAGE was administered to 79 patients hospitalized in a geriatric psychiatry department. A psychiatrist, who was blind to the subjects' RAGE scores, performed the diagnosis for aggressivity based on global clinical impression. The F-RAGE and MMSE were applied by a trained researcher blind to subjects' clinical diagnoses while the Cohen-Mansfield Agitation Inventory and Neuropsychiatric Inventory were administered by medical and nursing staff. Internal consistency, reliability, cut-off points, sensitivity and specificity for F-RAGE were estimated. Results: F-RAGE showed satisfactory validity and reliability measurements. Regarding reliability, Cronbach's a coefficient was satisfactory with a value of 0.758. For diagnostic accuracy, a cut-off point of 8 points (sensitivity=74.19%; specificity=97.98% and area under curve of 0.960 were estimated to distinguish between aggressive patients and control subjects. Discussion: F-RAGE showed acceptable psychometric properties, supported by evidence of validity and reliability for its use in the diagnosis of aggressive behaviour in elderly.

The Spectacle of Redemption: Guilt and Violence in Martin Scorsese’s Raging Bull

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Arturo Serrano

2015-06-01

Full Text Available Of all the characters that undertake a search for redemption in Martin Scorsese’s films, perhaps it is the story of Jake La Motta in Raging Bull that for many reasons presents the greatest challenge to understanding redemption’s role in the narratives of his films. Is Jake La Motta a redeemed character at the end of Raging Bull? I argue that Scorsese uses Raging Bull to criticize a ritualistic view of redemption by portraying the beginning of Jake’s search as a futile attempt to submit himself to a public spectacle of ritual violence in the boxing ring while visually relating this to the Catholic sacraments and the crucifixion. It will only be later—in the loneliness of a jail cell, estranged from his family and without having to have had gone through a rite—that Jake achieves the self-awareness redemption requires.

Current perspectives on the health risks associated with the consumption of advanced glycation end products: recommendations for dietary management

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Palimeri S

2015-09-01

Full Text Available Sotiria Palimeri,* Eleni Palioura,* Evanthia Diamanti-KandarakisEndocrine Unit, Medical School University of Athens, Athens, Greece*These authors contributed equally to this workAbstract: Advanced glycation end products (AGEs constitute a complex group of compounds produced endogenously during the aging process and under conditions of hyperglycemia and oxidative stress. AGEs also have an emerging exogenous origin. Cigarette smoke and diet are the two main exogenous sources of AGEs (glycotoxins. Modern Western diets are rich in AGEs which have been implicated in the pathogenesis of several metabolic and degenerative disorders. Accumulating evidence underlies the beneficial effect of the dietary restriction of AGEs not only in animal studies but also in patients with diabetic complications and metabolic diseases. This article reviews the evidence linking dietary glycotoxins to several disorders from diabetic complications and renal failure to liver dysfunction, female reproduction, eye and cognitive disorders as well as cancer. Furthermore, strategies for AGE reduction are discussed with a focus on dietary modification.Keywords: AGEs, dietary glycotoxins, dietary restriction, PCOS, MSR-1, RAGE

Road rage and road traffic accidents among commercial vehicle drivers in Lahore, Pakistan.

Science.gov (United States)

Shaikh, M A; Shaikh, I A; Siddiqui, Z

2012-04-01

Road rage and road traffic accidents increase the burden of morbidity and mortality in a population. A cross-sectional survey with convenience sampling was conducted among commercial vehicle drivers in Lahore, Pakistan (n = 901) to record their behaviours/experiences regarding road rage and road traffic accidents. Respondents were asked about incidents of shouting/cursing/rude gestures or threats to physically hurt the person/vehicle, by others or themselves, in the previous 24 hours or 3 months, and their involvement in road traffic accidents in the previous 12 months. Auto-rickshaw drivers were significantly more likely to report various road rage experiences/behaviours and involvement in accidents compared with bus and wagon drivers. A total of 112 respondents (12.4%) reported being involved in a road traffic accident in the previous 12 months but traffic police did not record the accident in 52.7% of cases. The results of this study underline the need to improve road safety in Pakistan.

Aged garlic has more potent antiglycation and antioxidant properties compared to fresh garlic extract in vitro

Science.gov (United States)

Elosta, Abdulhakim; Slevin, Mark; Rahman, Khalid; Ahmed, Nessar

2017-01-01

Protein glycation involves formation of early (Amadori) and late advanced glycation endproducts (AGEs) together with free radicals via autoxidation of glucose and Amadori products. Glycation and increased free radical activity underlie the pathogenesis of diabetic complications. This study investigated whether aged garlic has more potent antiglycation and antioxidant properties compared to fresh garlic extract in vitro in a cell-free system. Proteins were glycated by incubation with sugars (glucose, methylglyoxal or ribose) ±5–15 mg/mL of aged and fresh garlic extracts. Advanced glycation endproducts were measured using SDS-PAGE gels and by ELISA whereas Amadori products were assessed by the fructosamine method. Colorimetric methods were used to assess antioxidant activity, free radical scavenging capacity, protein-bound carbonyl groups, thiol groups and metal chelation activities in addition to phenolic, total flavonoid and flavonol content of aged and fresh garlic extracts. Aged garlic inhibited AGEs by 56.4% compared to 33.5% for an equivalent concentration of fresh garlic extract. Similarly, aged garlic had a higher total phenolic content (129 ± 1.8 mg/g) compared to fresh garlic extract (56 ± 1.2 mg/g). Aged garlic has more potent antiglycation and antioxidant properties compared to fresh garlic extract and is more suitable for use in future in vivo studies. PMID:28051097

Advanced Glycation End Products Impair Ca2+ Mobilization and Sensitization in Colonic Smooth Muscle Cells via the CAMP/PKA Pathway

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Ting Yu

2017-10-01

Full Text Available Background/Aims: Excessive production of advanced glycation end products (AGEs has been implicated in diabetes-related complications. This study aimed to investigate the mechanism by which AGEs potentially contribute to diabetes-associated colonic dysmotility. Methods: Control and streptozotocin (STZ-induced diabetic groups were treated with aminoguanidine (AG. The colonic transit time and contractility of circular muscle strips was measured. ELISA, immunohistochemistry and western blotting were used to measure Nε-carboxymethyl-lysine (CML levels. Primary cultured colonic smooth muscle cells (SMCs were used in complementary in vitro studies. Results: Diabetic rats showed prolonged colonic transit time, weak contractility of colonic smooth muscle strips, and elevated levels of AGEs in the serum and colon tissues. cAMP levels, protein kinase-A (PKA activities, and inositol 1,4,5-trisphosphate receptor type 3 (IP3R3 phosphorylation were increased in the colon muscle tissues of diabetic rats, whereas RhoA/Rho kinase activity and myosin phosphatase target subunit 1 (MYPT1 phosphorylation were reduced. The inhibition of the production of AGEs (AG treatment reduced these effects. In cultured colonic SMCs, AGE-BSA treatment increased IP3R3 phosphorylation and reduced intracellular Ca2+ concentration, myosin light chain (MLC phosphorylation, RhoA/Rho kinase activity, and MYPT1 phosphorylation. The PKA inhibitor H-89 and anti-RAGE antibody inhibited the AGE-BSA–induced impairment of Ca2+ signaling and cAMP/PKA activation. Conclusion: AGEs/RAGE participate in diabetes-associated colonic dysmotility by interfering with Ca2+ signaling in colonic SMCs through targeting IP3R3-mediated Ca2+ mobilization and RhoA/Rho kinase-mediated Ca2+ sensitization via the cAMP/PKA pathway.

Advanced glycation end-products (AGEs accumulation in skin: relations with chronic kidney disease-mineral and bone disorder

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Renata de Almeida França

2017-08-01

Full Text Available Abstract Introduction: Chronic kidney disease (CKD is associated with high morbidity and mortality rates, main causes related with cardiovascular disease (CVD and bone mineral disorder (CKD-BMD. Uremic toxins, as advanced glycation end products (AGEs, are non-traditional cardiovascular risk factor and play a role on development of CKD-BMD in CKD. The measurement of skin autofluorescence (sAF is a noninvasive method to assess the level of AGEs in tissue, validated in CKD patients. Objective: The aim of this study is analyze AGEs measured by sAF levels (AGEs-sAF and its relations with CVD and BMD parameters in HD patients. Methods: Twenty prevalent HD patients (HD group and healthy subjects (Control group, n = 24, performed biochemical tests and measurements of anthropometric parameters and AGEs-sAF. In addition, HD group performed measurement of intact parathormone (iPTH, transthoracic echocardiogram and radiographies of pelvis and hands for vascular calcification score. Results: AGEs-sAF levels are elevated both in HD and control subjects ranged according to the age, although higher at HD than control group. Single high-flux HD session does not affect AGEs-sAF levels. AGEs-sAF levels were not related to ventricular mass, interventricular septum or vascular calcification in HD group. AGEs-sAF levels were negatively associated with serum iPTH levels. Conclusion: Our study detected a negative correlation of AGEs-sAF with serum iPTH, suggesting a role of AGEs on the pathophysiology of bone disease in HD prevalent patients. The nature of this relation and the clinical application of this non-invasive methodology for evaluation AGEs deposition must be confirmed and clarified in future studies.

Inhibition of protein glycation and advanced glycation end products ...

African Journals Online (AJOL)

Fatima

2012-06-26

Jun 26, 2012 ... acid (AA) can react with proteins, including hemoglobin and possibly interfere with protein glycation process. .... 50 mM) and AA (100, 200, 300 and 400 mM) at 37°C for five weeks ... drops were removed by patting the plate over a paper towel. The .... adults participating in the Beaver Dam Eye Study. In.

Evaluating anorexia-related brain atrophy using MP2RAGE-based morphometry

International Nuclear Information System (INIS)

Boto, Jose; Loevblad, Karl-Olof; Vargas, Maria Isabel; Gkinis, Georgios; Ortiz, Nadia; Roche, Alexis; Kober, Tobias; Marechal, Benedicte; University Hospital; Ecole Polytechnique Federale de Lausanne; Lazeyras, Francois

2017-01-01

To evaluate brain atrophy in anorexic patients by automated cerebral segmentation with the magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) MRI sequence. Twenty patients (female; mean age, 27.9 years), presenting consecutively for brain MRI between August 2014-December 2016 with clinical suspicion of anorexia nervosa and BMI<18.5 kg/m 2 were included. Controls were ten healthy females (mean age, 26.5 years). Automated brain morphometry was performed based on MP2RAGE. Means of morphometric results in the two groups were compared and correlation with BMI was analysed. Significantly lower volumes of total brain, grey matter (GM), white matter (WM), cerebellum and insula were found in anorexic patients. Anorexics had higher volumes of CSF, ventricles, lateral ventricles and third ventricle. When adjusted means for weight and height were compared, the volume of WM and cerebellum were not significantly different. However, volume of WM was significantly affected by weight and positively correlated with BMI. Significant positive correlations were found between BMI and volumes of total brain, GM, cortical GM and WM. BMI was negatively correlated with volumes of CSF and third ventricle. Brain atrophy was demonstrated in anorexic patients with MP2RAGE-based automated segmentation, which seems to reliably estimate brain volume. (orig.)

Evaluating anorexia-related brain atrophy using MP2RAGE-based morphometry

Energy Technology Data Exchange (ETDEWEB)

Boto, Jose; Loevblad, Karl-Olof; Vargas, Maria Isabel [Geneva University Hospital (Switzerland). Div. of Neuroradiology and Faculty of Medicine of Geneva; Gkinis, Georgios; Ortiz, Nadia [Geneva University Hospital (Switzerland). Dept. of Mental Health and Psychiatry; Roche, Alexis; Kober, Tobias; Marechal, Benedicte [Siemens Healthcare HC CEMEA SUI DI BM PI, Lausanne (Switzerland). Siemens ACIT, Advanced Clinical Imaging Technology; University Hospital (CHUV), Lausanne (Switzerland). Dept. of Radiology; Ecole Polytechnique Federale de Lausanne (Switzerland). LTS5; Lazeyras, Francois [Geneva University Hospital (Switzerland). Div. of Radiology and Faculty of Medicine of Geneva

2017-12-15

To evaluate brain atrophy in anorexic patients by automated cerebral segmentation with the magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) MRI sequence. Twenty patients (female; mean age, 27.9 years), presenting consecutively for brain MRI between August 2014-December 2016 with clinical suspicion of anorexia nervosa and BMI<18.5 kg/m{sup 2} were included. Controls were ten healthy females (mean age, 26.5 years). Automated brain morphometry was performed based on MP2RAGE. Means of morphometric results in the two groups were compared and correlation with BMI was analysed. Significantly lower volumes of total brain, grey matter (GM), white matter (WM), cerebellum and insula were found in anorexic patients. Anorexics had higher volumes of CSF, ventricles, lateral ventricles and third ventricle. When adjusted means for weight and height were compared, the volume of WM and cerebellum were not significantly different. However, volume of WM was significantly affected by weight and positively correlated with BMI. Significant positive correlations were found between BMI and volumes of total brain, GM, cortical GM and WM. BMI was negatively correlated with volumes of CSF and third ventricle. Brain atrophy was demonstrated in anorexic patients with MP2RAGE-based automated segmentation, which seems to reliably estimate brain volume. (orig.)

Experiments at Scale with In-Situ Visualization Using ParaView/Catalyst in RAGE

Energy Technology Data Exchange (ETDEWEB)

Kares, Robert John [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

2014-10-31

In this paper I describe some numerical experiments performed using the ParaView/Catalyst in-situ visualization infrastructure deployed in the Los Alamos RAGE radiation-hydrodynamics code to produce images from a running large scale 3D ICF simulation on the Cielo supercomputer at Los Alamos. The detailed procedures for the creation of the visualizations using ParaView/Catalyst are discussed and several images sequences from the ICF simulation problem produced with the in-situ method are presented. My impressions and conclusions concerning the use of the in-situ visualization method in RAGE are discussed.

Evaluation of a reference material for glycated haemoglobin

NARCIS (Netherlands)

Weykamp, CW; Penders, TJ; Muskiet, FAJ; vanderSlik, W

The use of lyophilized blood as a reference material for glycated haemoglobin was investigated with respect to IFCC criteria for calibrators and control materials. Ninety-two laboratories, using 11 methods, detected no changes in glycated haemoglobin content when the lyophilizate was stored for one

Transcapillary escape rate and relative metabolic clearance of glycated and non-glycated albumin in type 1 (insulin-dependent) diabetes mellitus

DEFF Research Database (Denmark)

Bent-Hansen, L; Feldt-Rasmussen, B; Kverneland, A

1987-01-01

The transcapillary escape rate and relative plasma disappearance of glycated and non-glycated albumin were measured in 25 male Type 1 (insulin-dependent) diabetic patients using a double tracer technique. The patients were divided into three groups on the basis of their urinary albumin excretion......: group 1, normal albumin excretion (less than 30 mg/24 h) (n = 8); group 2, microalbuminuria (30-300 mg/24 h) (n = 9); and group 3, clinical nephropathy (greater than 300 mg/24 h) (n = 8). Six male age-matched non-diabetic persons served as control subjects. The transcapillary escape rate of glycated...... significant role in the development of late diabetic microvascular complications....

A facile route to glycated albumin detection.

Science.gov (United States)

Bohli, Nadra; Meilhac, Olivier; Rondeau, Philippe; Gueffrache, Syrine; Mora, Laurence; Abdelghani, Adnane

2018-07-01

In this paper we propose an easy way to detect the glycated form of human serum albumin which is biomarker for several diseases such as diabetes and Alzheimer. The detection platform is a label free impedimetric immunosensor, in which we used a monoclonal human serum albumin antibody as a bioreceptor and electrochemical impedance as a transducing method. The antibody was deposited onto a gold surface by simple physisorption technique. Bovine serum albumin was used as a blocking agent for non-specific binding interactions. Cyclic voltammetry and electrochemical impedance spectroscopy were used for the characterization of each layer. Human serum albumin was glycated at different levels with several concentrations of glucose ranging from 0 mM to 500 mM representing physiological, pathological (diabetic albumin) and suprapathological concentration of glucose. Through the calibration curves, we could clearly distinguish between two different areas related to physiological and pathological albumin glycation levels. The immunosensor displayed a linear range from 7.49% to 15.79% of glycated albumin to total albumin with a good sensitivity. Surface plasmon resonance imaging was also used to characterize the developed immunosensor. Copyright © 2018 Elsevier B.V. All rights reserved.

The RAGE radiation-hydrodynamic code

International Nuclear Information System (INIS)

Gittings, Michael; Clover, Michael; Betlach, Thomas; Byrne, Nelson; Ranta, Dale; Weaver, Robert; Coker, Robert; Dendy, Edward; Hueckstaedt, Robert; New, Kim; Oakes, W Rob; Stefan, Ryan

2008-01-01

We describe RAGE, the 'radiation adaptive grid Eulerian' radiation-hydrodynamics code, including its data structures, its parallelization strategy and performance, its hydrodynamic algorithm(s), its (gray) radiation diffusion algorithm, and some of the considerable amount of verification and validation efforts. The hydrodynamics is a basic Godunov solver, to which we have made significant improvements to increase the advection algorithm's robustness and to converge stiffnesses in the equation of state. Similarly, the radiation transport is a basic gray diffusion, but our treatment of the radiation-material coupling, wherein we converge nonlinearities in a novel manner to allow larger timesteps and more robust behavior, can be applied to any multi-group transport algorithm

Assessment of nonenzymatic glycation in protein by FTIR spectroscopy

Science.gov (United States)

Otero de Joshi, Virginia; Joshi, Narahari V.; Gil, Herminia; Velasquez, William; Contreras, Silvia; Marquez, Glevis

1999-04-01

Detection of nonenzymatic glycated proteins is a very significant feature in diabetes, aging and related diseases, therefore we have carried out an FTIR spectroscopic study for glycated and native proteins such as (gamma) -globulin, human serum albumin. For this purpose, commercially available proteins were glycated by a usual procedure and their FTIR spectra were recorded together with that of the native ones. In order to follow the changes in time, (gamma) -globulin was glycated during 1, 2, 3, 5 and 8 weeks and their spectra were recorded. Direct verification was obtained by examining a model unit where the -NH2 group was attached to glucose. The spectrum shows a strong peak at 3500 cm-1 confirming the observed variation in time dependent spectra. The general features of the spectra are very similar and there was no additional structure or change in the peaks. This is understandable as not all the lysine residues are glycated, only a small fraction. Glucose is attached to the (epsilon) -amino group of lysine to form Amadori products, and therefore, the vibrational modes corresponding to the (epsilon) -NH2 unit of lysine are expected to be altered. This region exactly lies in the Amide I region of protein structure. Careful investigation of this part, indeed, shows a complex structure originated from alternations of -NH2 group. Thus, the present investigation indicates that an optical approach could be a rapid and effective method to identify the nonenzymatic glycation process.

