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Sample records for adprt1 akr1b1 rage

  1. Association analysis of ADPRT1, AKR1B1, RAGE, GFPT2 and PAI-1 gene polymorphisms with chronic renal insufficiency among Asian Indians with type-2 diabetes

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    Gupta Arvind

    2010-03-01

    Full Text Available Abstract Background To determine association of nine single nucleotide polymorphisms (SNPs in ADP ribosyltransferase-1 (ADPRT1, aldo-keto reductase family 1 member B1 (AKR1B1, receptor for advanced glycation end-products (RAGE, glutamine:fructose-6-phosphate amidotransferase-2 (GFPT2, and plasminogen activator inhibitor-1 (PAI-1 genes with chronic renal insufficiency (CRI among Asian Indians with type 2 diabetes; and to identify epistatic interactionss between genes from the present study and those from renin-angiotensin-aldosterone system (RAAS, and chemokine-cytokine, dopaminergic and oxidative stress pathways (previously investigated using the same sample set. Methods Type 2 diabetes subjects with CRI (serum creatinine ≥3.0 mg/dl constituted the cases (n = 196, and ethnicity and age matched individuals with diabetes for a duration of ≥ 10 years, normal renal functions and normoalbuminuria recruited as controls (n = 225. Allelic and genotypic constitution of 10 polymorphisms (SNPs from five genes namely- ADPRT1, AKR1B1, RAGE, GFPT2 and PAI-1 with diabetic CRI was investigated. The genetic associations were evaluated by computation of odds ratio and 95% confidence interval. Multiple logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study epistatic interactions between SNPs in different genes. Results Single nucleotide polymorphisms -429 T>C in RAGE and rs7725 C>T SNP in 3' UTR in GFPT2 gene showed a trend towards association with diabetic CRI. Investigation using miRBase statistical tool revealed that rs7725 in GFPT2 was a perfect target for predicted miRNA (hsa miR-378 suggesting the presence of the variant 'T' allele may result in an upregulation of GFPT2 contributing to diabetic renal complication. Epistatic interaction between SNPs in transforming growth factor TGF-β1 (investigated using the same sample set and reported elsewhere and GFPT2 genotype was observed. Conclusions

  2. Overexpression and enhanced specific activity of aldoketo reductases (AKR1B1 & AKR1B10) in human breast cancers.

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    Reddy, K Ashok; Kumar, P Uday; Srinivasulu, M; Triveni, B; Sharada, K; Ismail, Ayesha; Reddy, G Bhanuprakash

    2017-02-01

    The incidence of breast cancer in India is on the rise and is rapidly becoming the primary cancer in Indian women. The aldoketo reductase (AKR) family has more than 190 proteins including aldose reductase (AKR1B1) and aldose reductase like protein (AKR1B10). Apart from liver cancer, the status of AKR1B1 and AKR1B10 with respect to their expression and activity has not been reported in other human cancers. We studied the specific activity and expression of AKR1B1 and AKR1B10 in breast non tumor and tumor tissues and in the blood. Fresh post-surgical breast cancer and non-cancer tissues and blood were collected from the subjects who were admitted for surgical therapy. Malignant, benign and pre-surgical chemotherapy samples were evaluated by histopathology scoring. Expression of AKR1B1 and AKR1B10 was carried out by immunoblotting and immunohistochemistry (IHC) while specific activity was determined spectrophotometrically. The specific activity of AKR1B1 was significantly higher in red blood cells (RBC) in all three grades of primary surgical and post-chemotherapy samples. Specific activity of both AKR1B1 and AKR1B10 increased in tumor samples compared to their corresponding non tumor samples (primary surgical and post-chemotherapy). Immunoblotting and IHC data also indicated overexpression of AKR1B1 in all grades of tumors compared to their corresponding non tumor samples. There was no change in the specific activity of AKR1B1 in benign samples compared to all grades of tumor and non-tumors.

  3. The prostaglandin F synthase activity of the human aldose reductase AKR1B1 brings new lenses to look at pathologic conditions.

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    Eva eBresson

    2012-05-01

    Full Text Available Prostaglandins are important regulators of female reproductive functions to which aldose reductases exhibiting hydroxysteroid dehydrogenase activity also contribute. Our work on the regulation of reproductive function by prostaglandins (PGs, lead us to the discovery that AKR1B5 and later AKR1B1 were highly efficient and physiologically relevant PGF synthases. PGE2 and PGF2α are the main prostanoids produced in the human endometrium and proper balance in their relative production is important for normal menstruation and optimal fertility. Recent evidence suggests that PGE2 and PGF2α may constitute a functional dyad with physiological relevance at least as important as the prostacyclin-thromboxane dyad in the vascular system. We have recently reported that AKR1B1 was expressed and modulated in association with PGF2α production in response to IL-1β in the human endometrium. In the present study, we show that the human AKR1B1 (gene ID: 231 also known as ALDR1 or ALR2 is a functional PGF2α synthase in different models of living cells and tissues. Using human endometrial cells, prostate and vascular smooth muscle cells, cardiomyocytes and endothelial cells we demonstrate that IL-1β is able to up regulate COX-2 and AKR1B1 proteins as well as PGF2α production under normal glucose concentrations. We show that the promoter activity of AKR1B1 gene is increased by IL-1β particularly around the multiple stress response region (MSRR containing two putative antioxidant response elements (ARE adjacent to TonE and AP1.We also show that AKR1B1 is able to regulate PGE2 production through PGF2α acting on its FP receptor and that aldose reductase inhibitors (ARIs like alrestatin, statil (ponalrestat and EBPC exhibit distinct and characteristic inhibition of PGF2α production in different cell models. The PGF synthase activity of AKR1B1 represents a new and important target to regulate ischemic and inflammatory responses associated with several human

  4. Expression of the prostaglandin F synthase AKR1B1 and the prostaglandin transporter SLCO2A1 in human fetal membranes in relation to spontaneous term and preterm labour

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    Hana A Alzamil

    2014-07-01

    Full Text Available Background: Human labour is a complex series of cellular and molecular events that occur at the materno-fetal and uterine levels. Many hypotheses have been proposed for the initiation of human labour, one hypothesis suggests that maturation of the fetus releases a signal in the amniotic fluid that will be transmitted to myometrium via the fetal membranes and initiate uterine contractions. There is strong evidence that prostaglandins (PGs play a central role in initiation and progression of human labour. Objectives: In this study we intended to investigate the expression of prostaglandin F synthase and the prostaglandin transporter in the human fetal membranes and to explore the relationship between cytokines and PGs in the mechanism of human labour. Methods: We used fetal membranes obtained before labour at term and after spontaneous labour at term or preterm to identify the changes in prostaglandin F synthase (AKR1B1 and human prostaglandin transporter (SLCO2A1 proteins in relation to parturition. Using fetal membranes explants we tested the effect of cytokines (interleukin-1 and tumour necrosis factor alpha on PG production and the concomitant changes in cyclooxygenase-2 (PTGS2, AKR1B1 and SLCO2A1 expression. Results: Expression of PTGS2 and AKR1B1 was upregulated in the fetal membranes in association with term labour while SLCO2A1 was downregulated with advancing gestation and during term labour. Before labour, IL-1 increased the expression of PTGS2, however during labour TNF upregulated PTGS2 and AKR1B1 proteins. Conclusions: The prostaglandin F synthase AKR1B1 is upregulated while prostaglandin transporter is downregulated during term labour. The amnion is more responsive than choriodecidua to stimulation with pro-inflammatory cytokines. The mechanisms of term and preterm labour are different.

  5. Narcissistic rage revisited.

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    Krizan, Zlatan; Johar, Omesh

    2015-05-01

    Narcissists are thought to exhibit "narcissistic rage," an explosive mix of anger and hostility arising from threats to narcissists' fractured sense of self. Building on clinical views of narcissism, we present empirical evidence on the nature and sources of narcissistic rage. Findings from 4 studies reveal narcissistic vulnerability (but not grandiosity) as a powerful driver of rage, hostility, and aggressive behavior, fueled by suspiciousness, dejection, and angry rumination. Consistent with theorizing about narcissistic rage, Study 1 showed that vulnerable (but not grandiose) narcissism predicted more anger internalization and externalization, as well as poorer anger control. Study 2 revealed vulnerable narcissism as a stronger indicator of shame and aggressiveness, especially hostility and anger. Study 3 identified distrust of others and angry rumination as key factors accounting for vulnerable narcissists' reactive and displaced aggression. Study 4 provided behavioral evidence that vulnerable (but not grandiose) narcissism amplifies reactive and displaced aggression in the face of provocation. Taken together, the findings not only establish narcissistic vulnerability as a key source of narcissistic rage but also reveal an important pathway to narcissistic aggression that does not involve competitiveness or exploitativeness. In addition, the results support clinical views of narcissistic aggression and implicate deficient self-esteem as an important driver of aggressive behavior.

  6. A race for RAGE ligands.

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    Schleicher, Erwin D

    2010-08-01

    In experimental animals a causal involvement of the multiligand receptor for advanced glycation end products (RAGE) in the development of diabetic vascular complications has been demonstrated. However, the nature of RAGE ligands present in patients with diabetic nephropathy has not yet been defined; this leaves open the relevance of the RAGE system to the human disease.

  7. RAGE on the Toll Road?

    Institute of Scientific and Technical Information of China (English)

    Li Lin

    2006-01-01

    Mammalian Toll-like receptors (TLRs) are cellular pattern-recognizing receptors (PRRs) that recognize the molecular patterns of pathogens. After engaging the pathogenic patterned ligands, the cytosolic portion of the TLRs in monocytes and macrophages, recruits adaptor proteins, via a receptor-driven signaling cascade, activates the transcription factor NF-κB, leading to the expression of proinflammatory cytokines, which trigger inflammation. Such rapid, innate cellular responses serve as the first line of host defense against infection by pathogens, and also stimulate the adaptive immune system to clear the invading microbes. Increasing evidence suggests that TLRs also recognize host-derived ligands, linking this group of PRRs to diseases that may not have an etiology that is associated directly with infections. Advanced glycation end products (AGEs) are nonenzymatically glycated or oxidated proteins, lipids and nucleic acids that are formed in the environment of oxidant stress and hyperglycemia. Binding of AGEs to their receptor RAGE initiates cellular signals that activate NF-κB, which results in transcription of proinflammatory factors. RAGE can also interact with other endogenous ligands generated by cell death and tissue injuries. RAGE has been implicated in chronic diseases such as diabetes,atherosclerosis, neurodisorders, cancers, as well as aging. This review discusses the possible role of RAGE as a PRR that may use signaling mechanisms parallel to TLRs', to solicit inflammatory reactions. Thus, in this scenario,RAGE may play a prominent role in the regulation of cellular homeostasis in the context of complex disease progression.

  8. RAGE and its ligands in retinal disease.

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    Barile, Gaetano R; Schmidt, Ann M

    2007-12-01

    RAGE, the receptor for advanced glycation endproducts (AGEs), is a multiligand signal transduction receptor of the immunoglobulin superfamily of cell surface molecules that has been implicated in the pathogenesis of diabetic complications, neurodegenerative diseases, inflammatory disorders, and cancer. These diverse biologic disorders reflect the multiplicity of ligands capable of cellular interaction via RAGE that include, in addition to AGEs, amyloid-beta (Abeta) peptide, the S100/calgranulin family of proinflammatory cytokines, and amphoterin, a member of the High Mobility Group Box (HMGB) DNA-binding proteins. In the retina, RAGE expression is present in neural cells, the vasculature, and RPE cells, and it has also been detected in pathologic cellular retinal responses including epiretinal and neovascular membrane formation. Ligands for RAGE, in particular AGEs, have emerged as relevant to the pathogenesis of diabetic retinopathy and age-related macular disease. While the understanding of RAGE and its role in retinal dysfunction with aging, diabetes mellitus, and/or activation of pro-inflammatory pathways is less complete compared to other organ systems, increasing evidence indicates that RAGE can initiate and sustain significant cellular perturbations in the inner and outer retina. For these reasons, antagonism of RAGE interactions with its ligands may be a worthwhile therapeutic target in such seemingly disparate, visually threatening retinal diseases as diabetic retinopathy, age-related macular degeneration, and proliferative vitreoretinopathy.

  9. Effects of atorvastatin on progression of diabetic nephropathy and local RAGE and soluble RAGE expressions in rats

    Institute of Scientific and Technical Information of China (English)

    Lin LU; Wen-hui PENG; Wei WANG; Ling-jie WANG; Qiu-jing CHEN; Wei-feng SHEN

    2011-01-01

    Objective:Advanced glycation end-products (AGEs) exert inflammatory and oxidative stress insults to produce diabetic nephropathy mainly through the receptor for AGEs (RAGE).This study aimed to assess the effect of atorvastatin on diabetic nephropathy via soluble RAGE (sRAGE) and RAGE expressions in the rat kidney.Methods:Thirty-two male Sprague-Dawley rats were divided into four groups based on the presence or absence of streptozotocin-induced diabetes with or without atorvastatin treatment (10 mg/kg for 24 weeks).Serum sRAGE and glycated albumin (GA) levels were measured with enzyme-linked immunosorbent assay (ELISA) and improved bromocresol purple methods.Renal AGEs,RAGE,endogenous secretory RAGE (esRAGE),and sRAGE were determined with reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting.Results:Mesangial expansion and microalbuminuria were aggravated in diabetic rats,and improved with atorvastatin treatment.Serum sRAGE levels were lower in diabetic than in normal rats.After atorvastatin treatment,serum and renal sRAGE levels were up-regulated,while renal RAGE expression was decreased in diabetic rats,associated with a reduction in accumulation of AGEs,though renal esRAGE mRNA expression was not significantly increased.Conclusions:Atorvastatin exerted a beneficial effect on diabetic nephropathy with reduced AGE accumulation,down-regulating RAGE expression and up-regulating sRAGE in the kidney.

  10. 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.

  11. "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.

  12. xRage Equation of State

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    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.

  13. RAGE Expression and ROS Generation in Neurons: Differentiation versus Damage.

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    Piras, S; Furfaro, A L; Domenicotti, C; Traverso, N; Marinari, U M; Pronzato, M A; Nitti, M

    2016-01-01

    RAGE is a multiligand receptor able to bind advanced glycation end-products (AGEs), amphoterin, calgranulins, and amyloid-beta peptides, identified in many tissues and cells, including neurons. RAGE stimulation induces the generation of reactive oxygen species (ROS) mainly through the activity of NADPH oxidases. In neuronal cells, RAGE-induced ROS generation is able to favor cell survival and differentiation or to induce death through the imbalance of redox state. The dual nature of RAGE signaling in neurons depends not only on the intensity of RAGE activation but also on the ability of RAGE-bearing cells to adapt to ROS generation. In this review we highlight these aspects of RAGE signaling regulation in neuronal cells.

  14. RAGE: a new frontier in chronic airways disease.

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    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.

  15. The S100B/RAGE Axis in Alzheimer's Disease

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    Estelle Leclerc

    2010-01-01

    Full Text Available Increasing evidence suggests that the small EF-hand calcium-binding protein S100B plays an important role in Alzheimer's disease. Among other evidences are the increased levels of both S100B and its receptor, the Receptor for Advanced Glycation Endproducts (RAGEs in the AD diseased brain. The regulation of RAGE signaling by S100B is complex and probably involves other ligands including the amyloid beta peptide (A, the Advanced Glycation Endproducts (AGEs, or transtheyretin. In this paper we discuss the current literature regarding the role of S100B/RAGE activation in Alzheimer's disease.

  16. Receptor for Advanced Glycation End Products (RAGE) Serves a Protective Role during Klebsiella pneumoniae - Induced Pneumonia.

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    Achouiti, Ahmed; de Vos, Alex F; van 't Veer, Cornelis; Florquin, Sandrine; Tanck, Michael W; Nawroth, Peter P; Bierhaus, Angelika; van der Poll, Tom; van Zoelen, Marieke A D

    2016-01-01

    Klebsiella species is the second most commonly isolated gram-negative organism in sepsis and a frequent causative pathogen in pneumonia. The receptor for advanced glycation end products (RAGE) is expressed on different cell types and plays a key role in diverse inflammatory responses. We here aimed to investigate the role of RAGE in the host response to Klebsiella (K.) pneumoniae pneumonia and intransally inoculated rage gene deficient (RAGE-/-) and normal wild-type (Wt) mice with K. pneumoniae. Klebsiella pneumonia resulted in an increased pulmonary expression of RAGE. Furthermore, the high-affinity RAGE ligand high mobility group box-1 was upregulated during K. pneumoniae pneumonia. RAGE deficiency impaired host defense as reflected by a worsened survival, increased bacterial outgrowth and dissemination in RAGE-/- mice. RAGE-/- neutrophils showed a diminished phagocytosing capacity of live K. pneumoniae in vitro. Relative to Wt mice, RAGE-/- mice demonstrated similar lung inflammation, and slightly elevated-if any-cytokine and chemokine levels and unchanged hepatocellular injury. In addition, RAGE-/- mice displayed an unaltered response to intranasally instilled Klebsiella lipopolysaccharide (LPS) with respect to pulmonary cell recruitment and local release of cytokines and chemokines. These data suggest that (endogenous) RAGE protects against K. pneumoniae pneumonia. Also, they demonstrate that RAGE contributes to an effective antibacterial defense during K. pneumoniae pneumonia, at least partly via its participation in the phagocytic properties of professional granulocytes. Additionally, our results indicate that RAGE is not essential for the induction of a local and systemic inflammatory response to either intact Klebsiella or Klebsiella LPS.

  17. RAGE visualization for Special Forces operations

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    Lanzagorta, Marco O.; Kuo, Eddy

    2000-05-01

    The RAGE system is a collaborative virtual environment which is being developed at the Naval Research Laboratory specifically for planning, training and situation awareness. IT consists of the CAVE-like device known as the GROTTO and a virtual workbench. The system offers many important capabilities for hostage rescue scenarios. First, it avoids the need to create physical mockups of rooms and buildings, instead computer models are generated. Second, it is possible to explore alternative scenarios to experiment with different tactical operations. Third, the system can be linked with other software modules such as simulators and analysis tools, and has the capability to dynamically change the environment as new intelligence information is received. This system has three potential applications. First, it can be used as a device for the training of Special Forces. Second, it can be used to study important military operations. Finally, it can be used as a command and control device used in real-time as the rescue operation is being carried out. We show some these capabilities by reproducing one famous special forces hostage rescue operation.

  18. Endogenous Secretory RAGE as a Novel Biomarker for Metabolic Syndrome and Cardiovascular Diseases

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    Hidenori Koyama

    2007-01-01

    Full Text Available Receptor for advanced glycation end-products (RAGE is known to be involved in both micro- and macrovascular complications in diabetes. Among numerous truncated forms of RAGE recently described, the C-terminally truncated form of RAGE has received much attention. This form of RAGE, carrying all of the extracellular domains but devoid of the transmembrane and intracytoplasmic domains, is released outside from cells, binds ligands including AGEs, and is capable of neutralizing RAGE signaling on endothelial cells in culture. This form of RAGE is generated as a splice variant and is named endogenous secretory RAGE (esRAGE. Adenoviral overexpression of esRAGE reverses diabetic impairment of vascular dysfunction, suggesting that esRAGE may be an important inhibitor of RAGE signaling in vivo and potentially be useful for prevention of diabetic vascular complications. An ELISA system to measure plasma esRAGE was recently developed, and the pathophysiological roles of esRAGE have begun to be unveiled clinically. Plasma esRAGE levels are decreased in patients with several metabolic diseases including type 1 and type 2 diabetes, metabolic syndrome and hypertension. In cross-sectional analysis, plasma esRAGE levels are inversely correlated with carotid or femoral atherosclerosis. In an observational cohort of patients with end-stage renal disease, cumulative incidence of cardiovascular death was significantly higher in subjects with lower plasma esRAGE levels. These fi ndings suggest that plasma esRAGE may act as a protective factor against and a novel biomarker for the occurrence of metabolic syndrome and cardiovascular diseases.

  19. Early Release of soluble RAGE After Severe Trauma in Humans

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    Cohen, Mitchell J.; Carles, Michel; Brohi, Karim; Calfee, Carolyn S.; Rahn, Pamela; Call, Mariah S; Chesebro, Brian B.; West, Michael A.; Pittet, Jean-François

    2012-01-01

    Objective The receptor for advanced glycation endproducts (RAGE) recognizes a variety of ligands that play an important role in the posttraumatic inflammatory response. However, whether soluble RAGE (sRAGE) is released early after trauma-hemorrhage in humans and whether such a release is associated with the development of an inflammatory response and coagulopathy is not known and therefore constitutes the aim of the present study. Methods One hundred sixty eight patients were studied as part of a prospective cohort study of severe trauma patients admitted to a single Level 1 Trauma center. Blood was drawn within 10 minutes of arrival to the Emergency Department (ED) before the administration of any fluid resuscitation. sRAGE, TNF-a, IL-6, von Willebrand Factor (vWF), Angiopoietin-2 (Ang-2), Prothrombin time, (PT), prothrombin fragments 1+2 (PF1+2), soluble thrombomodulin (sTM), protein C (PC), plasminogen activator inhibitor-1 (PAI-1), and D-Dimers (fibrin degradation products) were measured using standard techniques. Base deficit was used as a measure of tissue hypoperfusion. Measurements were compared to outcome measures obtained from the electronic medical record and trauma registry. Results Plasma levels of sRAGE were increased within 30 minutes after severe trauma in humans and correlated with the severity of injury, early posttraumatic coagulopathy and hyperfibrinolysis as well as with endothelial cell activation (angiopoietin-1 and complement). Furthermore, we found that there was a significant relationship between plasma levels of sRAGE and the development of acute renal failure. This relationship was not quite significant for patients who developed acute lung injury (p=.11), although patients with less than 26 ventilator-free days had significantly higher plasma levels of sRAGE than those with more than 26 ventilator-free days. Finally, there was no relationship between plasma levels of sRAGE and mortality rate in trauma patients. Conclusions The results

  20. Inner Milky Way Raging with Star Formation

    Science.gov (United States)

    2008-01-01

    More than 444,580 frames from NASA's Spitzer Space Telescope were stitched together to create this portrait of the raging star-formation occurring in the inner Milky Way. As inhabitants of a flat galactic disk, Earth and its solar system have an edge-on view of their host galaxy, like looking a glass dish from its edge. From our perspective, most of the galaxy is condensed into a blurry narrow band of light that stretches completely around the sky, also known as the galactic plane. In this mosaic the galactic plane is broken up into five components: the far-left side of the plane (top image); the area just left of the galactic center (second to top); galactic center (middle); the area to the right of galactic center (second to bottom); and the far-right side of the plane (bottom). Together, these panels represent more than 50 percent of our entire Milky Way galaxy. The red haze that permeates the picture comes from organic molecules called polycyclic aromatic hydrocarbons, which are illuminated by light from massive baby stars. On Earth, these molecules are found in automobile exhaust, or charred barbeque grills anywhere carbon molecules are burned incompletely. The patches of black are dense, obscuring dust clouds impenetrable by even Spitzer's super-sensitive infrared eyes. Bright arcs of white throughout the image are massive stellar incubators. The bluish-white haze that hovers heavily in the middle panel is starlight from the older stellar population towards the center of the galaxy. This picture was taken with Spitzer's infrared array camera, as part of the Galactic Legacy Infrared Mid-Plane Survey Extraordinaire (GLIMPSE) project. This is a four-color composite where blue is 3.6-micron light, green is 4.5 microns, orange is 5.8 microns and red is 8.0 microns.

  1. RAGE activation induces invasiveness of RA fibroblast-like synoviocytes in vitro

    NARCIS (Netherlands)

    Steenvoorden, M.M.C.; Toes, R.E.M.; Ronday, H.K.; Huizinga, T.W.J.; Groot, J. de

    2007-01-01

    Ligands for the receptor for advanced glycation endproducts (RAGE) are increased in RA synovial fluid (SF), serum and synovium. Since RAGE is present on fibroblast-like synoviocytes (FLS), the present study investigates whether the RAGE ligands HMGB-1 and AGEs are able to stimulate the characteristi

  2. 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 th

  3. RAGE Architecture for Reusable Serious Gaming Technology Components

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    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.

  4. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Elangovan, Indira; Thirugnanam, Sivasakthivel; Chen, Aoshuang; Zheng, Guoxing [Department of Biomedical Sciences, University of Illinois, College of Medicine, Rockford, IL 61107 (United States); Bosland, Maarten C.; Kajdacsy-Balla, Andre [Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Gnanasekar, Munirathinam, E-mail: mgnanas@uic.edu [Department of Biomedical Sciences, University of Illinois, College of Medicine, Rockford, IL 61107 (United States)

    2012-01-27

    Highlights: Black-Right-Pointing-Pointer Targeting RAGE by RNAi induces apoptosis in prostate cancer cells. Black-Right-Pointing-Pointer Silencing RAGE expression abrogates rHMGB1 mediated cell proliferation. Black-Right-Pointing-Pointer Down regulation of RAGE by RNAi inhibits PSA secretion of prostate cancer cells. Black-Right-Pointing-Pointer Knock down of RAGE abrogates prostate tumor growth in vivo. Black-Right-Pointing-Pointer 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.

  6. The effects of Advanced Glycation End Products (RAGE)-374T/A and Gly82Ser variants and soluble-RAGE levels to obesity in children.

    Science.gov (United States)

    Kucukhuseyin, O; Ozgen, T; Karagedik, E H; Cesur, Y; Yilmaz Aydogan, H; Yaylim, I; Ergen, H A

    2016-04-30

    In recent years, studies related to advanced glycation end products (AGE) and their interaction with their receptors (RAGE) have advanced our knowledge of the roles of these molecules in different diseases. However, studies concerning AGE-RAGE interaction in obesity are limited and the results are conflicting. RAGE gene is located on 6p21.3, has several polymorphic sites including -374T/A, a functional polymorphism in the promoter region, and Gly82Ser, present within the ligand-binding domain. In the present study, the determination of possible risks in the development of obesity according to RAGE polymorhisms and plasma levels of RAGE (sRAGE) was aimed. 87 obese and 78 healthy children were included in this study. Genomic DNA was isolated with salting-out procedure. RAGE polymorphisms were analyzed by PCR based techniques. In contrast to Gly82Ser, -374T/A allelic and genotypic frequencies were not different between study groups. Ser(SerSer+GlySer genotype) allele frequency was higher in obese cases than controls (74.20%→25.80%,OR:2.573,95%CI:1.789-3.699;pGlySer>GlyGly for HDL-C, and opposite for FT4. Besides, Ser carriers had lower insulin (p=0.038) and homa-IR (p=0.081) levels than GG genotype. sRAGE levels were different between obese and control seperately or in combination with RAGE polymorphisms (pTA>AA for -374T/A and SerSer>GlyGly>GlySer for Gly82Ser. According to our results SerSer genotype could have significant effects on sRAGE levels, and increased sRAGE levels and Gly82Ser polymorphism either combinatorially or seperately increased the propensity towards obesity.