Sulodexide prevents activation of the PLA2/COX-2/VEGF inflammatory pathway in human retinal endothelial cells by blocking the effect of AGE/RAGE.

Science.gov (United States)

Giurdanella, Giovanni; Lazzara, Francesca; Caporarello, Nunzia; Lupo, Gabriella; Anfuso, Carmelina Daniela; Eandi, Chiara M; Leggio, Gian Marco; Drago, Filippo; Bucolo, Claudio; Salomone, Salvatore

2017-10-15

Diabetic retinopathy is characterized by the breakdown of endothelial blood-retinal barrier. We tested the hypothesis that sulodexide (SDX), a highly purified glycosaminoglycan composed of 80% iduronylglycosaminoglycan sulfate and 20% dermatan sulfate, protects human retinal endothelial cells (HREC) from high glucose (HG)-induced damage, through the suppression of inflammatory ERK/cPLA2/COX-2/PGE 2 pathway, by blocking the effect of advanced glycation end-products (AGEs). HREC were treated with HG (25mM) or AGEs (glycated-BSA, 2mg/ml) for 48h, with or without SDX (60μg/ml) or aflibercept (AFL, 40μg/ml), a VEGF-trap. SDX protected HREC from HG-induced damage (MTT and LDH release) and preserved their blood-retinal barrier-like properties (Trans Endothelial Electrical Resistance and junction proteins, claudin-5, VE-cadherin and occludin, immunofluorescence and immunoblot) as well as their angiogenic potential (Tube Formation Assay). Both HG and AGEs increased phosphoERK and phospho-cPLA 2 , an effect counteracted by SDX and, less efficiently, by AFL. Both HG and exogenous VEGF (80ng/ml) increased PGE 2 release, an effect partially reverted by SDX for HG and by AFL for VEGF. Analysis of NFκB activity revealed that HG increased the abundance of p65 in the nuclear fraction (nuclear translocation), an effect entirely reverted by SDX, but only partially by AFL. SDX, AFL and SDX+AFL protected HREC even when added 24h after HG. These data show that SDX protects HREC from HG damage and suggest that it counteracts the activation of ERK/cPLA2/COX-2/PGE 2 pathway by reducing AGE-related signaling and downstream NFκB activity. This mechanism, partially distinct from VEGF blockade, may contribute to the therapeutic effect of SDX. Copyright © 2017 Elsevier Inc. All rights reserved.

In end stage osteoarthritis, cartilage tissue pentosidine levels are inversely related to parameters of cartilage damage

NARCIS (Netherlands)

Vos, P.A.J.M.; Mastbergen, S.C.; Huisman, A.M.; Boer, T.N.de; Groot, J.de; Polak, A.A.; Lafeber, F.P.J.G.

2012-01-01

Objectives: Age is the most prominent predisposition for development of osteoarthritis (OA). Age-related changes of articular cartilage are likely to play a role. Advanced glycation endproducts (AGEs) accumulate in cartilage matrix with increasing age and adversely affect the biomechanical

Skin autofluorescence and atherosclerosis

NARCIS (Netherlands)

Noordzij, Margaretha Johanna

2013-01-01

In ons lichaam stapelen bepaalde schadelijke stoffen (advanced glycation endproducts, afgekort AGE) zich op. Dit is deels onderdeel van het normale verouderingsproces, maar bij meerdere ziektebeelden is de opstapeling van AGE versneld en verhoogd. Dit was al aangetoond voor diabetes mellitus,

Skin Autofluorescence Based Decision Tree in Detection of Impaired Glucose Tolerance and Diabetes

NARCIS (Netherlands)

Smit, Andries J.; Smit, Jitske M.; Botterblom, Gijs J.; Mulder, Douwe

2013-01-01

Aim: Diabetes (DM) and impaired glucose tolerance (IGT) detection are conventionally based on glycemic criteria. Skin autofluorescence (SAF) is a noninvasive proxy of tissue accumulation of advanced glycation endproducts (AGE) which are considered to be a carrier of glycometabolic memory. We

The RAGE radiation-hydrodynamic code

Energy Technology Data Exchange (ETDEWEB)

Gittings, Michael; Clover, Michael; Betlach, Thomas; Byrne, Nelson; Ranta, Dale [Science Applications International Corp. MS A-1, 10260 Campus Point Drive, San Diego, CA 92121 (United States); Weaver, Robert; Coker, Robert; Dendy, Edward; Hueckstaedt, Robert; New, Kim; Oakes, W Rob [Los Alamos National Laboratory, MS T087, PO Box 1663, Los Alamos, NM 87545 (United States); Stefan, Ryan [TaylorMade-adidas Golf, 5545 Fermi Court, Carlsbad, CA 92008-7324 (United States)], E-mail: michael.r.clover@saic.com

2008-10-01

We describe RAGE, the 'radiation adaptive grid Eulerian' radiation-hydrodynamics code, including its data structures, its parallelization strategy and performance, its hydrodynamic algorithm(s), its (gray) radiation diffusion algorithm, and some of the considerable amount of verification and validation efforts. The hydrodynamics is a basic Godunov solver, to which we have made significant improvements to increase the advection algorithm's robustness and to converge stiffnesses in the equation of state. Similarly, the radiation transport is a basic gray diffusion, but our treatment of the radiation-material coupling, wherein we converge nonlinearities in a novel manner to allow larger timesteps and more robust behavior, can be applied to any multi-group transport algorithm.

Raman spectroscopy provides a powerful diagnostic tool for accurate determination of albumin glycation.

Science.gov (United States)

Dingari, Narahara Chari; Horowitz, Gary L; Kang, Jeon Woong; Dasari, Ramachandra R; Barman, Ishan

2012-01-01

We present the first demonstration of glycated albumin detection and quantification using Raman spectroscopy without the addition of reagents. Glycated albumin is an important marker for monitoring the long-term glycemic history of diabetics, especially as its concentrations, in contrast to glycated hemoglobin levels, are unaffected by changes in erythrocyte life times. Clinically, glycated albumin concentrations show a strong correlation with the development of serious diabetes complications including nephropathy and retinopathy. In this article, we propose and evaluate the efficacy of Raman spectroscopy for determination of this important analyte. By utilizing the pre-concentration obtained through drop-coating deposition, we show that glycation of albumin leads to subtle, but consistent, changes in vibrational features, which with the help of multivariate classification techniques can be used to discriminate glycated albumin from the unglycated variant with 100% accuracy. Moreover, we demonstrate that the calibration model developed on the glycated albumin spectral dataset shows high predictive power, even at substantially lower concentrations than those typically encountered in clinical practice. In fact, the limit of detection for glycated albumin measurements is calculated to be approximately four times lower than its minimum physiological concentration. Importantly, in relation to the existing detection methods for glycated albumin, the proposed method is also completely reagent-free, requires barely any sample preparation and has the potential for simultaneous determination of glycated hemoglobin levels as well. Given these key advantages, we believe that the proposed approach can provide a uniquely powerful tool for quantification of glycation status of proteins in biopharmaceutical development as well as for glycemic marker determination in routine clinical diagnostics in the future.

Raman Spectroscopy Provides a Powerful Diagnostic Tool for Accurate Determination of Albumin Glycation

Science.gov (United States)

Dingari, Narahara Chari; Horowitz, Gary L.; Kang, Jeon Woong; Dasari, Ramachandra R.; Barman, Ishan

2012-01-01

We present the first demonstration of glycated albumin detection and quantification using Raman spectroscopy without the addition of reagents. Glycated albumin is an important marker for monitoring the long-term glycemic history of diabetics, especially as its concentrations, in contrast to glycated hemoglobin levels, are unaffected by changes in erythrocyte life times. Clinically, glycated albumin concentrations show a strong correlation with the development of serious diabetes complications including nephropathy and retinopathy. In this article, we propose and evaluate the efficacy of Raman spectroscopy for determination of this important analyte. By utilizing the pre-concentration obtained through drop-coating deposition, we show that glycation of albumin leads to subtle, but consistent, changes in vibrational features, which with the help of multivariate classification techniques can be used to discriminate glycated albumin from the unglycated variant with 100% accuracy. Moreover, we demonstrate that the calibration model developed on the glycated albumin spectral dataset shows high predictive power, even at substantially lower concentrations than those typically encountered in clinical practice. In fact, the limit of detection for glycated albumin measurements is calculated to be approximately four times lower than its minimum physiological concentration. Importantly, in relation to the existing detection methods for glycated albumin, the proposed method is also completely reagent-free, requires barely any sample preparation and has the potential for simultaneous determination of glycated hemoglobin levels as well. Given these key advantages, we believe that the proposed approach can provide a uniquely powerful tool for quantification of glycation status of proteins in biopharmaceutical development as well as for glycemic marker determination in routine clinical diagnostics in the future. PMID:22393405

Glycation alters ligand binding, enzymatic, and pharmacological properties of human albumin.

Science.gov (United States)

Baraka-Vidot, Jennifer; Planesse, Cynthia; Meilhac, Olivier; Militello, Valeria; van den Elsen, Jean; Bourdon, Emmanuel; Rondeau, Philippe

2015-05-19

Albumin, the major circulating protein in blood plasma, can be subjected to an increased level of glycation in a diabetic context. Albumin exerts crucial pharmacological activities through its drug binding capacity, i.e., ketoprofen, and via its esterase-like activity, allowing the conversion of prodrugs into active drugs. In this study, the impact of the glucose-mediated glycation on the pharmacological and biochemical properties of human albumin was investigated. Aggregation product levels and the redox state were quantified to assess the impact of glycation-mediated changes on the structural properties of albumin. Glucose-mediated changes in ketoprofen binding properties and esterase-like activity were evaluated using fluorescence spectroscopy and p-nitrophenyl acetate hydrolysis assays, respectively. With the exception of oxidative parameters, significant dose-dependent alterations in biochemical and functional properties of in vitro glycated albumin were observed. We also found that the dose-dependent increase in levels of glycation and protein aggregation and average molecular mass changes correlated with a gradual decrease in the affinity of albumin for ketoprofen and its esterase-like property. In parallel, significant alterations in both pharmacological properties were also evidenced in albumin purified from diabetic patients. Partial least-squares regression analyses established a significant correlation between glycation-mediated changes in biochemical and pharmacological properties of albumin, highlighting the important role for glycation in the variability of the drug response in a diabetic situation.

Glycation induces formation of amyloid cross-beta structure in albumin.

Science.gov (United States)

Bouma, Barend; Kroon-Batenburg, Loes M J; Wu, Ya-Ping; Brünjes, Bettina; Posthuma, George; Kranenburg, Onno; de Groot, Philip G; Voest, Emile E; Gebbink, Martijn F B G

2003-10-24

Amyloid fibrils are components of proteinaceous plaques that are associated with conformational diseases such as Alzheimer's disease, transmissible spongiform encephalopathies, and familial amyloidosis. Amyloid polypeptides share a specific quarternary structure element known as cross-beta structure. Commonly, fibrillar aggregates are modified by advanced glycation end products (AGE). In addition, AGE formation itself induces protein aggregation. Both amyloid proteins and protein-AGE adducts bind multiligand receptors, such as receptor for AGE, CD36, and scavenger receptors A and B type I, and the serine protease tissue-type plasminogen activator (tPA). Based on these observations, we hypothesized that glycation induces refolding of globular proteins, accompanied by formation of cross-beta structure. Using transmission electron microscopy, we demonstrate here that glycated albumin condensates into fibrous or amorphous aggregates. These aggregates bind to amyloid-specific dyes Congo red and thioflavin T and to tPA. In contrast to globular albumin, glycated albumin contains amino acid residues in beta-sheet conformation, as measured with circular dichroism spectropolarimetry. Moreover, it displays cross-beta structure, as determined with x-ray fiber diffraction. We conclude that glycation induces refolding of initially globular albumin into amyloid fibrils comprising cross-beta structure. This would explain how glycated ligands and amyloid ligands can bind to the same multiligand "cross-beta structure" receptors and to tPA.

Raman Spectroscopy Provides a Powerful Diagnostic Tool for Accurate Determination of Albumin Glycation

OpenAIRE

Dingari, Narahara Chari; Kang, Jeon Woong; Dasari, Ramachandra R.; Barman, Ishan; Horowitz, Gary Leigh

2012-01-01

We present the first demonstration of glycated albumin detection and quantification using Raman spectroscopy without the addition of reagents. Glycated albumin is an important marker for monitoring the long-term glycemic history of diabetics, especially as its concentrations, in contrast to glycated hemoglobin levels, are unaffected by changes in erythrocyte life times. Clinically, glycated albumin concentrations show a strong correlation with the development of serious diabetes complications...

on skin keratinocytes by nuclear factor-kappa B

African Journals Online (AJOL)

DR. NJ TONUKARI

2012-06-21

Jun 21, 2012 ... Effects of advanced glycation end-products (AGEs) on ... AGE levels, nuclear factor-kappa B (NF-κB) localization and cell viability were measured in vivo. ..... and related alteration in NF-κB activity, we treated normal cells by ...

Improvement of succinate production by release of end-product inhibition in Corynebacterium glutamicum.

Science.gov (United States)

Chung, Soon-Chun; Park, Joon-Song; Yun, Jiae; Park, Jin Hwan

2017-03-01

Succinate is a renewable-based platform chemical that may be used to produce a wide range of chemicals including 1,4-butanediol, tetrahydrofurane, and γ-butyrolactone. However, industrial fermentation of organic acids is often subject to end-product inhibition, which significantly retards cell growth and limits metabolic activities and final productivity. In this study, we report the development of metabolically engineered Corynebacterium glutamicum for high production of succinate by release of end-product inhibition coupled with an increase of key metabolic flux. It was found that the rates of glucose consumption and succinate production were significantly reduced by extracellular succinate in an engineered strain, S003. To understand the mechanism underlying the inhibition by succinate, comparative transcriptome analysis was performed. Among the downregulated genes, overexpression of the NCgl0275 gene was found to suppress the inhibition of glucose consumption and succinate production, resulting in a 37.7% increase in succinate production up to 55.4g/L in fed-batch fermentation. Further improvement was achieved by increasing the metabolic flux from PEP to OAA. The final engineered strain was able to produce 152.2g/L succinate, the highest production reported to date, with a yield of 1.1g/g glucose under anaerobic condition. These results suggest that the release of end-product inhibition coupled with an increase in key metabolic flux is a promising strategy for enhancing production of succinate. Copyright © 2017. Published by Elsevier Inc.

Destructive effect of non-enzymatic glycation on catalase and remediation via curcumin.

Science.gov (United States)

Mofidi Najjar, Fayezeh; Taghavi, Fereshteh; Ghadari, Rahim; Sheibani, Nader; Moosavi-Movahedi, Ali Akbar

2017-09-15

Non-enzymatic glycation of proteins is a post-translational modification that is produced by a covalent binding between reducing sugars and amino groups of lysine and arginine residues. In this paper the effect of pathological conditions, derived from hyperglycemia on bovine liver catalase (BLC) as a model protein was considered by measuring enzyme activity, reactive oxygen species (ROS) generation, and changes in catalase conformational properties. We observed that in the presence of glucose, the catalase activity gradually decreased. ROS generation was also involved in the glycation process. Thus, decreased BLC activity was partly considered as a result of ROS generation through glycation. However, in the presence of curcumin the amount of ROS was reduced resulting in increased activity of the glycated catalase. The effect of high glucose level and the potential inhibitory effect of curcumin on aggregation and structural changes of catalase were also investigated. Molecular dynamic simulations also showed that interaction of catalase with curcumin resulted in changes in accessible surface area (ASA) and pKa, two effective parameters of glycation, in potential glycation lysine residues. Thus, the decrease in ASA and increase in pKa of important lysine residues were considered as predominant factors in decreased glycation of BLC by curcumin. Copyright © 2017 Elsevier Inc. All rights reserved.

[Vascular Calcification - Pathological Mechanism and Clinical Application - . Role of vascular smooth muscle cells in vascular calcification].

Science.gov (United States)

Kurabayashi, Masahiko

2015-05-01

Vascular calcification is commonly seen with aging, chronic kidney disese (CKD), diabetes, and atherosclerosis, and is closely associated with cardiovascular morbidity and mortality. Vascular calcification has long been regarded as the final stage of degeneration and necrosis of arterial wall and a passive, unregulated process. However, it is now known to be an active and tightly regulated process involved with phenotypic transition of vascular smooth muscle cells (VSMC) that resembles bone mineralization. Briefly, calcium deposits of atherosclerotic plaque consist of hydroxyapatite and may appear identical to fully formed lamellar bone. By using a genetic fate mapping strategy, VSMC of the vascular media give rise to the majority of the osteochondrogenic precursor- and chondrocyte-like cells observed in the calcified arterial media of MGP (- / -) mice. Osteogenic differentiation of VSMC is characterized by the expression of bone-related molecules including bone morphogenetic protein (BMP) -2, Msx2 and osteopontin, which are produced by osteoblasts and chondrocytes. Our recent findings are that (i) Runx2 and Notch1 induce osteogenic differentiation, and (ii) advanced glycation end-product (AGE) /receptor for AGE (RAGE) and palmitic acid promote osteogenic differentiation of VSMC. To understand of the molecular mechanisms of vascular calcification is now under intensive research area.