  7. Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction

    Science.gov (United States)

    Manigrasso, Michaele B.; Pan, Jinhong; Rai, Vivek; Zhang, Jinghua; Reverdatto, Sergey; Quadri, Nosirudeen; DeVita, Robert J.; Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie

    2016-01-01

    The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. 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. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer’s disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI). PMID:26936329

  8. Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction.

    Science.gov (United States)

    Manigrasso, Michaele B; Pan, Jinhong; Rai, Vivek; Zhang, Jinghua; Reverdatto, Sergey; Quadri, Nosirudeen; DeVita, Robert J; Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie

    2016-03-03

    The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. 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. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer's disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI).

  9. The Role of Receptor for Advanced Glycation End Products (RAGE in the Proliferation of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Wei Tian

    2012-05-01

    Full Text Available The receptor for advanced glycation end products (RAGE is oncogenic and overexpressed in human cancers, but its role in hepatocellular carcinoma remains unclear. Here we demonstrated that RAGE is overexpressed in primary hepatocellular carcinoma (PHC compared to adjacent para-neoplastic liver samples. Serum endogenous secretory RAGE levels were also increased in PHC patients (p < 0.01. Moreover, we demonstrated that RAGE regulates cellular proliferation in Hepatocellular carcinoma (HCC. Knockdown of RAGE by specific siRNA inhibited cellular growth in the hepatocellular carcinoma cell line, Huh7, whereas the RAGE ligand, high mobility group box 1 protein (HMGB1 increased cellular proliferation. In addition, knockdown of RAGE by siRNA arrested cells in the G1 phase and inhibited DNA synthesis (p < 0.01, while HMGB1 protein decreased the number of cells in the G1 phase and increased the number in the S phase (p < 0.05. Furthermore, quantitative real time RT-PCR (qRT-PCR and Western Blot results demonstrated that RAGE and HMGB1 positively regulate NF-κB p65 expression in Huh7 cells. These studies suggest that RAGE and RAGE ligands are important targets for therapeutic intervention in hepatocellular carcinoma.

  10. The receptor for advanced glycation end products (RAGE) affects T cell differentiation in OVA induced asthma.

    Science.gov (United States)

    Akirav, Eitan M; Henegariu, Octavian; Preston-Hurlburt, Paula; Schmidt, Ann Marie; Clynes, Raphael; Herold, Kevan C

    2014-01-01

    The receptor for glycation end products (RAGE) has been previously implicated in shaping the adaptive immune response. RAGE is expressed in T cells after activation and constitutively in T cells from patients with diabetes. The effects of RAGE on adaptive immune responses are not clear: Previous reports show that RAGE blockade affects Th1 responses. To clarify the role of RAGE in adaptive immune responses and the mechanisms of its effects, we examined whether RAGE plays a role in T cell activation in a Th2 response involving ovalbumin (OVA)-induced asthma in mice. WT and RAGE deficient wild-type and OT-II mice, expressing a T cell receptor specific for OVA, were immunized intranasally with OVA. Lung cellular infiltration and T cell responses were analyzed by immunostaining, FACS, and multiplex bead analyses for cytokines. RAGE deficient mice showed reduced cellular infiltration in the bronchial alveolar lavage fluid and impaired T cell activation in the mediastinal lymph nodes when compared with WT mice. In addition, RAGE deficiency resulted in reduced OT-II T cell infiltration of the lung and impaired IFNγ and IL-5 production when compared with WT mice and reduced infiltration when transferred into WT hosts. When cultured under conditions favoring the differentiation of T cells subsets, RAGE deficient T cells showed reduced production of IFNγ but increased production of IL-17. Our data show a stimulatory role for RAGE in T activation in OVA-induced asthma. This role is largely mediated by the effects of RAGE on T cell proliferation and differentiation. These findings suggest that RAGE may play a regulatory role in T cell responses following immune activation.

  11. Thalamus segmentation from MP2RAGE: a comparative study

    DEFF Research Database (Denmark)

    Eskildsen, Simon Fristed; Næss-Schmidt, Erhard; Blicher, Jakob

    methods may not work well with this new sequence. In this study we tested three different automatic methods for the important task of segmenting the thalamus from human brain MP2RAGE images. Methods: Twelve healthy control subjects (age range 19 – 38 years, two females) were scanned with a whole brain MP2.......g. diffusion or perfusion parameters obtained from other MRI sequences. For volumetric studies parameters of SNIPE can be adjusted to balance the over- and under-segmentation ratios......., such as Freesurfer and ANIMAL, do not work well with the new MP2RAGE sequence without modifications. Non-local patch based segmentation methods are better suited for the task, which is demonstrated by the improved accuracy of SNIPE compared to Freesurfer and ANIMAL. In addition, 25% of test images failed...

  12. 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......OBJECTIVES: Soluble receptor of advanced glycation end-products (sRAGE) may be a predictive biomarker in coronary artery disease (CAD). Patients with acute myocardial infarction (AMI) have higher sRAGE levels compared to healthy subjects. Accordingly, the aim of this study was to investigate...

  13. Soluble RAGE Treatment Delays Progression of Amyotrophic Lateral Sclerosis in SOD1 Mice

    Directory of Open Access Journals (Sweden)

    Judyta K Juranek

    2016-05-01

    Full Text Available The etiology of amyotrophic lateral sclerosis (ALS, a fatal motor neuron disorder characterized by progressive muscle weakness and spasticity, remains largely unknown. Approximately 5-10% of cases are familial, and of those, 15-20% are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1. Mutations of the SOD1 gene interrupt cellular homeostasis and contribute to cellular toxicity evoked by the presence of altered SOD1, along with other toxic species, such as advanced glycation end products (AGEs. AGEs trigger activation of their chief cell surface receptor, RAGE (receptor for advanced glycation end products, and induce RAGE-dependent cellular stress and inflammation in neurons, thereby affecting their function and leading to apoptosis. Here, we show for the first time that the expression of RAGE is higher in the SOD1 transgenic mouse model of ALS versus wild-type mouse spinal cord. We tested whether pharmacological blockade of RAGE may delay the onset and progression of disease in this mouse model. Our findings reveal that treatment of SOD1 transgenic mice with soluble RAGE (sRAGE, a natural competitor of RAGE that sequesters RAGE ligands and blocks their interaction with cell surface RAGE, significantly delays the progression of ALS and prolongs life span compared to vehicle treatment. We demonstrate that in sRAGE-treated SOD1 transgenic animals at the final stage of the disease, a significantly higher number of neurons and lower number of astrocytes is detectable in the spinal cord. We conclude that RAGE antagonism may provide a novel therapeutic strategy for ALS intervention.

  14. Knockdown of RAGE inhibits growth and invasion of gastric cancer cells

    Directory of Open Access Journals (Sweden)

    X.C. Xu

    2013-11-01

    Full Text Available The receptor for advanced glycation endproducts (RAGE is an oncogenic trans-membranous receptor, which is overexpressed in multiple human cancers. However, the role of RAGE in gastric cancer is still elusive. In this study, we investigated the expression and molecular mechanisms of RAGE in gastric cancer cells. Forty cases of gastric cancer and corresponding adjacent non-cancerous tissues (ANCT were collected, and the expression of RAGE was assessed using immunohistochemistry (IHC in biopsy samples. Furthermore, RAGE signaling was blocked by constructed recombinant small hairpin RNA lentiviral vector (Lv-shRAGE used to transfect into human gastric cancer SGC-7901 cells. The expression of AKT, proliferating cell nuclear antigen (PCNA and matrix metallopeptidase-2 (MMP-2 was detected by Real-time PCR and Western blot assays. Cell proliferative activities and invasive capability were respectively determined by MTT and Transwell assays. Cell apoptosis and cycle distribution were analyzed by flow cytometry. As a consequence, RAGE was found highly expressed in cancer tissues compared with the ANCT (70.0% vs 45.0%, P=0.039, and correlated with lymph node metastases (P=0.026. Knockdown of RAGE reduced cell proliferation and invasion of gastric cancer with decreased expression of AKT, PCNA and MMP-2, and induced cell apoptosis and cycle arrest. Altogether, upregulation of RAGE expression is associated with lymph node metastases of gastric cancer, and blockade of RAGE signaling suppresses growth and invasion of gastric cancer cells through AKT pathway, suggesting that RAGE may represent a potential therapeutic target for this aggressive malignancy.

  15. Critical role of RAGE and HMGB1 in inflammatory heart disease.

    Science.gov (United States)

    Bangert, Anna; Andrassy, Martin; Müller, Anna-Maria; Bockstahler, Mariella; Fischer, Andrea; Volz, Christian H; Leib, Christoph; Göser, Stefan; Korkmaz-Icöz, Sevil; Zittrich, Stefan; Jungmann, Andreas; Lasitschka, Felix; Pfitzer, Gabriele; Müller, Oliver J; Katus, Hugo A; Kaya, Ziya

    2016-01-12

    Autoimmune response to cardiac troponin I (TnI) induces inflammation and fibrosis in the myocardium. High-mobility group box 1 (HMGB1) is a multifunctional protein that exerts proinflammatory activity by mainly binding to receptor for advanced glycation end products (RAGE). The involvement of the HMGB1-RAGE axis in the pathogenesis of inflammatory cardiomyopathy is yet not fully understood. Using the well-established model of TnI-induced experimental autoimmune myocarditis (EAM), we demonstrated that both local and systemic HMGB1 protein expression was elevated in wild-type (wt) mice after TnI immunization. Additionally, pharmacological inhibition of HMGB1 using glycyrrhizin or anti-HMGB1 antibody reduced inflammation in hearts of TnI-immunized wt mice. Furthermore, RAGE knockout (RAGE-ko) mice immunized with TnI showed no structural or physiological signs of cardiac impairment. Moreover, cardiac overexpression of HMGB1 using adeno-associated virus (AAV) vectors induced inflammation in the hearts of both wt and RAGE-ko mice. Finally, patients with myocarditis displayed increased local and systemic HMGB1 and soluble RAGE (sRAGE) expression. Together, our study highlights that HMGB1 and its main receptor, RAGE, appear to be crucial factors in the pathogenesis of TnI-induced EAM, because inhibition of HMGB1 and ablation of RAGE suppressed inflammation in the heart. Moreover, the proinflammatory effect of HMGB1 is not necessarily dependent on RAGE only. Other receptors of HMGB1 such as Toll-like receptors (TLRs) may also be involved in disease pathogenesis. These findings could be confirmed by the clinical relevance of HMGB1 and sRAGE. Therefore, blockage of one of these molecules might represent a novel therapeutic strategy in the treatment of autoimmune myocarditis and inflammatory cardiomyopathy.

  16. 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.

  17. Rage Attacks in Pediatric Obsessive-Compulsive Disorder: Phenomenology and Clinical Correlates

    Science.gov (United States)

    Storch, Eric A.; Jones, Anna M.; Lack, Caleb W.; Ale, Chelsea M.; Sulkowski, Michael L.; Lewin, Adam B.; De Nadai, Alessandro S.; Murphy, Tanya K.

    2012-01-01

    Objective: Rage attacks have been documented in youth with varied psychiatric disorders, but few data have been reported on the clinical characteristics and correlates of rage attacks among children with obsessive-compulsive disorder (OCD). Method: Participants were 86 children (ages 6-16 years) with a primary diagnosis of OCD. Patients and their…

  18. 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

    2009-11-03

    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.

  19. Role of the RAGE Axis during the Immune Response after Severe Trauma: A Prospective Pilot Study

    Directory of Open Access Journals (Sweden)

    Florian Uhle

    2015-01-01

    Full Text Available Background. Severe traumatization induces a complex pathophysiology, driven by the patient’s own immune system. The initial activation is a result of damage-associated molecular patterns, which are released from disrupted and dying cells and recognized by immune receptors, for example, RAGE. In this study we aimed to evaluate the contribution of the RAGE axis to early and late immune responses. Methods. We enrolled 16 patients with severe trauma together with 10 patients after major abdominal surgery and 10 healthy volunteers. Blood samples were taken on admission and every 48 h for a total of 8 days. Plasma concentrations of various RAGE ligands as well as RAGE isoforms and IL-6 were measured by ELISA. Monocyte surface expression of RAGE and HLA-DR was assessed by flow cytometry. Results. High and transient levels of IL-6 and methylglyoxal characterize the early immune response after trauma, whereas samples from later time points provide evidence for a secondary release of RAGE ligands. Conclusion. Our results provide evidence for a persisting activation of the RAGE axis while classical mediators like IL-6 disappear early. Considering the immunocompromised phenotype of the monocytes, the RAGE ligands might be substantial contributors to the well-known secondary stage of impaired immune responsiveness in trauma patients.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. 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.

  2. The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs.

    Science.gov (United States)

    Xue, Jing; Ray, Rashmi; Singer, David; Böhme, David; Burz, David S; Rai, Vivek; Hoffmann, Ralf; Shekhtman, Alexander

    2014-05-27

    Diabetes-induced hyperglycemia increases the extracellular concentration of methylglyoxal. Methylglyoxal-derived hydroimidazolones (MG-H) form advanced glycation end products (AGEs) that accumulate in the serum of diabetic patients. The binding of hydroimidozolones to the receptor for AGEs (RAGE) results in long-term complications of diabetes typified by vascular and neuronal injury. Here we show that binding of methylglyoxal-modified albumin to RAGE results in signal transduction. Chemically synthesized peptides containing hydroimidozolones bind specifically to the V domain of RAGE with nanomolar affinity. The solution structure of an MG-H1-V domain complex revealed that the hydroimidazolone moiety forms multiple contacts with a positively charged surface on the V domain. The high affinity and specificity of hydroimidozolones binding to the V domain of RAGE suggest that they are the primary AGE structures that give rise to AGEs-RAGE pathologies.

  3. RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma

    Science.gov (United States)

    Arikkatt, Jaisy; Ullah, Md Ashik; Short, Kirsty Renfree; Zhang, Vivan; Gan, Wan Jun; Loh, Zhixuan; Werder, Rhiannon B; Simpson, Jennifer; Sly, Peter D; Mazzone, Stuart B; Spann, Kirsten M; Ferreira, Manuel AR; Upham, John W; Sukkar, Maria B; Phipps, Simon

    2017-01-01

    Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target. DOI: http://dx.doi.org/10.7554/eLife.21199.001 PMID:28099113

  4. Regulation of alternative splicing of the receptor for advanced glycation endproducts (RAGE) through G-rich cis-elements and heterogenous nuclear ribonucleoprotein H.

    Science.gov (United States)

    Ohe, Kazuyo; Watanabe, Takuo; Harada, Shin-ichi; Munesue, Seiichi; Yamamoto, Yasuhiko; Yonekura, Hideto; Yamamoto, Hiroshi

    2010-05-01

    Receptor for advanced glycation endproducts (RAGE) is a cell-surface receptor. The binding of ligands to membrane-bound RAGE (mRAGE) evokes cellular responses involved in various pathological processes. Previously, we identified a novel soluble form, endogenous secretory RAGE (esRAGE) generated by alternative 5' splice site selection in intron 9 that leads to extension of exon 9 (exon 9B). Because esRAGE works as an antagonistic decoy receptor, the elucidation of regulatory mechanism of the alternative splicing is important to understand RAGE-related pathological processes. Here, we identified G-rich cis-elements within exon 9B for regulation of the alternative splicing using a RAGE minigene. Mutagenesis of the G-rich cis-elements caused a drastic increase in the esRAGE/mRAGE ratio in the minigene-transfected cells and in loss of binding of the RNA motif to heterogenous nuclear ribonucleoprotein (hnRNP) H. On the other hand, the artificial introduction of a G-stretch in exon 9B caused a drastic decrease in the esRAGE/mRAGE ratio accompanied by the binding of hnRNP H to the RNA motif. Thus, the G-stretches within exon 9B regulate RAGE alternative splicing via interaction with hnRNP H. The findings should provide a molecular basis for the development of medicines for RAGE-related disorders that could modulate esRAGE/mRAGE ratio.

  5. sRAGE与糖尿病及其并发症%sRAGE, diabetes and its complications

    Institute of Scientific and Technical Information of China (English)

    苏旭东; 田亚强; 张光珍

    2011-01-01

    Interaction of advanced glycation end products (AGEs) with their receptor (RAGE)plays an important role in the occurance and development of diabetes and its complications. RAGE has an endogenous secretory receptor form, termed soluble RAGE( sRAGE), which might act as an endogenous competitive inhibitor of RAGE. The level of sRAGE decreases in patients with diabetes, while some drugs, such as statins, thiazolidinediones, inhibitors of angiotensin-converting enzyme also increase plasma sRAGE level.Further studies of sRAGE may provide a new drug for the treatment of diabetes and its complications.%晚期糖基化终末产物(AGEs)与其受体(RAGE)在糖尿病及其并发症的发生、发展中起重要作用.缺少胞内区的RAGE称为可溶性RAGE(sRAGE).其可阻断配体与RAGE的结合.糖尿病患者sRAGE水平明显降低,而他汀类、噻唑烷二酮类、血管紧张素转换酶抑制剂等药物可以提高血清sRAGE水平.对sRAGE的进一步研究有可能为糖尿病及其并发症的治疗提供新的药物.

  6. The Role of AGE/RAGE Signaling in Diabetes-Mediated Vascular Calcification

    Directory of Open Access Journals (Sweden)

    Amber M. Kay

    2016-01-01

    Full Text Available AGE/RAGE signaling has been a well-studied cascade in many different disease states, particularly diabetes. Due to the complex nature of the receptor and multiple intersecting pathways, the AGE/RAGE signaling mechanism is still not well understood. The purpose of this review is to highlight key areas of AGE/RAGE mediated vascular calcification as a complication of diabetes. AGE/RAGE signaling heavily influences both cellular and systemic responses to increase bone matrix proteins through PKC, p38 MAPK, fetuin-A, TGF-β, NFκB, and ERK1/2 signaling pathways in both hyperglycemic and calcification conditions. AGE/RAGE signaling has been shown to increase oxidative stress to promote diabetes-mediated vascular calcification through activation of Nox-1 and decreased expression of SOD-1. AGE/RAGE signaling in diabetes-mediated vascular calcification was also attributed to increased oxidative stress resulting in the phenotypic switch of VSMCs to osteoblast-like cells in AGEs-induced calcification. Researchers found that pharmacological agents and certain antioxidants decreased the level of calcium deposition in AGEs-induced diabetes-mediated vascular calcification. By understanding the role the AGE/RAGE signaling cascade plays diabetes-mediated vascular calcification will allow for pharmacological intervention to decrease the severity of this diabetic complication.

  7. Cell migration is regulated by AGE-RAGE interaction in human oral cancer cells in vitro.

    Directory of Open Access Journals (Sweden)

    Shun-Yao Ko

    Full Text Available Advanced glycation end products (AGEs are produced in an irreversible non-enzymatic reaction of carbohydrates and proteins. Patients with diabetes mellitus (DM are known to have elevated AGE levels, which is viewed as a risk factor of diabetes-related complications. In a clinical setting, it has been shown that patients with oral cancer in conjunction with DM have a higher likelihood of cancer metastasis and lower cancer survival rates. AGE-RAGE (a receptor of AGEs is also correlated with metastasis and angiogenesis. Recent studies have suggested that the malignancy of cancer may be enhanced by glyceraldehyde-derived AGEs; however, the underlying mechanism remains unclear. This study examined the apparently close correlation between AGE-RAGE and the malignancy of SAS oral cancer cell line. In this study, AGEs increased ERK phosphorylation, enhanced cell migration, and promoted the expression of RAGE, MMP2, and MMP9. Using PD98059, RAGE antibody, and RAGE RNAi to block RAGE pathway resulted in the inhibition of ERK phosphorylation. Cell migration, MMP2 and MMP9 expression were also reduced by this treatment. Our findings demonstrate the importance of AGE-RAGE with regard to the malignancy of oral cancer, and help to explain the poor prognosis of DM subjects with oral cancer.

  8. Associations between Soluble Receptor for Advanced Glycation End Products (sRAGE) and S100A12 (EN-RAGE) with Mortality in Long-term Hemodialysis Patients.

    Science.gov (United States)

    Jung, Eul Sik; Chung, Wookyung; Kim, Ae Jin; Ro, Han; Chang, Jae Hyun; Lee, Hyun Hee; Jung, Ji Yong

    2017-01-01

    Hemodialysis (HD) patients experience vascular calcification, ultimately leading to high mortality rates. Previously, we reported associations between soluble receptor for advanced glycation end products (sRAGEs) and extracellular newly identified RAGE-binding protein S100A12 (EN-RAGE) and vascular calcification. Here, we extended our observations, investigating whether these biomarkers may be useful for predicting cardiovascular morbidity and mortality in these subjects. Thus, we evaluated the relationship between sRAGE and S100A12 and mortality in long-term HD patients. This was a prospective observational cohort study in 199 HD patients from an extended analysis of our previous study. Plasma sRAGE, S100A12, comorbidities, and other traditional risk factors were investigated. The cumulative incidences for death using Cox proportional hazards regression were evaluated in multivariable analyses. The observation period was 44 months. During the observation period, 27 (13.6%) patients died. Univariate analysis demonstrated that S100A12 was correlated with diabetes (P = 0.040) and high-sensitivity C-reactive protein (hsCRP) (P = 0.006). In multivariable analyses, plasma sRAGE (hazard ratio [HR] = 1.155; 95% confidence interval [CI] = 0.612-2.183; P = 0.656) and S100A12 (HR = 0.960; 95% CI = 0.566-1.630; P = 0.881) were not associated with mortality in HD patients, although traditional predictors of mortality, including age, history of cardiovascular diseases (CVDs), and serum levels of albumin and hsCRP were related to mortality. Powerful predictors of mortality were age, CVD, and albumin levels. Plasma sRAGE and S100A12 may be weak surrogate markers for predicting all-cause mortality in patients undergoing HD, although S100A12 was partly related to diabetes and inflammation.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  10. Blockade of RAGE in Zucker obese rats with experimental periodontitis

    DEFF Research Database (Denmark)

    Grauballe, M B; Østergaard, J A; Schou, Søren

    2017-01-01

    BACKGROUND AND OBJECTIVE: Periodontitis and type 2 diabetes mellitus (T2D) are two interrelated chronic diseases. Periodontitis is more prevalent in patients with T2D than in healthy subjects, and studies indicate that periodontitis impacts the metabolic control of patients with T2D. Hyperglycemia...... on the interrelationship between periodontitis and T2D in a rat model of both diseases. MATERIAL AND METHODS: Zucker obese rats (HsdHlr:ZUCKER-Lepr (fa/fa) ) and their lean littermates were divided into five treatment groups, with and without periodontitis. Monoclonal anti-RAGE IgG3 were injected into the rats three times...... evaluated in plasma. Kidney complications were evaluated by quantitative real-time PCR, the creatinine clearance rate, the albumin excretion rate and kidney hypertrophy. Periodontitis was evaluated by morphometric registration of alveolar bone loss and radiographic recording of bone support. RESULTS...

  11. Rage in a Time of Millennial Raving: Rage Against the Machine’s Critical Disruption of Y2K Excitement

    OpenAIRE

    2009-01-01

    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...

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Soluble RAGE as a severity marker in community acquired pneumonia associated sepsis

    OpenAIRE

    2012-01-01

    Abstract Background Community-acquired pneumonia (CAP) is considered the most important cause of death from infectious disease in developed countries. Severity assessment scores partially address the difficulties in identifying high-risk patients. A lack of specific and valid pathophysiologic severity markers affect early and effective sepsis therapy. HMGB-1, sRAGE and RAGE have been involved in sepsis and their potential as severity markers has been proposed. The aim of this study was to eva...

  14. Retinol up-regulates the receptor for advanced glycation endproducts (RAGE) by increasing intracellular reactive species.

    Science.gov (United States)

    Gelain, Daniel Pens; de Bittencourt Pasquali, Matheus Augusto; Caregnato, Fernanda Freitas; Zanotto-Filho, Alfeu; Moreira, José Cláudio Fonseca

    2008-08-01

    Retinol (vitamin A) and other retinoids have been suggested to exert an important antioxidant function in biological systems, besides their more established role as regulators of cell growth and differentiation. On the other hand, many authors have recently observed pro-oxidant activities of vitamin A and other retinoids in vitro and in vivo, resulting in cell death and/or transformation associated to increased oxidative damage. However, the mechanisms by which retinol causes oxidative stress are still not fully understood. Receptors for advanced glycation endproducts (RAGE) have been recently implied as promoters and/or amplifiers of oxidant-mediated cell death induced by diverse agents, and increased RAGE expression is observed in conditions related to unbalanced production of reactive species, such as in atherosclerosis and neurodegeneration. In the present work, we observed that retinol supplementation increases RAGE protein expression in cultured Sertoli cells, and antioxidant co-treatment reversed this effect. Retinol-increased RAGE expression was observed only at concentrations that induce intracellular reactive species production, as assessed by the DCFH assay. These results indicate that retinol is able to increase RAGE expression by an oxidant-dependent mechanism, and suggest that RAGE signaling may be involved in some of the deleterious effects observed in some retinol-supplementation therapies.

  15. RAGE inhibits human respiratory syncytial virus syncytium formation by interfering with F-protein function.

    Science.gov (United States)

    Tian, Jane; Huang, Kelly; Krishnan, Subramaniam; Svabek, Catherine; Rowe, Daniel C; Brewah, Yambasu; Sanjuan, Miguel; Patera, Andriani C; Kolbeck, Roland; Herbst, Ronald; Sims, Gary P

    2013-08-01

    Human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infection. Infection is critically dependent on the RSV fusion (F) protein, which mediates fusion between the viral envelope and airway epithelial cells. The F protein is also expressed on infected cells and is responsible for fusion of infected cells with adjacent cells, resulting in the formation of multinucleate syncytia. The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor that is constitutively highly expressed by type I alveolar epithelial cells. Here, we report that RAGE protected HEK cells from RSV-induced cell death and reduced viral titres in vitro. RAGE appeared to interact directly with the F protein, but, rather than inhibiting RSV entry into host cells, virus replication and budding, membrane-expressed RAGE or soluble RAGE blocked F-protein-mediated syncytium formation and sloughing. These data indicate that RAGE may contribute to protecting the lower airways from RSV by inhibiting the formation of syncytia, viral spread, epithelial damage and airway obstruction.