Toxic AGE (TAGE Theory for the Pathophysiology of the Onset/Progression of NAFLD and ALD

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Masayoshi Takeuchi

2017-06-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD and alcoholic liver disease (ALD are among the most common causes of chronic liver diseases in the westernized world. NAFLD and ALD are frequently accompanied by extrahepatic complications, including hepatocellular carcinoma and cardiovascular diseases, which have a negative impact on patient survival. The chronic ingestion of an excessive daily diet containing sugar/high-fructose corn syrup increases the level of the fructose/glucose metabolite, glyceraldehyde (GA, while the chronic consumption of an excessive number of alcoholic beverages increases the level of the alcohol metabolite, acetaldehyde (AA in the liver. GA and AA are known to react non-enzymatically with the ε- or α-amino groups of proteins, thereby generating advanced glycation end-products (AGEs, GA-AGEs, and AA-AGEs, respectively in vivo. The interaction between GA-AGEs and the receptor for AGEs (RAGE alters intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the production of reactive oxygen species by human hepatocytes and hepatic stellate cells, all of which may contribute to the pathological changes associated with chronic liver diseases. We herein discuss the pathophysiological roles of GA-AGEs and AA-AGEs (toxic AGEs, TAGE and a related novel theory for preventing the onset/progression of NAFLD and ALD.

Electroacupuncture Attenuates CFA-induced Inflammatory Pain by suppressing Nav1.8 through S100B, TRPV1, Opioid, and Adenosine Pathways in Mice.

Science.gov (United States)

Liao, Hsien-Yin; Hsieh, Ching-Liang; Huang, Chun-Ping; Lin, Yi-Wen

2017-02-13

Pain is associated with several conditions, such as inflammation, that result from altered peripheral nerve properties. Electroacupuncture (EA) is a common Chinese clinical medical technology used for pain management. Using an inflammatory pain mouse model, we investigated the effects of EA on the regulation of neurons, microglia, and related molecules. Complete Freund's adjuvant (CFA) injections produced a significant mechanical and thermal hyperalgesia that was reversed by EA or a transient receptor potential V1 (TRPV1) gene deletion. The expression of the astrocytic marker glial fibrillary acidic protein (GFAP), the microglial marker Iba-1, S100B, receptor for advanced glycation end-products (RAGE), TRPV1, and other related molecules was dramatically increased in the dorsal root ganglion (DRG) and spinal cord dorsal horn (SCDH) of CFA-treated mice. This effect was reversed by EA and TRPV1 gene deletion. In addition, endomorphin (EM) and N 6 -cyclopentyladenosine (CPA) administration reliably reduced mechanical and thermal hyperalgesia, thereby suggesting the involvement of opioid and adenosine receptors. Furthermore, blocking of opioid and adenosine A1 receptors reversed the analgesic effects of EA. Our study illustrates the substantial therapeutic effects of EA against inflammatory pain and provides a novel and detailed mechanism underlying EA-mediated analgesia via neuronal and non-neuronal pathways.

The narrow therapeutic window of glycated hemoglobin and assay variability.

Science.gov (United States)

Hosseini, S S; Bibler, I; Charles, M A

1999-12-01

Glycated hemoglobin is measured by a variety of assays, each of which has a unique normal level. Our purpose is to show that among the different assays available in the United States, using the same patient's blood sample, assay results may vary widely and may more or less easily achieve a glycated hemoglobin value within the normal range. The following assays were compared using the same patient's blood sample for each pair of assays: glycohemoglobin affinity assay (GHB Reader; Isolab, Akron, OH) versus gel electrophoresis assay (n = 76); Isolab versus ion capture assay (IMX; Abbott Laboratories, Irving, TX) (n = 57); monoclonal antibody assay (DCA2000; Bayer Diagnostics, Pittsburgh, PA) versus IMX (n = 100); and high-performance liquid chromatography (HPLC) assay (Bio-Rad Variant A1c; Bio-Rad Laboratories, Richmond, CA) versus IMX assay (n = 55). Our analyses indicate that a relative ranking can be established for the ease of achieving a normal glycated hemoglobin level. The ranking indicates that the most stringent or difficult assays for achieving a normal level are the Isolab and DCA2000 assays. The intermediate assays are the IMX and Bio-Rad Variant, and the easiest method for achieving a normal value is the gel electrophoresis assay. Our results indicate that various glycated hemoglobin assays vary widely and are associated with more or less difficulty for an individual patient to achieve a glycated hemoglobin level within the normal range. These results are especially significant with respect to (1) the clinically narrow therapeutic window of glycated hemoglobin values in type 1 diabetes to avoid rapidly advancing severe hypoglycemia rates and chronic microvascular complication rates, and (2) the glycated hemoglobin threshold for rapidly advancing macrovascular disease in both type 1 and type 2 patients.

Calorimetric investigation of diclofenac drug binding to a panel of moderately glycated serum albumins.

Science.gov (United States)

Indurthi, Venkata S K; Leclerc, Estelle; Vetter, Stefan W

2014-08-01

Glycation alters the drug binding properties of serum proteins and could affect free drug concentrations in diabetic patients with elevated glycation levels. We investigated the effect of bovine serum albumin glycation by eight physiologically relevant glycation reagents (glucose, ribose, carboxymethyllysine, acetoin, methylglyoxal, glyceraldehyde, diacetyl and glycolaldehyde) on diclofenac drug binding. We used this non-steroidal anti-inflammatory drug diclofenac as a paradigm for acidic drugs with high serum binding and because of its potential cardiovascular risks in diabetic patients. Isothermal titration calorimetry showed that glycation reduced the binding affinity Ka of serum albumin and diclofenac 2 to 6-fold by reducing structural rigidity of albumin. Glycation affected the number of drug binding sites in a glycation reagent dependent manner and lead to a 25% decrease for most reagent, expect for ribose, with decreased by 60% and for the CML-modification, increased the number of binding sites by 60%. Using isothermal titration calorimetry and differential scanning calorimetry we derived the complete thermodynamic characterization of diclofenac binding to all glycated BSA samples. Our results suggest that glycation in diabetic patients could significantly alter the pharmacokinetics of the widely used over-the-counter NSDAI drug diclofenac and with possibly negative implications for patients. Copyright © 2014 Elsevier B.V. All rights reserved.

Products by Glycation Process

Directory of Open Access Journals (Sweden)

Liliana Ortega

2015-01-01

Full Text Available The antioxidant properties of sweet and acid whey products were incremented by polymerization of their proteins by glycation of whey protein concentrates (WPC and their hydrolyzates (WPCH with ribose and glucose in individual experiments under similar concentration. Heating at 50°C during 20 h maximum and pH 7 and pH 9 were used in all tests. The higher activity was found in WPC glycosylates products with ribose at pH 7 and heating during 10–15 h. In comparable form, antioxidant activity in WPCH was incremented by prior hydrolysis to glycation with 25–45% of hydrolysis degree. Further functional properties of whey proteins (solubility, emulsion, and foam were also improved by the polymerization with ribose. The color of polymerized products due to Maillard reactions was associated with antioxidant activity of each compound; however comparative color in glycosylates products with glucose and ribose did not show this effect.

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Indian Academy of Sciences (India)

2015-04-20

Apr 20, 2015 ... 1999). As carbonylation results .... ifies the charge-selective filtration properties of the basement membrane .... experimental diabetes in animal models (Yamagishi et al. 2005). ..... Taga Y and Akalin S 2006 Effects of ACE inhibition and ...... vent the formation of advanced glycation endproducts. Arch.

Skin color independent assessment of aging using skin autofluorescence

NARCIS (Netherlands)

Koetsier, M.; Nur, Erfan; Chunmao, Han; Lutgers, Helen L.; Links, Thera P.; Smit, Andries J.; Rakhorst, Gerhard; Graaff, Reindert

2010-01-01

Skin autofluorescence (AF) for the non-invasive assessment of the amount of accumulated tissue Advanced Glycation Endproducts (AGEs) increases with aging. In subjects with darker skin colors, measurements typically result in lower AF values than in subjects with fair skin colors, e.g. due to

Skin color independent assessment of aging using skin autofluorescence

NARCIS (Netherlands)

Koetsier, M.; Nur, E.; Chunmao, H.; Lutgers, H.L.; Links, T.P.; Smit, A.J.; Rakhorst, G.; de Graaff, R.

2010-01-01

Skin autofluorescence (AF) for the non-invasive assessment of the amount of accumulated tissue Advanced Glycation Endproducts (AGEs) increases with aging. In subjects with darker skin colors, measurements typically result in lower AF values than in subjects with fair skin colors, e. g. due to

Polymorphisms in glyoxalase 1 gene are not associated with vascular complications: the Hoorn and CoDAM studies

NARCIS (Netherlands)

Engelen, L.; Ferreira, I.; Brouwers, O.; Henry, R.M.A.; Dekker, J.M.; Nijpels, G.; Heine, R.J.; Greevenbroek, van M.M.J.; Kallen, van der C.J.H.; Blaak, E.E.; Feskens, E.J.M.; Cate, ten H.; Stehouwer, C.D.A.; Schalkwijk, C.G.

2009-01-01

Objectives Methylglyoxal is a major precursor in the formation of advanced glycation endproducts (AGEs), which are known to contribute to vascular complications such as hypertension and arterial stiffness. Methylglyoxal can be detoxified by glyoxalase 1 (GLO1). Because genetic variation in the GLO1

Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats.

Science.gov (United States)

Stracke, H; Hammes, H P; Werkmann, D; Mavrakis, K; Bitsch, I; Netzel, M; Geyer, J; Köpcke, W; Sauerland, C; Bretzel, R G; Federlin, K F

2001-01-01

In rats with streptozotocin (STZ) induced diabetes the effect of (watersoluble) thiamine nitrate and of (lipidsoluble) benfotiamine on peripheral nerve function (motor nerve conduction velocity) as well as on the formation of advanced glycation end-products in peripheral nerve tissue was studied. In one group of animals drug administration was started immediately after diabetes induction (prevention study) and in another group two months after diabetes induction (treatment study). Motor nerve conduction velocity (NCV) dropped by 10.5% in diabetic animals, carboxymethyl-lysine (CML) rose to a 3.5fold concentration, deoxyglucosone (3DG)-type AGE formation was increased 5.1fold compared with controls. After three months preventive administration of both vitamin B(1) preparations NCV had increased substantially compared with results in diabetic controls. It was nearly normal after six months with benfotiamine, while the administration of thiamine nitrate resulted in no further amelioration. NCV was nearly normalized after six months of benfotiamine application but not with thiamine. Furthermore, benfotiamine induced a major inhibition of neural imidazole-type AGE formation and completely prevented diabetes induced glycoxidation products (CML). Treatment with thiamine did not significantly affect AGE or cmL levels. Unlike treatment with water-soluble thiamine nitrate timely administration of liposoluble prodrug benfotiamine was effective in the prevention of functional damage and of AGE and cmL formation in nerves of diabetic rats.

HMGB1 Contributes to the Expression of P-Glycoprotein in Mouse Epileptic Brain through Toll-Like Receptor 4 and Receptor for Advanced Glycation End Products.

Directory of Open Access Journals (Sweden)

Yan Chen

Full Text Available The objective of the present study was to investigate the role of high-mobility group box-1 (HMGB1 in the seizure-induced P-glycoprotein (P-gp overexpression and the underlying mechanism. Kainic acid (KA-induced mouse seizure model was used for in vivo experiments. Male C57BL/6 mice were divided into four groups: normal saline control (NS group, KA-induced epileptic seizure (EP group, and EP group pretreated with HMGB1 (EP+HMGB1 group or BoxA (HMGB1 antagonist, EP+BoxA group. Compared to the NS group, increased levels of HMGB1 and P-gp in the brain were observed in the EP group. Injection of HMGB1 before the induction of KA further increased the expression of P-gp while pre-treatment with BoxA abolished this up-regulation. Next, the regulatory role of HMGB1 and its potential involved signal pathways were investigated in mouse microvascular endothelial bEnd.3 cells in vitro. Cells were treated with HMGB1, HMGB1 plus lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS [toll-like receptor 4 (TLR4 antagonist], HMGB1 plus FPS-ZM1 [receptor for advanced glycation end products (RAGE inhibitor], HMGB1 plus SN50 [nuclear factor-kappa B (NF-κB inhibitor], or vehicle. Treatment with HMGB1 increased the expression levels of P-gp, TLR4, RAGE and the activation of NF-κB in bEnd.3 cells. These effects were inhibited by the pre-treatment with either LPS-RS or FPS-ZM1, and were abolished by the pre-treatment of SN50 or a combination treatment of both LPS-RS and FPS-ZM1. Luciferase reporter assays showed that exogenous expression of NF-κB p65 increased the promoter activity of multidrug resistance 1a (P-gp-encoding gene in endothelial cells. These data indicate that HMGB1 contributes to the overexpression of P-gp in mouse epileptic brain tissues via activation of TLR4/RAGE receptors and the downstream transcription factor NF-κB in brain microvascular endothelial cells.

High-Mobility Group Box 1 Mediates Fibroblast Activity via RAGE-MAPK and NF-κB Signaling in Keloid Scar Formation.

Science.gov (United States)

Kim, Jihee; Park, Jong-Chul; Lee, Mi Hee; Yang, Chae Eun; Lee, Ju Hee; Lee, Won Jai

2017-12-28

Emerging studies have revealed the involvement of high-mobility group box 1 (HMGB1) in systemic fibrotic diseases, yet its role in the cutaneous scarring process has not yet been investigated. We hypothesized that HMGB1 may promote fibroblast activity to cause abnormal cutaneous scarring. In vitro wound healing assay with normal and keloid fibroblasts demonstrated that HMGB1 administration promoted the migration of both fibroblasts with increased speed and a greater traveling distance. Treatment of the HMGB1 inhibitor glycyrrhizic acid (GA) showed an opposing effect on both activities. To analyze the downstream mechanism, the protein levels of extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (AKT), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were measured by western blot analysis. HMGB1 increased the expression levels of ERK1/2, AKT, and NF-κB compared to the control, which was suppressed by GA. HMGB1 promoted both normal and keloid fibroblasts migration to a degree equivalent to that achieved with TGF-β. We concluded that HMGB1 activates fibroblasts via the receptor for advanced glycation end product (RAGE)-mitogen-activated protein kinases (MAPK) and NF-κB interaction signaling pathways. Further knowledge of the relationship of HMGB1 with skin fibrosis may lead to a promising clinical approach to manage abnormal scarring.

Soluble and Endogenous Secretory Receptors for Advanced Glycation End Products in Threatened Preterm Labor and Preterm Premature Rupture of Fetal Membranes

Science.gov (United States)

Dołegowska, Barbara; Kwiatkowski, Sebastian; Sałata, Daria; Budkowska, Marta; Domański, Leszek; Mikołajek-Bedner, Wioletta; Torbé, Andrzej

2015-01-01

The aim of the study was to compare sRAGE and esRAGE plasma levels in pregnant women with (A) threatened premature labor (n = 41), (B) preterm premature rupture of membranes (n = 49), and (C) preterm rupture of membranes at term (n = 48). The relationship between these and classic intrauterine infection markers and the latent time from symptoms up to delivery depending on RAGE's concentration were investigated. In groups A and B, a positive correlation was found between plasma sRAGE and latent time (r = 0,422; p = 0,001; r = 0,413, p = 0,004, resp.). High prognostic values were found in both groups for plasma sRAGE concentration and the latent time from symptoms up to delivery. Groups B and C presented higher levels of esRAGE than group A (526,315 ± 129,453 pg/mL and 576,212 ± 136,237 pg/mL versus 485,918 ± 133,127 pg/mL, ppremature labor. Higher esRAGE plasma level in case of the rupture of membranes in mature and premature pregnancy suggests its participation in fetal membranes destruction. PMID:26413536

Inhibitory effect of alliin from Allium sativum on the glycation of superoxide dismutase.

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Anwar, Shehwaz; Younus, Hina

2017-10-01

Inhibition of glycation is an important approach for alleviating diabetic complications. Alliin, the most abundant sulphur compound in garlic has been demonstrated to possess antidiabetic activity. However, there is no scientific evidence supporting its antiglycating activity. The objective of this study was to determine the inhibitory effect of alliin on glucose and methyglyoxal (MG)-induced glycation of an important antioxidant enzyme, superoxide dismutase (SOD). Glycation of SOD resulted in a decrease in enzyme activity, fragmentation/cross-linking, reduced cross-reactivity with anti-SOD antibodies, both tertiary and secondary structural changes, and formation of AGEs and fibrils. Alliin offered protection against glucose or MG induced glycation of SOD. The antiglycating potential of alliin appears to be comparable with that of quercetin which is reported to be a potent natural inhibitor of glycation. Alliin has a good antiglycating effect and hence is expected to have therapeutic potential in the prevention of glycation-mediated diabetic complications. Copyright © 2017 Elsevier B.V. All rights reserved.

The methylglyoxal-derived AGE tetrahydropyrimidine is increased in plasma of individuals with type 1 diabetes mellitus and in atherosclerotic lesions and is associated with sVCAM-1

DEFF Research Database (Denmark)

van Eupen, M G A; Schram, M T; Colhoun, H M

2013-01-01

Methylglyoxal (MGO) is a major precursor for advanced glycation end-products (AGEs), which are thought to play a role in vascular complications in diabetes. Known MGO-arginine-derived AGEs are 5-hydro-5-methylimidazolone (MG-H1), argpyrimidine and tetrahydropyrimidine (THP). We studied THP in rel...

Increase in Skin Autofluorescence and Release of Heart-Type Fatty Acid Binding Protein in Plasma Predicts Mortality of Hemodialysis Patients

NARCIS (Netherlands)

Arsov, Stefan; Trajceska, Lada; van Oeveren, Wim; Smit, Andries J.; Dzekova, Pavlina; Stegmayr, Bernd; Sikole, Aleksandar; Rakhorst, Gerhard; Graaff, Reindert

Advanced glycation end-products (AGEs) are uremic toxins that accumulate progressively in hemodialysis (HD) patients. The aim of this study was to assess the 1-year increase in skin autofluorescence (DAF), a measure of AGEs accumulation and plasma markers, as predictors of mortality in HD patients.