  16. Expression and Clinical Significance of HMGB1 and RAGE in Cervical Carcinoma

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    OBJECTIVE To study the expression level and clinical significance of HMGB1 and RAGE in cervical squamous epithelial carcinoma.METHODS Real time quantitative polymerase chain reaction (qRT-PCR)was employed to examine the expression of HMGB1 (high mobility group box protein1), and RAGE (receptor for advanced glycation endproducts)in 60 cervical squamous epithelial carcinomas (CSEC), their paraneoplastic tissues (PS) and 30 normal cervix tissues (NCS).RESULTS The expression of HMGB1 in the CSEC samples and PS was similar (P>0.05), but higher compared to NCS (P<0.05). Overexpression of HMGB1 in the CESC tissues was significantly correlated with the tumor (P<0.05), and the presence of metastasis (P<0.01), but not correlated with the tumor diameter or tumor grade. RAGE expression was not significantly different among these tissue types, and showed no significant correlation with the the tumor stage, diameter or grade. But there was a significant positive correlation between RAGE expression and CSEC metastasis.CONCLUSION The results suggest that HMGB1 may be related to the proliferation, progression and metastasis of CSEC. The relationship of HMGB1/RAGE may be of importance for CSEC metastasis. HMGB1 presents a new potential gene target for prevention and treatment of CSEC.Study of HMGB1/RAGE expression will offer an experimental foundation for understanding the pathogenesis of CSES.

  17. Diagnostic Potential of Evaluation of SDF-1α and sRAGE Levels in Threatened Premature Labor

    Directory of Open Access Journals (Sweden)

    Rafał Rzepka

    2016-01-01

    Full Text Available Preterm birth remains the most prevalent cause of neonatal morbidity. This study aimed to evaluate the diagnostic value of SDF-1α, resistin, secretory RAGE (sRAGE, and endogenous secretory RAGE (esRAGE in preterm labor. A total of 211 pregnant women participated in the study. Group A contained 72 women between 22 and 36 weeks of gestation, with premature labor, who finally had preterm birth. Group B contained 66 women in labor between 37 and 41 weeks of gestation. Women in group A had lower SDF-1α and sRAGE levels than those in group B. Moreover, in group A, SDF-1α and sRAGE levels were correlated with the latency period from the occurrence of premature labor symptoms until delivery. Sensitivity and specificity of studied parameters for prediction of preterm birth were 95% and 40% for SDF-1α and 51.3% and 93.5% for sRAGE, respectively. The prognostic value of plasma SDF-1α and sRAGE levels was comparable with that of cervical length ultrasound measurement and serum C-reactive protein levels. We conclude that SDF-1α and sRAGE appear to play a major role in the diagnosis of preterm birth and its evaluation could be convenient and useful for predicting preterm birth.

  18. Evaluation of functional RAGE gene polymorphisms in childhood acute lymphoblastic leukemia-A case-control study from Iran.

    Science.gov (United States)

    Eskandari-Nasab, Ebrahim; Hashemi, Mohammad; Hasani, Seyed-Shahab-Adin; Naderi, Majid; Sadeghi-Bojd, Simin; Taheri, Mohsen

    2017-03-04

    We examined the possible relationship between three RAGE polymorphisms, -429C/T, -374 T/A, and 63-bp deletion, and susceptibility to childhood acute lymphoblastic leukemia (ALL) in an Iranian population. This study included 75 ALL patients and 115 healthy subjects. Genotyping was performed using HEXA-ARMS-polymerase chain reaction. We found no significant association among RAGE gene polymorphisms and the risk for ALL at genotype, allelic and haplotype levels (P > 0.05). The hemoglobin levels were higher in patients with RAGE -374 TT than in the TA carriers (P = 0.019). Our results demonstrated that the RAGE gene variations were not associated with risk of pediatrics ALL.

  19. Modeling the interaction between quinolinate and the receptor for advanced glycation end products (RAGE: relevance for early neuropathological processes.

    Directory of Open Access Journals (Sweden)

    Iris N Serratos

    Full Text Available The receptor for advanced glycation end products (RAGE is a pattern-recognition receptor involved in neurodegenerative and inflammatory disorders. RAGE induces cellular signaling upon binding to a variety of ligands. Evidence suggests that RAGE up-regulation is involved in quinolinate (QUIN-induced toxicity. We investigated the QUIN-induced toxic events associated with early noxious responses, which might be linked to signaling cascades leading to cell death. The extent of early cellular damage caused by this receptor in the rat striatum was characterized by image processing methods. To document the direct interaction between QUIN and RAGE, we determined the binding constant (Kb of RAGE (VC1 domain with QUIN through a fluorescence assay. We modeled possible binding sites of QUIN to the VC1 domain for both rat and human RAGE. QUIN was found to bind at multiple sites to the VC1 dimer, each leading to particular mechanistic scenarios for the signaling evoked by QUIN binding, some of which directly alter RAGE oligomerization. This work contributes to the understanding of the phenomenon of RAGE-QUIN recognition, leading to the modulation of RAGE function.

  20. Road Rage: Prevalence Pattern and Web Based Survey Feasibility

    Directory of Open Access Journals (Sweden)

    Shaily Mina

    2014-01-01

    Full Text Available Introduction. Incidents of road rage are on a rise in India, but the literature is lacking in the aspect. There is an increasing realization of possibility of effective web based interventions to deliver public health related messages. Objective. The aim was to quantitatively evaluate risk factors among motor vehicle drivers using an internet based survey. Methods. Facebook users were evaluated using Life Orientation Test-Revised (LOT-R and Driving Anger Scale (DAS. Results. An adequate response rate of 65.9% and satisfactory reliability with sizable correlation were obtained for both scales. Age was found to be positively correlated to LOT-R scores (r=0.21; P=0.02 and negatively correlated to DAS scores (r=-0.19; P=0.03. Years of education were correlated to LOT-R scores (r=0.26; P=0.005 but not DAS scores (r=-0.14; P=0.11. LOT-R scores did not correlate to DAS scores. Conclusion. There is high prevalence of anger amongst drivers in India particularly among younger males. A short web survey formatted in easy to use question language can result in a feasible conduction of an online survey.

  1. HMGB1 and RAGE in skeletal muscle inflammation: Implications for protein accumulation in inclusion body myositis.

    Science.gov (United States)

    Muth, Ingrid E; Zschüntzsch, Jana; Kleinschnitz, Konstanze; Wrede, Arne; Gerhardt, Ellen; Balcarek, Peter; Schreiber-Katz, Olivia; Zierz, Stephan; Dalakas, Marinos C; Voll, Reinhard E; Schmidt, Jens

    2015-09-01

    Inflammation is associated with protein accumulation in IBM, but precise mechanisms are elusive. The "alarmin" HMGB1 is upregulated in muscle inflammation. Its receptor RAGE is crucial for β-amyloid-associated neurodegeneration. Relevant signaling via HMGB1/RAGE is expected in IBM pathology. By real-time-PCR, mRNA-expression levels of HMGB1 and RAGE were upregulated in muscle biopsies of patients with IBM and PM, but not in muscular dystrophy or non-myopathic controls. By immunohistochemistry, both molecules displayed the highest signal in IBM, where they distinctly co-localized to intra-fiber accumulations of β-amyloid and neurofilament/tau. In these fibers, identification of phosphorylated Erk suggested that relevant downstream activation is present upon HMGB1 signaling via RAGE. Protein expressions of HMGB1, RAGE, Erk and phosphorylated Erk were confirmed by Western blot. In a well established cell-culture model for pro-inflammatory cell-stress, exposure of human muscle-cells to IL-1β+IFN-γ induced cytoplasmic translocation of HMGB1 and subsequent release as evidenced by ELISA. Upregulation of RAGE on the cell surface was demonstrated by immunocytochemistry and flow-cytometry. Recombinant HMGB1 was equally potent as IL-1β+IFN-γ in causing amyloid-accumulation and cell-death, and both were abrogated by the HMGB1-blocker BoxA. The findings strengthen the concept of unique interactions between degenerative and inflammatory mechanisms and suggest that HMGB1/RAGE signaling is a critical pathway in IBM pathology.

  2. Receptor for Advanced Glycation End Products (RAGE) Deficiency Attenuates the Development of Atherosclerosis in Diabetes

    Science.gov (United States)

    Soro-Paavonen, Aino; Watson, Anna M.D.; Li, Jiaze; Paavonen, Karri; Koitka, Audrey; Calkin, Anna C.; Barit, David; Coughlan, Melinda T.; Drew, Brian G.; Lancaster, Graeme I.; Thomas, Merlin; Forbes, Josephine M.; Nawroth, Peter P.; Bierhaus, Angelika; Cooper, Mark E.; Jandeleit-Dahm, Karin A.

    2008-01-01

    OBJECTIVE—Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE−/− model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS—ApoE−/− and RAGE−/−/apoE−/− double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS—Although diabetic apoE−/− mice showed increased plaque accumulation (14.9 ± 1.7%), diabetic RAGE−/−/apoE−/− mice had significantly reduced atherosclerotic plaque area (4.9 ± 0.4%) to levels not significantly different from control apoE−/− mice (4.3 ± 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-κB subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE−/− mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE−/−/apoE−/− mice. CONCLUSIONS—This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications. PMID:18511846

  3. 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.

  4. Soluble RAGE as a severity marker in community acquired pneumonia associated sepsis

    Directory of Open Access Journals (Sweden)

    Narvaez-Rivera Rodrigo M

    2012-01-01

    Full Text Available Abstract Background Community-acquired pneumonia (CAP is considered the most important cause of death from infectious disease in developed countries. Severity assessment scores partially address the difficulties in identifying high-risk patients. A lack of specific and valid pathophysiologic severity markers affect early and effective sepsis therapy. HMGB-1, sRAGE and RAGE have been involved in sepsis and their potential as severity markers has been proposed. The aim of this study was to evaluate HMGB-1, RAGE and sRAGE levels in patients with CAP-associated sepsis and determine their possible association with clinical outcome. Method We evaluated 33 patients with CAP-associated sepsis admitted to the emergency room and followed in the medical wards. Severity assessment scores (CURB-65, PSI, APACHE II, SOFA and serologic markers (HMGB-1, RAGE, sRAGE were evaluated on admission. Results Thirty patients with a diagnosis of CAP-associated sepsis were enrolled in the study within 24 hours after admission. Fourteen (46.6% had pandemic (H1N1 influenza A virus, 2 (6.6% had seasonal influenza A and 14 other diagnoses. Of the patients in the study group, 16 (53.3% had a fatal outcome. ARDS was observed in 17 (56.6% and a total of 22 patients had severe sepsis on admission (73%. The SOFA score showed the greatest difference between surviving and non-surviving groups (P = .003 with similar results in ARDS patients (P = .005. sRAGE levels tended to be higher in non-surviving (P = .058 and ARDS patients (P = .058. Logistic regression modeling demonstrated that SOFA (P = .013 and sRAGE (P = .05 were the only variables that modified the probability of a fatal outcome. Conclusion The association of elevated sRAGE with a fatal outcome suggests that it may have an independent causal effect in CAP. SOFA scores were the only clinical factor with the ability to identify surviving and ARDS patients.

  5. Donnees Serologiques sur la rage Vulpine Etudiee en Iran

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    Y. KARIMI

    1975-01-01

    Full Text Available During the epidemiological research of zoonoses, the authors have studied the rabies of wild animals : fox. For the scro lo-uical tests. the blood . was taken by heart puncture of foxes. 193 specimens were tested and 26 (13. 5% o r the foxes had neut ralizing antibody in their blood. This study confirms that during the rabies epizooty. the Vulpin population, may contract a non-fatal disease and produce the neutralizing antibody. Thus, the fox has a real place in the epidemiology of rabies in Iran."n* * *"nA la sui te des etudes effectuees par nous-merne (8, nous rapportons ici, les resultats scrologiques, des travaux acheves dans Ie but d'enrichir et  de completer les donnees precedentcs, Le present travail, ainsi que notre etude prcliminairc, ont etc realises dans la meme region, ccntree par le village d'AGH BOULAGH MORCHED, dans Ie Kurdistan, i186 Km au Nord-Ouest de HAMADAN (Ca rte N° I . Le role primordial du Renard, dans Ie processus de la Rage naturelle a deja fait l'objet de plusieurs articles (4, (5, (7, (17, (14, Cependant l'existence chez les animaux sauvages danticorps antirabiques n'est que rarement mentionnee dans ccs travaux. Les donnees experimentales ne peuvent pas toujours expliquer ce qui se passe dans les conditions naturelles de l'enzootie rabique, au point de vue de la reponse serologique chez Ie renard. C'est pourquoi nous nous sommes attaches a completer la recherche d'anticorps neutralisants antirabiques, chez Ie renard, dans son milieu nature!

  6. The importance of Ca2+/Zn2+ signaling S100 proteins and RAGE in translational medicine.

    Science.gov (United States)

    Leclerc, Estelle; Heizmann, Claus W

    2011-06-01

    The Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand receptor involved in a large number of human disorders. Identified first as the receptor for the Advanced Glycation Endproducts (AGEs), RAGE has emerged in recent years as a major receptor for many members of the S100 calcium and zinc binding protein family. The interaction with and the signaling triggered by several S100 proteins such as S100B and S100A12 have been studied in details and have shown concentration and cell type dependent signaling cascades. The S100 protein family consists of more than 20 members which present high amino-acid sequence and structural similarities. These small EF-hand calcium binding proteins interact with a large number of protein targets and are almost all been shown to be involved in cancer. In this review we discuss the recent knowledge about the role of S100 proteins and RAGE in human disorders.

  7. THE SPECTACLE OF REDEMPTION: GUILT AND VIOLENCE IN MARTIN SCORSESE’S RAGING BULL

    Directory of Open Access Journals (Sweden)

    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.

  8. Specific siRNA Targeting Receptor for Advanced Glycation End Products (RAGE Decreases Proliferation in Human Breast Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Sheng Liu

    2013-04-01

    Full Text Available Receptor for Advanced Glycation End Products (RAGE is an oncogenic trans-membranous receptor overexpressed in various human cancers. However, the role of RAGE in breast cancer development and proliferation is still unclear. In this study, we demonstrated that RAGE expression levels are correlated to the degree of severity of breast cancer. Furthermore, there is a decrease in the proliferation of all sub-types of breast cancer, MCF-7, SK-Br-3 and MDA-MB-231, as a result of the effect of RAGE siRNA. RAGE siRNA arrested cells in the G1 phase and inhibited DNA synthesis (p < 0.05. Moreover, qRT-PCR and Western Blot results demonstrated that RAGE siRNA decreases the expression of transcriptional factor NF-κB p65 as well as the expression of cell proliferation markers PCNA and cyclinD1. RAGE and RAGE ligands can thus be considered as possible targets for breast cancer management and therapy.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Detection of RAGE expression and its application to diabetic wound age estimation.

    Science.gov (United States)

    Ji, Xin-Yi; Chen, Yang; Ye, Guang-Hua; Dong, Miao-Wu; Lin, Ke-Zhi; Han, Jun-Ge; Feng, Xiang-Ping; Li, Xing-Biao; Yu, Lin-Sheng; Fan, Yan-Yan

    2017-01-11

    With the prevalence of diabetes, it is becoming important to analyze the diabetic wound age in forensic practice. The present study investigated the time-dependent expression of receptor for advanced glycation end products (RAGE) during diabetic wound healing in mice and its applicability to wound age determination by immunohistochemistry, double immunofluorescence, and Western blotting. After an incision was created in genetically diabetic db/db mice and control mice, mice were killed at posttraumatic intervals ranging from 6 h to 14 days, followed by the sampling of wound margin. Compared with control mice, diabetic mice showed the delayed wound healing. In control and diabetic wound specimens, RAGE immunoreactivity was observed in a small number of polymorphonuclear cells (PMNs), a number of macrophages, and fibroblasts. Morphometrically, the positive ratios of RAGE in macrophages or fibroblasts considerably increased in diabetic wounds during late repair, which exceeded 60% at 7 and 10 days post-injury. There were no control wound specimens to show a ratio of >60% in macrophages or fibroblasts. By Western blotting analysis, the ratios of RAGE to GAPDH were >1.4 in all diabetic wound samples from 7 to 10 days post-injury, which were >1.8 at 10 days after injury. By comparison, no control wound specimens indicated a ratio of >1.4. In conclusion, the expression of RAGE is upregulated and temporally distributed in macrophages and fibroblasts during diabetic wound healing, which might be closely involved in prolonged inflammation and deficient healing. Moreover, RAGE is promising as a useful marker for diabetic wound age determination.

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

    Directory of Open Access Journals (Sweden)

    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

  12. Molecular mechanisms of AGE/RAGE-mediated fibrosis in the diabetic heart

    Science.gov (United States)

    Zhao, Jia; Randive, Rushil; Stewart, James A

    2014-01-01

    Chronic hyperglycemia is one of the main characteristics of diabetes. Persistent exposure to elevated glucose levels has been recognized as one of the major causal factors of diabetic complications. In pathologies, like type 2 diabetes mellitus (T2DM), mechanical and biochemical stimuli activate profibrotic signaling cascades resulting in myocardial fibrosis and subsequent impaired cardiac performance due to ventricular stiffness. High levels of glucose nonenzymatically react with long-lived proteins, such as collagen, to form advanced glycation end products (AGEs). AGE-modified collagen increase matrix stiffness making it resistant to hydrolytic turnover, resulting in an accumulation of extracellular matrix (ECM) proteins. AGEs account for many of the diabetic cardiovascular complications through their engagement of the receptor for AGE (RAGE). AGE/RAGE activation stimulates the secretion of numerous profibrotic growth factors, promotes increased collagen deposition leading to tissue fibrosis, as well as increased RAGE expression. To date, the AGE/RAGE cascade is not fully understood. In this review, we will discuss one of the major fibrotic signaling pathways, the AGE/RAGE signaling cascade, as well as propose an alternate pathway via Rap1a that may offer insight into cardiovascular ECM remodeling in T2DM. In a series of studies, we demonstrate a role for Rap1a in the regulation of fibrosis and myofibroblast differentiation in isolated diabetic and non-diabetic fibroblasts. While these studies are still in a preliminary stage, inhibiting Rap1a protein expression appears to down-regulate the molecular switch used to activate the ζ isotype of protein kinase C thereby promote AGE/RAGE-mediated fibrosis. PMID:25512788

  13. Molecular mechanisms of AGE/RAGE-mediated fibrosis in the diabetic heart

    Institute of Scientific and Technical Information of China (English)

    Jia; Zhao; Rushil; Randive; James; A; Stewart

    2014-01-01

    Chronic hyperglycemia is one of the main characteristics of diabetes. Persistent exposure to elevated glucose levels has been recognized as one of the major causal factors of diabetic complications. In pathologies, like type 2 diabetes mellitus(T2DM), mechanical and biochemical stimuli activate profibrotic signaling cascades resulting in myocardial fibrosis and subsequent impaired cardiac performance due to ventricular stiffness. High levels of glucose nonenzymatically react with long-lived proteins, such as collagen, to form advanced glycation end products(AGEs). AGE-modified collagen increase matrix stiffness making it resistant to hydrolytic turnover, resulting in an accumulation of extracellular matrix(ECM) proteins. AGEs account for many of the diabetic cardiovascular complications through their engagement of the receptor for AGE(RAGE). AGE/RAGE activation stimulates the secretion of numerous profibrotic growth factors, promotes increased collagen deposition leading to tissue fibrosis, as well as increased RAGE expression. To date, the AGE/RAGE cascade is not fully understood. In this review, we willdiscuss one of the major fibrotic signaling pathways, the AGE/RAGE signaling cascade, as well as propose an alternate pathway via Rap1 a that may offer insight into cardiovascular ECM remodeling in T2 DM. In a series of studies, we demonstrate a role for Rap1 a in the regulation of fibrosis and myofibroblast differentiation in isolated diabetic and non-diabetic fibroblasts. While these studies are still in a preliminary stage, inhibiting Rap1 a protein expression appears to down-regulate the molecular switch used to activate the ζ isotype of protein kinase C thereby promote AGE/RAGE-mediated fibrosis.

  14. RAGE modulates hypoxia/reoxygenation injury in adult murine cardiomyocytes via JNK and GSK-3beta signaling pathways.

    Directory of Open Access Journals (Sweden)

    Linshan Shang

    Full Text Available BACKGROUND: Advanced glycation end-products (AGEs have been implicated in diverse pathological settings including diabetes, inflammation and acute ischemia/reperfusion injury in the heart. AGEs interact with the receptor for AGEs (RAGE and transduce signals through activation of MAPKs and proapoptotic pathways. In the current study, adult cardiomyocytes were studied in an in vitro ischemia/reperfusion (I/R injury model to delineate the molecular mechanisms underlying RAGE-mediated injury due to hypoxia/reoxygenation (H/R. METHODOLOGY/PRINCIPAL FINDINGS: Cardiomyocytes isolated from adult wild-type (WT, homozygous RAGE-null (RKO, and WT mice treated with soluble RAGE (sRAGE were subjected to hypoxia for 30 minutes alone or followed by reoxygenation for 1 hour. In specific experiments, RAGE ligand carboxymethyllysine (CML-AGE (termed "CML" in this manuscript was evaluated in vitro. LDH, a marker of cellular injury, was assayed in the supernatant in the presence or absence of signaling inhibitor-treated cardiomyocytes. Cardiomyocyte levels of heterogeneous AGEs were measured using ELISA. A pronounced increase in RAGE expression along with AGEs was observed in H/R vs. normoxia in WT cardiomyocytes. WT cardiomyocytes after H/R displayed increased LDH release compared to RKO or sRAGE-treated cardiomyocytes. Our results revealed significant increases in phospho-JNK in WT cardiomyocytes after H/R. In contrast, neither RKO nor sRAGE-treated cardiomyocytes exhibited increased phosphorylation of JNK after H/R stress. The impact of RAGE deletion on GSK-3beta phosphorylation in the cardiomyocytes subjected to H/R revealed significantly higher levels of phospho-GSK-3beta/total GSK-3beta in RKO, as well as in sRAGE-treated cardiomyocytes versus WT cardiomyocytes after H/R. Further investigation established a key role for Akt, which functions upstream of GSK-3beta, in modulating H/R injury in adult cardiomyocytes. CONCLUSIONS/SIGNIFICANCE: These data illustrate

  15. 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.

  16. Differential activation of RAGE by HMGB1 modulates neutrophil-associated NADPH oxidase activity and bacterial killing.

    Science.gov (United States)

    Tadié, Jean-Marc; Bae, Hong-Beom; Banerjee, Sami; Zmijewski, Jaroslaw W; Abraham, Edward

    2012-01-01

    The receptor for advanced glycation end products (RAGE) plays an important role in host defense against bacterial infection. In the present experiments, we investigated the mechanisms by which RAGE contributes to the ability of neutrophils to eradicate bacteria. Wild-type (RAGE(+/+)) neutrophils demonstrated significantly greater ability to kill Escherichia coli compared with RAGE(-/-) neutrophils. After intraperitoneal injection of E. coli, increased numbers of bacteria were found in the peritoneal fluid from RAGE(-/-) as compared with RAGE(+/+) mice. Exposure of neutrophils to the protypical RAGE ligand AGE resulted in activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and enhanced killing of E. coli, and intraperitoneal injection of AGE enhanced bacterial clearance during peritonitis. However, incubation of neutrophils with high mobility group box 1 protein (HMGB1), which also binds to RAGE, diminished E. coli-induced activation of NADPH oxidase in neutrophils and bacterial killing both in vitro and in vivo. Deletion of the COOH-terminal tail of HMGB1, a region necessary for binding to RAGE, abrogated the ability of HMGB1 to inhibit bacterial killing. Incubation of neutrophils with HMGB1 diminished bacterial or AGE-dependent activation of NADPH oxidase. The increase in phosphorylation of the p40(phox) subunit of NADPH oxidase that occurred after culture of neutrophils with E. coli was inhibited by exposure of the cells to HMGB1. These results showing that HMGB1, through RAGE-dependent mechanisms, diminishes bacterial killing by neutrophils as well as NADPH oxidase activation provide a novel mechanism by which HMGB1 can potentiate sepsis-associated organ dysfunction and mortality.

  17. "Love and Rage" in the Classroom: Planting the Seeds of Community Empowerment

    Science.gov (United States)

    Love, Kurt

    2012-01-01

    Although no one unified anarchist theory exists, educational approaches can be taken to support the full liberation of the self and the construction of an interconnected community that strives to rid itself of eco-sociocultural oppressions. An anarchist pedagogical approach could be one that is rooted in a love/rage unit of analysis occurring…

  18. 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.

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

    Directory of Open Access Journals (Sweden)

    D.X. Li

    2014-12-01

    Full Text Available 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.

  20. Levetiracetam-induced rage and suicidality: Two case reports and review of literature

    Directory of Open Access Journals (Sweden)

    Orakwue A. Molokwu

    2015-01-01

    Conclusion: Neuropsychiatric evaluation for prior mood or psychiatric disorders in those initiating levetiracetam therapy is suggested alongside monitoring for early features of levetiracetam-induced rage by both caregivers and physicians. This will help stem the morbidity and potential mortality associated with this life-threatening adverse drug reaction.

  1. 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 compo

  2. Thinking through Moments of Sexual Refusal in "Looking for Alibrandi" and "The Rage in Placid Lake"

    Science.gov (United States)

    Clarke, Kyra

    2016-01-01

    This paper explores two scenarios in which young women refuse the sexual advances of young men in the films "Looking for Alibrandi" and "The Rage in Placid Lake." The paper highlights the heteronormative nature of education around refusing sex, which reinstates gendered stereotypes of masculine as active and feminine as…

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

    Science.gov (United States)

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

    2014-12-01

    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%, PAGE-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.

  4. RAGE genetic polymorphisms are associated with risk, chemotherapy response and prognosis in patients with advanced NSCLC.

    Directory of Open Access Journals (Sweden)

    Xiang Wang

    Full Text Available AIM: To explore the association between genetic polymorphisms of the receptor for advanced glycation end-products (RAGE and susceptibility, chemotherapy response rate and prognosis of non-small cell lung cancer (NSCLC. METHOD: This is a prospective study in which 562 patients with NSCLC and 764 healthy controls were enrolled. Three RAGE genetic polymorphisms, namely, -429T/C, -374T/A and 82G/S were genotyped. Platinum-based chemotherapy was given to 432 subjects with advanced inoperable NSCLC and their responses to chemotherapy were evaluated. RESULTS: All the polymorphic genotypes of RAGE polymorphisms were associated with susceptibility for NSCLC. Only the 82G/S polymorphisms denoted a significant difference between responders and non-responders to chemotherapy. The 82SS genotype and 82S allele distribution not only increased the NSCLC risk, but also was associated with a lower chemotherapy response rate and poor prognosis, indicated by overall survival and progression free survival. CONCLUSION: The 82G/S genetic polymorphism of RAGE gene might be used as a genetic marker to screen for patients sensitive to thermotherapy and to predict the prognosis of NSCLC.

  5. Soluble Levels of Receptor for Advanced Glycation Endproducts (RAGE) and Progression of Atherosclerosis in Individuals Infected with Human Immunodeficiency Virus: ACTG NWCS 332.

    Science.gov (United States)

    Danoff, Ann; Kendall, Michelle A; Currier, Judith S; Kelesidis, Theodoros; Schmidt, Ann Marie; Aberg, Judith A

    2016-08-01

    Identification of biomarkers and/or mediators of cardiovascular disease (CVD) associated with HIV infection would be of diagnostic and therapeutic value. As soluble receptor for advanced glycation endproducts (sRAGE) and endogenous secretory (esRAGE) have been implicated in vascular complications in other settings, we investigated whether either soluble form of RAGE was associated with changes in carotid intima-media thickness (CIMT) in HIV-infected patients and HIV-uninfected controls. We found no differences in sRAGE, esRAGE, or CIMT among groups at study entry, or in yearly rates of change in sRAGE, esRAGE, or CIMT by HIV-serostatus (all p > 0.10). However, yearly rates of change in sRAGE (p = 0.07) and esRAGE (p < 0.001) were higher in those taking protease inhibitors, and lower baseline esRAGE levels (p = 0.06) were associated with increased odds of CIMT progression in HIV-infected individuals. Although esRAGE was not altered by HIV-serostatus (p = 0.17), its inverse relationship with CIMT progression in HIV-infected patients suggests a possible role as a mediator of CVD in HIV-infected persons.

  6. Helicobacter pylori Activates HMGB1 Expression and Recruits RAGE into Lipid Rafts to Promote Inflammation in Gastric Epithelial Cells

    Science.gov (United States)

    Lin, Hwai-Jeng; Hsu, Fang-Yu; Chen, Wei-Wei; Lee, Che-Hsin; Lin, Ying-Ju; Chen, Yi-Ywan M.; Chen, Chih-Jung; Huang, Mei-Zi; Kao, Min-Chuan; Chen, Yu-An; Lai, Hsin-Chih; Lai, Chih-Ho

    2016-01-01

    Helicobacter pylori infection is associated with several gastrointestinal disorders in the human population worldwide. High-mobility group box 1 (HMGB1), a ubiquitous nuclear protein, mediates various inflammation functions. The interaction between HMGB1 and receptor for advanced glycation end-products (RAGE) triggers nuclear factor (NF)-κB expression, which in turn stimulates the release of proinflammatory cytokines, such as interleukin (IL)-8, and enhances the inflammatory response. However, how H. pylori activates HMGB1 expression and mobilizes RAGE into cholesterol-rich microdomains in gastric epithelial cells to promote inflammation has not been explored. In this study, we found that HMGB1 and RAGE expression increased significantly in H. pylori-infected cells compared with -uninfected cells. Blocking HMGB1 by neutralizing antibody abrogated H. pylori-elicited RAGE, suggesting that RAGE expression follows HMGB1 production, and silenced RAGE-attenuated H. pylori-mediated NF-κB activation and IL-8 production. Furthermore, significantly more RAGE was present in detergent-resistant membranes extracted from H. pylori-infected cells than in those from -uninfected cells, indicating that H. pylori exploited cholesterol to induce the HMGB1 signaling pathway. These results indicate that HMGB1 plays a crucial role in H. pylori-induced inflammation in gastric epithelial cells, which may be valuable in developing treatments for H. pylori-associated diseases. PMID:27667993

  7. Association of 2184AG Polymorphism in the RAGE Gene with Diabetic Nephropathy in Chinese Patients with Type 2 Diabetes

    OpenAIRE

    Wei Cai; Jian Li; Ji-Xiong Xu; Ying Liu; Wei Zhang; Jun-Ren Xiao; Ling-Yan Zhu; Jian-Ying Liu

    2015-01-01

    Objective. The interaction between advanced glycation end products and their cellular receptor (RAGE) has an important role in the pathogenesis of diabetic microvascular complications. The aim of this study was to investigate the relationship between the 2184A/G polymorphism in the RAGE gene and diabetic nephropathy in Chinese Han patients with type 2 diabetes mellitus. Methods. A total of 868 patients with type 2 diabetes mellitus (486 without and 382 with diabetic nephropathy) were enrolled...

  8. Nuclear DAMP complex-mediated RAGE-dependent macrophage cell death

    Energy Technology Data Exchange (ETDEWEB)

    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.

  9. Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies

    Institute of Scientific and Technical Information of China (English)

    Masayoshi; Takeuchi; Jun-ichi; Takino; Akiko; Sakasai-Sakai; Takanobu; Takata; Tadashi; Ueda; Mikihiro; Tsutsumi; Hideyuki; Hyogo; Sho-ichi; Yamagishi

    2014-01-01

    Non-alcoholic fatty liver disease(NAFLD)is a major cause of liver disease around the world.It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis(NASH)and can lead to fibrosis,cirrhosis,liver failure,and/or hepatocellular carcinoma.NAFLD is also associated with other medical conditions such as obesity,diabetes mellitus(DM),metabolic syn-drome,hypertension,insulin resistance,hyperlipidemia,and cardiovascular disease(CVD).In diabetes,chronic hyperglycemia contributes to the development of both macro-and microvascular conditions through a variety of metabolic pathways.Thus,it can cause a variety of metabolic and hemodynamic conditions,including upregulated advanced glycation end-products(AGEs)synthesis.In our previous study,the most abundant type of toxic AGEs(TAGE);i.e.,glyceraldehyde-derived AGEs,were found to make a significant contribution to the pathogenesis of DM-induced angiopathy.Furthermore,accumulating evidence suggests that the binding of TAGE with their receptor(RAGE)induces oxidative damage,promotes inflammation,and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells.All of these effects could facilitate the pathogenesis of hypertension,cancer,diabetic vascular complications,CVD,dementia,and NASH.Thus,inhibiting TAGE synthesis,preventing TAGE from binding to RAGE,and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH.Here,we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH.

  10. RAGE inhibits human respiratory syncytial virus syncytium formation by interfering with F-protein function

    OpenAIRE

    2013-01-01

    Human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infection. Infection is critically dependent on the RSV fusion (F) protein, which mediates fusion between the viral envelope and airway epithelial cells. The F protein is also expressed on infected cells and is responsible for fusion of infected cells with adjacent cells, resulting in the formation of multinucleate syncytia. The receptor for advanced glycation end products (RAGE) is a pattern-recognitio...

  11. Glycation of the high affinity NGF-receptor and RAGE leads to reduced ligand affinity.

    Science.gov (United States)

    Bennmann, Dorit; Kannicht, Christoph; Fisseau, Claudine; Jacobs, Kathleen; Navarette-Santos, Alexander; Hofmann, Britt; Horstkorte, Rüdiger

    2015-09-01

    AGEs are posttranslational modifications generated by irreversible non-enzymatic crosslinking reactions between sugars and proteins - a reaction referred to as glycation. Glycation, a feature of ageing, can lead to non-degradable and less functional proteins and enzymes and can additionally induce inflammation and further pathophysiological processes such as neurodegeneration. In this study we investigated the influence of glycation on the high affinity NGF-receptor TrkA and the AGE-receptor RAGE. We quantified the binding affinity of the TrkA-receptor and RAGE to their ligands by surface plasmon resonance (SPR) and compared these to the binding affinity after glycation. At the same time, we established a glycation procedure using SPR. We found that glycation of TrkA reduced the affinity to NGF by a factor of three, which could be shown to lead to a reduction of NGF-dependent neurite outgrowth in PC12 cells. Glycation of RAGE reduced binding affinity of AGEs by 10-fold.

  12. Simultaneous Quantitative MRI Mapping of T1, T2* and Magnetic Susceptibility with Multi-Echo MP2RAGE

    Science.gov (United States)

    Kober, Tobias; Möller, Harald E.; Schäfer, Andreas

    2017-01-01

    The knowledge of relaxation times is essential for understanding the biophysical mechanisms underlying contrast in magnetic resonance imaging. Quantitative experiments, while offering major advantages in terms of reproducibility, may benefit from simultaneous acquisitions. In this work, we demonstrate the possibility of simultaneously recording relaxation-time and susceptibility maps with a prototype Multi-Echo (ME) Magnetization-Prepared 2 RApid Gradient Echoes (MP2RAGE) sequence. T1 maps can be obtained using the MP2RAGE sequence, which is relatively insensitive to inhomogeneities of the radio-frequency transmit field, B1+. As an extension, multiple gradient echoes can be acquired in each of the MP2RAGE readout blocks, which permits the calculation of T2* and susceptibility maps. We used computer simulations to explore the effects of the parameters on the precision and accuracy of the mapping. In vivo parameter maps up to 0.6 mm nominal resolution were acquired at 7 T in 19 healthy volunteers. Voxel-by-voxel correlations and the test-retest reproducibility were used to assess the reliability of the results. When using optimized paramenters, T1 maps obtained with ME-MP2RAGE and standard MP2RAGE showed excellent agreement for the whole range of values found in brain tissues. Simultaneously obtained T2* and susceptibility maps were of comparable quality as Fast Low-Angle SHot (FLASH) results. The acquisition times were more favorable for the ME-MP2RAGE (≈ 19 min) sequence as opposed to the sum of MP2RAGE (≈ 12 min) and FLASH (≈ 10 min) acquisitions. Without relevant sacrifice in accuracy, precision or flexibility, the multi-echo version may yield advantages in terms of reduced acquisition time and intrinsic co-registration, provided that an appropriate optimization of the acquisition parameters is performed. PMID:28081157

  13. RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis.

    Science.gov (United States)

    Turovskaya, Olga; Foell, Dirk; Sinha, Pratima; Vogl, Thomas; Newlin, Robbin; Nayak, Jonamani; Nguyen, Mien; Olsson, Anna; Nawroth, Peter P; Bierhaus, Angelika; Varki, Nissi; Kronenberg, Mitchell; Freeze, Hudson H; Srikrishna, Geetha

    2008-10-01

    Patients with inflammatory bowel diseases are at increased risk for colorectal cancer, but the molecular mechanisms linking inflammation and cancer are not well defined. We earlier showed that carboxylated N-glycans expressed on receptor for advanced glycation end products (RAGE) and other glycoproteins mediate colitis through activation of nuclear factor kappa B (NF-kappaB). Because NF-kappaB signaling plays a critical role in the molecular pathogenesis of colitis-associated cancer (CAC), we reasoned that carboxylated glycans, RAGE and its ligands might promote CAC. Carboxylated glycans are expressed on a subpopulation of RAGE on colon cancer cells and mediate S100A8/A9 binding to RAGE. Colon tumor cells express binding sites for S100A8/A9 and binding leads to activation of NF-kappaB and tumor cell proliferation. Binding, downstream signaling and tumor cell proliferation are blocked by mAbGB3.1, an anti-carboxylate glycan antibody, and by anti-RAGE. In human colon tumor tissues and in a mouse model of CAC, we found that myeloid progenitors expressing S100A8 and S100A9 infiltrate regions of dysplasia and adenoma. mAbGB3.1 administration markedly reduces chronic inflammation and tumorigenesis in the mouse model of CAC and RAGE-deficient mice are resistant to the onset of CAC. These findings show that RAGE, carboxylated glycans and S100A8/A9 play essential roles in tumor-stromal interactions, leading to inflammation-associated colon carcinogenesis.

  14. Interaction of the S100A6 mutant (C3S) with the V domain of the receptor for advanced glycation end products (RAGE)

    Energy Technology Data Exchange (ETDEWEB)

    Mohan, Sepuru K., E-mail: mohansepuri@gmail.com; Gupta, Arun A., E-mail: ninja14gupta@gmail.com; Yu, Chin, E-mail: cyu.nthu@gmail.com

    2013-05-03

    Highlights: •The halo human S100A6 (C3S) NMR chemical shifts were assigned. •The interactions between S100A6m and RAGE V domain was investigated by ITC. •The residues involved in the S100A6m–RAGE V domain binding were mapped by {sup 1}H–{sup 15}N HSQC titration. •S100A6–RAGE V domain tetrameric complex model was generated from NMR studies. •The S100A6–RAGE V domain interface regions were elucidated based on HADDOCK model. -- Abstract: S100A6 is involved in several vital biological functions, such as calcium sensing and cell proliferation. It is a homodimeric protein that belongs to the S100 protein family. The receptor for advanced glycation end products (RAGE) has been shown to play a role in the progression of various disease conditions, such as diabetes and immune/inflammatory disorders. Information regarding the association of RAGE with S100 proteins at a molecular level is useful to understand the diversity of the RAGE signaling pathways. In this report, biomolecular NMR techniques were utilized for the resonance assignment of the C3S mutation in human S100A6 and characterizing its interaction with the RAGE V domain. Further binding affinity between S100A6m and the RAGE V domain was determined by isothermal titration calorimetric studies. HADDOCK was used to generate a heterotetramer model of the S100A6m–RAGE V domain complex. This model provides an important insights into the S100–RAGE cellular signaling pathway.

  15. Beneficial effects of metformin and irbesartan on advanced glycation end products (AGEs)-RAGE-induced proximal tubular cell injury.

    Science.gov (United States)

    Ishibashi, Yuji; Matsui, Takanori; Takeuchi, Masayoshi; Yamagishi, Sho-ichi

    2012-03-01

    Advanced glycation end products (AGEs) and their receptor (RAGE) axis contributes to diabetic nephropathy. An oral hypoglycemic agent, metformin may have a potential effect on the inhibition of glycation reactions. Further, since a pathophysiological crosstalk between renin-angiotensin system (RAS) and AGEs-RAGE axis is involved in diabetic nephropathy, it is conceivable that metformin and irbesartan additively could protect against the AGEs-RAGE-induced tubular cell injury. In this study, we addressed the issues. Metformin dose-dependently inhibited the formation of AGEs modification of bovine serum albumin (BSA). Compared with AGEs-modified BSA prepared without metformin (AGEs-MF0), those prepared in the presence of 30 mM or 100 mM metformin (AGEs-MF30 or AGEs-MF100) significantly reduced RAGE mRNA level, reactive oxygen species (ROS) generation, apoptosis, monocyte chemoattractant protein-1 and transforming growth factor-β mRNA level in tubular cells. Irbesartan further inhibited the harmful effects of AGEs-MF0 or AGEs-MF30 on tubular cells. Our present study suggests that combination therapy with metformin and irbesartan may have therapeutic potential in diabetic nephropathy; it could play a protective role against tubular injury in diabetes not only by inhibiting AGEs formation, but also by attenuating the deleterious effects of AGEs via down-regulating RAGE expression and subsequently suppressing ROS generation.

  16. Sleep Now in the Fire: An Analysis of A Song By Rage Against the Machine using Marxism

    Directory of Open Access Journals (Sweden)

    Abdul Aziz Turhan Kariko

    2011-09-01

    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.

  17. Soluble receptor for advanced glycation end-product (sRAGE)/pentosidine ratio: a potential risk factor determinant for type 2 diabetic retinopathy.

    Science.gov (United States)

    Ng, Zhi Xiang; Chua, Kek Heng; Iqbal, Tajunisah; Kuppusamy, Umah Rani

    2013-04-03

    This study aims to investigate potential diabetic retinopathy (DR) risk factors by evaluating the circulating levels of pentosidine, soluble receptor for advanced glycation end-product (sRAGE), advanced oxidation protein product (AOPP) as well as glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities in DR patients. A total of 235 healthy controls, 171 type 2 diabetic without retinopathy (DNR) and 200 diabetic retinopathy (DR) patients were recruited. Plasma was extracted for the estimation of pentosidine, sRAGE, AOPP levels and GPx activity whereas peripheral blood mononuclear cells were disrupted for SOD activity measurement. DNR and DR patients showed significantly higher levels of plasma pentosidine, sRAGE and AOPP but lower GPx and SOD activities when compared to healthy controls. The sRAGE/pentosidine ratio in DR patients was significantly lower than the ratio detected in DNR patients. Proliferative DR patients had significantly higher levels of plasma pentosidine, sRAGE, AOPP and sRAGE/pentosidine ratio than non-proliferative DR patients. High HbA1c level, long duration of diabetes and low sRAGE/pentosidine ratio were determined as the risk factors for DR. This study suggests that sRAGE/pentosidine ratio could serve as a risk factor determinant for type 2 DR as it has a positive correlation with the severity of DR.

  18. 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

    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...

  19. Reduction of advanced-glycation end products levels and inhibition of RAGE signaling decreases rat vascular calcification induced by diabetes.

    Directory of Open Access Journals (Sweden)

    Mathieu R Brodeur

    Full Text Available Advanced-glycation end products (AGEs were recently implicated in vascular calcification, through a process mediated by RAGE (receptor for AGEs. Although a correlation between AGEs levels and vascular calcification was established, there is no evidence that reducing in vivo AGEs deposition or inhibiting AGEs-RAGE signaling pathways can decrease medial calcification. We evaluated the impact of inhibiting AGEs formation by pyridoxamine or elimination of AGEs by alagebrium on diabetic medial calcification. We also evaluated if the inhibition of AGEs-RAGE signaling pathways can prevent calcification. Rats were fed a high fat diet during 2 months before receiving a low dose of streptozotocin. Then, calcification was induced with warfarin. Pyridoxamine was administered at the beginning of warfarin treatment while alagebrium was administered 3 weeks after the beginning of warfarin treatment. Results demonstrate that AGEs inhibitors prevent the time-dependent accumulation of AGEs in femoral arteries of diabetic rats. This effect was accompanied by a reduced diabetes-accelerated calcification. Ex vivo experiments showed that N-methylpyridinium, an agonist of RAGE, induced calcification of diabetic femoral arteries, a process inhibited by antioxidants and different inhibitors of signaling pathways associated to RAGE activation. The physiological importance of oxidative stress was demonstrated by the reduction of femoral artery calcification in diabetic rats treated with apocynin, an inhibitor of reactive oxygen species production. We demonstrated that AGE inhibitors prevent or limit medial calcification. We also showed that diabetes-accelerated calcification is prevented by antioxidants. Thus, inhibiting the association of AGE-RAGE or the downstream signaling reduced medial calcification in diabetes.

  20. The RAGE receptor and its ligands are highly expressed in astrocytes in a grade-dependant manner in the striatum and subependymal layer in Huntington's disease.

    Science.gov (United States)

    Kim, Joanne; Waldvogel, Henry J; Faull, Richard L M; Curtis, Maurice A; Nicholson, Louise F B

    2015-09-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the CAG repeat in the huntingtin gene. One of the brain changes that occurs in HD is the expression of the receptor for advanced glycation end products (RAGE), a receptor protein capable of activating multiple signalling pathways by interacting with a range of ligands leading to either beneficial or harmful effects to the cell. Here, we demonstrate in human HD brains a high degree of co-localization of RAGE with its putative ligands S100B and N-carboxymethyllysine (CML) in the caudate nucleus (CN) and the subependymal layer (SEL). The level of co-staining for both RAGE-S100B and RAGE-CML was the highest in the astrocytes but was low in neurons and microglia. The immunostaining for RAGE, S100B and CML extended in a medio-lateral (SEL-CN) direction with increasing grade, such that any change in the expression and co-localization pattern between grades was less prominent in the lateral CN. Additionally, signalling molecules that are downstream of RAGE activation showed changes in their activation status in HD brains. A larger number of RAGE-positive astrocytic cells had NF-kB translocated to the nucleus and the level of phospho-ERK1/2 was also increased in HD brains. Interestingly, the level of mDia-1, that interacts directly with the cytoplasmic domain of RAGE, decreased in HD. Overall, the results suggest a correlation between the functions of RAGE and the HD pathology, but the influence of RAGE on astrocytes and the impact of this on HD progression requires further study. RAGE (receptor for advanced glycation end products) binds multiple types of ligand to produce either neurotrophic or neurotoxic effects. Immunohistochemical staining of HD human brains showed that both RAGE and its ligands were expressed primarily in astrocytes. The pattern of staining corresponded to the grade and region-wise pattern of neurodegeneration suggesting a possible role for RAGE in HD

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Serum Amyloid A Stimulates PKR Expression and HMGB1 Release Possibly through TLR4/RAGE Receptors.

    Science.gov (United States)

    Li, Wei; Zhu, Shu; Li, Jianhua; D'Amore, Jason; D'Angelo, John; Yang, Huan; Wang, Ping; Tracey, Kevin J; Wang, Haichao

    2015-06-02

    Serum amyloid A (SAA) proteins are known to be surrogate markers of sepsis, but their pathogenic roles remain poorly elucidated. Here we provide evidence to support a possible role of SAA as a pathogenic mediator of lethal sepsis. In a subset of septic patients for which serum high mobility group box 1 (HMGB1) levels paralleled the clinical scores, some anti-HMGB1 antibodies detected a 12-kDa protein belonging to the SAA family. In contrast to the most abundant SAA1, human SAA induced double-stranded RNA-activated protein kinase R (PKR) expression and HMGB1 release in the wild-type, but not toll-like receptor 4/receptor for advanced glycation end products (TLR4/RAGE)-deficient, macrophages. Pharmacological inhibition of PKR phosphorylation blocked SAA-induced HMGB1 release, suggesting an important role of PKR in SAA-induced HMGB1 release. In animal models of lethal endotoxemia and sepsis, recombinant SAA exacerbated endotoxemic lethality, whereas SAA-neutralizing immunoglobulins G (IgGs) significantly improved animal survival. Collectively, these findings have suggested SAA as an important mediator of inflammatory diseases. Highlights of this study include: human SAA is possibly only expressed in a subset of septic patients; SAA induces HMGB1 release via TLR4 and RAGE receptors; SAA supplementation worsens the outcome of lethal endotoxemia; whereas SAA-neutralizing antibodies confer protection against lethal endotoxemia and sepsis.

  3. Agresividad vial en la población general Road-rage in the general population

    Directory of Open Access Journals (Sweden)

    Inmaculada Fierro

    2010-10-01

    Full Text Available Objetivos: Analizar la prevalencia y los factores sociodemográficos asociados con la agresividad vial en la población. Métodos: Se han realizado 2.500 entrevistas a la población de Castilla y León de entre 14 y 70 años de edad. Se evaluó la agresividad vial en el año previo a la realización de la encuesta utilizando un test de ocho preguntas. Resultados: El 31,1% refirió haber vivido alguna situación de agresividad vial en el último año, y el 26,8% en más de una ocasión. El 2,6% fueron agresores viales «graves». Entre los conductores, la probabilidad de experimentar agresividad vial aumenta a medida que aumentan los miles de kilómetros conducidos a la semana (odds ratio [OR]=1,52, es menor cuanto mayor es la edad del entrevistado (OR=0,975 y es mayor en los hombres (OR=1,287, en los que tienen estudios universitarios (OR=1,408 y en los que viven en localidades de más de 10.000 habitantes (OR=1,25. Conclusiones: Los datos del presente estudio muestran que la agresividad vial afecta a casi un tercio de la población general de Castilla y León, lo que justificaría la adopción de medidas para su prevención y reducción.Objective: To analyze the prevalence of road rage in the general population and the sociodemographic factors associated with this phenomenon. Methods: A total of 2,500 interviews were carried out in the population of Castile and Leon aged 14-70 years. Road rage was evaluated in the year prior to the survey using a test with eight questions. Results: One-third (31.1% of the interviewees reported they had experienced a situation involving road rage during the previous 12 months (26.8% on more than one occasion. Among these episodes, 2.6% involved "serious" aggressors. In drivers, the probability of experiencing road rage increased in line with the number of kilometers driven per week (odds ratio [OR]=1.52, decreased as the age of the driver increased (OR=0.975, and was highest in men (OR=1.287, university

  4. Puerarin enhances superoxide dismutase activity and inhibits RAGE and VEGF expression in retinas of STZ-induced early diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Fang Chen; Hong-Quan Zhang; Jun Zhu; Kai-Yang Liu; Hong Cheng; Guo-Li Li; Shan Xu; Wei-Hong Lv; Zheng-Gao Xie

    2012-01-01

    Objective:To investigate the effects of puerarin on the activity of superoxide dismutase (SOD), and expressions of advanced glycation end-product (AGE) receptor (RAGE) and vascular endothelial growth factor (VEGF) in retinas of streptozotocin (STZ)-induced early diabetic rats. Methods: Diabetic rat models were established by inducing diabetes via intra-peritoneal injection of STZ. Rats were randomly divided into normal (control), diabetic (DM), and DM+puerarin groups. After intra-gastric administration of puerarin (500 mg/kg/day for 4 weeks), levels of SOD and malondialdehyde (MDA) were determined in serum and retina. mRNA and protein expression levels of RAGE and VEGF in retinas were determined by real-time polymerase chain reaction (RT-PCR) (mRNA) and Western blot analysis (protein levels). Results:There was significantly lower SOD activity and significantly higher MDA in serum and retinas of the DM group compared with the two other groups (P<0.05). After treatment with puerarin, SOD activity increased and MDA content decreased in this group (P<0.05). mRNA and protein expression levels of RAGE and VEGF in the DM group were significantly higher than those of the other groups (P<0.05), and decreased after puerarin treatment (P<0.05). Conclusions: Puerarin is able to enhance SOD activity, and inhibit RAGE and VEGF expressions in retinas of STZ-induced early diabetic rats.

  5. Usefulness of CDK5RAP3, CCNB2, and RAGE genes for the diagnosis of lung adenocarcinoma.

    Science.gov (United States)

    Stav, D; Bar, I; Sandbank, J

    2007-01-01

    We used oligonucleotide microarrays with probe sets to 22,283 genes to analyze the gene expression profile of lung adenocarcinoma. Cancerous and noncancerous tissue samples were obtained from 23 patients with stage I or II lung cancer; 18 tissue pairs and 5 cancerous tissues. A list of 2065 genes that differentiate between cancerous and noncancerous tissues was generated using Winsorized paired t-tests. We analyzed CDK5RAP3 and CCNB2, which are involved in cell cycle progression, and RAGE. The first 2 of these 3 genes proved to be overexpressed in tumor tissue, whereas the RAGE gene was suppressed in tumor tissue. When CDK5RAP3 and CCNB2 were examined in individual patients we found that in cases where one of these genes was only slightly overexpressed the other was highly overexpressed. The combined expression of the 2 cell cycle genes was found to be statistically significant for differentiating between cancerous and noncancerous tissues. Inclusion of the data for the RAGE gene made the differentiation more powerful. The gene expression ratio gave a clear result: when CDK5RAP3 was expressed more than RAGE, the tissue was carcinomatous, and vice versa. We therefore conclude that these 3 genes may be used as a very reliable biomarker of lung adenocarcinoma.

  6. Paeoniflorin protects HUVECs from AGE-BSA-induced injury via an autophagic pathway by acting on the RAGE.

    Science.gov (United States)

    Chen, Yufang; Du, Xing; Zhou, Yande; Zhang, Yanlin; Yang, Yaping; Liu, Zhihua; Liu, Chunfeng; Xie, Ying

    2015-01-01

    The aim of our study was to investigate the protective effects of Paeoniflorin (PF) against injury induced by AGE-modified bovine serum albumin (AGE-BSA) in human umbilical vein endothelial cells (HUVECs), and to examine the underlying mechanisms of these effects. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to determine cell viability. Protein expression levels were determined by western blotting. For function-blocking experiments, we used small interfering RNA molecules (siRNA) for function-blocking experiments. At 6 h, we found that 100 μg/mL AGE-BSA reduced the viability of HUVECs. However, pretreatment with PF restored cell viability in a dose-dependent manner. AGE-BSA increased the levels of microtubule-associated protein light chain 3-II (LC3-II) and the receptor for advanced glycation end products (RAGE). Expression of p62 protein was also increased, but not at a statistically significant level. Pretreatment with PF further increased levels of LC3-II and RAGE, but reduced the expression of p62. In cells transfected with Atg5 and RAGE siRNA, cell viability and expression of LC3-II decreased in both the AGE-BSA and PF + AGE-BSA treatments. PF can protect HUVECs from AGE-BSA-induced injury by upregulating autophagy and promoting the completion of autophagy flux. RAGE plays an important role in this autophagic protection effect.