Sleep Now in The Fire: An Analysis of A Song by Rage Against The Machine Using Marxism

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Abdul Azis Turhan Kariko

2011-10-01

Full Text Available Rage against the Machine is known for their politics as well as their music, which the later helped creating an aggressive-heavy rock-rap genre. Article presents a song by Rage against the Machine band related to ideological movement in America, titled Sleep Now in the Fire. This effort brings an understanding of ideology that is embraced by the band. The method is through literature study. Presentation begins with a short biography of the band, theoretical concepts, and analysis of the song as well its music video. It is concluded that the song represents ideological criticism toward capitalism using Marxism. Both of these lyric and music video represents Marxism as it shares the same movement to fight capitalism—which in this case, Rage against the Machine is using their music, lyric, and video to fight the crime against humanity and cultural imperialism. 

Biological Potential of Sixteen Legumes in China

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Guixing Ren

2011-10-01

Full Text Available Phenolic acids have been identified in a variety of legumes including lima bean, broad bean, common bean, pea, jack bean, goa bean, adzuki bean, hyacinth bean, chicking vetch, garbanzo bean, dral, cow bean, rice bean, mung bean and soybean. The present study was carried out with the following aims: (1 to identify and quantify the individual phenolic acid and determine the total phenolic content (TPC; (2 to assess their antioxidant activity, inhibition activities of α-glucosidase, tyrosinase, and formation of advanced glycation endproducts; and (3 to investigate correlations among the phytochemicals and biological activity. Common bean possesses the highest antioxidant activity and advanced glycation endproducts formation inhibition activity. Adzuki bean has the highest α-glucosidase inhibition activity, and mung bean has the highest tyrosinase inhibition activity. There are significant differences in phytochemical content and functional activities among the bean species investigated. Selecting beans can help treat diseases such as dermatological hyperpigmentation illness, type 2 diabetes and associated cardiovascular diseases.

Whole wheat bread: Effect of bran fractions on dough and end-product quality

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Consumption of whole-wheat based products is encouraged due to its important nutritional elements that beneficial to human health. However, processing of whole-wheat based products, such as whole-wheat bread, results in poor end-product quality. Bran was postulated as the major problem. In this stud...

HMGB1 induces an inflammatory response in endothelial cells via the RAGE-dependent endoplasmic reticulum stress pathway

International Nuclear Information System (INIS)

Luo, Ying; Li, Shu-Jun; Yang, Jian; Qiu, Yuan-Zhen; Chen, Fang-Ping

2013-01-01

Highlights: •Mechanisms of inflammatory response induced by HMGB1 are incompletely understood. •We found that endoplasmic reticulum stress mediate the inflammatory response induced by HMGB1. •RAGE-mediated ERS pathways are involved in those processes. •We reported a new mechanism for HMGB1 induced inflammatory response. -- Abstract: The high mobility group 1B protein (HMGB1) mediates chronic inflammatory responses in endothelial cells, which play a critical role in atherosclerosis. However, the underlying mechanism is unknown. The goal of our study was to identify the effects of HMGB1 on the RAGE-induced inflammatory response in endothelial cells and test the possible involvement of the endoplasmic reticulum stress pathway. Our results showed that incubation of endothelial cells with HMGB1 (0.01–1 μg/ml) for 24 h induced a dose-dependent activation of endoplasmic reticulum stress transducers, as assessed by PERK and IRE1 protein expression. Moreover, HMGB1 also promoted nuclear translocation of ATF6. HMGB1-mediated ICAM-1 and P-selectin production was dramatically suppressed by PERK siRNA or IRE1 siRNA. However, non-targeting siRNA had no such effects. HMGB1-induced increases in ICAM-1 and P-selectin expression were also inhibited by a specific eIF2α inhibitor (salubrinal) and a specific JNK inhibitor (SP600125). Importantly, a blocking antibody specifically targeted against RAGE (anti-RAGE antibody) decreased ICAM-1, P-selectin and endoplasmic reticulum stress molecule (PERK, eIF2α, IRE1 and JNK) protein expression levels. Collectively, these novel findings suggest that HMGB1 promotes an inflammatory response by inducing the expression of ICAM-1 and P-selectin via RAGE-mediated stimulation of the endoplasmic reticulum stress pathway

Role of IL-1 beta and 5-HT2 receptors in midbrain periaqueductal gray (PAG) in potentiating defensive rage behavior in cat.

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Bhatt, Suresh; Bhatt, Rekha; Zalcman, Steven S; Siegel, Allan

2008-02-01

Feline defensive rage, a form of aggressive behavior that occurs in response to a threat can be elicited by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Our laboratory has recently begun a systematic examination of the role of cytokines in the regulation of rage and aggressive behavior. It was shown that the cytokine, interleukin-2 (IL-2), differentially modulates defensive rage when microinjected into the medial hypothalamus and PAG by acting through separate neurotransmitter systems. The present study sought to determine whether a similar relationship exists with respect to interleukin 1-beta (IL-1 beta), whose receptor activation in the medial hypothalamus potentiates defensive rage. Thus, the present study identified the effects of administration of IL-1 beta into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of IL-1 beta into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus in a dose and time dependent manner. In addition, the facilitative effects of IL-1 beta were blocked by pre-treatment with anti-IL-1 beta receptor antibody, while IL-1 beta administration into the PAG had no effect upon predatory attack elicited from the lateral hypothalamus. The findings further demonstrated that IL-1 beta's effects were mediated through 5-HT(2) receptors since pretreatment with a 5-HT(2C) receptors antagonist blocked the facilitating effects of IL-1 beta. An extensive pattern of labeling of IL-1 beta and 5-HT(2C) receptors in the dorsal PAG supported these findings. The present study demonstrates that IL-beta in the dorsal PAG, similar to the medial hypothalamus, potentiates defensive rage behavior and is mediated through a 5-HT(2C) receptor mechanism.

Coptis chinensis Polysaccharides Inhibit Advanced Glycation End Product Formation.

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Yang, Ye; Li, Yun; Yin, Dengke; Chen, Song; Gao, Xiangdong

2016-06-01

Coptis chinensis Franch (Huanglian) is commonly used to treat diabetes in China. In this study, the effects of the C. chinensis Franch polysaccharides (CCP) on advanced glycation end product (AGE) formation in vitro and in streptozotocin-induced diabetic mice were investigated. CCP significantly inhibited all the three periods of nonenzymatic protein glycation in vitro, including Amadori product, dicarbonyl compound, and AGE formation (P < .01). In diabetic mice, the administration of CCP not only improved both bodyweight and serum insulin and decreased fasting blood glucose and glycated serum protein concentrations but also decreased the AGE accumulations and morphological abnormalities in pancreas and liver. The inhibitory effects of CCP on AGE formation afford a potential therapeutic use in the prevention and treatment of diabetes.

N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats

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Karolline S. da Silva

2017-09-01

Full Text Available Background: Advanced glycation endproducts elicit inflammation. However, their role in adipocyte macrophage infiltration and in the development of insulin resistance, especially in the absence of the deleterious biochemical pathways that coexist in diabetes mellitus, remains unknown. We investigated the effect of chronic administration of advanced glycated albumin (AGE-albumin in healthy rats, associated or not with N-acetylcysteine (NAC treatment, on insulin sensitivity, adipose tissue transcriptome and macrophage infiltration and polarization.Methods: Male Wistar rats were intraperitoneally injected with control (C or AGE-albumin alone, or, together with NAC in the drinking water. Biochemical parameters, lipid peroxidation, gene expression and protein contents were, respectively, determined by enzymatic techniques, reactive thiobarbituric acid substances, RT-qPCR and immunohistochemistry or immunoblot. Carboxymethyllysine (CML and pyrraline (PYR were determined by LC/mass spectrometry (LC-MS/MS and ELISA.Results: CML and PYR were higher in AGE-albumin as compared to C. Food consumption, body weight, systolic blood pressure, plasma lipids, glucose, hepatic and renal function, adipose tissue relative weight and adipocyte number were similar among groups. In AGE-treated animals, insulin resistance, adipose macrophage infiltration and Col12a1 mRNA were increased with no changes in M1 and M2 phenotypes as compared to C-albumin-treated rats. Total GLUT4 content was reduced by AGE-albumin as compared to C-albumin. NAC improved insulin sensitivity, reduced urine TBARS, adipose macrophage number and Itgam and Mrc mRNA and increased Slc2a4 and Ppara. CD11b, CD206, Ager, Ddost, Cd36, Nfkb1, Il6, Tnf, Adipoq, Retn, Arg, and Il12 expressions were similar among groups.Conclusions: AGE-albumin sensitizes adipose tissue to inflammation due to macrophage infiltration and reduces GLUT4, contributing to insulin resistance in healthy rats. NAC antagonizes AGE

Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent

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Pascale Crissey L

2011-07-01

Full Text Available Abstract Background Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD. There is an accumulation of amyloid-beta peptides (Aβ in both the AD brain and the normal aging brain. Clearance of Aβ from the brain occurs via active transport at the blood-brain barrier (BBB and blood-cerebrospinal fluid barrier (BCSFB. With increasing age, the expression of the Aβ efflux transporters is decreased and the Aβ influx transporter expression is increased at the BBB, adding to the amyloid burden in the brain. Expression of the Aβ transporters at the choroid plexus (CP epithelium as a function of aging was the subject of this study. Methods This project investigated the changes in expression of the Aβ transporters, the low density lipoprotein receptor-related protein-1 (LRP-1, P-glycoprotein (P-gp, LRP-2 (megalin and the receptor for advanced glycation end-products (RAGE at the BCSFB in Brown-Norway/Fischer rats at ages 3, 6, 9, 12, 20, 30 and 36 months, using real time RT-PCR to measure transporter mRNA expression, and immunohistochemistry (IHC to measure transporter protein in isolated rat CP. Results There was an increase in the transcription of the Aβ efflux transporters, LRP-1 and P-gp, no change in RAGE expression and a decrease in LRP-2, the CP epithelium influx transporter, at the BCSFB with aging. Decreased Aβ42 concentration in the CP, as measured by quantitative IHC, was associated with these Aβ transporter alterations. Conclusions Age-dependent alterations in the CP Aβ transporters are associated with a decrease in Aβ42 accumulation in the CP, and are reciprocal to the changes seen in these transporters at the BBB, suggesting a possible compensatory role for the BCSFB in Aβ clearance in aging.

EGb761 provides a protective effect against Aβ1-42 oligomer-induced cell damage and blood-brain barrier disruption in an in vitro bEnd.3 endothelial model.

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Wen-bin Wan

Full Text Available Alzheimer's disease (AD is the most common form of senile dementia which is characterized by abnormal amyloid beta (Aβ accumulation and deposition in brain parenchyma and cerebral capillaries, and leads to blood-brain barrier (BBB disruption. Despite great progress in understanding the etiology of AD, the underlying pathogenic mechanism of BBB damage is still unclear, and no effective treatment has been devised. The standard Ginkgo biloba extract EGb761 has been widely used as a potential cognitive enhancer for the treatment of AD. However, the cellular mechanism underlying the effect remain to be clarified. In this study, we employed an immortalized endothelial cell line (bEnd.3 and incubation of Aβ(1-42 oligomer, to mimic a monolayer BBB model under conditions found in the AD brain. We investigated the effect of EGb761 on BBB and found that Aβ1-42 oligomer-induced cell injury, apoptosis, and generation of intracellular reactive oxygen species (ROS, were attenuated by treatment with EGb761. Moreover, treatment of the cells with EGb761 decreased BBB permeability and increased tight junction scaffold protein levels including ZO-1, Claudin-5 and Occludin. We also found that the Aβ(1-42 oligomer-induced upregulation of the receptor for advanced glycation end-products (RAGE, which mediates Aβ cytotoxicity and plays an essential role in AD progression, was significantly decreased by treatment with EGb761. To our knowledge, we provide the first direct in vitro evidence of an effect of EGb761 on the brain endothelium exposed to Aβ(1-42 oligomer, and on the expression of tight junction (TJ scaffold proteins and RAGE. Our results provide a new insight into a possible mechanism of action of EGb761. This study provides a rational basis for the therapeutic application of EGb761 in the treatment of AD.

COPD as an endothelial disorder: endothelial injury linking lesions in the lungs and other organs? (2017 Grover Conference Series)

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Polverino, Francesca; Celli, Bartolome R.

2018-01-01

Chronic obstructive pulmonary disease (COPD) is characterized by chronic expiratory airflow obstruction that is not fully reversible. COPD patients develop varying degrees of emphysema, small and large airway disease, and various co-morbidities. It has not been clear whether these co-morbidities share common underlying pathogenic processes with the pulmonary lesions. Early research into the pathogenesis of COPD focused on the contributions of injury to the extracellular matrix and pulmonary epithelial cells. More recently, cigarette smoke-induced endothelial dysfunction/injury have been linked to the pulmonary lesions in COPD (especially emphysema) and systemic co-morbidities including atherosclerosis, pulmonary hypertension, and chronic renal injury. Herein, we review the evidence linking endothelial injury to COPD, and the pathways underlying endothelial injury and the “vascular COPD phenotype” including: (1) direct toxic effects of cigarette smoke on endothelial cells; (2) generation of auto-antibodies directed against endothelial cells; (3) vascular inflammation; (4) increased oxidative stress levels in vessels inducing increases in lipid peroxidation and increased activation of the receptor for advanced glycation end-products (RAGE); (5) reduced activation of the anti-oxidant pathways in endothelial cells; (6) increased endothelial cell release of mediators with vasoconstrictor, pro-inflammatory, and remodeling activities (endothelin-1) and reduced endothelial cell expression of mediators that promote vasodilation and homeostasis of endothelial cells (nitric oxide synthase and prostacyclin); and (7) increased endoplasmic reticular stress and the unfolded protein response in endothelial cells. We also review the literature on studies of drugs that inhibit RAGE signaling in other diseases (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), or vasodilators developed for idiopathic pulmonary arterial hypertension that have been tested

Peripheral administration of antisense oligonucleotides targeting the amyloid-β protein precursor reverses AβPP and LRP-1 overexpression in the aged SAMP8 mouse brain.

Science.gov (United States)

Erickson, Michelle A; Niehoff, Michael L; Farr, Susan A; Morley, John E; Dillman, Lucy A; Lynch, Kristin M; Banks, William A

2012-01-01

The senescence accelerated mouse-prone 8 (SAMP8) mouse model of Alzheimer's disease has a natural mutation leading to age-related increases in the amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) in the brain, memory impairment, and deficits in Aβ removal from the brain. Previous studies show that centrally administered antisense oligonucleotide directed against AβPP can decrease AβPP expression and Aβ production in the brains of aged SAMP8 mice, and improve memory. The same antisense crosses the blood-brain barrier and reverses memory deficits when injected intravenously. Here, we give 6 μg of AβPP or control antisense 3 times over 2 week intervals to 12 month old SAMP8 mice. Object recognition test was done 48 hours later, followed by removal of whole brains for immunoblot analysis of AβPP, low-density lipoprotein-related protein-1 (LRP-1), p-glycoprotein (Pgp), receptor for advanced glycation endproducts (RAGE), or ELISA of soluble Aβ(40). Our results show that AβPP antisense completely reverses a 30% age-associated increase in AβPP signal (p < 0.05 versus untreated 4 month old SAMP8). Soluble Aβ(40) increased with age, but was not reversed by antisense. LRP-1 large and small subunits increased significantly with age (147.7%, p < 0.01 and 123.7%, p < 0.05 respectively), and AβPP antisense completely reversed these increases (p < 0.05). Pgp and RAGE were not significantly altered with age or antisense. Antisense also caused improvements in memory (p < 0.001). Together, these data support the therapeutic potential of AβPP antisense and show a unique association between AβPP and LRP-1 expression in the SAMP8 mouse.

Effect of Temperature on Tolbutamide Binding to Glycated Serum Albumin

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Agnieszka Szkudlarek

2017-03-01

Full Text Available Glycation process occurs in protein and becomes more pronounced in diabetes when an increased amount of reducing sugar is present in bloodstream. Glycation of protein may cause conformational changes resulting in the alterations of its binding properties even though they occur at a distance from the binding sites. The changes in protein properties could be related to several pathological consequences such as diabetic and nondiabetic cardiovascular diseases, cataract, renal dysfunction and Alzheimer’s disease. The experiment was designed to test the impact of glycation process on sulfonylurea drug tolbutamide-albumin binding under physiological (T = 309 K and inflammatory (T = 311 K and T = 313 K states using fluorescence and UV-VIS spectroscopies. It was found in fluorescence analysis experiments that the modification of serum albumin in tryptophanyl and tyrosyl residues environment may affect the tolbutamide (TB binding to albumin in subdomain IIA and/or IIIA (Sudlow’s site I and/or II, and also in subdomains IB and IIB. We estimated the binding of tolbutamide to albumin described by a mixed nature of interaction (specific and nonspecific. The association constants Ka (L∙mol−1 for tolbutamide at its high affinity sites on non-glycated albumin were in the range of 1.98–7.88 × 104 L∙mol−1 (λex = 275 nm, 1.20–1.64 × 104 L∙mol−1 (λex = 295 nm and decreased to 1.24–0.42 × 104 L∙mol−1 at λex = 275 nm (T = 309 K and T = 311 K and increased to 2.79 × 104 L∙mol−1 at λex = 275 nm (T = 313 K and to 4.43–6.61 × 104 L∙mol−1 at λex = 295 nm due to the glycation process. Temperature dependence suggests the important role of van der Waals forces and hydrogen bonding in hydrophobic interactions between tolbutamide and both glycated and non-glycated albumin. We concluded that the changes in the environment of TB binding of albumin in subdomain IIA and/or IIIA as well as in subdomains IB and IIB influence on

Glycation of polyclonal IgGs: Effect of sugar excipients during stability studies.

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Leblanc, Y; Bihoreau, N; Jube, M; Andre, M-H; Tellier, Z; Chevreux, G

2016-05-01

A number of intravenous immunoglobulin preparations are stabilized with sugar additives that may lead over time to undesirable glycation reactions especially in liquid formulation. This study aimed to evaluate the reactivity of sugar excipients on such preparations in condition of temperature, formulation and concentration commonly used for pharmaceutical products. Through an innovative LC-MS method reported to characterize post-translational modifications of IgGs Fc/2 fragments, a stability study of IVIg formulated with reducing and non-reducing sugars has been undertaken. The rate of polyclonal IgGs glycation was investigated during 6months at 5, 25, 30 and 40°C. High levels of glycation were observed with reducing sugars such as glucose and maltose in the first months of the stability study from 25°C. Non-reducing sugars presented a low reactivity even at the highest tested temperature (40°C). Furthermore, a site by site analysis was performed by MS/MS to determine the glycation sites which were mainly identified at Lys246, Lys248 and Lys324. This work points out the high probability of glycation reactions in some commercialized products and describes a useful method to characterize IVIg glycated products issued from reducing sugar excipients. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

RAGE Reusable Game Software Components and Their Integration into Serious Game Engines

NARCIS (Netherlands)

Van der Vegt, Wim; Nyamsuren, Enkhbold; Westera, Wim

2016-01-01

This paper presents and validates a methodology for integrating reusable software components in diverse game engines. While conforming to the RAGE com-ponent-based architecture described elsewhere, the paper explains how the interac-tions and data exchange processes between a reusable software

Advanced glycation end products in the skin are enhanced in COPD

NARCIS (Netherlands)

Hoonhorst, Susan J. M.; Loi, Adele T. Lo Tam; Hartman, Jorine E.; Telenga, Eef D.; van den Berge, Maarten; Koenderman, Leo; Lammers, Jan Willem J.; Boezen, H. Marike; Postma, Dirkje S.; ten Hacken, Nick H. T.

Background. Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD) inducing oxidative stress and local tissue injury, resulting in pulmonary inflammation. Advanced glycation end products (AGEs) are produced by glycation and oxidation processes and their formation is

Vessel Ultrasound Sonographic Assessment of Soluble Receptor for Advanced Glycation End Products Efficacy in a Rat Balloon Injury Model

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Hyun-Jin Tae, DVM, PhD

2014-12-01

Conclusions: Sonograph results are consistent with those obtained from histology; that is, sRAGE produced in Chinese hamster ovary cells has significantly higher efficacy than insect cell-originated sRAGE cells.

Soluble and Endogenous Secretory Receptors for Advanced Glycation End Products in Threatened Preterm Labor and Preterm Premature Rupture of Fetal Membranes

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Rafał Rzepka

2015-01-01

Full Text Available The aim of the study was to compare sRAGE and esRAGE plasma levels in pregnant women with (A threatened premature labor (n=41, (B preterm premature rupture of membranes (n=49, and (C preterm rupture of membranes at term (n=48. The relationship between these and classic intrauterine infection markers and the latent time from symptoms up to delivery depending on RAGE’s concentration were investigated. In groups A and B, a positive correlation was found between plasma sRAGE and latent time (r = 0,422; p = 0,001; r = 0,413, p = 0,004, resp.. High prognostic values were found in both groups for plasma sRAGE concentration and the latent time from symptoms up to delivery. Groups B and C presented higher levels of esRAGE than group A (526,315 ± 129,453 pg/mL and 576,212 ± 136,237 pg/mL versus 485,918 ± 133,127 pg/mL, p< 0,05. The conclusion is that sRAGE concentration can be a favorable prognostic factor in the presence of symptoms of threatened premature labor. Higher esRAGE plasma level in case of the rupture of membranes in mature and premature pregnancy suggests its participation in fetal membranes destruction.

Glycated albumin as a marker of glycemia in diabetes and its vascular complications

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Maria Warwas

2015-05-01

Full Text Available Effective glycemic control is very important to prevent the onset and the progression of chronic complications in diabetic patients. It is known that glycation of various proteins is increased in diabetic patients compared with non-diabetics. Among these glycated proteins, glycated hemoglobin (HbA1c is commonly used as a gold standard index of glycemic control in the clinical setting. However, it can be unreliable in conditions affecting the lifespan of erythrocytes (120 days as well as in the clinical state in which glycemic control alleviates or deteriorates in a short period. By overcoming the shortcomings of HbA1c, glycated albumin (GA has gained interest as a useful index for an intermediate glycation period (2 weeks and pathogenic protein.After giving a brief overview of the key role of HbA1c as a long-term glycemic marker, this review focuses on (a glycation of human albumin and its main properties, (b methods of GA determination, (c the recent clinical status of GA as a glycemic index in diabetic patients and its association with vascular complications. Finally, conditions with a possible inaccurate GA level are also mentioned.

The effect of Cerasus avium stalk extract on albumin glycation reaction

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Mohadeseh Abdoli

2014-10-01

Full Text Available Background: Non-enzymatic glycosylation of proteins is the major cause of diabetic complications. The inhibition of glycation process can reduce complications of diabetes. In the Iranian traditional medicine, the decoction (boiled extraction of Cerasus avium stalk is used as a hypoglycemic agent. The aim of this study was to investigate the in vitro inhibitory effects of decoction and ethanolic and aqueous extracts of Cerasus avium stalk on albumin glycation reaction. Methods: In this experimental study, first, the ethanolic, aqueous and decoction extracts of Cerasus avium stalk were prepared. Then, different concentrations of these extracts were prepared and added to albumin and glucose solutions. Finally, compared to control group that was not treated with any extracts, the albumin glycation rate in the groups treated with various concentrations of extracts was evaluated using TBA (thio-barbituric acid method. Results: The results showed that compared to control group, decoction of Cerasus avium stalk in the concentrations of 20, 10 and 2 mg/dl could reduce albumin glycation to 85.10±1.55, 72.35±1.75 and 51.25±1.22 %, respectively (P>0.001. Moreover, in the concentration of 20 mg/dl, the inhibitory effect of decoction of Cerasus avium stalk on the albumin glycation reaction was higher than those of aqueous (P=0.021 and ethanolic (P=0.009 extracts. Conclusion: The findings showed that the extracs of Cerasus avium stalk, in particular in the decoction form, could significantly reduce the rate of albumin glycation; therefore, it can be used for decreasing diabetes mellitus complications.

"STUDY ON THE EFFECT OF GARLIC ON THE IN VITRO ALBUMIN GLYCATION REACTION"

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N. Sheikh

2004-05-01

Full Text Available Garlic, an antioxidant plant, can react with amino groups of proteins to form Schiff bases. As diabetes leads to glycation of various proteins and this in turn has some effects on the structure of proteins and biochemical activity of them, the inhibition of this process seems very vital. For several years researchers in this field have done their best to recognize the antidiabetic compounds. The aim of this study is to determine the effects of garlic on albumin glycation in vitro.In the presence of various concentrations of garlic, albumin was glycated and evaluated using TBA (thio-barbituric acid method. The results showed that garlic has a statistically significant (P<0.05 effect in inhibiting or decreasing the reaction of albumin glycation. The findings of this research shows that garlic probably inhibits the reaction of glycation and decreases complications occurring in diabetes.

Human Achilles tendon glycation and function in diabetes

DEFF Research Database (Denmark)

Couppe, Christian; Svensson, Rene Brüggebusch; Kongsgaard, Mads

2016-01-01

Diabetic patients have an increased risk of foot ulcers, and glycation of collagen may increase tissue stiffness. We hypothesized that the level of glycemic control (glycation) may affect Achilles tendon stiffness, which can influence gait pattern. We therefore investigated the relationship between...... tissue cross-linking were greater in diabetic patients compared to controls. The higher foot pressure indicates that material stiffness of tendon and other tissue (e.g skin and joint capsule) may influence on foot gait. The difference in foot pressure distribution may contribute to the development...... of foot ulcers in diabetic patients....

Effect of glycation of albumin on its renal clearance in normal and diabetic rats

International Nuclear Information System (INIS)

Layton, G.J.; Jerums, G.

1988-01-01

Two independent techniques have been used to study the renal clearances of nonenzymatically glycated albumin and nonglycated albumin in normal and streptozotocin-induced diabetic rats, 16 to 24 weeks after the onset of diabetes. In the first technique, serum and urinary endogenous glycated and nonglycated albumin were separated using m-aminophenylboronate affinity chromatography and subsequently quantified by radioimmunoassay. Endogenous glycated albumin was cleared approximately twofold faster than nonglycated albumin in normal and diabetic rats. However, no difference was observed in the glycated albumin/nonglycated albumin clearance ratios (Cga/Calb) in normal and diabetic rats, respectively (2.18 +/- 0.39 vs 1.83 +/- 0.22, P greater than 0.05). The second technique measured the renal clearance of injected 125I-labelled glycated albumin and 125I-labelled albumin. The endogenous results were supported by the finding that 125I-labelled glycated albumin was cleared more rapidly than 125I-labelled albumin in normal (P less than 0.01) and diabetic (P less than 0.05) rats. The Cga/Calb ratio calculated for the radiolabelled albumins was 1.4 and 2.0 in normal and diabetic rats, respectively. This evidence suggests that nonenzymatic glycation of albumin increases its renal clearance to a similar degree in normal and diabetic rats

The Effect of Turmeric , Cardamom and Ginger on in vitro Albumin Glycation

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N. Sheikh

2004-01-01

Full Text Available Diabetes mellitus is one of the most common disease in the world that imposes a tremendous health and societal burden whether that burden is measured in terms of sickness , use of health systems resources or costs. Hyperglycemia is the most important clinical sign of diabetes leading to glycation of the various proteins in the body that leads to change in their nature , structure and biochemical activity. One of the probable methods in the treatment of diabetes mellitus is decrease or inhibition of this reaction. It seems that Turmeric , Cardamom and Ginger are useful for this purpose. The main goal of this research is to determine the effect of above agents on in vitro albumin glycation. In the presence of various concentration of these agents , albumin was glycated and evaluated using TBA method. Results showed that these food additives have inhibitory effects on albumin glycation reaction with the concentraction of 1 g/dl , 0.2 g/dl and 0.1 g/dl. Among these agents , Ginger had the most inhibitory effect (78% with the concentration of 1 g/dl. The sequence of effect is : Ginger > Cardamom > Turmeric These findings showed that these agents decrease albumin glycation reaction.

Increased Oxidation as an Additional Mechanism Underlying Reduced Clot Permeability and Impaired Fibrinolysis in Type 2 Diabetes

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Anna Lados-Krupa

2015-01-01

Full Text Available Aims. We sought to investigate whether enhanced oxidation contributes to unfavorable fibrin clot properties in patients with diabetes. Methods. We assessed plasma fibrin clot permeation (Ks, a measure of the pore size in fibrin networks and clot lysis time induced by recombinant tissue plasminogen activator (CLT in 163 consecutive type 2 diabetic patients (92 men and 71 women aged 65 ± 8.8 years with a mean glycated hemoglobin (HbA1c of 6.8%. We also measured oxidative stress markers, including nitrotyrosine, the soluble form of receptor for advanced glycation end products (sRAGE, 8-iso-prostaglandin F2α (8-iso-PGF2α, oxidized low-density lipoprotein (oxLDL, and advanced glycation end products (AGE. Results. There were inverse correlations between Ks and nitrotyrosine, sRAGE, 8-iso-PGF2α, and oxLDL. CLT showed a positive correlation with oxLDL and nitrotyrosine but not with other oxidation markers. All these associations remained significant for Ks after adjustment for fibrinogen, disease duration, and HbA1c (all P<0.05, while oxLDL was the only independent predictor of CLT. Conclusions. Our study shows that enhanced oxidative stress adversely affects plasma fibrin clot properties in type 2 diabetic patients, regardless of disease duration and glycemia control.

Rage in a Time of Millennial Raving: Rage Against the Machine’s Critical Disruption of Y2K Excitement Rage Against the Machine, ou la critique raisonnée de la frénésie millénariste

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Phillip Serrato

2009-11-01

Full Text Available Nous étudierons l’intrusion brillante et salutaire du groupe Rage Against the Machine, avec son album The Battle of Los Angeles (1999, dans la frénésie euphorique du passage au deuxième millénaire à la fin de l’année 1999. Les genres musicaux les plus populaires de l’époque – dance music et pop « bubble gum » – reflètent un intérêt décroissant pour le politique, notamment sur les questions ethniques et le problème de l’immigration. Face à la popularité d’artistes latinos comme Jennifer Lopez et Marc Anthony semblant annoncer une ère d’où aurait disparu toute discrimination raciale, le disque de Rage Against the Machine détonne singulièrement, de par son insistance à défendre des positions politiques tranchées. Au vu de la place prépondérante des questions d’immigration au début de l’an 2000, l’album de ce groupe engagé peut être envisagé comme un avertissement aux allures prophétiques contre la tentation de l’étourdissement dans une euphorie millénariste.

Effect of some high consumption spices on hemoglobin glycation.

Science.gov (United States)

Naderi, G H; Dinani, Narges J; Asgary, S; Taher, M; Nikkhoo, N; Boshtam, M

2014-01-01

Formation of glycation products is major factor responsible in complications of diabetes. Worldwide trend is toward the use of natural additives in reducing the complications of diseases. Therefore, there is a growing interest in natural antiglycation found in plants. Herbs and spices are one of the most important targets to search for natural antiglycation from the point of view of safety. This study investigated the ability of some of the spices to inhibit glycation process in a hemoglobin/glucose model system and compared their potency with each other. For this subject the best concentration and time to incubate glucose with hemoglobin was investigated. Then the glycosylation degree of hemoglobin in the presence of extracts by the three concentrations 0.25, 0.5 and 1 μg/ml was measured colorimetrically at 520 nm. Results represent that some of extracts such as wild caraway, turmeric, cardamom and black pepper have inhibitory effects on hemoglobin glycation. But some of the extracts such as anise and saffron have not only inhibitory effects but also aggravated this event and have proglycation properties. In accordance with the results obtained we can conclude that wild caraway, turmeric, cardamom and black pepper especially wild caraway extracts are potent antiglycation agents, which can be of great value in the preventive glycation-associated complications in diabetes.

Effects of advanced glycation end-products (AGEs) on skin ...

African Journals Online (AJOL)

kappa B (NF-κB) localization and cell viability were measured in vivo. Keratinocytes from normal skin were cultured in AGE-enriched conditional media, and the cell viability, apoptosis, adhesion and migration were detected in order to find the ...

Simple non-invasive assessment of advanced glycation endproduct accumulation

NARCIS (Netherlands)

Meerwaldt, R; Graaff, R; Links, TP; Jager, JJ; Alderson, NL; Thorpe, [No Value; Baynes, JW; Gans, ROB; Smit, AJ

Aims/hypothesis. The accumulation of AGE is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. All current measurements of AGE accumulation require invasive sampling. We exploited the fact that several AGE exhibit autofluorescence to develop a

A novel monoclonal antibody targeting carboxymethyllysine, an advanced glycation end product in atherosclerosis and pancreatic cancer.

Directory of Open Access Journals (Sweden)

Ulrika Wendel

Full Text Available Advanced glycation end products are formed by non-enzymatic reactions between proteins and carbohydrates, causing irreversible lysine and arginine alterations that severely affect protein structure and function. The resulting modifications induce inflammation by binding to scavenger receptors. An increase in advanced glycation end products is observed in a number of diseases e.g. atherosclerosis and cancer. Since advanced glycation end products also are present in healthy individuals, their detection and quantification are of great importance for usage as potential biomarkers. Current methods for advanced glycation end product detection are though limited and solely measure total glycation. This study describes a new epitope-mapped single chain variable fragment, D1-B2, against carboxymethyllysine, produced from a phage library that was constructed from mouse immunizations. The phage library was selected against advanced glycation end product targets using a phage display platform. Characterization of its binding pattern was performed using large synthetic glycated peptide and protein libraries displayed on microarray slides. D1-B2 showed a preference for an aspartic acid, three positions N-terminally from a carboxymethyllysine residue and also bound to a broad collection of glycated proteins. Positive immunohistochemical staining of mouse atherosclerotic plaques and of a tissue microarray of human pancreatic tumors confirmed the usability of the new scFv for advanced glycation end product detection in tissues. This study demonstrates a promising methodology for high-throughput generation of epitope-mapped monoclonal antibodies against AGE.

Images en mouvement stockage, repérage, indexation

CERN Document Server

Turner, James

1998-01-01

L'avènement puis la fusion des nouveaux modes de communication que sont l'informatique, les télécommunications et l'audiovisuel ont mis à la portée de tous une grande quantité d'images fixes et en mouvement dont la conservation et le repérage risquent de prendre des proportions démesurées. Le présent ouvrage veut offrir aux responsables de collection des repères pour aborder la problématique de l'indexation des images et faciliter l'accès des usagers à ces images.

The alpha-fetoprotein third domain receptor binding fragment: in search of scavenger and associated receptor targets.

Science.gov (United States)

Mizejewski, G J

2015-01-01

Recent studies have demonstrated that the carboxyterminal third domain of alpha-fetoprotein (AFP-CD) binds with various ligands and receptors. Reports within the last decade have established that AFP-CD contains a large fragment of amino acids that interact with several different receptor types. Using computer software specifically designed to identify protein-to-protein interaction at amino acid sequence docking sites, the computer searches identified several types of scavenger-associated receptors and their amino acid sequence locations on the AFP-CD polypeptide chain. The scavenger receptors (SRs) identified were CD36, CD163, Stabilin, SSC5D, SRB1 and SREC; the SR-associated receptors included the mannose, low-density lipoprotein receptors, the asialoglycoprotein receptor, and the receptor for advanced glycation endproducts (RAGE). Interestingly, some SR interaction sites were localized on the AFP-derived Growth Inhibitory Peptide (GIP) segment at amino acids #480-500. Following the detection studies, a structural subdomain analysis of both the receptor and the AFP-CD revealed the presence of epidermal growth factor (EGF) repeats, extracellular matrix-like protein regions, amino acid-rich motifs and dimerization subdomains. For the first time, it was reported that EGF-like sequence repeats were identified on each of the three domains of AFP. Thereafter, the localization of receptors on specific cell types were reviewed and their functions were discussed.

蛋白の糖化 : メイラード反応を中心にして

OpenAIRE

堀川, 博朗; Hiroaki, HORIKAWA

2004-01-01

The Maillard reaction is a complex and poorly understood series of reactions between reducing sugars and the primary amino groups of proteins. The resulting advanced glycation end-products (AGEs) and active oxygen species are thought to contribute to the development of diabetic complications and aging. This review describes the basic chemistry of the Maillard reaction.