  7. High Mobility Group Box Protein 1 Boosts Endothelial Albumin Transcytosis through the RAGE/Src/Caveolin-1 Pathway

    Science.gov (United States)

    Shang, Dan; Peng, Tao; Gou, Shanmiao; Li, Yiqing; Wu, Heshui; Wang, Chunyou; Yang, Zhiyong

    2016-01-01

    High-mobility group box protein 1 (HMGB1), an inflammatory mediator, has been reported to destroy cell-cell junctions, resulting in vascular endothelial hyperpermeability. Here, we report that HMGB1 increases the endothelial transcytosis of albumin. In mouse lung vascular endothelial cells (MLVECs), HMGB1 at a concentration of 500 ng/ml or less did not harm cell-cell junctions but rapidly induced endothelial hyperpermeability to 125I-albumin. HMGB1 induced an increase in 125I-albumin and AlexaFluor 488-labeled albumin internalization in endocytosis assays. Depletion of receptor for advanced glycation end products (RAGE), but not TLR2 or TLR4, suppressed HMGB1-induced albumin transcytosis and endocytosis. Genetic and pharmacological destruction of lipid rafts significantly inhibited HMGB1-induced albumin endocytosis and transcytosis. HMGB1 induced the rapid phosphorylation of caveolin (Cav)-1 and Src. Either RAGE gene silencing or soluble RAGE suppressed Cav-1 Tyr14 phosphorylation and Src Tyr418 phosphorylation. The Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP2) blocked HMGB1-induced Cav-1 Tyr14 phosphorylation. PP2 and overexpression of Cav-1 with a T14F mutation significantly inhibited HMGB1-induced transcytosis and albumin endocytosis. Our findings suggest that HMGB1 induces the transcytosis of albumin via RAGE-dependent Src phosphorylation and Cav-1 phosphorylation. These studies revealed a new mechanism of HMGB1-induced endothelial hyperpermeability. PMID:27572515

  8. Simvastatin suppresses vascular inflammation and atherosclerosis in ApoE-/-mice by downregulating the HMGB1-RAGE axis

    Institute of Scientific and Technical Information of China (English)

    Ming LIU; Ying YU; Hong JIANG; Lei ZHANG; Pei-pei ZHANG; Peng YU; Jian-guo JIA

    2013-01-01

    Aim:High mobility group box protein 1 (HMGB1) and receptor for the advanced glycation end product (RAGE) play pivotal roles in vascular inflammation and atherosclerosis.The aim of this study was to determine whether the HMGB1-RAGE axis was involved in the actions of simvastatin on vascular inflammation and atherosclerosis in ApoE-/-mice.Methods:Five-week old ApoE-/-mice and wild-type C57BL/6 mice were fed a Western diet.At 8 weeks of age,ApoE-/-mice were administered simvastatin (50 mg.kg1.d-1) or vehicle by gavage,and the wild-type mice were treated with vehicle.The mice were sacrificed at 11 weeks of age,and the atherosclerotic lesions in aortic sinus were assessed with Oil Red 0 staining.Macrophage migration was determined with scanning EM and immunohistochemistry.Human umbilical vein endothelial cells (HUVECs) were used for in vitro study.Western blots were used to quantify the protein expression of HMGB1,RAGE,vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1).Results:Vehicle-treated ApoE-/-mice exhibited significant increases in aortic inflammation and atherosclerosis as well as enhanced expression of HMGB1,RAGE,VCAM-1,and MCP-1 in aortic tissues as compared to the wild-type mice.Furthermore,serum total cholesterol,triglyceride and LDL levels were markedly increased,while serum HDL level was decreased in vehicle-treated ApoE-/-mice.Administration with simvastatin in ApoE-/-mice markedly attenuated the vascular inflammation and atherosclerotic lesion area,and decreased the aortic expression of HMGB1,RAGE,VCAM-1,and MCP-1.However,simvastatin did not affect the abnormal levels of serum total cholesterol,triglyceride,LDL and HDL in ApoE-/-mice.Exposure of HUVECs to HMGB1 (100 ng/mL) markedly increased the expression of HMGB1,RAGE and VCAM-1,whereas pretreatment of the cells with simvastatin (10 μmol/L) blocked the HMGB1-caused changes.Conclusion:Simvastatin inhibits vascular inflammation and atherosclerosis in Apo

  9. The receptor for advanced glycation end-products (RAGE) plays a key role in the formation of nanotubes (NTs) between peritoneal mesothelial cells and in murine kidneys.

    Science.gov (United States)

    Ranzinger, Julia; Rustom, Amin; Heide, Danijela; Morath, Christian; Schemmer, Peter; Nawroth, Peter P; Zeier, Martin; Schwenger, Vedat

    2014-09-01

    The receptor for advanced glycation end-products (RAGE), a multiligand receptor of the immunoglobulin superfamily, takes part in various inflammatory processes. The role of this receptor in the context of intercellular communication, like nanotube (NT)-mediated interaction, is largely unknown. Here, we use cell cultures of human and murine peritoneal mesothelial cells as well as murine kidneys from wild-type and RAGE knockout mouse models to assess the role of RAGE in NT formation and function. We show that loss of RAGE function results in reduced NT numbers under physiological conditions and demonstrate the involvement of MAP kinase signaling in NT formation. Additionally, we show for the first time the existence of NTs in murine kidney tissue and confirm the correlation of RAGE expression and NT numbers. Under elevated oxidative stress conditions like renal ischemia or peritoneal dialysis, we demonstrate that RAGE absence does not prevent NT formation. Rather, increased NT numbers and attenuated kidney tissue damage could be observed, indicating that, depending on the predominant conditions, RAGE affects NT formation with implications for cellular communication.

  10. HMGB1 induces an inflammatory response in endothelial cells via the RAGE-dependent endoplasmic reticulum stress pathway

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Ying [Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha 410078 (China); Li, Shu-Jun [Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha 410078 (China); Yang, Jian [Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha 410078 (China); Qiu, Yuan-Zhen [Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha 410078 (China); Chen, Fang-Ping, E-mail: xychenfp@163.com [Department of Hematology, Xiangya Hospital, Central South University, Changsha 410078 (China)

    2013-09-06

    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.

  11. Analysis of xRAGE and flag high explosive burn models with PBX 9404 cylinder tests

    Energy Technology Data Exchange (ETDEWEB)

    Harrier, Danielle [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Andersen, Kyle Richard [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-08-05

    High explosives are energetic materials that release their chemical energy in a short interval of time. They are able to generate extreme heat and pressure by a shock driven chemical decomposition reaction, which makes them valuable tools that must be understood. This study investigated the accuracy and performance of two Los Alamos National Laboratory hydrodynamic codes, which are used to determine the behavior of explosives within a variety of systems: xRAGE which utilizes an Eulerian mesh, and FLAG with utilizes a Lagrangian mesh. Various programmed and reactive burn models within both codes were tested using a copper cylinder expansion test. The test was based on a recent experimental setup which contained the plastic bonded explosive PBX 9404. Detonation velocity versus time curves for this explosive were obtained using Photon Doppler Velocimetry (PDV). The modeled results from each of the burn models tested were then compared to one another and to the experimental results. This study validate

  12. Further RAGE modeling of asteroid mitigation: surface and subsurface explosions in porous objects

    Energy Technology Data Exchange (ETDEWEB)

    Weaver, Robert P [Los Alamos National Laboratory; Plesko, Catherine S [Los Alamos National Laboratory; Dearholt, William R [Los Alamos National Laboratory

    2011-01-03

    Disruption or mitigation of a potentially hazardous object (PHO) by a high-energy subsurface burst is considered. This is just one possible method of impact-hazard mitigation. We present RAGE hydrocode models of the shock-generated disruption of PHOs by subsurface nuclear bursts using scenario-specific models from realistic RADAR shape models. We will show 2D and 3D models for the disruption by a large energy source at the center of such PHO models ({approx}100 kt-10 Mt) specifically for the shape of the asteroid 25143 Itokawa. We study the effects of non-uniform composition (rubble pile), shallow buried bursts for the optimal depth of burial and porosity.

  13. Robust T1-weighted structural brain imaging and morphometry at 7T using MP2RAGE.

    Directory of Open Access Journals (Sweden)

    Kieran R O'Brien

    Full Text Available PURPOSE: To suppress the noise, by sacrificing some of the signal homogeneity for numerical stability, in uniform T1 weighted (T1w images obtained with the magnetization prepared 2 rapid gradient echoes sequence (MP2RAGE and to compare the clinical utility of these robust T1w images against the uniform T1w images. MATERIALS AND METHODS: 8 healthy subjects (29.0 ± 4.1 years; 6 Male, who provided written consent, underwent two scan sessions within a 24 hour period on a 7T head-only scanner. The uniform and robust T1w image volumes were calculated inline on the scanner. Two experienced radiologists qualitatively rated the images for: general image quality; 7T specific artefacts; and, local structure definition. Voxel-based and volume-based morphometry packages were used to compare the segmentation quality between the uniform and robust images. Statistical differences were evaluated by using a positive sided Wilcoxon rank test. RESULTS: The robust image suppresses background noise inside and outside the skull. The inhomogeneity introduced was ranked as mild. The robust image was significantly ranked higher than the uniform image for both observers (observer 1/2, p-value = 0.0006/0.0004. In particular, an improved delineation of the pituitary gland, cerebellar lobes was observed in the robust versus uniform T1w image. The reproducibility of the segmentation results between repeat scans improved (p-value = 0.0004 from an average volumetric difference across structures of ≈ 6.6% to ≈ 2.4% for the uniform image and robust T1w image respectively. CONCLUSIONS: The robust T1w image enables MP2RAGE to produce, clinically familiar T1w images, in addition to T1 maps, which can be readily used in uniform morphometry packages.

  14. Possible participation of receptor for advanced glycation end products (RAGE) in the origin of cancer stem cells in diabetic patients with colon cancer.

    Science.gov (United States)

    Hu, Xiang; Cheng, Yong

    2013-05-01

    The association between diabetes and the associated increased risk of several solid malignancies has been the subject of investigation for many years, while potential biologic links between the two diseases are incompletely understood. The receptor for advanced glycation end-products (RAGE) signal transduction may represent a focal point in their respective contributions to malignant transformation associated diabetes. While the physiopathology of RAGE axis in promoting malignancies cannot be explained completely by the available mechanism as perpetuating inflammation at tumor microenvironment. In addition, experimental researches revealed a crucial role for upstreams of RAGE signaling pathway in maintaining the stemness properties and tumorigenicity of cancer stem cells. Hence, we hypothesized that RAGE inducing cancer stem cells may be a key determinant in the origin and progression of colon malignant tumors concomitant diabetes. Such an opinion not only bands together the seemingly disparate various complications in diabetes and colon cancers, but also has future implications for risk assessment and biopharmaceutical treatment.

  15. Concurrent alterations of RAGE, RECK, and MMP9 protein expression are relevant to Epstein-Barr virus infection, metastasis, and survival in nasopharyngeal carcinoma.

    Science.gov (United States)

    Zhou, Dong-Ni; Deng, Yan-Fei; Li, Rong-Hua; Yin, Ping; Ye, Chun-Sheng

    2014-01-01

    This study aimed to concurrently investigate the expressions of receptor for advanced glycation end products (RAGE), reversion inducing cysteine-rich protein with Kazal motifs (RECK) and matrix metalloproteinase 9 (MMP9) in nasopharyngeal carcinoma (NPC) and their correlations with clinicopathological properties. Using immunohistochemistry, we found that RECK expression was downregulated in NPC tissues compared with chronic nasopharyngitis (CNT) tissues, while RAGE and MMP9 expressions were upregulated. We further found that RECK expression level was inversely correlated with MMP9 expression level in NPC, whereas RAGE expression level was positively correlated with MMP9 expression level. Moreover, aberrant expressions of these proteins had a positive correlation with the titers of EBVCA-IgA, lymphatic metastasis, recurrence and survival. Together, these findings suggest that dysregulations of RECK and RAGE expressions may be collectively involved in tumor progression of NPC by regulating MMP9 expression and that they may be a good prognostic predictors for NPC.

  16. Concurrent alterations of RAGE, RECK, and MMP9 protein expression are relevant to Epstein-Barr virus infection, metastasis, and survival in nasopharyngeal carcinoma

    OpenAIRE

    2014-01-01

    This study aimed to concurrently investigate the expressions of receptor for advanced glycation end products (RAGE), reversion inducing cysteine-rich protein with Kazal motifs (RECK) and matrix metalloproteinase 9 (MMP9) in nasopharyngeal carcinoma (NPC) and their correlations with clinicopathological properties. Using immunohistochemistry, we found that RECK expression was downregulated in NPC tissues compared with chronic nasopharyngitis (CNT) tissues, while RAGE and MMP9 expressions were u...

  17. Contribution à l’étude du tempérage du chocolat en cuves agitées

    OpenAIRE

    Rius Fonoll, Joan

    2008-01-01

    Le tempérage du chocolat est une opération clé dans son processus de production. Le chocolat doit être tempéré pour obtenir la forme cristalline voulue parmi les six que présente le beurre de cacao. Les clés pour le bien tempérer sont suivre un cycle thermique dépendant du type de chocolat ainsi qu’un cisaillement adéquat dans une cuve. Ce mémoire veut analyser une nouvelle technique de tempérage appelée easy temper. Pour ce faire, il faut commencer par bien comprendre les p...

  18. Helicobacter pylori Activates HMGB1 Expression and Recruits RAGE into Lipid Rafts to Promote Inflammation in Gastric Epithelial Cells

    OpenAIRE

    Lin, Hwai-Jeng; Hsu, Fang-Yu; Chen, Wei-Wei; Lee, Che-Hsin; Lin, Ying-Ju; Yi-Ywan M Chen; Chen, Chih-Jung; Huang, Mei-Zi; Kao, Min-Chuan; Chen, Yu-An; Lai, Hsin-Chih; Lai, Chih-Ho

    2016-01-01

    Helicobacter pylori infection is associated with several gastrointestinal disorders in the human population worldwide. High-mobility group box 1 (HMGB1), a ubiquitous nuclear protein, mediates various inflammation functions. The interaction between HMGB1 and receptor for advanced glycation end-products (RAGE) triggers nuclear factor (NF)-κB expression, which in turn stimulates the release of proinflammatory cytokines, such as interleukin (IL)-8, and enhances the inflammatory response. However...

  19. Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer’s disease mouse model

    Science.gov (United States)

    Criscuolo, Chiara; Fontebasso, Veronica; Middei, Silvia; Stazi, Martina; Ammassari-Teule, Martine; Yan, Shirley ShiDu; Origlia, Nicola

    2017-01-01

    The Entorhinal cortex (EC) has been implicated in the early stages of Alzheimer’s disease (AD). In particular, spreading of neuronal dysfunction within the EC-Hippocampal network has been suggested. We have investigated the time course of EC dysfunction in the AD mouse model carrying human mutation of amyloid precursor protein (mhAPP) expressing human Aβ. We found that in mhAPP mice plasticity impairment is first observed in EC superficial layer and further affected with time. A selective impairment of LTP was observed in layer II horizontal connections of EC slices from 2 month old mhAPP mice, whereas at later stage of neurodegeneration (6 month) basal synaptic transmission and LTD were also affected. Accordingly, early synaptic deficit in the mhAPP mice were associated with a selective impairment in EC-dependent associative memory tasks. The introduction of the dominant-negative form of RAGE lacking RAGE signalling targeted to microglia (DNMSR) in mhAPP mice prevented synaptic and behavioural deficit, reducing the activation of stress related kinases (p38MAPK and JNK). Our results support the involvement of the EC in the development and progression of the synaptic and behavioural deficit during amyloid-dependent neurodegeneration and demonstrate that microglial RAGE activation in presence of Aβ-enriched environment contributes to the EC vulnerability. PMID:28205565

  20. AGEs-Induced IL-6 Synthesis Precedes RAGE Up-Regulation in HEK 293 Cells: An Alternative Inflammatory Mechanism?

    Directory of Open Access Journals (Sweden)

    Andreea Iren Serban

    2015-08-01

    Full Text Available Advanced glycation end products (AGEs can activate the inflammatory pathways involved in diabetic nephropathy. Understanding these molecular pathways could contribute to therapeutic strategies for diabetes complications. We evaluated the modulation of inflammatory and oxidative markers, as well as the protective mechanisms employed by human embryonic kidney cells (HEK 293 upon exposure to 200 μg/mL bovine serum albumine (BSA or AGEs–BSA for 12, 24 and 48 h. The mRNA and protein expression levels of AGEs receptor (RAGE and heat shock proteins (HSPs 27, 60 and 70, the activity of antioxidant enzymes and the expression levels of eight cytokines were analysed. Cell damage via oxidative mechanisms was evaluated by glutathione and malondialdehyde levels. The data revealed two different time scale responses. First, the up-regulation of interleukin-6 (IL-6, HSP 27 and high catalase activity were detected as early as 12 h after exposure to AGEs–BSA, while the second response, after 24 h, consisted of NF-κB p65, RAGE, HSP 70 and inflammatory cytokine up-regulation, glutathione depletion, malondialdehyde increase and the activation of antioxidant enzymes. IL-6 might be important in the early ignition of inflammatory responses, while the cellular redox imbalance, RAGE activation and NF-κB p65 increased expression further enhance inflammatory signals in HEK 293 cells.

  1. Food-advanced glycation end products aggravate the diabetic vascular complications via modulating the AGEs/RAGE pathway.

    Science.gov (United States)

    Lv, Xing; Lv, Gao-Hong; Dai, Guo-Ying; Sun, Hong-Mei; Xu, Hui-Qin

    2016-11-01

    The aim of this study was to investigate the effects of high-advanced glycation end products (AGEs) diet on diabetic vascular complications. The Streptozocin (STZ)-induced diabetic mice were fed with high-AGEs diet. Diabetic characteristics, indicators of renal and cardiovascular functions, and pathohistology of pancreas, heart and renal were evaluated. AGEs/RAGE/ROS pathway parameters were determined. During the experiments, the diabetic mice exhibited typical characteristics including weight loss, polydipsia, polyphagia, polyuria, high-blood glucose, and low-serum insulin levels. However, high-AGEs diet effectively aggravated these diabetic characteristics. It also increased the 24-h urine protein levels, serum levels of urea nitrogen, creatinine, c-reactive protein (CRP), low density lipoprotein (LDL), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in the diabetic mice. High-AGEs diet deteriorated the histology of pancreas, heart, and kidneys, and caused structural alterations of endothelial cells, mesangial cells and podocytes in renal cortex. Eventually, high-AGEs diet contributed to the high-AGE levels in serum and kidneys, high-levels of reactive oxygen species (ROS) and low-levels of superoxide dismutase (SOD) in serum, heart, and kidneys. It also upregulated RAGE mRNA and protein expression in heart and kidneys. Our results showed that high-AGEs diet deteriorated vascular complications in the diabetic mice. The activation of AGEs/RAGE/ROS pathway may be involved in the pathogenesis of vascular complications in diabetes.

  2. Role of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in vascular damage in diabetes.

    Science.gov (United States)

    Yamagishi, Sho-ichi

    2011-04-01

    A non-enzymatic reaction between ketones or aldehydes and the amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules and to the development and progression of various age-related disorders such as vascular complications of diabetes, Alzheimer's disease, cancer growth and metastasis, insulin resistance and degenerative bone disease. Under hyperglycemic and/or oxidative stress conditions, this process begins with the conversion of reversible Schiff base adducts, and then to more stable, covalently-bound Amadori rearrangement products. Over a course of days to weeks, these early glycation products undergo further reactions and rearrangements to become irreversibly crossed-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs). There is a growing body of evidence that AGE and their receptor RAGE (receptor for AGEs) interaction elicits oxidative stress, inflammatory reactions and thrombosis, thereby being involved in vascular aging and damage. These observations suggest that the AGE-RAGE system is a novel therapeutic target for preventing diabetic vascular complications. In this paper, we review the pathophysiological role of the AGE-RAGE-oxidative stress system and its therapeutic intervention in vascular damage in diabetes. We also discuss here the potential utility of the restriction of food-derived AGEs in diabetic vascular complications.

  3. Glycer-AGEs-RAGE signaling enhances the angiogenic potential of hepatocellular carcinoma by upregulating VEGF expression

    Institute of Scientific and Technical Information of China (English)

    Junichi Takino; Shoichi Yamagishi; Masayoshi Takeuchi

    2012-01-01

    AIM:To investigate the effect of glyceraldehyde-derived advanced glycation end-products (Glycer-AGEs)on hepatocellular carcinoma (HCC) cells.METHODS:Two HCC cell lines (Hep3B and HepG2cells) and human umbilical vein endothelial cells (HUVEC) were used.Cell viability was determined using the WST-8 assay.Western blotting,enzyme linked immunosorbent assay,and real-time reverse transcriptionpolymerase chain reactions were used to detect protein and mRNA.Angiogenesis was evaluated by assessing the proliferation,migration,and tube formation of HUVEC.RESULTS:The receptor for AGEs (RAGE) protein was detected in Hep3B and HepG2 cells.HepG2 cells were not affected by the addition of Glycer-AGEs.GlycerAGEs markedly increased vascular endothelial growth factor (VEGF) mRNA and protein expression,which is one of the most potent angiogenic factors.Compared with the control unglycated bovine serum albumin (BSA)treatment,VEGF mRNA expression levels induced by the Glycer-AGEs treatment were 1.00 ± 0.10 vs 1.92± 0.09 (P < 0.01).Similarly,protein expression levels induced by the Glycer-AGEs treatment were 1.63 ± 0.04ng/mL vs 2.28 ± 0.17 ng/mL for the 24 h treatment and 3.36 ± 0.10 ng/mL vs 4.79 ± 0.31 ng/mL for the 48 h treatment,respectively (P < 0.01).Furthermore,compared with the effect of the control unglycated BSA-treated conditioned medium,the Glycer-AGEstreated conditioned medium significantly increased the proliferation,migration,and tube formation of HUVEC,with values of 122.4% ± 9.0% vs 144.5% ± 11.3% for cell viability,4.29 ± 1.53 vs 6.78 ± 1.84 for migration indices,and 71.0 ± 7.5 vs 112.4 ± 8.0 for the number of branching points,respectively (P < 0.01).CONCLUSION:These results suggest that Glycer-AGEs-RAGE signaling enhances the angiogenic potential of HCC cells by upregulating VEGF expression.

  4. Involvement of formyl peptide receptors in receptor for advanced glycation end products (RAGE - and amyloid beta 1-42-induced signal transduction in glial cells

    Directory of Open Access Journals (Sweden)

    Slowik Alexander

    2012-11-01

    Full Text Available Abstract Background Recent studies suggest that the chemotactic G-protein-coupled-receptor (GPCR formyl-peptide-receptor-like-1 (FPRL1 and the receptor-for-advanced-glycation-end-products (RAGE play an important role in the inflammatory response involved in neurodegenerative disorders such as Alzheimer’s disease (AD. Therefore, the expression and co-localisation of mouse formyl peptide receptor (mFPR 1 and 2 as well as RAGE in an APP/PS1 transgenic mouse model using immunofluorescence and real-time RT-PCR were analysed. The involvement of rat or human FPR1/FPRL1 (corresponds to mFPR1/2 and RAGE in amyloid-β 1–42 (Aβ1-42-induced signalling were investigated by extracellular signal regulated kinase 1/2 (ERK1/2 phosphorylation. Furthermore, the cAMP level in primary rat glial cells (microglia and astrocytes and transfected HEK 293 cells was measured. Formyl peptide receptors and RAGE were inhibited by a small synthetic antagonist WRW4 and an inactive receptor variant delta-RAGE, lacking the intracytoplasmatic domains. Results We demonstrated a strong increase of mFPR1/2 and RAGE expression in the cortex and hippocampus of APP/PS1 transgenic mice co-localised to the glial cells. In addition, the Aβ1-42-induced signal transduction is dependant on FPRL1, but also on FPR1. For the first time, we have shown a functional interaction between FPRL1/FPR1 and RAGE in RAGE ligands S100B- or AGE-mediated signalling by ERK1/2 phosphorylation and cAMP level measurement. In addition a possible physical interaction between FPRL1 as well as FPR1 and RAGE was shown with co-immunoprecipitation and fluorescence microscopy. Conclusions The results suggest that both formyl peptide receptors play an essential role in Aβ1-42-induced signal transduction in glial cells. The interaction with RAGE could explain the broad ligand spectrum of formyl peptide receptors and their important role for inflammation and the host defence against infections.

  5. Plasma miR-185 is decreased in patients with esophageal squamous cell carcinoma and might suppress tumor migration and invasion by targeting RAGE.

    Science.gov (United States)

    Jing, Rongrong; Chen, Wen; Wang, Huimin; Ju, Shaoqing; Cong, Hui; Sun, Baolan; Jin, Qin; Chu, Shaopeng; Xu, Lili; Cui, Ming

    2015-11-01

    The receptor for advanced-glycation end products (RAGE) is upregulated in various cancers and has been associated with tumor progression, but little is known about its expression and regulation by microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC). Here, we describe miR-185, which represses RAGE expression, and investigate the biological role of miR-185 in ESCC. In this study, we found that the high level of RAGE expression in 29 pairs of paraffin-embedded ESCC tissues was correlated positively with the depth of invasion by immunohistochemistry, suggesting that RAGE was involved in ESCC. We used bioinformatics searches and luciferase reporter assays to investigate the prediction that RAGE was regulated directly by miR-185. Besides, overexpression of miR-185 in ESCC cells was accompanied by 27% (TE-11) and 49% (Eca-109) reduced RAGE expression. The effect was further confirmed in RAGE protein by immunofluorescence in both cell lines. The effects were reversed following cotransfection with miR-185 and high-level expression of the RAGE vector. Furthermore, the biological role of miR-185 in ESCC cell lines was investigated using assays of cell viability, Ki-67 staining, and cell migration and invasion, as well as in a xenograft model. We found that overexpression of miR-185 inhibited migration and invasion by ESCC cells in vitro and reduced their capacity to develop distal pulmonary metastases in vivo partly through the RAGE/heat shock protein 27 pathway. Interestingly, in clinical specimens, the level of plasma miR-185 expression was decreased significantly (P = 0.002) in patients with ESCC [0.500; 95% confidence interval (CI) 0.248-1.676] compared with healthy controls (2.410; 95% CI 0.612-5.671). The value of the area under the receiver-operating characteristic curve was 0.73 (95% CI 0.604-0.855). In conclusion, our findings shed novel light on the role of miR-185/RAGE in ESCC metastasis, and plasma miR-185 has potential as a novel diagnostic biomarker

  6. Association of advanced glycation end products with A549 cells, a human pulmonary epithelial cell line, is mediated by a receptor distinct from the scavenger receptor family and RAGE.