Anti-glycated and antiradical activities in vitro of polysaccharides from Ganoderma capense.

Science.gov (United States)

Yan, Chunyan; Kong, Fansheng; Zhang, Dezhi; Cui, Jiangxia

2013-01-01

Ganoderma capense is a Ganoderma species and is widely used, especially in Asia, as a well-known medicinal mushroom for health-promoting effect and for treatment of chronic diseases, such as diabetes, aging, etc. G. capense is rich of polysaccharide. To isolate the polysaccharides from G. capense and evaluate their anti-glycated and antiradical activities in vitro. The dried powder of submerged fermentation culturing mycelium of G. capense was defatted, extracted with water/alkaline water followed by ethanol precipitation and deproteinated. And four crude polysaccharides, named as GC50, GC70, GC90 and GCB, were obtained. For the first time, the in vitro anti-glycated activities of the four samples were studied by non-enzymatic glycation reaction. Then, the DPPH radical and hydroxyl radical assays were established to estimate the antiradical capacity of the four samples. Meanwhile the contents of polysaccharides were determined by phenol-sulphuric acid colorimetry. Preliminary antiradical in vitro studies indicated that the four crude polysaccharides showed concentration-dependent scavenging abilities on DPPH and hydroxyl radicals. The evaluation of anti-glycation activity suggested that GC70 had good potential for inhibiting the formation of advanced glycation end products. Time- and dose-dependent effects were also observed for all GC70 samples.

Cross-linking in collagen by nonenzymatic glycation increases the matrix stiffness in rabbit achilles tendon.

Science.gov (United States)

Reddy, G Kesava

2004-01-01

Nonenzymatic glycation of connective tissue matrix proteins is a major contributor to the pathology of diabetes and aging. Previously the author and colleagues have shown that nonenzymatic glycation significantly enhances the matrix stability in the Achilles tendon (Reddy et al., 2002, Arch. Biochem. Biophys., 399, 174-180). The present study was designed to gain further insight into glycation-induced collagen cross-linking and its relationship to matrix stiffness in the rabbit Achilles tendon. The glycation process was initiated by incubating the Achilles tendons (n = 6) in phosphate-buffered saline containing ribose, whereas control tendons (n = 6) were incubated in phosphate-buffered saline without ribose. Eight weeks following glycation, the biomechanical attributes as well as the degree of collagen cross-linking were determined to examine the potential associations between matrix stiffness and molecular properties of collagen. Compared to nonglycated tendons, the glycated tendons showed increased maximum load, stress, strain, Young's modulus of elasticity, and toughness indicating that glycation increases the matrix stiffness in the tendons. Glycation of tendons resulted in a considerable decrease in soluble collagen content and a significant increase in insoluble collagen and pentosidine. Analysis of potential associations between the matrix stiffness and degree of collagen cross-linking showed that both insoluble collagen and pentosidine exhibited a significant positive correlation with the maximum load, stress, and strain, Young's modulus of elasticity, and toughness (r values ranging from.61 to.94) in the Achilles tendons. However, the soluble collagen content present in neutral salt buffer, acetate buffer, and acetate buffer containing pepsin showed an inverse relation with the various biomechanical attributes tested (r values ranging from.22 to.84) in the Achilles tendons. The results of the study demonstrate that glycation-induced collagen cross

Benfotiamine protects against peritoneal and kidney damage in peritoneal dialysis.

Science.gov (United States)

Kihm, Lars P; Müller-Krebs, Sandra; Klein, Julia; Ehrlich, Gregory; Mertes, Laura; Gross, Marie-Luise; Adaikalakoteswari, Antonysunil; Thornalley, Paul J; Hammes, Hans-Peter; Nawroth, Peter P; Zeier, Martin; Schwenger, Vedat

2011-05-01

Residual renal function and the integrity of the peritoneal membrane contribute to morbidity and mortality among patients treated with peritoneal dialysis. Glucose and its degradation products likely contribute to the deterioration of the remnant kidney and damage to the peritoneum. Benfotiamine decreases glucose-induced tissue damage, suggesting the potential for benefit in peritoneal dialysis. Here, in a model of peritoneal dialysis in uremic rats, treatment with benfotiamine decreased peritoneal fibrosis, markers of inflammation, and neovascularization, resulting in improved characteristics of peritoneal transport. Furthermore, rats treated with benfotiamine exhibited lower expression of advanced glycation endproducts and their receptor in the peritoneum and the kidney, reduced glomerular and tubulointerstitial damage, and less albuminuria. Increased activity of transketolase in tissue and blood contributed to the protective effects of benfotiamine. In primary human peritoneal mesothelial cells, the addition of benfotiamine led to enhanced transketolase activity and decreased expression of advanced glycation endproducts and their receptor. Taken together, these data suggest that benfotiamine protects the peritoneal membrane and remnant kidney in a rat model of peritoneal dialysis and uremia. Copyright © 2011 by the American Society of Nephrology

Exploring the antioxidant property of bioflavonoid quercetin in preventing DNA glycation: A calorimetric and spectroscopic study

International Nuclear Information System (INIS)

Sengupta, Bidisa; Uematsu, Takashi; Jacobsson, Per; Swenson, Jan

2006-01-01

Reducing sugars for example glucose, fructose, etc., and their phosphate derivatives non-enzymatically glycate biological macromolecules (e.g., proteins, DNA and lipids) and is related to the production of free radicals. Here we present a novel study, using differential scanning calorimetry (DSC) along with UV/Vis absorption and photon correlation spectroscopy (PCS), on normal and glycated human placenta DNA and have explored the antioxidant property of the naturally occurring polyhydroxy flavone quercetin (3,3',4',5,7-pentahydroxyflavone) in preventing the glycation. The decrease in the absorption intensity of DNA in presence of sugars clearly indicates the existence of sugar molecules between the two bases of a base pair in the duplex DNA molecule. Variations were perceptible in the PCS relaxation profiles of normal and glycated DNA. The melting temperature of placenta DNA was decreased when glycated suggesting a decrease in the structural stability of the double-stranded glycated DNA. Our DSC and PCS data showed, for the first time, that the dramatic changes in the structural properties of glycated DNA can be prevented to a significant extent by adding quercetin. This study provides valuable insights regarding the structure, function, and dynamics of normal and glycated DNA molecules, underlying the manifestation of free radical mediated diseases, and their prevention using therapeutically active naturally occurring flavonoid quercetin

Vanillin restrains non-enzymatic glycation and aggregation of albumin by chemical chaperone like function.

Science.gov (United States)

Awasthi, Saurabh; Saraswathi, N T

2016-06-01

Vanillin a major component of vanilla bean extract is commonly used a natural flavoring agent. Glycation is known to induce aggregation and fibrillation of globular proteins such as albumin, hemoglobin. Here we report the inhibitory potential of vanillin toward early and advanced glycation modification and amyloid like aggregation of albumin based on the determination of both early and advanced glycation and conformational changes in albumin using circular dichroism. Inhibition of aggregation and fibrillation of albumin was determined based on amyloid specific dyes i.e., Congo red and Thioflavin T and microscopic imaging. It was evident that vanillin restrains glycation of albumin and exhibits protective effect toward its native conformation. Copyright © 2016 Elsevier B.V. All rights reserved.

Manejo da irrigação na cultura do crisântemo em vaso, cultivar rage, cultivado em ambiente protegido Irrigation schedule in pot chrysanthemum, cultivar rage, grown in greenhouse

Directory of Open Access Journals (Sweden)

Maryzélia F. de Farias

2004-04-01

Full Text Available Dentre as dificuldades que os produtores têm encontrado ao adotarem o cultivo em ambiente protegido, destaca-se a falta de dados específicos sobre o uso racional da água e o desconhecimento da quantidade e do momento de irrigar. Esta pesquisa foi desenvolvida na propriedade de um produtor, no Distrito de Holambra II, região de Paranapanema - SP, em cultivos rotineiramente desenvolvidos pelo produtor, buscando melhor representatividade dos dados obtidos. O objetivo principal deste experimento foi identificar a tensão de água no solo que pudesse resultar em melhor qualidade comercial da cultivar de crisântemo "Rage", cultivado em vaso e mantido em ambiente protegido. O delineamento experimental foi o inteiramente casualizado, com duas repetições. Os tratamentos foram definidos por seis níveis de tensão de água: -2; -3; -4; -6; -10 e -30 kPa. Para cada tensão, foram calculadas a altura correspondente na coluna de mercúrio do tensiômetro, as lâminas e o tempo de irrigação. Os resultados obtidos demonstraram que a cultivar Rage obteve a maior porcentagem de vasos de alta qualidade (A1 no tratamento irrigado com a tensão de -4 kPa. O tratamento irrigado, quando atingia -30 kPa, resultou na menor porcentagem de vasos A1.The most important difficulty that the producers have been found to adopt the cultivation in plastic greenhouses is the lack of specific data on the rational use of the water and informations about when and how much water apply. This research was developed in a farm in Paranapanema - SP, Brazil, with tradition in pot chrysanthemum grow. The main objective was to identify the soil water tension that could result in better commercial quality of chrysanthemum Rage, cultivated in pot and maintained in greenhouse. The treatments were defined for six levels of substrate water tension: -2; -3; -4; -6; -10 and -30 kPa. The irrigation time was defined for each tension and also the equivalent height int the mercury column of

Monotopic modifications derived from in vitro glycation of albumin with ribose

Czech Academy of Sciences Publication Activity Database

Pataridis, Statis; Šťastná, Zdeňka; Sedláková, Pavla; Mikšík, Ivan

2013-01-01

Roč. 34, č. 12 (2013), s. 1757-1763 ISSN 0173-0835 R&D Projects: GA ČR(CZ) GAP206/12/0453; GA ČR(CZ) GA203/08/1428 Institutional support: RVO:67985823 Keywords : advanced glycation end product (AGE) * albumin * CE-MS * glycation * LC-MS/MS Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 3.161, year: 2013

Monitoring the progress of non-enzymatic glycation in vitro

International Nuclear Information System (INIS)

Shaw, S.M.; Crabbe, M.J.

1994-01-01

The progress of in vitro non-enzymatic glycation of bovine serum albumin was followed by using 14 C-glucose and a nitroblue tetrazolium assay, absorption and fluorescence spectroscopy, SDS gel electrophoresis and protease digestion. The number of adducts detectable using both 14 C-tracers and a fructosamine assay remained low at physiological glucose concentrations, fewer than five adducts being detectable. When glucose concentrations > 1.0 M were used the number of adducts was found to greatly exceed the number of lysyl residues available in BSA, indicative of cross-linking between Maillard products. Incubation of BSA with glucose concentrations of up to 160 mM for one month produced no observable increase in molecular weight by SDS gel electrophoresis, showing that at physiological glucose concentrations, increases in molecular weight were minimal for short incubation periods. Increases in absorption were proportial to both the glucose concentration and the incubation time. Several absorption peaks, at 370, 488 and 554 nm, were consistent in appearance throughout the course of each incubation. Fluorescence spectroscopy of the modified proteins showed a disappearance of the fluorescence associated with peptide bonds and aromatic residues and the appearance of a broad peak at longer wavelengths due to the wide range of absorptive/fluorescent wavelengths of the developing Maillard products. Protease digestion gave similar patterns with non-glycated and glycated protein, suggesting that glycation did not block digestion sites, and that partial digestion did not cause significant further exposure of susceptible sites. Our results show that while glycation ultimately results in protein conformational changes and the formation of large molecular weight species, these occur at a relatively late stage in the maturation of protein Maillard products, after ≥ nine months of incubation with glucose concentration of ≥ 20 mM. Monitoring of AGE maturation in vitro is better

Relationship between glycated haemoglobin and fasting plasma ...

African Journals Online (AJOL)

Emmanuel Musenge

2016-07-30

Jul 30, 2016 ... Relationship between glycated haemoglobin and fasting plasma glucose ... major stakeholders in the management of diabetes mellitus to consider FPG as an ..... HbA1c among customers of health examination services.

Posttranslational nitro-glycative modifications of albumin in Alzheimer's disease: implications in cytotoxicity and amyloid-β peptide aggregation.

Science.gov (United States)

Ramos-Fernández, Eva; Tajes, Marta; Palomer, Ernest; Ill-Raga, Gerard; Bosch-Morató, Mònica; Guivernau, Biuse; Román-Dégano, Irene; Eraso-Pichot, Abel; Alcolea, Daniel; Fortea, Juan; Nuñez, Laura; Paez, Antonio; Alameda, Francesc; Fernández-Busquets, Xavier; Lleó, Alberto; Elosúa, Roberto; Boada, Mercé; Valverde, Miguel A; Muñoz, Francisco J

2014-01-01

Glycation and nitrotyrosination are pathological posttranslational modifications that make proteins prone to losing their physiological properties. Since both modifications are increased in Alzheimer's disease (AD) due to amyloid-β peptide (Aβ) accumulation, we have studied their effect on albumin, the most abundant protein in cerebrospinal fluid and blood. Brain and plasmatic levels of glycated and nitrated albumin were significantly higher in AD patients than in controls. In vitro turbidometry and electron microscopy analyses demonstrated that glycation and nitrotyrosination promote changes in albumin structure and biochemical properties. Glycated albumin was more resistant to proteolysis and less uptake by hepatoma cells occurred. Glycated albumin also reduced the osmolarity expected for a solution containing native albumin. Both glycation and nitrotyrosination turned albumin cytotoxic in a cell type-dependent manner for cerebral and vascular cells. Finally, of particular relevance to AD, these modified albumins were significantly less effective in avoiding Aβ aggregation than native albumin. In summary, nitrotyrosination and especially glycation alter albumin structural and biochemical properties, and these modifications might contribute for the progression of AD.

Multicenter evaluation of an enzymatic method for glycated albumin.

Science.gov (United States)

Paleari, Renata; Bonetti, Graziella; Callà, Cinzia; Carta, Mariarosa; Ceriotti, Ferruccio; Di Gaetano, Nicola; Ferri, Marilisa; Guerra, Elena; Lavalle, Gabriella; Cascio, Claudia Lo; Martino, Francesca Gabriela; Montagnana, Martina; Moretti, Marco; Santini, Gabriele; Scribano, Donata; Testa, Roberto; Vero, Anna; Mosca, Andrea

2017-06-01

The use of glycated albumin (GA) has been proposed as an additional glycemic control marker particularly useful in intermediate-term monitoring and in situation when HbA 1c test is not reliable. We have performed the first multicenter evaluation of the analytical performance of the enzymatic method quantILab Glycated Albumin assay implemented on the most widely used clinical chemistry analyzers (i.e. Abbott Architect C8000, Beckman Coulter AU 480 and 680, Roche Cobas C6000, Siemens ADVIA 2400 and 2400 XPT). The repeatability of the GA measurement (expressed as CV, %) implemented in the participating centers ranged between 0.9% and 1.2%. The within-laboratory CVs ranged between 1.2% and 1.6%. A good alignment between laboratories was found, with correlation coefficients from 0.996 to 0.998. Linearity was confirmed in the range from 7.6 to 84.7%. The new enzymatic method for glycated albumin evaluated by our investigation is suitable for clinical use. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of the site specific protein glycation and antioxidant capacity of rare sugar-protein/peptide conjugates.

Science.gov (United States)

Sun, Yuanxia; Hayakawa, Shigeru; Ogawa, Masahiro; Izumori, Ken

2005-12-28

Protein-sugar conjugates generated in nonenzymatic glycation of alpha-lactalbumin (LA) with rare sugars [D-allose (All) and D-psicose (Psi)] and alimentary sugars as controls [D-glucose (Glc) and D-fructose (Fru)] were qualitatively determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Mass spectra revealed that the extent of glycation at lysine residues on LA with D-aldose molecules was very much higher than that of glycation with d-ketose molecules. To identify the specific site of glycation, the peptide mapping was established from protease V8 digestion, using a combination of computational cutting of proteins and MALDI-TOF-MS. As compared to peptide mapping, three and seven glycation sites were located in the primary structure of LA-ketose and LA-aldose conjugates, respectively. On the other hand, the antioxidant activities of protein-sugar conjugates and their peptic hydrolysates were investigated by 1,1-diphenyl-2-picrylhydrazyl radical scavenging method. The antioxidant activities of proteins/peptides glycated with rare sugars were significantly higher than those modified with the control sugars. The results indicated that the glycation degree and position were not markedly different between rare sugar and corresponding control sugar, but the antioxidant properties of protein and its hydrolysate were significantly enhanced by modifying with rare sugar.

Inhibitory effect of Piper betle Linn. leaf extract on protein glycation--quantification and characterization of the antiglycation components.

Science.gov (United States)

Bhattacherjee, Abhishek; Chakraborti, Abhay Sankar

2013-12-01

Piper betle Linn. is a Pan-Asiatic plant having several beneficial properties. Protein glycation and advanced glycation end products (AGEs) formation are associated with different pathophysiological conditions, including diabetes mellitus. Our study aims to find the effect of methanolic extract of P. betle leaves on in vitro protein glycation in bovine serum albumin (BSA)-glucose model. The extract inhibits glucose-induced glycation, thiol group modification and carbonyl formation in BSA in dose-dependent manner. It inhibits different stages of protein glycation, as demonstrated by using glycation models: hemoglobin-delta-gluconolactone (for early stage, Amadori product formation), BSA-methylglyoxal (for middle stage, formation of oxidative cleavage products) and BSA-glucose (for last stage, formation of AGEs) systems. Several phenolic compounds are isolated from the extract. Considering their relative amounts present in the extract, rutin appears to be the most active antiglycating agent. The extract of P. betle leaf may thus have beneficial effect in preventing protein glycation and associated complications in pathological conditions.

Cross-Linking in Collagen by Nonenzymatic Glycation Increases the Matrix Stiffness in Rabbit Achilles Tendon

OpenAIRE

Reddy, G. Kesava

2004-01-01

Nonenzymatic glycation of connective tissue matrix proteins is a major contributor to the pathology of diabetes and aging. Previously the author and colleagues have shown that nonenzymatic glycation significantly enhances the matrix stability in the Achilles tendon (Reddy et al., 2002, Arch. Biochem. Biophys., 399, 174–180). The present study was designed to gain further insight into glycation-induced collagen cross-linking and its relationship to matrix stiffness in the rabbit Achilles tendo...

Fluorescence lifetime measurements of native and glycated human serum albumin and bovine serum albumin

Science.gov (United States)

Joshi, Narahari V.; Joshi, Virgina O. d.; Contreras, Silvia; Gil, Herminia; Medina, Honorio; Siemiarczuk, Aleksander

1999-05-01

Nonenzymatic glycation, also known as Maillard reaction, plays an important role in the secondary complications of the diabetic pathology and aging, therefore, human serum albumin (HSA) and bovine serum albumin (BSA) were glycated by a conventional method in our laboratory using glucose as the glycating agent. Fluorescence lifetime measurements were carried out with a laser strobe fluorometer equipped with a nitrogen/dye laser and a frequency doubler as a pulsed excitation source. The samples were excited at 295 nm and the emission spectra were recorded at 345 nm. The obtained decay curves were tried for double and triple exponential functions. It has been found that the shorter lifetime increases for glycated proteins as compared with that of the native ones. For example, in the case of glycated BSA the lifetime increased from 1.36 ns to 2.30 ns. Similarly, for HSA, the lifetime increases from 1.58 ns to 2.26 ns. Meanwhile, the longer lifetime changed very slightly for both proteins (from 6.52 ns to 6.72 ns). The increase in the lifetime can be associated with the environmental effect; originated from the attachment of glucose to some lysine residues. A good example is Trp 214 which is in the cage of Lys 225, Lys 212, Lys 233, Lys 205, Lys 500, Lys 199 and Lys 195. If fluorescence lifetime technique is calibrated and properly used it could be employed for assessing glycation of proteins.

Germanium recovery from gasification fly ash: evaluation of end-products obtained by precipitation methods.

Science.gov (United States)

Arroyo, Fátima; Font, Oriol; Fernández-Pereira, Constantino; Querol, Xavier; Juan, Roberto; Ruiz, Carmen; Coca, Pilar

2009-08-15

In this study the purity of the germanium end-products obtained by two different precipitation methods carried out on germanium-bearing solutions was evaluated as a last step of a hydrometallurgy process for the recovery of this valuable element from the Puertollano Integrated Gasification Combined Cycle (IGCC) fly ash. Since H(2)S is produced as a by-product in the gas cleaning system of the Puertollano IGCC plant, precipitation of germanium as GeS(2) was tested by sulfiding the Ge-bearing solutions. The technological and hazardous issues that surround H(2)S handling conducted to investigate a novel precipitation procedure: precipitation as an organic complex by adding 1,2-dihydroxy benzene pyrocatechol (CAT) and cetyltrimethylammonium bromide (CTAB) to the Ge-bearing solutions. Relatively high purity Ge end-products (90 and 93% hexagonal-GeO(2) purity, respectively) were obtained by precipitating Ge from enriched solutions, as GeS(2) sulfiding the solutions with H(2)S, or as organic complex with CAT/CTAB mixtures and subsequent roasting of the precipitates. Both methods showed high efficiency (>99%) to precipitate selectively Ge using a single precipitation stage from germanium-bearing solutions.

The Preventive Effect of L-Lysine on Lysozyme Glycation in Type 2 Diabetes

Directory of Open Access Journals (Sweden)

Hossein Mirmiranpour

2016-01-01

Full Text Available Lysozyme is a bactericidal enzyme whose structure and functions change in diabetes. Chemical chaperones are small molecules including polyamines (e.g. spermine, amino acids (e.g. L-lysine and polyols (e.g. glycerol. They can improve protein conformation in several stressful conditions such as glycation. In this study, the authors aimed to observe the effect of L-lysine as a chemical chaperone on structure and function of glycated lysozyme. In this study, in vitro and in vivo effects of L-lysine on lysozyme glycation were investigated. Lysozyme was incubated with glucose and/or L-lysine, followed by an investigation of its structure by electrophoresis, fluorescence spectroscopy, and circular dichroism spectroscopy and also assessment of its bactericidal activity against M. lysodeikticus. In the clinical trial, patients with type 2 diabetes mellitus (T2DM were randomly divided into two groups of 25 (test and control. All patients received metformin and glibenclamide for a three months period. The test group was supplemented with 3 g/day of L-lysine. The quantity and activity of lysozyme and other parameters were then measured. Among the test group, L-lysine was found to reduce the advanced glycation end products (AGEs in the sera of patients with T2DM and in vitro condition. This chemical chaperone reversed the alteration in lysozyme structure and function due to glycation and resulted in increased lysozyme activity. Structure and function of glycated lysozyme are significantly improved by l-lysine; therefore it can be considered an effective therapeutic supplementation in T2DM, decreasing the risk of infection in these patients.

Book review: The Wilderness Debate Rages On: Continuing the Great New Wilderness Debate

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Peter Landres

2009-01-01

The Wilderness Debate Rages On is a collection of mostly previously published papers about the meaning, value, and role of wilderness and continues the discussion that was propelled by the editors' previous book The Great New Wilderness Debate (also a collection of papers) published in 1998. The editors state that this sequel to their previous book is mandated...

Advanced glycation end products induce differential structural modifications and fibrillation of albumin

Science.gov (United States)

Awasthi, Saurabh; Sankaranarayanan, Kamatchi; Saraswathi, N. T.

2016-06-01

Glycation induced amyloid fibrillation is fundamental to the development of many neurodegenerative and cardiovascular complications. Excessive non-enzymatic glycation in conditions such as hyperglycaemia results in the increased accumulation of advanced glycation end products (AGEs). AGEs are highly reactive pro-oxidants, which can lead to the activation of inflammatory pathways and development of oxidative stress. Recently, the effect of non-enzymatic glycation on protein structure has been the major research area, but the role of specific AGEs in such structural alteration and induction of fibrillation remains undefined. In this study, we determined the specific AGEs mediated structural modifications in albumin mainly considering carboxymethyllysine (CML), carboxyethyllysine (CEL), and argpyrimidine (Arg-P) which are the major AGEs formed in the body. We studied the secondary structural changes based on circular dichroism (CD) and spectroscopic analysis. The AGEs induced fibrillation was determined by Congo red binding and examination of scanning and transmission electron micrographs. The amyloidogenic regions in the sequence of BSA were determined using FoldAmyloid. It was observed that CEL modification of BSA leads to the development of fibrillar structures, which was evident from both secondary structure changes and TEM analysis.

Beyond genetic factors in familial amyloidotic polyneuropathy: protein glycation and the loss of fibrinogen's chaperone activity.

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Gonçalo da Costa

Full Text Available Familial amyloidotic polyneuropathy (FAP is a systemic conformational disease characterized by extracellular amyloid fibril formation from plasma transthyretin (TTR. This is a crippling, fatal disease for which liver transplantation is the only effective therapy. More than 80 TTR point mutations are associated with amyloidotic diseases and the most widely accepted disease model relates TTR tetramer instability with TTR point mutations. However, this model fails to explain two observations. First, native TTR also forms amyloid in systemic senile amyloidosis, a geriatric disease. Second, age at disease onset varies by decades for patients bearing the same mutation and some mutation carrier individuals are asymptomatic throughout their lives. Hence, mutations only accelerate the process and non-genetic factors must play a key role in the molecular mechanisms of disease. One of these factors is protein glycation, previously associated with conformational diseases like Alzheimer's and Parkinson's. The glycation hypothesis in FAP is supported by our previous discovery of methylglyoxal-derived glycation of amyloid fibrils in FAP patients. Here we show that plasma proteins are differentially glycated by methylglyoxal in FAP patients and that fibrinogen is the main glycation target. Moreover, we also found that fibrinogen interacts with TTR in plasma. Fibrinogen has chaperone activity which is compromised upon glycation by methylglyoxal. Hence, we propose that methylglyoxal glycation hampers the chaperone activity of fibrinogen, rendering TTR more prone to aggregation, amyloid formation and ultimately, disease.

Glycation of human cortical and cancellous bone captures differences in the formation of Maillard reaction products between glucose and ribose.

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Grażyna E Sroga

Full Text Available To better understand some aspects of bone matrix glycation, we used an in vitro glycation approach. Within two weeks, our glycation procedures led to the formation of advanced glycation end products (AGEs at the levels that corresponded to approx. 25-30 years of the natural in vivo glycation. Cortical and cancellous bones from human tibias were glycated in vitro using either glucose (glucosylation or ribose (ribosylation. Both glucosylation and ribosylation led to the formation of higher levels of AGEs and pentosidine (PEN in cancellous than cortical bone dissected from all tested donors (young, middle-age and elderly men and women. More efficient glycation of bone matrix proteins in cancellous bone most likely depended on the higher porosity of this tissue, which facilitated better accessibility of the sugars to the matrix proteins. Notably, glycation of cortical bone from older donors led to much higher AGEs levels as compared to young donors. Such efficient in vitro glycation of older cortical bone could result from aging-related increase in porosity caused by the loss of mineral content. In addition, more pronounced glycation in vivo would be driven by elevated oxidation processes. Interestingly, the levels of PEN formation differed pronouncedly between glucosylation and ribosylation. Ribosylation generated very high levels of PEN (approx. 6- vs. 2.5-fold higher PEN level than in glucosylated samples. Kinetic studies of AGEs and PEN formation in human cortical and cancellous bone matrix confirmed higher accumulation of fluorescent crosslinks for ribosylation. Our results suggest that in vitro glycation of bone using glucose leads to the formation of lower levels of AGEs including PEN, whereas ribosylation appears to support a pathway toward PEN formation. Our studies may help to understand differences in the progression of bone pathologies related to protein glycation by different sugars, and raise awareness for excessive sugar

SERUM MAGNESIUM, LIPID PROFILE AND GLYCATED HAEMOGLOBIN IN DIABETIC RETINOPATHY

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Sunanda Vusikala

2016-07-01

Full Text Available BACKGROUND Diabetic retinopathy is one of the important microvascular complications of diabetes mellitus of long duration. Alterations in trace metals like magnesium and lipid profile was observed in diabetic retinopathy with hyperglycaemic status. AIM The study was taken up to assess the role of magnesium, lipid profile and glycated haemoglobin in diabetic retinopathy. MATERIALS AND METHODS A total of 80 subjects between 40-65 years were included in the study. Group 1 includes 20 age and sex matched healthy controls. Group 2 includes 30 cases of Diabetes mellitus without retinopathy. Group 3 includes 30 cases of Diabetes mellitus with retinopathy. RESULTS Magnesium was found to be significantly low in the diabetic group with retinopathy. Serum cholesterol and triglycerides were significantly elevated in the diabetic group with retinopathy. Fasting and Postprandial plasma glucose and glycated haemoglobin (HbA1c levels confirmed the glycaemic status of each of the groups. CONCLUSIONS Hypomagnesemia, hypercholesterolaemia, hypertriglyceridemia was observed in diabetic retinopathy along with increased levels of glycated haemoglobin in our study.

Thalamus segmentation from MP2RAGE: a comparative study

DEFF Research Database (Denmark)

Eskildsen, Simon Fristed; Næss-Schmidt, Erhard; Blicher, Jakob

RAGE sequence on a Siemens Magnetom Skyra 3T MRI system with a 32 channel head coil. Parameters were TR=5 s, TI1=0.7 s, TI2=2.5 s, α1=4°, α2=5° and acquired at a nominal, isotropic, resolution of 1mm (acquisition matrix: 240x256, 176 sagittal slices). An experienced neuro-radiologist manually traced......, increasing the number of training images in the library of SNIPE improves segmentation accuracy (Figure 4). Even though the DSI seems to plateau around a library size of 10-11 images, increasing the library may improve the accuracy even further. Conclusions: Widely used atlas based segmentation methods...

The effect of glycation on bovine serum albumin conformation and ligand binding properties with regard to gliclazide

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Żurawska-Płaksej, Ewa; Rorbach-Dolata, Anna; Wiglusz, Katarzyna; Piwowar, Agnieszka

2018-01-01

Albumin, the major serum protein, plays a variety of functions, including binding and transporting endogenous and exogenous ligands. Its molecular structure is sensitive to different environmental modifiers, among which glucose is one of the most significant. In vivo albumin glycation occurs under physiological conditions, but it is increased in diabetes. Since bovine serum albumin (BSA) may serve as a model protein in in vitro experiments, we aimed to investigate the impact of glucose-mediated BSA glycation on the binding capacity towards gliclazide, as well as the ability of this drug to prevent glycation of the BSA molecule. To reflect normo- and hyperglycemia, the conditions of the glycation process were established. Structural changes of albumin after interaction with gliclazide (0-14 μM) were determined using fluorescence quenching and circular dichroism spectroscopy. Moreover, thermodynamic parameters as well as energy transfer parameters were determined. Calculated Stern-Volmer quenching constants, as well as binding constants for the BSA-gliclazide complex, were lower for the glycated form of albumin than for the unmodified protein. The largest, over 2-fold, decrease in values of binding parameters was observed for the sample with 30 mM of glucose, reflecting the poorly controlled diabetic state, which indicates that the degree of glycation had a critical influence on binding with gliclazide. In contrast to significant changes in the tertiary structure of BSA upon binding with gliclazide, only slight changes in the secondary structure were observed, which was reflected by about a 3% decrease of the α-helix content of glycated BSA (regardless of glucose concentration) in comparison to unmodified BSA. The presence of gliclazide during glycation did not affect its progress. The results of this study indicate that glycation significantly changed the binding ability of BSA towards gliclazide and the scale of these changes depended on glucose concentration. It

Chronic cerebral hypoperfusion-induced impairment of Aβ clearance requires HB-EGF-dependent sequential activation of HIF1α and MMP9.

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Ashok, Anushruti; Rai, Nagendra Kumar; Raza, Waseem; Pandey, Rukmani; Bandyopadhyay, Sanghamitra

2016-11-01

Chronic cerebral hypoperfusion (CCH) manifests Alzheimer's Disease (AD) neuropathology, marked by increased amyloid beta (Aβ). Besides, hypoxia stimulates Heparin-binding EGF-like growth factor (HB-EGF) mRNA expression in the hippocampus. However, involvement of HB-EGF in CCH-induced Aβ pathology remains unidentified. Here, using Bilateral Common Carotid Artery Occlusion mouse model, we explored the mechanism of HB-EGF regulated Aβ induction in CCH. We found that HB-EGF inhibition suppressed, while exogenous-HB-EGF triggered hippocampal Aβ, proving HB-EGF-dependent Aβ increase. We also detected that HB-EGF affected the expression of primary Aβ transporters, receptor for advanced glycation end-products (RAGE) and lipoprotein receptor-related protein-1 (LRP-1), indicating impaired Aβ clearance across the blood-brain barrier (BBB). An HB-EGF-dependent loss in BBB integrity supported impaired Aβ clearance. The effect of HB-EGF on Amyloid Precursor Protein pathway was relatively insignificant, suggesting a lesser effect on Aβ generation. Delving into BBB disruption mechanism demonstrated HB-EGF-mediated stimulation of Matrix metalloprotease-9 (MMP9), which affected BBB via HB-EGF-ectodomain shedding and epidermal growth factor receptor activation. Examining the intersection of HB-EGF-regulated pathway and hypoxia revealed HB-EGF-dependent increase in transcription factor, Hypoxia-inducible factor-1alpha (HIF1α). Further, via binding to hypoxia-responsive elements in MMP9 gene, HIF1α stimulated MMP9 expression, and therefore appeared as a prominent intermediary in HB-EGF-induced BBB damage. Overall, our study reveals the essential role of HB-EGF in triggering CCH-mediated Aβ accumulation. The proposed mechanism involves an HB-EGF-dependent HIF1α increase, generating MMP9 that stimulates soluble-HB-EGF/EGFR-induced BBB disintegration. Consequently, CCH-mediated hippocampal RAGE and LRP-1 deregulation together with BBB damage impair Aβ transport and clearance

Using an enzymatic galactose assay to detect lactose glycation extents of two proteins caseinate and soybean protein isolate via the Maillard reaction.

Science.gov (United States)

Wang, Xiao-Peng; Zhao, Xin-Huai

2017-06-01

Glycation of food proteins via the Maillard reaction has been widely studied in the recent years; however, the amount of saccharide connected to proteins is usually not determined. An enzymatic galactose assay was proposed firstly in this study to detect lactose glycation extents of caseinate and soybean protein isolate (SPI) during the Maillard reaction at two temperatures and different times. The separated glycated proteins were hydrolysed to release galactose necessary for the enzymatic assay and glycation calculation. Caseinate and SPI both obtained the highest lactose glycation extents at 100 °C or 121 °C by a reaction time of 180 or 20 min. Short- and long-time reaction resulted in lower glycation extents. During the reaction, three chemical indices (absorbences at 294/490 nm and fluorescence intensities) of reaction mixtures increased continually, but another index reactable NH 2 of glycated proteins showed the opposite trend. In general, changing profiles of the four indices were inconsistent with those profiles of lactose glycation extents of glycated proteins, implying practical limitation of the four indices in studies. This proposed enzymatic assay could directly detect lactose glycation of the two proteins, and thus was more useful than the four chemical indices to monitor glycation of the two proteins. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Inhibitory effect of gold nanoparticles on the D-ribose glycation of bovine serum albumin

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Liu W

2014-11-01

Full Text Available Weixi Liu,1 Menashi A Cohenford,1–3 Leslie Frost,3 Champika Seneviratne,4 Joel A Dain1 1Department of Chemistry, University of Rhode Island, Kingston, RI, USA; 2Department of Integrated Science and Technology, 3Department of Chemistry, Marshall University, Huntington, WV, USA; 4Department of Chemistry, College of the North Atlantic, Labrador, NL, Canada Abstract: Formation of advanced glycation end products (AGEs by nonenzymatic glycation of proteins is a major contributory factor to the pathophysiology of diabetic conditions including senile dementia and atherosclerosis. This study describes the inhibitory effect of gold nanoparticles (GNPs on the D-ribose glycation of bovine serum albumin (BSA. A combination of analytical methods including ultraviolet–visible spectrometry, high performance liquid chromatography, circular dichroism, and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF mass spectrometry were used to determine the extent of BSA glycation in the presence of citrate reduced spherical GNPs of various sizes and concentrations. GNPs of particle diameters ranging from 2 nm to 20 nm inhibited BSA’s AGE formation. The extent of inhibition correlated with the total surface area of the nanoparticles. GNPs of highest total surface area yielded the most inhibition whereas those with the lowest total surface area inhibited the formation of AGEs the least. Additionally, when GNPs’ total surface areas were set the same, their antiglycation activities were similar. This inhibitory effect of GNPs on BSA’s glycation by D-ribose suggests that colloidal particles may have a therapeutic application for the treatment of diabetes and conditions that promote hyperglycemia. Keywords: gold nanoparticles, glycation, AGEs, GNPs, BSA

Effects of preservation conditions of canine feces on in vitro gas production kinetics and fermentation end-products

NARCIS (Netherlands)

Bosch, G.; Wrigglesworth, D.J.; Cone, J.W.; Pellikaan, W.F.; Hendriks, W.H.