    Science.gov (United States)

    Nakano, Nahoko; Fukuhara-Takaki, Kaori; Jono, Tadashi; Nakajou, Keisuke; Eto, Nobuaki; Horiuchi, Seikoh; Takeya, Motohiro; Nagai, Ryoji

    2006-05-01

    Cellular interactions with advanced glycation end products (AGE)-modified proteins are known to induce several biological responses, not only endocytic uptake and degradation, but also the induction of cytokines and growth factors, combined responses that may be linked to the development of diabetic vascular complications. In this study we demonstrate that A549 cells, a human pulmonary epithelial cell line, possess a specific binding site for AGE-modified bovine serum albumin (AGE-BSA) (K(d) = 27.8 nM), and additionally for EN-RAGE (extracellular newly identified RAGE binding protein) (K(d) = 118 nM). Western blot and RT-PCR analysis showed that RAGE (receptor for AGE) is highly expressed on A549 cells, while the expression of other known AGE-receptors such as galectin-3 and SR-A (class A scavenger receptor), are below the level of detection. The binding of (125)I-AGE-BSA to these cells is inhibited by unlabeled AGE-BSA, but not by EN-RAGE. In contrast, the binding of (125)I-EN-RAGE is significantly inhibited by unlabeled EN-RAGE and soluble RAGE, but not by AGE-BSA. Our results indicate that A549 cells possess at least two binding sites, one specific for EN-RAGE and the other specific for AGE-BSA. The latter receptor on A549 cells is distinct from the scavenger receptor family and RAGE.

  7. Verification Test of the SURF and SURFplus Models in xRage: Part II

    Energy Technology Data Exchange (ETDEWEB)

    Menikoff, Ralph [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-06-20

    The previous study used an underdriven detonation wave (steady ZND reaction zone profile followed by a scale invariant rarefaction wave) for PBX 9502 as a validation test of the implementation of the SURF and SURFplus models in the xRage code. Even with a fairly fine uniform mesh (12,800 cells for 100mm) the detonation wave profile had limited resolution due to the thin reaction zone width (0.18mm) for the fast SURF burn rate. Here we study the effect of finer resolution by comparing results of simulations with cell sizes of 8, 2 and 1 μm, which corresponds to 25, 100 and 200 points within the reaction zone. With finer resolution the lead shock pressure is closer to the von Neumann spike pressure, and there is less noise in the rarefaction wave due to fluctuations within the reaction zone. As a result the average error decreases. The pointwise error is still dominated by the smearing the pressure kink in the vicinity of the sonic point which occurs at the end of the reaction zone.

  8. In-Situ Visualization Experiments with ParaView Cinema in RAGE

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-10-15

    A previous paper described 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. One challenge of the in-situ approach apparent in these experiments was the difficulty of choosing parameters likes isosurface values for the visualizations to be produced from the running simulation without the benefit of prior knowledge of the simulation results and the resultant cost of recomputing in-situ generated images when parameters are chosen suboptimally. A proposed method of addressing this difficulty is to simply render multiple images at runtime with a range of possible parameter values to produce a large database of images and to provide the user with a tool for managing the resulting database of imagery. Recently, ParaView/Catalyst has been extended to include such a capability via the so-called Cinema framework. Here I describe some initial experiments with the first delivery of Cinema and make some recommendations for future extensions of Cinema’s capabilities.

  9. Verification test of the SURF and SURFplus models in xRage

    Energy Technology Data Exchange (ETDEWEB)

    Menikoff, Ralph [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-05-18

    As a verification test of the SURF and SURFplus models in the xRage code we use a propagating underdriven detonation wave in 1-D. This is about the only test cases for which an accurate solution can be determined based on the theoretical structure of the solution. The solution consists of a steady ZND reaction zone profile joined with a scale invariant rarefaction or Taylor wave and followed by a constant state. The end of the reaction profile and the head of the rarefaction coincide with the sonic CJ state of the detonation wave. The constant state is required to match a rigid wall boundary condition. For a test case, we use PBX 9502 with the same EOS and burn rate as previously used to test the shock detector algorithm utilized by the SURF model. The detonation wave is propagated for 10 μs (slightly under 80mm). As expected, the pointwise errors are largest in the neighborhood of discontinuities; pressure discontinuity at the lead shock front and pressure derivative discontinuities at the head and tail of the rarefaction. As a quantitative measure of the overall accuracy, the L2 norm of the difference of the numerical pressure and the exact solution is used. Results are presented for simulations using both a uniform grid and an adaptive grid that refines the reaction zone.

  10. Using xRage to Model Heat Flow for Experiments to Measure Opacities in HED Plasmas

    Science.gov (United States)

    Elgin, L.; Vandervort, R.; Keiter, P.; Drake, R. P.; Mussack, K.; Orban, C.

    2015-11-01

    We are developing a NIF proposal to measure opacities of C, N and O at temperatures and densities relevant to the base of the solar convection zone. Our proposed experiments would provide the first opacity measurements for these elements within this HED regime. A critical feature of our experimental platform is a super-sonic radiation front propagating within the targets. Under these conditions, density remains constant across the radiation front for a couple nanoseconds, enabling a window during which the opacities of the hot and cold target may be measured simultaneously. Afterwards, hydrodynamic effects create temperature and density gradients, which would obfuscate analysis of opacity data. We are using xRage to simulate heat flow within our targets in order to estimate the time scale over which temperature and density gradients evolve. These simulations will better inform our target design and diagnostic requirements. If successful, our experiments could yield the data necessary to validate existing opacity models or provide physical insights to inform the development of new opacity models. Accurate opacity models are essential to the understanding of radiation transport within HED systems, with applications ranging from astrophysics to ICF. U.S. Department of Energy, through the NNSA-DS and SC-OFES Joint Program in High-Energy-Density Laboratory Plasmas, grant #DE-NA0001840. Los Alamos National Laboratory, LA-UR-15-25490.

  11. Association of the receptor for advanced glycation end-products (RAGE gene polymorphisms in Malaysian patients with chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Foo Nian Wong

    2016-04-01

    Full Text Available Background: Chronic kidney disease (CKD is a condition associated with progressive loss of kidney function and kidney damage. The two common causes of CKD are diabetes mellitus and hypertension. Other causes of CKD also include polycystic kidney disease, obstructive uropathy and primary glomerulonephritis. The receptor for advanced glycation end-products (RAGE is a multi-ligand cell surface receptor of the immunoglobulin superfamily and it has been associated with kidney disease in both non-diabetic and diabetic patients. Presently, data on the association between RAGE polymorphisms and CKD in the Malaysian population is limited, while numerous studies have reported associations of RAGE polymorphisms with diabetic complications in other populations. The present study aims to explore the possibility of using RAGE polymorphisms as candidate markers of CKD in Malaysian population by using association analysis. Methods: A total of 102 non-diabetic CKD patients, 204 diabetic CKD patients and 345 healthy controls were enrolled in the study. DNA isolated from blood samples were subjected to genotyping of RAGE G82S, −374T/A, −429T/C, 1704G/T and 2184A/G polymorphisms using real-time polymerase chain reaction (PCR. The 63-bp deletion, a polymorphism in the RAGE gene promoter, was genotyped using conventional PCR method and visualized using agarose gel electrophoresis. The collective frequencies of genotypes with at least one copy of the minor alleles of the four polymorphisms were compared between the non-diabetic CKD patients, diabetic CKD patients and healthy controls. Results: After adjustment of age, gender and ethnic groups in binary logistic regression analysis, the G82S CT + TT genotypes were associated with non-diabetic CKD patients when compared with diabetic CKD patients (p = 0.015, OR = 1.896, 95% CI = 1.132–3.176. After further adjustment of CKD comorbidities, the G82S CT + TT genotypes were still associated with non-diabetic CKD

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Voltammetric Detection of S100B Protein Using His-Tagged Receptor Domains for Advanced Glycation End Products (RAGE Immobilized onto a Gold Electrode Surface

    Directory of Open Access Journals (Sweden)

    Edyta Mikuła

    2014-06-01

    Full Text Available In this work we report on an electrochemical biosensor for the determination of the S100B protein. The His-tagged VC1 domains of Receptors for Advanced Glycation End (RAGE products used as analytically active molecules were covalently immobilized on a monolayer of a thiol derivative of pentetic acid (DPTA complex with Cu(II deposited on a gold electrode surface. The recognition processes between the RAGE VC1 domain and the S100B protein results in changes in the redox activity of the DPTA-Cu(II centres which were measured by Osteryoung square-wave voltammetry (OSWV. In order to verify whether the observed analytical signal originates from the recognition process between the His6–RAGE VC1 domains and the S100B protein, the electrode modified with the His6–RAGE C2 and His6–RAGE VC1 deleted domains which have no ability to bind S100B peptides were applied. The proposed biosensor was quite sensitive, with a detection limit of 0.52 pM recorded in the buffer solution. The presence of diluted human plasma and 10 nM Aβ1-40 have no influence on the biosensor performance.

  15. EARLY AFFECT-CONFUSION: THE BORDERLINE BETWEEN DESPAIR AND RAGE - PART 1 OF A CASE STUDY TRILOGY

    Directory of Open Access Journals (Sweden)

    Richard G. Erskine

    2012-12-01

    Full Text Available This three part case study illustrates the principles, theoretical concepts, and relational methods of Integrative Psychotherapy in the treatment of a client who continually experienced early affect-confusion and lived on a “borderline” between intense neediness and rage, despair and self-reliance, impulsivity and manipulation. Part 1 describes the behavioral dynamics of a 38 year old female client who required a two-part treatment approach that emphasized an inter-subjective relationship, consistency, and respect while helping her to acknowledge and value her relational-needs and to engage in a relationally contactful form of anger.

  16. Vitamin A (retinol) up-regulates the receptor for advanced glycation endproducts (RAGE) through p38 and Akt oxidant-dependent activation.

    Science.gov (United States)

    Gelain, Daniel Pens; de Bittencourt Pasquali, Matheus Augusto; Caregnato, Fernanda Freitas; Moreira, José Claudio Fonseca

    2011-10-28

    Retinol (vitamin A) is believed to exert preventive/protective effects against malignant, neurodegenerative and cardiovascular diseases by acting as an antioxidant. However, later clinical and experimental data show a pro-oxidant action of retinol and other retinoids at specific conditions. The receptor for advanced glycation endproducts (RAGE) is a pattern recognition receptor, being activated by different ligands such as S100 proteins, HMGB1 (amphoterin), β-amyloid peptide and advanced glycation endproducts (AGE). RAGE activation influences a wide range of pathological conditions such as diabetes, pro-inflammatory states and neurodegenerative processes. Here, we investigated the involvement of different mitogen-activated protein kinases (MAPK: ERK1/2, p38 and JNK), PKC, PKA and Akt in the up-regulation of RAGE by retinol. As previously reported, we observed that the increase in RAGE immunocontent by retinol is reversed by antioxidant co-treatment, indicating the involvement of oxidative stress in this process. Furthermore, the p38 inhibitor SB203580 and the Akt inhibitor LY294002 also decreased the effect of retinol on RAGE levels, suggesting the involvement of these protein kinases in such effect. Both p38 and Akt phosphorylation were increased by treatment with pro-oxidant concentrations of retinol, and the antioxidant co-treatment blocked this effect, indicating that activation of p38 and Akt during retinol treatment is dependent on reactive species production. The 2',7'-dichlorohydrofluorescein diacetate (DCFH) assay also indicated that retinol treatment enhances cellular reactive species production. Altogether, these data indicate that RAGE up-regulation by retinol is mediated by the free radical-dependent activation of p38 and Akt.

  17. 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

  18. Blocking the interaction between S100A9 and RAGE V domain using CHAPS molecule: A novel route to drug development against cell proliferation.

    Science.gov (United States)

    Chang, Chin-Chi; Khan, Imran; Tsai, Kun-Lin; Li, Hongchun; Yang, Lee-Wei; Chou, Ruey-Hwang; Yu, Chin

    2016-11-01

    Human S100A9 (Calgranulin B) is a Ca(2+)-binding protein, from the S100 family, that often presents as a homodimer in myeloid cells. It becomes an important mediator during inflammation once calcium binds to its EF-hand motifs. Human RAGE protein (receptor for advanced glycation end products) is one of the target-proteins. RAGE binds to a hydrophobic surface on S100A9. Interactions between these proteins trigger signal transduction cascades, promoting cell growth, proliferation, and tumorigenesis. Here, we present the solution structure of mutant S100A9 (C3S) homodimer, determined by multi-dimensional NMR experiments. We further characterize the solution interactions between mS100A9 and the RAGE V domain via NMR spectroscopy. CHAPS is a zwitterionic and non-denaturing molecule widely used for protein solubilizing and stabilization. We found out that CHAPS and RAGE V domain would interact with mS100A9 by using (1)H-(15)N HSQC NMR titrations. Therefore, using the HADDOCK program, we superimpose two binary complex models mS100A9-RAGE V domain and mS100A9-CHAPS and demonstrate that CHAPS molecules could play a crucial role in blocking the interaction between mS100A9 and the RAGE V domain. WST-1 assay results also support the conclusion that CHAPS inhibits the bioactivity of mS100A9. This report will help to inform new drug development against cell proliferation.

  19. Metformin inhibits advanced glycation end products (AGEs)-induced renal tubular cell injury by suppressing reactive oxygen species generation via reducing receptor for AGEs (RAGE) expression.

    Science.gov (United States)

    Ishibashi, Y; Matsui, T; Takeuchi, M; Yamagishi, S

    2012-11-01

    Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in tubulointerstitial damage in diabetic nephropathy. Recently, metformin has been shown to ameliorate tubular injury both in cell culture and diabetic animal model. However, effects of metformin on AGEs-induced tubular cell apoptosis and damage remain unknown. We examined here whether and how metformin could block the AGEs-RAGE-elicited tubular cell injury in vitro. Gene expression level was evaluated by real-time reverse-transcription polymerase chain reactions. Reactive oxygen species (ROS) generation was measured with dihydroethidium staining. Apoptosis was evaluated by DNA fragmentation and annexin V expression level. AGEs upregulated RAGE mRNA levels and subsequently increased ROS generation and intercellular adhesion molecule-1, monocyte chemoattractant protein-1 and transforming growth factor-β gene expression in human renal proximal tubular cells, all of which were significantly blocked by the treatment of 0.01 and 0.1 mM metformin. Compound C, an inhibitor of AMP-activated protein kinase significantly blocked the effects of metformin on RAGE gene expression and ROS generation in AGEs-exposed tubular cells. Furthermore, metformin dose-dependently inhibited the AGEs-induced apoptotic cell death of tubular cells; 1 mM metformin completely suppressed the pro-apoptotic effects of AGEs in 2 different assay systems. Our present study suggests that metformin could inhibit the AGEs-induced apoptosis and inflammatory and fibrotic reactions in tubular cells probably by reducing ROS generation via suppression of RAGE expression through AMP-activated protein kinase activation. Metformin may protect against tubular cell injury in diabetic nephropathy by blocking the AGEs-RAGE-ROS axis.

  20. Pravastatin inhibits advanced glycation end products (AGEs)-induced proximal tubular cell apoptosis and injury by reducing receptor for AGEs (RAGE) level.

    Science.gov (United States)

    Ishibashi, Yuji; Yamagishi, Sho-ichi; Matsui, Takanori; Ohta, Keisuke; Tanoue, Ryuichiro; Takeuchi, Masayoshi; Ueda, Seiji; Nakamura, Kei-ichiro; Okuda, Seiya

    2012-08-01

    Advanced glycation end products (AGEs) and their receptor (RAGE) axis play a role in diabetic nephropathy. Statins have been shown to ameliorate renal function and reduce proteinuria in patients with chronic kidney disease. However, the effects of statin on AGEs-induced tubular cell damage remain unknown. We examined here whether and how pravastatin could block the AGEs-RAGE-elicited tubular cell injury in vitro. Gene expression level was evaluated by real-time reverse-transcription polymerase chain reactions. Reactive oxygen species (ROS) generation was measured with dihydroethidium staining. Apoptosis was analyzed in an enzyme-linked immunosorbent assay. Asymmetric dimethylarginine (ADMA) expression was evaluated by immunostaining. Pravastatin dose-dependently inhibited the AGEs-induced up-regulation of RAGE mRNA level, ROS generation and apoptosis in human renal proximal tubular cells. Further, AGEs decreased mRNA level of dimethylarginine dimethylaminohydrolase-2, an enzyme that mainly degrades asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase and subsequently increased ADMA generation in tubular cells, both of which were also prevented by pravastatin. Geranylgeranyl pyrophosphate (GGPP) treatment blocked all of the effects of pravastatin on tubular cells. We found that rosuvastatin also significantly blocked the AGEs-induced increase in RAGE mRNA level and ROS generation, both of which were prevented by GGPP. Our present study suggests that pravastatin could inhibit the AGEs-induced apoptosis and ADMA generation in tubular cells by suppressing RAGE expression probably via inhibition of GGPP synthesis. Pravastatin may exert beneficial effects on tubular damage in diabetic nephropathy by blocking the AGEs-RAGE axis.

  1. 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...... dysfunction, low-grade inflammation, arterial stiffness, and advanced glycation end products (AGEs)....

  2. Abnormal Expressions of Age, RAGE, TGF- b1 and TGF- b1 Receptor in Colonic Wall Contributed to STZ-Induced Diabetic Colon Remodeling

    DEFF Research Database (Denmark)

    Zhao, Jingbo; Gregersen, Hans

    2016-01-01

    Background and aim: Diabetic colon dysfunction is common in longstanding diabetes. Previously the histomorphological and biomechanical remodeling of colon has been demonstrated in the diabetic rat model (1). However, the molecular mechanisms are not well understood. It was reported that advanced...... in different layers were up-regulated in the DM group (Figure 1). Glucose level and wall area mainly correlated with AGE and RAGE expressions. Outer residual strain correlated with all proteins expressions in the mucosa layer and with RAGE expressions in the muscle and submucosa layers. Opening angle...

  3. Novel sulfated polysaccharides disrupt cathelicidins, inhibit RAGE and reduce cutaneous inflammation in a mouse model of rosacea.

    Directory of Open Access Journals (Sweden)

    Jianxing Zhang

    Full Text Available BACKGROUND: Rosacea is a common disfiguring skin disease of primarily Caucasians characterized by central erythema of the face, with telangiectatic blood vessels, papules and pustules, and can produce skin thickening, especially on the nose of men, creating rhinophyma. Rosacea can also produce dry, itchy eyes with irritation of the lids, keratitis and corneal scarring. The cause of rosacea has been proposed as over-production of the cationic cathelicidin peptide LL-37. METHODOLOGY/PRINCIPAL FINDINGS: We tested a new class of non-anticoagulant sulfated anionic polysaccharides, semi-synthetic glycosaminoglycan ethers (SAGEs on key elements of the pathogenic pathway leading to rosacea. SAGEs were anti-inflammatory at ng/ml, including inhibition of polymorphonuclear leukocyte (PMN proteases, P-selectin, and interaction of the receptor for advanced glycation end-products (RAGE with four representative ligands. SAGEs bound LL-37 and inhibited interleukin-8 production induced by LL-37 in cultured human keratinocytes. When mixed with LL-37 before injection, SAGEs prevented the erythema and PMN infiltration produced by direct intradermal injection of LL-37 into mouse skin. Topical application of a 1% (w/w SAGE emollient to overlying injected skin also reduced erythema and PMN infiltration from intradermal LL-37. CONCLUSIONS: Anionic polysaccharides, exemplified by SAGEs, offer potential as novel mechanism-based therapies for rosacea and by extension other LL-37-mediated and RAGE-ligand driven skin diseases.

  4. 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

    Directory of Open Access Journals (Sweden)

    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.

  5. Rages or Temper Tantrums? The Behavioral Organization, Temporal Characteristics, and Clinical Significance of Angry-Agitated Outbursts in Child Psychiatry Inpatients

    Science.gov (United States)

    Potegal, Michael; Carlson, Gabrielle; Margulies, David; Gutkovitch, Zinoviy; Wall, Melanie

    2009-01-01

    Angry, agitated outbursts (AAOs) are a common precipitant of children's psychiatric hospitalization. In the hospital, AAOs present both management and diagnostic challenges, e.g., while they have recently been described as manic "rages", older studies suggest that they may be exacerbated temper tantrums. Factor analyses of 109 AAOs had by 46…

  6. Morphological adaptation of muscle collagen and receptor of advanced glycation end product (RAGE) in osteoarthritis patients with 12 weeks of resistance training

    DEFF Research Database (Denmark)

    Mattiello-Sverzut, Ana Claudia; Petersen, Susanne G; Kjaer, Michael

    2013-01-01

    The aim of this study was to investigate the effect of 12-week resistance training on morphological presence of collagen and RAGE (receptor for advanced glycation end products) in skeletal muscle of patients with knee osteoarthritis (OA). Little is known about the influence of exercise on the ske......The aim of this study was to investigate the effect of 12-week resistance training on morphological presence of collagen and RAGE (receptor for advanced glycation end products) in skeletal muscle of patients with knee osteoarthritis (OA). Little is known about the influence of exercise....... The patients (age 55-69 years) were divided into three groups, treated with NSAID, glucosamine or placebo. In addition, the muscle samples were analysed by immunohistochemistry for collagen types, RAGE and capillaries ratio. An increment in immunoreactivity for type IV collagen after the training period...... was observed in 72 % of all biopsies when compared with their respective baseline samples. Reduced immunoreactivity of collagen type I was observed in all patients treated with glucosamine. A significant increase with training in the amount of RAGE was detected in the placebo group only (p ...

  7. 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

    Science.gov (United States)

    Belstrøm, D.; Østergaard, J.A.; Paster, B.J.; Schou, S.; Flyvbjerg, A.; Holmstrup, P.

    2017-01-01

    Abstract 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 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 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‐associated bacterial profiles were analyzed using Human Oral Microbe Identification Microarray (HOMIM). Ligature‐associated bacterial profiles differed between lean and obese rats. Furthermore, treatment with antibodies against TNF‐α or RAGE had an impact on subgingival bacterial profiles. T2D phenotypes are associated with different ligature‐associated bacterial profiles and influenced by treatment with antibodies against TNF‐α or RAGE.

  8. Protective effect of mangiferin on myocardial ischemia-reperfusion injury in streptozotocin-induced diabetic rats: role of AGE-RAGE/MAPK pathways.

    Science.gov (United States)

    Suchal, Kapil; Malik, Salma; Khan, Sana Irfan; Malhotra, Rajiv Kumar; Goyal, Sameer N; Bhatia, Jagriti; Kumari, Santosh; Ojha, Shreesh; Arya, Dharamvir Singh

    2017-02-09

    Hyperglycemia induced advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) activation is thought to involve in the development of cardiovascular disease in diabetics. Activation of AGE-RAGE axis results in the oxidative stress and inflammation. Mangiferin is found in the bark of mango tree and is known to treat diseases owing to its various biological activities. Thus, this study was designed to evaluate the effect of mangiferin in ischemia-reperfusion (IR) induced myocardial injury in diabetic rats. A single injection of STZ (70 mg/kg; i.p.) was injected to male albino Wistar rats to induce diabetes. After confirmation of diabetes, rats were administered vehicle (2 ml/kg; i.p.) and mangiferin (40 mg/kg; i.p.) for 28 days. On 28(th) day, left anterior descending coronary artery was ligated for 45 min and then reperfused for 60 min. Mangiferin treatment significantly improved cardiac function, restored antioxidant status, reduced inflammation, apoptosis and maintained myocardial architecture. Furthermore, mangiferin significantly inhibited the activation of AGE-RAGE axis, c-Jun N-terminal kinase (JNK) and p38 and increased the expression of extracellular regulated kinase 1/2 (ERK1/2) in the myocardium. Thus, mangiferin attenuated IR injury in diabetic rats by modulation of AGE-RAGE/MAPK pathways which further prevented oxidative stress, inflammation and apoptosis in the myocardium.

  9. Lycopene powers the inhibition of glycation-induced diabetic nephropathy: a novel approach to halt the AGE-RAGE axis menace.

    Science.gov (United States)

    Tabrez, Shams; Al-Shali, Khalid Zaki; Ahmad, Saheem

    2015-01-01

    There are accumulating evidences suggesting that interaction between advanced glycation end products (AGEs) and their receptors (RAGEs) induces oxidative stress and subsequently encourages inflammatory reactions, thereby resulting in progressive alteration in renal architecture and function. Interventions that reduce the tissue burden of AGEs have yielded significant positive results in inhibiting the progression of diabetic complications such as diabetic nephropathy. Lycopene, a carotenoid, plays an important role in protection against oxidative stress and hence might prove an efficient antiglycating agent. Current study investigates the effect of lycopene in downregulating the menace caused by ribose-induced glycation both in vitro and in vivo. We observed that treatment with lycopene decelerated the ribose induced AGE formation in HK-2 cells and in rat kidneys thereby downregulating the expression RAGE. HK-2 cells with decreased levels of RAGE showed a decline in nuclear factor κB (NFκB) and matrix metalloproteinase 2 (MMP 2) expressions. Administration of ribose not only induced hyperglycemia in Wistar rats but also developed diabetic nephropathy (DN). However, lycopene was found effective in relieving the biochemical symptoms of DN. Thus lycopene provides protection against development of diabetic nephropathy and ameliorates renal function by halting AGE-RAGE axis.

  10. DNA aptamer raised against advanced glycation end products (AGEs) improves glycemic control and decreases adipocyte size in fructose-fed rats by suppressing AGE-RAGE axis.

    Science.gov (United States)

    Ojima, A; Matsui, T; Nakamura, N; Higashimoto, Y; Ueda, S; Fukami, K; Okuda, S; Yamagishi, S

    2015-04-01

    Advanced glycation end products (AGEs) decrease adiponectin expression and suppress insulin signaling in cultured adipocytes through the interaction with a receptor for AGEs (RAGE) via oxidative stress generation. We have recently found that high-affinity DNA aptamer directed against AGE (AGE-aptamer) prevents the progression of experimental diabetic nephropathy by blocking the harmful actions of AGEs in the kidney. This study examined the effects of AGE-aptamer on adipocyte remodeling, AGE-RAGE-oxidative stress axis, and adiponectin expression in fructose-fed rats. Although AGE-aptamer treatment by an osmotic mini pump for 8 weeks did not affect serum insulin levels, it significantly decreased average fasting blood glucose and had a tendency to inhibit body weight gain in fructose-fed rats. Furthermore, AGE-aptamer significantly suppressed the increase in adipocyte size and prevented the elevation in AGEs, RAGE, and an oxidative stress marker, 8-hydroxydeoxyguanosine (8-OHdG), levels in adipose tissues of fructose-fed rats at 14-week-old, while it restored the decrease in adiponectin mRNA levels. Our present study suggests that AGE-aptamer could improve glycemic control and prevent adipocyte remodeling in fructose-fed rats partly by suppressing the AGE-RAGE-mediated oxidative stress generation. AGE-aptamer might be a novel therapeutic strategy for fructose-induced metabolic derangements.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. A capture method based on the VC1 domain reveals new binding properties of the human receptor for advanced glycation end products (RAGE

    Directory of Open Access Journals (Sweden)

    Genny Degani

    2017-04-01

    Full Text Available The Advanced Glycation and Lipoxidation End products (AGEs and ALEs are a heterogeneous class of compounds derived from the non-enzymatic glycation or protein adduction by lipoxidation break-down products. The receptor for AGEs (RAGE is involved in the progression of chronic diseases based on persistent inflammatory state and oxidative stress. RAGE is a pattern recognition receptor (PRR and the inhibition of the interaction with its ligands or of the ligand accumulation have a potential therapeutic effect. The N-terminal domain of RAGE, the V domain, is the major site of AGEs binding and is stabilized by the adjacent C1 domain. In this study, we set up an affinity assay relying on the extremely specific biological interaction AGEs ligands have for the VC1 domain. A glycosylated form of VC1, produced in the yeast Pichia pastoris, was attached to magnetic beads and used as insoluble affinity matrix (VC1-resin. The VC1 interaction assay was employed to isolate specific VC1 binding partners from in vitro generated AGE-albumins and modifications were identified/localized by mass spectrometry analysis. Interestingly, this method also led to the isolation of ALEs produced by malondialdehyde treatment of albumins. Computational studies provided a rational-based interpretation of the contacts established by specific modified residues and amino acids of the V domain. The validation of VC1-resin in capturing AGE-albumins from complex biological mixtures such as plasma and milk, may lead to the identification of new RAGE ligands potentially involved in pro-inflammatory and pro-fibrotic responses, independently of their structures or physical properties, and without the use of any covalent derivatization process. In addition, the method can be applied to the identification of antagonists of RAGE-ligand interaction.

  13. Verification Test of the SURF and SURFplus Models in xRage: Part III Affect of Mesh Alignment

    Energy Technology Data Exchange (ETDEWEB)

    Menikoff, Ralph [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-08-15

    The previous studies used an underdriven detonation wave in 1-dimension (steady ZND reaction zone profile followed by a scale-invariant rarefaction wave) for PBX 9502 as a verification test of the implementation of the SURF and SURFplus models in the xRage code. Since the SURF rate is a function of the lead shock pressure, the question arises as to the effect on accuracy of variations in the detected shock pressure due to the alignment of the shock front with the mesh. To study the effect of mesh alignment we simulate a cylindrically diverging detonation wave using a planar 2-D mesh. The leading issue is the magnitude of azimuthal asymmetries in the numerical solution. The 2-D test case does not have an exact analytic solution. To quantify the accuracy, the 2-D solution along rays through the origin are compared to a highly resolved 1-D simulation in cylindrical geometry.

  14. A Correlational Study of How Airline Customer Service and Consumer Perception of Airline Customer Service Affect the Air Rage Phenomenon

    Science.gov (United States)

    Hunter, Joyce A.

    2007-01-01

    Between 1995 and 2000, customer service declined throughout the airline industry, as reported in February 2001 by the U.S. Department of Transportation (2001). One of the biggest problems today within the airline industry is the constant complaining from customers regarding the deterioraton of service (McCollough, Berry, & Yadav, 2000). Since 1995, unfortunately no airline has been immune from service deterioration, as reported by the Airline Quality Rating, an annual report by two airline industry experts who analyzed Department of Transportation statistics (Harrison & Kleinsasser, 1999). The airline' refusal to recognize the issue of customer service has perpetuated an environment that has become dangerous and detrimental to the traveling public as well as to airline employees, which in turn has fueled a new phenomenon, now referred to as "air rage".

  15. 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

    OpenAIRE

    2009-01-01

    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...

  16. Repérage d’Images Ordinaires : Analyse des Requêtes des Chercheurs d’Images

    Directory of Open Access Journals (Sweden)

    Elaine Ménard

    2009-06-01

    also emphasizes the pressing necessity to optimize the methods used for image processing, in order to facilitate image retrieval and dissemination in multilingual environments. Résumé Depuis quelques années, le web est devenu un média incontournable pour la diffusion de ressources multilingues. Cependant, les différences linguistiques constituent souvent un obstacle majeur aux échanges de documents scientifiques, culturels, pédagogiques et commerciaux. En plus de cette diversité linguistique, on constate le développement croissant de bases de données et de collections composées de différents types de documents textuels ou multimédias, ce qui complexifie également le processus de repérage documentaire. Par exemple, les collections d’images numériques sont aussi nombreuses que diversifiées. Le besoin de repérer une image spécifique dans diverses collections est devenu une préoccupation partagée par plusieurs communautés. La croissance du web a mis en relief le besoin pressant de se doter d’outils propres à la description des images dans le but de faciliter leur repérage, puisque l’on retrouve celles-ci dans la plupart des ressources disponibles. Cette recherche compare le repérage d’images dans deux contextes linguistiques différents : un contexte monolingue, c’est-à-dire que la langue de la requête (français est la même que la langue d’indexation (français; et un contexte multilingue où la langue de la requête (français est différente de la langue d’indexation (anglais. Cet article présente les résultats de l’analyse des requêtes formulées par les participants pour repérer un ensemble d’images ordinaires représentant des objets de la vie quotidienne, en contexte de repérage multilingue. L’examen des termes contenus dans les requêtes des chercheurs d’images révèle les tendances observées sur le plan terminologique, perceptuel et structurel. Les participants emploient généralement des requêtes simples

  17. The “2T” ion-electron semi-analytic shock solution for code-comparison with xRAGE: A report for FY16

    Energy Technology Data Exchange (ETDEWEB)

    Ferguson, Jim Michael [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-10-05

    This report documents an effort to generate the semi-analytic "2T" ion-electron shock solution developed in the paper by Masser, Wohlbier, and Lowrie, and the initial attempts to understand how to use this solution as a code-verification tool for one of LANL's ASC codes, xRAGE. Most of the work so far has gone into generating the semi-analytic solution. Considerable effort will go into understanding how to write the xRAGE input deck that both matches the boundary conditions imposed by the solution, and also what physics models must be implemented within the semi-analytic solution itself to match the model assumptions inherit within xRAGE. Therefore, most of this report focuses on deriving the equations for the semi-analytic 1D-planar time-independent "2T" ion-electron shock solution, and is written in a style that is intended to provide clear guidance for anyone writing their own solver.

  18. 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.

  19. The “2T” ion-electron semi-analytic shock solution for code-comparison with xRAGE: A report for FY16

    Energy Technology Data Exchange (ETDEWEB)

    Ferguson, Jim Michael [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-10-05

    This report documents an effort to generate the semi-analytic "2T" ion-electron shock solution developed in the paper by Masser, Wohlbier, and Lowrie [1], and the initial attempts to understand how to use this solution as a code-verification tool for one of LANL's ASC codes, xRAGE. Most of the work so far has gone into generating the semi-analytic solution. Considerable effort will go into understanding how to write the xRAGE input deck that both matches the boundary conditions imposed by the solution, and also what physics models must be implemented within the semi-analytic solution itself to match the model assumptions inherit within xRAGE. Therefore, most of this report focuses on deriving the equations for the semi-analytic 1D-planar time-independent "2T" ion-electron shock solution, and is written in a style that is intended to provide clear guidance for anyone writing their own solver.

  20. Glycolaldehyde-derived advanced glycation end products (glycol-AGEs)-induced vascular smooth muscle cell dysfunction is regulated by the AGES-receptor (RAGE) axis in endothelium.

    Science.gov (United States)

    Nam, Mi-Hyun; Son, Won-Rak; Lee, Young Sik; Lee, Kwang-Won

    Advanced glycation end-products (AGEs) are involved in the development of vascular smooth muscle cell (VSMC) dysfunction and the progression of atherosclerosis. However, AGEs may indirectly affect VSMCs via AGEs-induced signal transduction between monocytes and human umbilical endothelial cells (HUVECs), rather than having a direct influence. This study was designed to elucidate the signaling pathway underlying AGEs-RAGE axis influence on VSMC dysfunction using a co-culture system with monocytes, HUVECs and VSMCs. AGEs stimulated production of reactive oxygen species and pro-inflammatory mediators such as tumor necrosis factor-α and interleukin-1β via extracellular-signal-regulated kinases phosphorylation and nuclear factor-κB activation in HUVECs. It was observed that AGEs-induced pro-inflammatory cytokines increase VSMC proliferation, inflammation and vascular remodeling in the co-culture system. This result implies that RAGE plays a role in AGEs-induced VSMC dysfunction. We suggest that the regulation of signal transduction via the AGEs-RAGE axis in the endothelium can be a therapeutic target for preventing atherosclerosis.

  1. De la rage à l'enthousiasme : le parcours d'un jeune électeur saoudien

    Directory of Open Access Journals (Sweden)

    Pascal Ménoret

    2004-12-01

    Full Text Available Comment apprend-on le métier d'électeur dans une société autoritairement dépolitisée ? Cet entretien approfondi, réalisé avec un jeune électeur saoudien au lendemain de la victoire du courant religieux modéré aux élections municipale de février 2005 à Riyad, permet d'avancer quelques éléments de réponse. On verra ainsi que des dispositions politiques susceptibles d'être réinvesties dans l'activisme électoral ont pu être puisées par les plus fervents partisans du processus électoral dans les schèmes de pensée et d'acion propres aux groupes islamiques des écoles, aux cercles coraniques des mosquées et aux centres d'été du ministère des Affaires islamiques. L'activisme islamique n'est pas foncièrement incompatible avec un processus de démocratisation ; encore faut-il que la « rage » contractée au spectacle de la dictature et des injustices occidentales puisse se transformer en « enthousiasme » politique et électoral.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Comstock, Sarah S; Lewis, Markita M; Pathak, Dorothy R; Hortos, Kari; Kovan, Bruce; Fenton, Jenifer I

    2014-01-01

    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 diverticulosis. The relationship was similar for waist circumference. Individuals with a waist circumference >45 inches were 8.1 (CI: 2.8-23.8) times more likely to have diverticulosis than those with a waist circumference 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.

  5. 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

    Directory of Open Access Journals (Sweden)

    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.

  6. 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.

    Science.gov (United States)

    Liu, Fahui; Teodorowicz, Małgorzata; Wichers, Harry J; van Boekel, Martinus A J S; Hettinga, Kasper A

    2016-08-24

    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 receptor (sRAGE). Samples consisting of mixtures of whey protein and lactose were heated at 130 °C. An in vitro infant digestion model was used to study the influence of heat treatment on the digestibility of whey proteins. The amount of sRAGE-binding ligands before and after digestion was measured by an ELISA-based sRAGE-binding assay. Water activity did not significantly affect the extent of digestibility of whey proteins dry heated at pH 5 (ranging from 3.3 ± 0.2 to 3.6 ± 0.1% for gastric digestion and from 53.5 ± 1.5 to 64.7 ± 1.1% for duodenal digestion), but there were differences in cleavage patterns of peptides among the samples heated at different pH values. Formation of sRAGE-binding ligands depended on the formation of aggregates and was limited in the samples heated at pH 5. Moreover, the sRAGE-binding activity of digested sample was changed by protease degradation and correlated with the digestibility of samples. In conclusion, generation of sRAGE-binding ligands during extensive heat treatment of whey protein/lactose mixtures is limited in acidic heating condition and dependent on glycation and aggregation.

  7. Aβ(1-42) oligomer-induced leakage in an in vitro blood-brain barrier model is associated with up-regulation of RAGE and metalloproteinases, and down-regulation of tight junction scaffold proteins.

    Science.gov (United States)

    Wan, Wenbin; Cao, Lan; Liu, Lumei; Zhang, Chunyan; Kalionis, Bill; Tai, Xiantao; Li, Yaming; Xia, Shijin

    2015-07-01

    Accumulating evidence indicates that abnormal deposition of amyloid-β (Aβ) peptide in the brain is responsible for endothelial cell damage and consequently leads to blood-brain barrier (BBB) leakage. However, the mechanisms underlying BBB disruption are not well described. We employed an monolayer BBB model comprising bEnd.3 cell and found that BBB leakage was induced by treatment with Aβ(1-42), and the levels of tight junction (TJ) scaffold proteins (ZO-1, Claudin-5, and Occludin) were decreased. Through comparisons of the effects of the different components of Aβ(1-42), including monomer (Aβ(1-42)-Mono), oligomer (Aβ(1-42)-Oligo), and fibril (Aβ(1-42)-Fibril), our data confirmed that Aβ(1-42)-Oligo is likely to be the most important damage factor that results in TJ damage and BBB leakage in Alzheimer's disease. We found that the incubation of bEnd.3 cells with Aβ(1-42) significantly up-regulated the level of receptor for advanced glycation end-products (RAGE). Co-incubation of a polyclonal antibody to RAGE and Aβ(1-42)-Oligo in bEnd.3 cells blocked RAGE suppression of Aβ(1-42)-Oligo-induced alterations in TJ scaffold proteins and reversed Aβ(1-42)-Oligo-induced up-regulation of RAGE, matrix metalloproteinase (MMP)-2, and MMP-9. Furthermore, we found that these effects induced by Aβ(1-42)-Oligo treatment were effectively suppressed by knockdown of RAGE using small interfering RNA (siRNA) transfection. We also found that GM 6001, a broad-spectrum MMP inhibitor, partially reversed the Aβ(1-42)-Oligo-induced inhibitor effects in bEnd.3 cells. Thus, these results suggested that RAGE played an important role in Aβ-induced BBB leakage and alterations of TJ scaffold proteins, through a mechanism that involved up-regulation of MMP-2 and MMP-9.

  8. Hypoxia-increased RAGE and P2X7R expression regulates tumor cell invasion through phosphorylation of Erk1/2 and Akt and nuclear translocation of NF-{kappa}B.

    Science.gov (United States)

    Tafani, Marco; Schito, Luana; Pellegrini, Laura; Villanova, Lidia; Marfe, Gabriella; Anwar, Tahira; Rosa, Roberta; Indelicato, Manuela; Fini, Massimo; Pucci, Bruna; Russo, Matteo A

    2011-08-01

    The role of hypoxia in regulating tumor progression is still controversial. Here, we demonstrate that, similarly to what previously observed by us in human prostate and breast tumor samples, hypoxia increases expression of the receptor for advanced glycation end products (RAGE) and the purinergic receptor P2X7 (P2X7R). The role of hypoxia was shown by the fact that hypoxia-inducible factor (HIF)-1α silencing downregulated RAGE and P2X7R protein levels as well as nuclear factor-kappaB (NF-κB) expression. In contrast, NF-κB silencing reduced P2X7R expression without affecting RAGE protein levels or nuclear accumulation of HIF-1α. Treatment of hypoxic tumor cells with HMGB1 and BzATP ligands, respectively, of RAGE and P2X7R, activated a signaling pathway that, through Akt and Erk phosphorylation, determines nuclear accumulation of NF-κB and increases cell invasion. Inhibition of Akt by SH5 and Erk by INH1 prevented both nuclear translocation of NF-κB and cell invasion. Moreover, silencing RAGE and P2X7R abolished nuclear accumulation of NF-κB as well as cell invasion without affecting HIF-1α stabilization. Once in the nucleus, NF-κB would contribute to cell survival and invasion under hypoxia, by maintaining RAGE and P2X7R expression levels and matrix metalloproteinases 2 and 9 synthesis. These results show that, hypoxia can upregulate expression levels of membrane receptors that, by binding extracellular molecules eventually released by necrotic cells, contribute to the increased invasiveness of transformed tumor cells. Moreover, these observations strengthen our working hypothesis that upregulation of damage-associated molecular patterns receptors by HIF-1α represents the crucial event bridging hypoxia and inflammation in obtaining the malignant phenotype.

  9. 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...... dysfunction, low-grade inflammation, arterial stiffness, and advanced glycation end products (AGEs)....

  10. Expressions of RAGE,S100A8 and S100P in benigne prostate hypertrophy and prostate cancer%RAGE、S100A8和S100P在良性前列腺增生和前列腺癌组织中的表达

    Institute of Scientific and Technical Information of China (English)

    陆兵; 黄玉华; 江俊; 李磊; 陈春涛; 曹道军; 严春寅

    2016-01-01

    Objective To investigate the expressions and clinical significance of the receptor for advanced glycation end‐products (RAGE ) and its ligands S100A8 and S100P in benigne prostate hypertrophy(BPH) and prostate cancer(PC) tissues .Methods Immunohistochemical method was employed to examine the expressions of RAGE and its ligands S100A8 and S100P in 32 PC patients . The expressions in BPH and PC were compared .Results The expressions of RAGE ,S100A8 and S100P in PC tissues were significantly higher than those in BPH(P<0 .05) .The expression of RAGE in PC tissues was related to prostate‐specific antigen(P<0 .05) .The expressions of RAGE ,S100A8 and S100P in PC tissues were closely related to TNM and clinical stages(P<0 .05 ) .The expression of RAGE was possitively correlated to that of S100A8 and S100P(P<0 .05) .Conclusion RAGE and its ligands S100A8 and S100P may participate in the development ,invasion and metastasis of PC and could become the targets for the diagnosis and treatment of PC .%目的:探讨晚期糖基化终末产物受体(RAGE)及其配体钙粒蛋白 A8(S100A8)和钙粒蛋白P(S100P)在良性前列腺增生(BPH)和前列腺癌组织中的表达及临床意义。方法应用免疫组化方法检测30例BPH组织和32例前列腺癌组织中RAGE及其配体S100A8和S100P的表达,并结合临床资料进行统计学分析。结果与BPH比较,前列腺癌组织RAGE及其配体S100A8和S100P的表达明显升高。RAGE的表达与前列腺癌患者术前前列腺特异性抗原(PSA )水平有关(P<0.05);RAGE及其配体 S100A8和 S100P 的表达与前列腺癌的临床和肿瘤分期密切相关(P<0.05);RAGE分别与S100A8和S100P结合,在前列腺癌组织中的表达呈正相关(P<0.05)。结论 RAGE及其配体S100A8和S100P可能参与了前列腺癌的发生、发展、浸润和转移,三者有可能成为前列腺癌诊断和治疗的新靶点。

  11. Neuroprotective effect of Amaranthus lividus and Amaranthus tricolor and their effects on gene expression of RAGE during oxidative stress in SH-SY5Y cells.

    Science.gov (United States)

    Amornrit, W; Santiyanont, R

    2016-04-26

    Amaranthus plants, or spinach, are used as food sources worldwide. Amaranthus leaves are rich in antioxidant compounds, which act as free radical scavengers. Oxidative stress caused by the aberrant production of reactive oxygen species (ROS) represents an important mechanism for neuronal dysfunction and cell loss in different neurodegenerative disorders. The neuroprotective effects of antioxidant-containing plants have been extensively demonstrated in different models of neurotoxicity. However, few studies have investigated the antioxidant properties of Amaranthus extracts and their effect on the nervous system. In the present study, the leaves of Amaranthus lividus and Amaranthus tricolor were extracted using petroleum ether, dichloromethane, and methanol. Results indicated that antioxidant activities were the highest in methanol extracts from both kinds of Amaranthus leaves. In addition, oxidative stress was induced in human neuroblastoma cell lines (SH-SY5Y) by using H2O2. Intracellular oxidative stress, cytotoxicity, and gene expression of RAGE were then determined. In vitro results demonstrated that pretreatment with A. lividus and A. tricolor extracts can significantly decrease cell toxicity and intracellular ROS production in SH-SY5Y cells. Interestingly, the extracts also significantly downregulated the expression of oxidative stress genes such as HMOX-1, RAGE, and RelA/ NF-κB. Our results suggested that Amaranthus leaves may be useful for reducing oxidative stress and may be beneficial for age-related diseases and neurodegenerative disorders.

  12. Human S100A7 Induces Mature Interleukin1α Expression by RAGE-p38 MAPK-Calpain1 Pathway in Psoriasis

    Science.gov (United States)

    Lei, Hu; Li, Xiangyun; Jing, Bo; Xu, Hanzhang; Wu, Yingli

    2017-01-01

    Psoriatic keratinocytes express exaggerated levels of inflammatory cytokines, and show aberrant hyperproliferation and terminal differentiation in the pathogenesis of psoriasis. The antimicrobial protein hS100A7 (psoriasin) has been found highly expressed in psoriatic skin, but the mechanism and physiological function remain largely unknown. We observed that hS100A7 induces mature interleukin 1α (17kDa) expression in normal human epidermal keratinocytes, which is dependent on RAGE-p38 MAPK and calpain-1 as the inhibitors or knockdown of them completely decreased the expression of mature interleukin1α. Then, we proved mS100a7a15, mature IL-1α and calpain-1 were highly expressed in imquimod-induced psoriasis model and mouse IL-17a-neutralizing antibody treatment attenuated mS100a7a15 expression. At last, PD 151746 (calpain-1 inhibitor) treatment decreased epidermal thickness in imquimod-induced psoriasis model. Taken together, our results suggest that mature IL-1α induced by hS100A7 is via RAGE-p38 MAPK and calpain-1 pathway in keratinocyte and this mechanism may play an important role during psoriasis. PMID:28060905

  13. Extracellularly secreted APE1/Ref-1 triggers apoptosis in triple-negative breast cancer cells via RAGE binding, which is mediated through acetylation.

    Science.gov (United States)

    Lee, Yu Ran; Kim, Ki Mo; Jeon, Byeong Hwa; Choi, Sunga

    2015-09-15

    The present study evaluated the mechanism of apoptosis caused by post-translational modification, hyperacetylation in triple-negative breast cancer (TNBC) cells. We previously showed that trichostatin A (TSA) induced secretion of acetylated apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1). This is the first report showing that Ac-APE1/Ref-1 initiates apoptosis in TNBC cells by binding to the receptor for advanced glycation end products (RAGE). The functional significance of secreted Ac-APE1/Ref-1 was studied by induction of intracellular hyperacetylation through co-treatment with acetylsalicylic acid and TSA in MDA-MB-231 cells. In response to hyperacetylation, secretion of Ac-APE1/Ref-1 in vesicles was observed, resulting in significantly decreased cell viability and induction of apoptosis with increased expression of RAGE. The hyperacetylation-induced apoptosis was similar in two other TNBC cell lines: BT-459 and MDA-MB-468. Therefore, hyperacetylation may be a therapeutic target for treatment of TNBCs. This study introduces a novel paradigm whereby post-translational modification induces apoptotic cell death in breast cancer cells resistant to standard chemotherapeutic agents through secretion of auto- or paracrine molecules such as Ac-APE1/Ref-1.

  14. Cardioprotective effect of pioglitazone in diabetic and non-diabetic rats subjected to acute myocardial infarction involves suppression of AGE-RAGE axis and inhibition of apoptosis.

    Science.gov (United States)

    Khodeer, Dina M; Zaitone, Sawsan A; Farag, Noha E; Moustafa, Yasser M

    2016-05-01

    Insulin resistance increases risk of cardiovascular diseases. This work investigated the protective effect of pioglitazone on myocardial infarction (MI) in non-diabetic and diabetic rats, focusing on its role on advanced glycated endproducts (AGEs) and cardiac apoptotic machinery. Male rats were divided into 2 experiments: experiment I and II (non-diabetic and diabetic rats) were assigned as saline, MI (isoproterenol, 85 mg/kg, daily), and MI+pioglitazone (5, 10, and 20 mg/kg). Injection of isoproterenol in diabetic rats produced greater ECG disturbances compared to non-diabetic rats. Treatment with pioglitazone (5 mg/kg) reduced the infarct size and improved some ECG findings. Pioglitazone (10 mg/kg) enhanced ECG findings, improved the histopathological picture and downregulated apoptosis in cardiac tissues. Whereas the higher dose of pioglitazone (20 mg/kg) did not improve most of the measured parameters but rather worsened some of them, such as proapoptotic markers. Importantly, a positive correlation was found between serum AGEs and cardiac AGE receptors (RAGEs) versus caspase 3 expression in the two experiments. Therefore, the current effect of pioglitazone was, at least in part, mediated through downregulation of AGE-RAGE axis and inhibition of apoptosis. Consequently, these data suggest that pioglitazone, at optimized doses, may have utility in protection from acute MI.

  15. Choline and Cystine Deficient Diets in Animal Models with Hepatocellular Injury: Evaluation of Oxidative Stress and Expression of RAGE, TNF-α, and IL-1β.

    Science.gov (United States)

    Santos, Juliana Célia F; de Araújo, Orlando R P; Valentim, Iara B; de Andrade, Kívia Queiroz; Moura, Fabiana Andréa; Smaniotto, Salete; dos Santos, John Marques; Gasparotto, Juciano; Gelain, Daniel P; Goulart, Marília O F

    2015-01-01

    This study aims to evaluate the effects of diets deficient in choline and/or cystine on hepatocellular injury in animal models (young male Wistar rats, aged 21 days), by monitoring some of the oxidative stress biomarkers and the expression of RAGE, TNF-α, and IL-1β. The animals were divided into 6 groups (n = 10) and submitted to different diets over 30 days: AIN-93 diet (standard, St), AIN-93 choline deficient (CD) diet and AIN-93 choline and cystine deficient (CCD) diet, in the pellet (pl) and powder (pw) diet forms. Independently of the diet form, AIN-93 diet already led to hepatic steatosis and CD/CCD diets provoked hepatic damage. The increase of lipid peroxidation, represented by the evaluation of thiobarbituric acid reactive species, associated with the decrease of levels of antioxidant enzymes, were the parameters with higher significance toward redox profile in this model of hepatic injury. Regarding inflammation, in relation to TNF-α, higher levels were evidenced in CD(pl), while, for IL-1β, no significant alteration was detected. RAGE expression was practically the same in all groups, with exception of CCD(pw) versus CCD(pl). These results together confirm that AIN-93 causes hepatic steatosis and choline and/or cysteine deficiencies produce important hepatic injury associated with oxidative stress and inflammatory profiles.

  16. Choline and Cystine Deficient Diets in Animal Models with Hepatocellular Injury: Evaluation of Oxidative Stress and Expression of RAGE, TNF-α, and IL-1β

    Directory of Open Access Journals (Sweden)

    Juliana Célia F. Santos

    2015-01-01

    Full Text Available This study aims to evaluate the effects of diets deficient in choline and/or cystine on hepatocellular injury in animal models (young male Wistar rats, aged 21 days, by monitoring some of the oxidative stress biomarkers and the expression of RAGE, TNF-α, and IL-1β. The animals were divided into 6 groups (n=10 and submitted to different diets over 30 days: AIN-93 diet (standard, St, AIN-93 choline deficient (CD diet and AIN-93 choline and cystine deficient (CCD diet, in the pellet (pl and powder (pw diet forms. Independently of the diet form, AIN-93 diet already led to hepatic steatosis and CD/CCD diets provoked hepatic damage. The increase of lipid peroxidation, represented by the evaluation of thiobarbituric acid reactive species, associated with the decrease of levels of antioxidant enzymes, were the parameters with higher significance toward redox profile in this model of hepatic injury. Regarding inflammation, in relation to TNF-α, higher levels were evidenced in CD(pl, while, for IL-1β, no significant alteration was detected. RAGE expression was practically the same in all groups, with exception of CCD(pw versus CCD(pl. These results together confirm that AIN-93 causes hepatic steatosis and choline and/or cysteine deficiencies produce important hepatic injury associated with oxidative stress and inflammatory profiles.