2013-01-01

This study investigated the effect of chilling and freezing (for 24 h) canine feces on in vitro gas production kinetics and fermentation end-product profiles from carbohydrate-rich (in vitro run 1) and protein-rich substrates (in vitro run 2). Feces were collected from 3 adult Retriever-type dogs

A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia

Energy Technology Data Exchange (ETDEWEB)

Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying [Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan (China); Hsu, Ya-Wen [SunWay Biotechnology Company, Taipei, Taiwan (China); Pan, Tzu-Ming, E-mail: tmpan@ntu.edu.tw [Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan (China)

2013-11-01

Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able to elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to D-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. - Highlights: • Monascin acts as a PPARgamma agonist. • Monascin activates Nrf2 and AMPK. • Monascin promotes MG metabolism into D-lactic acid. • Monascin attenuates inflammation and diabetes in vivo.

Purple sweet potato color alleviates D-galactose-induced brain aging in old mice by promoting survival of neurons via PI3K pathway and inhibiting cytochrome C-mediated apoptosis.

Science.gov (United States)

Lu, Jun; Wu, Dong-mei; Zheng, Yuan-lin; Hu, Bin; Zhang, Zi-feng

2010-05-01

Purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, protects brain function against oxidative stress induced by D-galactose (D-gal) (Sigma-Aldrich, St. Louis, MO, USA). Our data showed that PSPC enhanced open-field activity, decreased step-through latency, and improved spatial learning and memory ability in D-gal-treated old mice by decreasing advanced glycation end-products' (AGEs) formation and the AGE receptor (RAGE) expression, and by elevating Cu,Zn-superoxide dismutase (Cu,Zn-SOD) (Sigma-Aldrich) and catalase (CAT) expression and activity. Cleavage of caspase-3 and increased terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end-labeling (TUNEL)-positive cells in D-gal-treated old mice were inhibited by PSPC, which might be attributed to its antioxidant property. PSPC also suppressed the activation of c-Jun NH(2)-terminal kinase (JNK) and the release of cytochrome c from mitochondria that counteracted the onset of neuronal apoptosis in D-gal-treated old mice. Furthermore, it was demonstrated that phosphoinositide 3-kinase (PI3K) activation was required for PSPC to promote the neuronal survival accompanied with phosphorylation and activation of Akt and p44/42 mitogen-activated protein kinase (MAPK) by using PI3K inhibitor LY294002 (Cell Signaling Technology, Inc., Beverly, MA, USA), implicating a neuronal survival mechanism. The present results suggest that neuronal survival promoted by PSPC may be a potentially effective method to enhance resistance of neurons to age-related disease.

Gadolinium-Enhanced Three-Dimensional Magnetization - Prepared Rapid Gradient-Echo (3D MP-RAGE) Imaging is Superior to Spin-Echo Imaging in Delineating Brain Metastases

International Nuclear Information System (INIS)

Takeda, T.; Takeda, A.; Nagaoka, T.; Kunieda, E.; Takemasa, K.; Watanabe, M.; Hatou, T.; Oguro, S.; Katayama, M.

2008-01-01

Background: Precisely defining the number and location of brain metastases is very important for establishing a treatment strategy for malignancies. Although magnetic resonance imaging (MRI) is now considered the best modality, various improvements in sequences are still being made. Purpose: To prospectively compare the diagnostic ability of three-dimensional, magnetization-prepared rapid gradient-echo (3D MP-RAGE) imaging in detecting metastatic brain tumors, with that of two-dimensional spin-echo (2D SE) T1-weighted imaging. Material and Methods: A total of 123 examinations were included in this study, and 119 examinations from 88 patients with known malignancies were analyzed. All patients underwent T1- and T2-weighted 2D SE transverse imaging, followed by gadolinium-enhanced T1-weighted transverse and coronal 2D SE imaging and 3D MP-RAGE transverse imaging. Four radiologists interpreted the images to compare the accuracy and the time required for interpretation for each imaging. Results: 3D MP-RAGE imaging was significantly better than 2D SE imaging for detecting metastatic brain lesions, regardless of the readers' experience. The sensitivities of the 3D MP-RAGE and 2D SE imaging for all observers were 0.81 vs. 0.80 (P>0.05), specificities were 0.93 vs. 0.87 (P 0.05), and accuracies were 0.84 vs. 0.78 (P<0.05), respectively. There was no significant difference in the time required for image interpretation between the two modalities (15.6±4.0 vs. 15.4±4.1 min). Conclusion: 3D MP-RAGE imaging proved superior to 2D SE imaging in the detection of brain metastases

The Extract of Aster Koraiensis Prevents Retinal Pericyte Apoptosis in Diabetic Rats and Its Active Compound, Chlorogenic Acid Inhibits AGE Formation and AGE/RAGE Interaction

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Junghyun Kim

2016-09-01

Full Text Available Retinal capillary cell loss is a hallmark of early diabetic retinal changes. Advanced glycation end products (AGEs are believed to contribute to retinal microvascular cell loss in diabetic retinopathy. In this study, the protective effects of Aster koraiensis extract (AKE against damage to retinal vascular cells were investigated in streptozotocin (STZ-induced diabetic rats. To examine this issue further, AGE accumulation, nuclear factor-kappaB (NF-κB and inducible nitric oxide synthase (iNOS were investigated using retinal trypsin digests from streptozotocin-induced diabetic rats. In the diabetic rats, TUNEL (Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling-positive retinal microvascular cells were markedly increased. Immunohistochemical studies revealed that AGEs were accumulated within the retinal microvascular cells, and this accumulation paralleled the activation of NF-κB and the expression of iNOS in the diabetic rats. However, AKE prevented retinal microvascular cell apoptosis through the inhibition of AGE accumulation and NF-κB activation. Moreover, to determine the active compounds of AKE, two major compounds, chlorogenic acid and 3,5-di-O-caffeoylquinic acid, were tested in an in vitro assay. Among these compounds, chlorogenic acid significantly reduced AGE formation as well as AGE/RAGE (receptor for AGEs binding activity. These results suggest that AKE, particularly chlorogenic acid, is useful in inhibiting AGE accumulation in retinal vessels and exerts a preventive effect against the injuries of diabetic retinal vascular cells.

Accumulation of glycation products in. cap alpha. -H pig lens crystallin and its bearing to diabetic cataract genesis

Energy Technology Data Exchange (ETDEWEB)

Vidal, P; Cabezas-Cerrato, J

1988-01-01

The incorporation of /sup 11/C-glucose in native pig crystalline by in vitro incubation was found, after subsequent dialysis, to affect all 5 classes of crystallin separated by Sepharose CL-6B column chromatography. Though the radioactivity of the ..cap alpha..-H fraction was three times greater than that of any of the others, autoradiographs of SDS-PAGE gels showed /sup 11/C-glucose adducts to be present in all soluble protein subunits, without there being any evidence of preferential glycation of the ..cap alpha..-H subunits. The concentration of stable glycation products in the ..cap alpha..-H chromatographic fraction of soluble crystallins is suggested to be due the addition of glycated material to this fraction as result of glycation-induced hyperaggregation, and not because the ..cap alpha..-H subunits were especially susceptible to glycation.

Recent advances in α-synuclein functions, advanced glycation, and toxicity: implications for Parkinson's disease.

Science.gov (United States)

Guerrero, Erika; Vasudevaraju, P; Hegde, Muralidhar L; Britton, G B; Rao, K S

2013-04-01

The toxicity of α-synuclein in the neuropathology of Parkinson's disease which includes its hallmark aggregation has been studied scrupulously in the last decade. Although little is known regarding the normal functions of α-synuclein, its association with membrane phospholipids suggests its potential role in signaling pathways. Following extensive evidences for its nuclear localization, we and others recently demonstrated DNA binding activity of α-synuclein that modulates its conformation as well as aggregation properties. Furthermore, we also underscored the similarities among various amyloidogenic proteins involved in neurodegenerative diseases including amyloid beta peptides and tau. Our more recent studies show that α-synuclein is glycated and glycosylated both in vitro and in neurons, significantly affecting its folding, oligomeric, and DNA binding properties. Glycated α-synuclein causes increased genome damage both via its direct interaction with DNA and by increased generation of reactive oxygen species as glycation byproduct. In this review, we discuss the mechanisms of glycation and other posttranslational modifications of α-synuclein, including phosphorylation and nitration, and their role in neuronal death in Parkinson's disease.

THE EFFECTS OF GLYCATION ON THE BINDING OF HUMAN SERUM ALBUMIN TO WARFARIN AND L-TRYPTOPHAN

OpenAIRE

Joseph, K.S.; Hage, David S.

2010-01-01

Diabetes leads to elevated levels of glucose in blood which, in turn, can lead to the non-enzymatic glycation of serum proteins such as human serum albumin (HSA). It has been suggested that this increase in glycation can alter the ability of HSA to bind to drugs and other small solutes. This study used high-performance affinity chromatography (HPAC) to see if there is any significant change related to glycation in the binding of HSA to warfarin and L-tryptophan, which are often used as probe ...

Ovalbumin with Glycated Carboxyl Groups Shows Membrane-Damaging Activity

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Ching-Chia Tang

2017-02-01

Full Text Available The aim of the present study was to investigate whether glycated ovalbumin (OVA showed novel activity at the lipid-water interface. Mannosylated OVA (Man-OVA was prepared by modification of the carboxyl groups with p-aminophenyl α-dextro (d-mannopyranoside. An increase in the number of modified carboxyl groups increased the membrane-damaging activity of Man-OVA on cell membrane-mimicking vesicles, whereas OVA did not induce membrane permeability in the tested phospholipid vesicles. The glycation of carboxyl groups caused a notable change in the gross conformation of OVA. Moreover, owing to their spatial positions, the Trp residues in Man-OVA were more exposed, unlike those in OVA. Fluorescence quenching studies suggested that the Trp residues in Man-OVA were located on the interface binds with the lipid vesicles, and their microenvironment was abundant in positively charged residues. Although OVA and Man-OVA showed a similar binding affinity for lipid vesicles, the lipid-interacting feature of Man-OVA was distinct from that of OVA. Chemical modification studies revealed that Lys and Arg residues, but not Trp residues, played a crucial role in the membrane-damaging activity of Man-OVA. Taken together, our data suggest that glycation of carboxyl groups causes changes in the structural properties and membrane-interacting features of OVA, generating OVA with membrane-perturbing activities at the lipid-water interface.

Lack of association of glycated haemoglobin with blood pressure ...

African Journals Online (AJOL)

2013-04-12

Apr 12, 2013 ... Therefore, we examined the relationships of fasting glucose and glycated ... but factors that did associate significantly were age, male gender, rural location, abdominal obesity, alcohol intake .... in continuous variables were.

Comparative LC-MS/MS profiling of free and protein-bound early and advanced glycation-induced lysine modifications in dairy products

International Nuclear Information System (INIS)

Hegele, Joerg; Buetler, Timo; Delatour, Thierry

2008-01-01

Free and protein-bound forms of early and advanced glycation-induced lysine (Lys) modifications were quantified in dairy products by LC-MS/MS using a stable isotope dilution assay. The glycation profiles for N ε -fructoselysine (FL), N ε -carboxymethyllysine (CML) and pyrraline (Pyr) were monitored in raw and processed cow milk to investigate whether free glycation products could serve as fast and simple markers to assess the extent of protein glycation in dairy products. In all milk samples, the fraction of free glycation adducts was predominantly composed of advanced modifications, e.g. 8.34 ± 3.81 nmol CML per μmol of free Lys (Lys free ) and 81.5 ± 87.8 nmol Pyr μmol -1 Lys free -1 vs. 3.72 ± 1.29 nmol FL μmol -1 Lys free -1 . In contrast, the protein-bound early glycation product FL considerably outweighed the content of CML and Pyr in milk proteins of raw and processed cow milk, whereas severely heat treated milk products, e.g. condensed milk, contained a higher amount of protein-bound advanced glycation adducts. Typical values recorded for milk samples processed under mild conditions were 0.47 ± 0.08 nmol FL μmol -1 of protein-bound Lys (Lys p-b ), 0.04 ± 0.03 nmol CML μmol -1 Lys p-b -1 and 0.06 ± 0.02 nmol Pyr μmol -1 Lys p-b -1 . It was particularly noticeable, however, that mild heat treatment of raw milk, i.e. pasteurization and UHT treatment, did not significantly increase the amount of both free and protein-bound Lys modifications. In conclusion, the profiles of free and protein-bound glycation-induced Lys modifications were found to be different and a screening of free glycation adducts does, therefore, not allow for a conclusion about the protein glycation status of dairy products

Nonenzymatic glycation of phosphatidylethanolamine in erythrocyte vesicles

International Nuclear Information System (INIS)

Patkowska, M.J.; Horowitz, M.I.

1986-01-01

Unsealed inside-out and right-side out vesicles were prepared from human red cells. The vesicles were incubated with D-glucose [ 14 C(U)] and sodium cyanoborohydride in phosphate buffer, pH 7.4. After incubation, lipids were extracted with 1-butanol and non-lipid contaminants removed by Sephadex G-25 chromatography. Phosphatidylethanolamine-sorbitol was purified by chromatography on columns of silicic acid and phenylboronate agarose gel. Phospholipase C (B. cereus) liberated phosphoethanolamine-sorbitol (I) which comigrated on TLC with synthetic I prepared by reductive condensation of phosphoethanolamine and D-glucose and also with the product of phospholipase C (B. cereus) hydrolysis of reference phosphatidylethanolamine-sorbitol. Exposure of I to alkaline phosphatase (E. coli) gave P/sub i/ and ethanolamine-sorbitol (II) which comigrated on TLC with synthetic II prepared by reductive condensation of ethanolamine and D-glucose or by phospholipase D hydrolysis of reference phosphatidylethanolamine-sorbitol. These studies demonstrate that vesicular phosphatidylethanolamine can be reductively glycated and illustrate the applicability of both phospholipase C and phospholipase D in characterizing glycated phosphoglycerides

In vitro inhibitory activities of selected Australian medicinal plant extracts against protein glycation, angiotensin converting enzyme (ACE) and digestive enzymes linked to type II diabetes.

Science.gov (United States)

Deo, Permal; Hewawasam, Erandi; Karakoulakis, Aris; Claudie, David J; Nelson, Robert; Simpson, Bradley S; Smith, Nicholas M; Semple, Susan J

2016-11-04

There is a need to develop potential new therapies for the management of diabetes and hypertension. Australian medicinal plants collected from the Kuuku I'yu (Northern Kaanju) homelands, Cape York Peninsula, Queensland, Australia were investigated to determine their therapeutic potential. Extracts were tested for inhibition of protein glycation and key enzymes relevant to the management of hyperglycaemia and hypertension. The inhibitory activities were further correlated with the antioxidant activities. Extracts of five selected plant species were investigated: Petalostigma pubescens, Petalostigma banksii, Memecylon pauciflorum, Millettia pinnata and Grewia mesomischa. Enzyme inhibitory activity of the plant extracts was assessed against α-amylase, α-glucosidase and angiotensin converting enzyme (ACE). Antiglycation activity was determined using glucose-induced protein glycation models and formation of protein-bound fluorescent advanced glycation endproducts (AGEs). Antioxidant activity was determined by measuring the scavenging effect of plant extracts against 1, 1-diphenyl-2-picryl hydrazyl (DPPH) and using the ferric reducing anti-oxidant potential assay (FRAP). Total phenolic and flavonoid contents were also determined. Extracts of the leaves of Petalostigma banksii and P. pubescens showed the strongest inhibition of α-amylase with IC 50 values of 166.50 ± 5.50 μg/mL and 160.20 ± 27.92 μg/mL, respectively. The P. pubescens leaf extract was also the strongest inhibitor of α-glucosidase with an IC 50 of 167.83 ± 23.82 μg/mL. Testing for the antiglycation potential of the extracts, measured as inhibition of formation of protein-bound fluorescent AGEs, showed that P. banksii root and fruit extracts had IC 50 values of 34.49 ± 4.31 μg/mL and 47.72 ± 1.65 μg/mL, respectively, which were significantly lower (p < 0.05) than other extracts. The inhibitory effect on α-amylase, α-glucosidase and the antiglycation potential of

Plasma Levels of Advanced Glycation Endproducts N-is an element of-(carboxymethyl)lysine, N-is an element of-(carboxyethyl)lysine, and Pentosidine Are not Independently Associated With Cardiovascular Disease in Individuals With or Without Type 2 Diabetes: The Hoorn and CODAM Studies

NARCIS (Netherlands)

Hanssen, N.M.J.; Engelen, L.; Ferreira, I.; Scheijen, J.L.J.M.; Huijberts, M.S.; van Greevenbroek, M.M.J.; van der Kallen, C.J.H.; Dekker, J.M.; Nijpels, G.; Stehouwer, C.D.A.; Schalkwijk, C.G.

2013-01-01

Objective: Experimental and histological data suggest a role for advanced glycation end products (AGEs) in cardiovascular disease (CVD), particularly in type 2 diabetes (T2DM). However, the epidemiological evidence of an adverse association between AGEs and CVD remains inconclusive. We therefore