  17. Mild exposure of RIN-5F β-cells to human islet amyloid polypeptide aggregates upregulates antioxidant enzymes via NADPH oxidase-RAGE: An hormetic stimulus

    Directory of Open Access Journals (Sweden)

    Elisabetta Borchi

    2014-01-01

    Full Text Available The presence of amyloid aggregates of human islet amyloid polypeptide (hIAPP, a hallmark of type 2 diabetes, contributes to pancreatic β-cell impairment, where oxidative stress plays a key role. A contribution of NADPH oxidase to reactive oxygen species (ROS generation after cell exposure to micromolar concentrations of hIAPP aggregates has been suggested. However, little is known about β-cells exposure to lower amounts of hIAPP aggregates, similar to those found in human pancreas. Thus, we aimed to investigate the events resulting from RIN-5F cells exposure to nanomolar concentrations of toxic hIAPP aggregates. We found an early and transient rise of NADPH oxidase activity resulting from increased Nox1 expression following the engagement of receptor for advanced glycation end-products (RAGE by hIAPP aggregates. Unexpectedly, NADPH oxidase activation was not accompanied by a significant ROS increase and the lipoperoxidation level was significantly reduced. Indeed, cell exposure to hIAPP aggregates affected the antioxidant defences, inducing a significant increase of the expression and activity of catalase and glutathione peroxidase. We conclude that exposure of pancreatic β-cells to nanomolar concentrations of hIAPP aggregates for a short time induces an hormetic response via the RAGE-Nox1 axis; the latter stimulates the enzymatic antioxidant defences that preserve the cells against oxidative stress damage.

  18. Inhibition of AGEs/RAGE/Rho/ROCK pathway suppresses non-specific neuroinflammation by regulating BV2 microglial M1/M2 polarization through the NF-κB pathway.

    Science.gov (United States)

    Chen, Jingkao; Sun, Zhaowei; Jin, Minghua; Tu, Yalin; Wang, Shengnan; Yang, Xiaohong; Chen, Qiuhe; Zhang, Xiao; Han, Yifan; Pi, Rongbiao

    2017-04-15

    The microglia-mediated neuroinflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Advanced glycation end products (AGEs)/receptor for advanced glycation end products (RAGE) or Rho/Rho kinase (ROCK) are both involved in the development of non-specific inflammation. However, there are few reports about their effects on neuroinflammation. Here, we explored the mechanism of AGEs/RAGE/Rho/ROCK pathway underlying the non-specific inflammation and microglial polarization in BV2 cells. AGEs could activate ROCK pathway in a concentration-dependent manner. ROCK inhibitor fasudil and RAGE-specific blocker FPS-ZM1 significantly inhibited AGEs-mediated activation of BV2 cells and induction of reactive oxygen species (ROS). FPS-ZM1 and fasudil exerted their anti-inflammatory effects by downregulating inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), NLRP3 and nuclear translocation of nuclear factor kappa B (NF-κB) p65. In addition, AGEs induced both M1 (CD16/32, M1 marker) and M2 (CD206, M2 marker) phenotype in BV2 cells. Fasudil and FPS-ZM1 led to a decreased M1 and increased M2 phenotype. Together, these results indicate that the AGEs/RAGE/Rho/ROCK pathway in BV2 cells could intensify the non-specific inflammation of AD, which will provide novel strategies for the development of anti-AD drugs.

  19. Morphological adaptation of muscle collagen and receptor of advanced glycation end product (RAGE) in osteoarthritis patients with 12 weeks of resistance training: influence of anti-inflammatory or glucosamine treatment.

    Science.gov (United States)

    Mattiello-Sverzut, Ana Claudia; Petersen, Susanne G; Kjaer, Michael; Mackey, Abigail L

    2013-09-01

    The aim of this study was to investigate the effect of 12-week resistance training on morphological presence of collagen and RAGE (receptor for advanced glycation end products) in skeletal muscle of patients with knee osteoarthritis (OA). Little is known about the influence of exercise on the skeletal muscle matrix that supports joints affected by OA mainly when it is associated with medication taken by OA patients (non-steroid anti-inflammatory drugs (NSAID) and glucosamine). A biopsy was collected from the vastus lateralis muscle in all patients before and after 12-week period of training. The patients (age 55-69 years) were divided into three groups, treated with NSAID, glucosamine or placebo. In addition, the muscle samples were analysed by immunohistochemistry for collagen types, RAGE and capillaries ratio. An increment in immunoreactivity for type IV collagen after the training period was observed in 72 % of all biopsies when compared with their respective baseline samples. Reduced immunoreactivity of collagen type I was observed in all patients treated with glucosamine. A significant increase with training in the amount of RAGE was detected in the placebo group only (p muscle fibres after 12 weeks of resistance training. Glucosamine with training appeared to attenuate RAGE accumulation more than was seen with NSAID or placebo in skeletal muscle of OA patients.

  20. Curbing Relocation Rage

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    once dubbed "the most defiant house" in Beijing, a 283-square- meter house on Lincui Road outside the North Fifth Ring Road in Haidian District was finally demol- ished on December 18, 2010, nearly five years after demolition of the area’s houses began.

  1. Where is your rage?

    Science.gov (United States)

    Sawyer, E

    1998-12-01

    A new round of activism is needed to address both new and old problems related to HIV/AIDS, problems such as access to treatment, confidential reporting, testing, funding, drug pricing, and government aid. Despite the media message that a cure is on the horizon, a cure is actually a long way off, and not accessible to all. Questions are raised about the future direction of the Centers for Disease Control's (CDC) effort to require names reporting and about the lack of HIV educational material and needle exchange programs. Concern is expressed about welfare reform, the political leadership of New York City and New York State, and the plight of poor people suffering from AIDS. AIDS activism is a useful tool in lowering drug prices for the poor and in pilot programs in developing countries that provide free AIDS drugs through UNAIDS. Government funding, HIV prevention programs, and attention to human rights are needed to bring about changes. Activism can take many forms, and people with AIDS need to get involved to make a difference.

  2. N(ε)-Carboxymethyllysine (CML), a Maillard reaction product, stimulates serotonin release and activates the receptor for advanced glycation end products (RAGE) in SH-SY5Y cells.

    Science.gov (United States)

    Holik, Ann-Katrin; Rohm, Barbara; Somoza, Mark M; Somoza, Veronika

    2013-07-01

    Maillard reaction products, which are formed in highly thermally treated foods, are commonly consumed in a Western diet. In this study, we investigated the impact of N(ε)-carboxymethyllysine (CML), a well-characterized product of the Maillard reaction, on the gene regulation of the human neuroblastoma cell line SH-SY5Y. Pathway analysis of data generated from customized DNA microarrays revealed 3 h incubation with 50 μM and 500 μM CML to affect serotonin receptor expression. Further experiments employing qRT-PCR showed an up-regulation of serotonin receptors 2A, 1A and 1B after 0.25 h and 3 h. In addition, 500 μM CML increased serotonin release, thus showing effects of CML not only at a genetic, but also at a functional level. Intracellular calcium mobilization, which mediates serotonin release, was increased by CML at concentrations of 0.05-500 μM. Since calcium mobilization has been linked to the activation of the receptor for advanced glycation end products (RAGE), we further investigated the effects of CML on RAGE expression. RAGE was found to be up-regulated after incubation with 500 μM CML for 0.25 h. Co-incubation with the calcium blocker neomycin for 0.25 h blocked the up-regulation of RAGE and the serotonin receptors 2A, 1A and 1B. These results indicate a possible link between a CML-induced calcium-mediated serotonin release and RAGE.

  3. Crosstalk between advanced glycation end products (AGEs)-receptor RAGE axis and dipeptidyl peptidase-4-incretin system in diabetic vascular complications.

    Science.gov (United States)

    Yamagishi, Sho-ichi; Fukami, Kei; Matsui, Takanori

    2015-01-13

    Advanced glycation end products (AGEs) consist of heterogenous group of macroprotein derivatives, which are formed by non-enzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids, and whose process has progressed at an accelerated rate under diabetes. Non-enzymatic glycation and cross-linking of protein alter its structural integrity and function, contributing to the aging of macromolecules. Furthermore, engagement of receptor for AGEs (RAGE) with AGEs elicits oxidative stress generation and subsequently evokes proliferative, inflammatory, and fibrotic reactions in a variety of cells. Indeed, accumulating evidence has suggested the active involvement of accumulation of AGEs in diabetes-associated disorders such as diabetic microangiopathy, atherosclerotic cardiovascular diseases, Alzheimer's disease and osteoporosis. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins, gut hormones secreted from the intestine in response to food intake, both of which augment glucose-induced insulin release, suppress glucagon secretion, and slow gastric emptying. Since GLP-1 and GIP are rapidly degraded and inactivated by dipeptidyl peptidase-4 (DPP-4), inhibition of DPP-4 and/or DPP-4-resistant GLP-1 analogues have been proposed as a potential target for the treatment of diabetes. Recently, DPP-4 has been shown to cleave multiple peptides, and blockade of DPP-4 could exert diverse biological actions in GLP-1- or GIP-independent manner. This article summarizes the crosstalk between AGEs-RAGE axis and DPP-4-incretin system in the development and progression of diabetes-associated disorders and its therapeutic intervention, especially focusing on diabetic vascular complications.

  4. Aldose reductase (AKR1B3) regulates the accumulation of advanced glycosylation end products (AGEs) and the expression of AGE receptor (RAGE).

    Science.gov (United States)

    Baba, Shahid P; Hellmann, Jason; Srivastava, Sanjay; Bhatnagar, Aruni

    2011-05-30

    Diabetes results in enhanced chemical modification of proteins by advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs) precursors. These modifications have been linked to the development of several secondary diabetic complications. Our previous studies showed that aldose reductase (AR; AKR1B3) catalyzes the reduction of ALEs and AGEs precursors; however, the in vivo significance of this metabolic pathway during diabetes and obesity has not been fully assessed. Therefore we examined the role of AR in regulating ALEs and AGEs formation in murine models of diet-induced obesity and streptozotocin-induced diabetes. In comparison with wild-type (WT) and AR-null mice fed normal chow, mice fed a high-fat (HF) diet (42% kcal fat) showed increased accumulation of AGEs and protein-acrolein adducts in the plasma. AGEs and acrolein adducts were also increased in the epididymal fat of WT and AR-null mice fed a HF diet. Deletion of AR increased the accumulation of 4-hydroxy-trans-2-nonenal (HNE) protein adduct in the plasma and increased the expression of the AGE receptor (RAGE) in HF fed mice. No change in AGEs formation was observed in the kidneys of HF-fed mice. In comparison, renal tissue from AR-null mice treated with streptozotocin showed greater AGE accumulation than streptozotocin-treated WT mice. These data indicated that AR regulated the accumulation of lipid peroxidation derived aldehydes and AGEs under conditions of severe, but not mild, hyperglycemia and that deletion of AR increased RAGE-induction via mechanisms that were independent of AGEs accumulation.

  5. Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE-independent signaling pathways and regulating mitochondrion-mediated apoptosis

    Directory of Open Access Journals (Sweden)

    Liu Rui

    2012-09-01

    Full Text Available Abstract Background It is known that amyloid-β peptide (Aβ plays a pivotal role in the pathogenesis of Alzheimer's disease (AD. Interaction between Aβ and the receptor for advanced glycation end products (RAGE has been implicated in neuronal degeneration associated with this disease. Pinocembrin, a flavonoid abundant in propolis, has been reported to possess numerous biological activities beneficial to health. Our previous studies have demonstrated that pinocembrin has neuroprotective effects on ischemic and vascular dementia in animal models. It has been approved by the State Food and Drug Administration of China for clinical use in stroke patients. Against this background, we investigated the effects of pinocembrin on cognitive function and neuronal protection against Aβ-induced toxicity and explored its potential mechanism. Methods Mice received an intracerebroventricular fusion of Aβ25-35. Pinocembrin was administrated orally at 20 mg/kg/day and 40 mg/kg/day for 8 days. Behavioral performance, cerebral cortex neuropil ultrastructure, neuronal degeneration and RAGE expression were assessed. Further, a RAGE-overexpressing cell model and an AD cell model were used for investigating the mechanisms of pinocembrin. The mechanisms underlying the efficacy of pinocembrin were conducted on target action, mitochondrial function and potential signal transduction using fluorescence-based multiparametric technologies on a high-content analysis platform. Results Our results showed that oral administration of pinocembrin improved cognitive function, preserved the ultrastructural neuropil and decreased neurodegeneration of the cerebral cortex in Aβ25-35-treated mice. Pinocembrin did not have a significant effect on inhibiting Aβ1-42 production and scavenging intracellular reactive oxygen species (ROS. However, pinocembrin significantly inhibited the upregulation of RAGE transcripts and protein expression both in vivo and in vitro, and also markedly

  6. Comparison of contrast-enhanced modified T1-weighted 3D TSE black-blood and 3D MP-RAGE sequences for the detection of cerebral metastases and brain tumours

    Energy Technology Data Exchange (ETDEWEB)

    Kammer, N.N.; Coppenrath, E.; Treitl, K.M.; Saam, T. [Ludwig-Maximilians-University Hospital Munich, Institute for Clinical Radiology, Munich (Germany); Kooijman, H. [Philips Healthcare, Hamburg (Germany); Dietrich, O. [Ludwig-Maximilians-University Hospital Munich, Josef Lissner Laboratory for Biomedical Imaging, Institute for Clinical Radiology, Munich (Germany)

    2016-06-15

    To compare a modified T1-weighted 3D TSE black-blood sequence with sub-millimetre resolution (T1-mVISTA) with a magnetization-prepared rapid gradient echo (MP-RAGE) sequence for the diagnosis of cerebral malignomas. Forty-six patients with known or suspected intracranial tumours and 15 control patients were included in this retrospective study. All patients underwent T1-mVISTA (0.75-mm isotropic resolution, 4:43 min) and MP-RAGE (0.8-mm isotropic resolution, 4:46 minutes) at 3-Tesla in random order after application of contrast agent. Two experienced radiologists determined the number of lesions. Maximum diameter, diagnostic confidence (DC), visual assessment of contrast enhancement (VCE) and CNR{sub lesion/parenchyma} were assessed for each lesion. Significantly more lesions were detected with T1-mVISTA compared to the MP-RAGE (61 vs. 36; p < 0.05). Further, DC and VCE was rated significantly higher in the T1-mVISTA (p < 0.05 and p < 0.001). Mean CNR{sub lesion/parenchyma} was twofold higher for T1-mVISTA (24.2 ± 17.5 vs. 12.7 ± 11.5, p < 0.001). The 25 lesions detected only in T1-mVISTA were significantly smaller than those detected in both sequences (4.3 ± 3.7 mm vs. 11.3 ± 10.7 mm; p < 0.01). T1-mVISTA increases the contrast of lesions significantly compared to MP-RAGE and might therefore improve detection rates of small lesions in early stages of disease. (orig.)

  7. High-mobility group box 1 inhibits HCO3- absorption in the medullary thick ascending limb through RAGE-Rho-ROCK-mediated inhibition of basolateral Na+/H+ exchange.

    Science.gov (United States)

    Watts, Bruns A; George, Thampi; Badalamenti, Andrew; Good, David W

    2016-09-01

    High-mobility group box 1 (HMGB1) is a nuclear protein released extracellularly in response to infection or injury, where it activates immune responses and contributes to the pathogenesis of kidney dysfunction in sepsis and sterile inflammatory disorders. Recently, we demonstrated that HMGB1 inhibits HCO3 (-) absorption in perfused rat medullary thick ascending limbs (MTAL) through a basolateral receptor for advanced glycation end products (RAGE)-dependent pathway that is additive to Toll-like receptor 4 (TLR4)-ERK-mediated inhibition by LPS (Good DW, George T, Watts BA III. Am J Physiol Renal Physiol 309: F720-F730, 2015). Here, we examined signaling and transport mechanisms that mediate inhibition by HMGB1. Inhibition of HCO3 (-) absorption by HMGB1 was eliminated by the Rho-associated kinase (ROCK) inhibitor Y27632 and by a specific inhibitor of Rho, the major upstream activator of ROCK. HMGB1 increased RhoA and ROCK1 activity. HMGB1-induced ROCK1 activation was eliminated by the RAGE antagonist FPS-ZM1 and by inhibition of Rho. The Rho and ROCK inhibitors had no effect on inhibition of HCO3 (-) absorption by bath LPS. Inhibition of HCO3 (-) absorption by HMGB1 was eliminated by bath amiloride, 0 Na(+) bath, and the F-actin stabilizer jasplakinolide, three conditions that selectively prevent inhibition of MTAL HCO3 (-) absorption mediated through NHE1. HMGB1 decreased basolateral Na(+)/H(+) exchange activity through activation of ROCK. We conclude that HMGB1 inhibits HCO3 (-) absorption in the MTAL through a RAGE-RhoA-ROCK1 signaling pathway coupled to inhibition of NHE1. The HMGB1-RAGE-RhoA-ROCK1 pathway thus represents a potential target to attenuate MTAL dysfunction during sepsis and other inflammatory disorders. HMGB1 and LPS inhibit HCO3 (-) absorption through different receptor signaling and transport mechanisms, which enables these pathogenic mediators to act directly and independently to impair MTAL function.

  8. 晚期糖基化终末产物受体在腹腔感染脓毒症中的研究进展%Recent progress of RAGE in sepsis induced by intra-abdominal infection

    Institute of Scientific and Technical Information of China (English)

    廖延年(综述); 黄骞; 黎介寿(审校)

    2015-01-01

    Sepsis caused by complicated intra-abdominal infection has a poor prognosis since the mechanism of sepsis has not been fully clarified .Research about the effect of Receptor of Advanced Glycation Endproducts on sepsis was paid extensive attention . In this paper , the construction and function of RAGE , the relationship between RAGE and inflammation and action of RAGE during sepsis are summarized .%严重腹腔感染导致的脓毒症预后不佳,与其机制的未充分阐明有关。近年来关于晚期糖基化终末产物受体( re-ceptor of advanced glycation endproducts , RAGE)在脓毒症中的作用的研究受到广泛关注。文中就RAGE的结构与功能,RAGE与炎症的关系以及RAGE在腹腔感染脓毒症中的作用等问题作一综述。

  9. 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

    Energy Technology Data Exchange (ETDEWEB)

    Matsui, Takanori [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011 (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, 67 Asahi-machi, Kurume 830-0011 (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)

    2009-07-24

    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-{gamma} (PPAR-{gamma}). Although nifedipine did not affect expression levels of PPAR-{gamma}, it increased the PPAR-{gamma} 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-{gamma} activation.

  10. A diffusive radiation hydrodynamics code, xRage, is implemented to compare radiation flow with experimental data from the Omega laser facility

    Science.gov (United States)

    Vandervort, Robert; Elgin, Laura; Farag, Ebraheem; Mussack, Katie; Baumgaertel, Jessica Ann; Keiter, Paul; Klein, Sallee; Orban, Christopher; Drake, R. Paul

    2015-11-01

    A sound speed discrepancy between solar models and data collected using helioseismology exists. The sound speed discrepancy is the most pronounced at the base of the convective zone (CZ) for otherwise consistent solar models. One potential solution is that the opacity models for important elements such as carbon, nitrogen and oxygen are incomplete. At these high energy-density conditions few relevant opacity measurements exist to compare to the models. Only relatively recently have user facilities been able to reach the temperatures and densities that resemble the convective zone base. It is our long term goal to determine the opacities of carbon, nitrogen and oxygen at the relevant conditions. Preliminary testing has occurred at the Omega Laser Facility in Rochester, New York. Presented are the results of the shots taken on April 22, 2015. A half hohlraum was used to drive a supersonic radiation front through a dominantly carbon, CRF, foam. These results are compared to diffusive xRage simulations. (LA-UR-15-25495)

  11. 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

    Directory of Open Access Journals (Sweden)

    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.

  12. Baicalin and chrysin mixture imparts cyto-protection against methylglyoxal induced cytotoxicity and diabetic tubular injury by modulating RAGE, oxidative stress and inflammation.

    Science.gov (United States)

    Singh, Jyotsna; Chaudhari, Bhushan P; Kakkar, Poonam

    2017-03-01

    Protective effect of mixture of flavonoids baicalin and chrysin (BCH) was studied against methylglyoxal (MG, a precursor of AGEs) induced cytotoxicity in NRK 52E kidney epithelial cells. Flow cytometry and microscopic analysis showed increased ROS generation, compromised antioxidant status, depolarization of mitochondria and apoptosis in MG stressed cells which were significantly transformed (p≤0.01) during BCH co-treatment. In vivo studies in streptozotocin induced diabetic rats increased protein levels of iNOS, protein kinase C (PKC) and decreased IκB which was modulated by oral BCH treatment (75mg baicalin and 10mg chrysin/kg b.wt.). Increased levels of AGEs and their receptor proteins (RAGE) in diabetic rats were reduced significantly (p≤0.01) in BCH treated group. Renal tubular injuries and deranged kidney function were significantly improved in BCH treated animals. The results indicate that the protection accorded by BCH through its antioxidant and anti-inflammatory effects can be explored for management of diabetic nephropathy.

  13. An outbreak of post-vaccinal rabies (rage de laboratoire) in Fortaleza, Brazil, in 1960. Residual fixed virus as the etiological agent.

    Science.gov (United States)

    Pará, M

    1965-01-01

    The repeated isolation of fixed rabies virus from the CNS tissues of victims of an acute and lethal outbreak of encephalomyelitis in Fortaleza, Brazil, in November 1960, following vaccination with a locally produced killed-virus anti-rabies vaccine of the Fermi type is considered as definitive evidence of the rabic etiology (vaccinal fixed-virus rabies, rage de laboratoire) of this outbreak. Eighteen persons were affected, all of whom died.The clinical picture of paralytic rabies was recognizable in all of these 18 patients. The well-marked characteristics of an acute infection permit the easy differentiation of the paralysis caused by fixed rabies virus from post-vaccinal accidents that occur as allergic reactions.The incriminated anti-rabies vaccine was found to contain fixed live rabies virus at a titre of 10(-3.0). After one year of storage under refrigeration, the vaccine still contained fixed rabies virus, at a titre of 0,2x10(-1.0).Subsequent laboratory studies tend to indicate that the curve of inactivation of fixed virus by phenol does not follow a linear function but rather resembles the curve of inactivation of poliomyelitis virus by heat and formol according to the Salk technique. It is suggested that the antigenicity of the so-called "killed-virus" anti-rabies vaccines is actually due to the presence in them of residual amounts of live virus.

  14. Non-professional marathon running: RAGE axis and ST2 family changes in relation to open-window effect, inflammation and renal function

    Science.gov (United States)

    Bekos, Christine; Zimmermann, Matthias; Unger, Lukas; Janik, Stefan; Hacker, Philipp; Mitterbauer, Andreas; Koller, Michael; Fritz, Robert; Gäbler, Christian; Kessler, Mario; Nickl, Stefanie; Didcock, Jessica; Altmann, Patrick; Haider, Thomas; Roth, Georg; Klepetko, Walter; Ankersmit, Hendrik Jan; Moser, Bernhard

    2016-01-01

    Conflicting data exist on the relevance of marathon (M) and half marathon (HM) running for health. The number of non-professional athletes finishing M and HM events is steadily growing. In order to investigate molecular changes occurring in amateur athletes, we enrolled 70 non-professional runners finishing a single M (34) or HM (36) event at baseline, the finish line and during recovery, and 30 controls. The measurement of the Receptor for Advanced Glycation Endproducts, Interleukin 1 receptor antagonist, ST2 and cytokeratin 18 was combined with molecules measured during clinical routine. Results were analyzed in the light of blood cell analysis, lactate measurements, correction for changes in plasma volume and body composition assessments. There were intrinsic differences in body mass index, abdominal body fat percentage and training time between M and HM runners. C-reactive protein changes in M and HM runners. While soluble RAGE, AGEs and ST2 increased immediately after the race in HM runners, HMGB1 increased in HM and M after the race and declined to baseline after a recovery period. We give insights into the regulation of various molecules involved in physical stress reactions and their possible implications for the cardiovascular system or renal function. PMID:27653273

  15. Exorcising the demons of collectivism in art history’: Branko Mitrović, Rage and Denials. Collectivist Philosophy, Politics, and Art Historiography, 1890-1947, University Park, Pennsylvania University Press 2015

    Directory of Open Access Journals (Sweden)

    Ladislav Kesner

    2016-12-01

    Full Text Available Branko Mitrović´s Rage and Denials. Collectivist Philosophy, Politics, and Art Historiography, 1890-1947 traces the history of collectivist approaches in (art historiography and debates between the individualist and collectivist positions, with the dominant focus on German-speaking scholarship. Author further suggests that denials and false appropriations and other forms of bizzare and irrational claims inherent in many of these collectivist historiographies originated in the failures of self-esteem regulation of their authors. The review then critically examines some problematic claims and assumptions which constitute the theoretical and conceptual backbone of the historical survey.

  16. Méthodes et défis du repérage d’images sur le Web : Jean et John cherchent-ils de la même manière ?

    Directory of Open Access Journals (Sweden)

    Elaine Ménard

    2012-06-01

    Full Text Available Nous faisons ici le point sur les principales méthodes employées pour le repérage d’images numériques que l’on trouve dans la majorité des sites et pages Web. Les méthodes d’indexation manuelles et automatiques facilitant le repérage d’images sont également décrites. Nous nous attardons plus particulièrement sur les problèmes rencontrés par les chercheurs d’images lors du repérage en contexte multilingue, c’est-à-dire lorsque la langue de la requête diffère de la langue d’indexation. Le principal objectif de cette étude était d’identifier les similarités et les différences dans la manière de formuler les requêtes de quatre groupes de participants de langue maternelle différente au moment du repérage d’images sur le Web. Nous avons demandé à quatre groupes de dix participants de quatre communautés linguistiques différentes (française, anglaise, russe et chinoise de préciser quelles catégories de termes ils utilisent en général dans leurs requêtes lors de la recherche d’images sur le Web. Les résultats de notre étude sur les comportements de recherche des chercheurs d’images de quatre communautés linguistiques différentes ont révélé des différences significatives dans la manière de chercher (nombre de requêtes utilisées, longueur des requêtes, attributs conceptuels et terminologiques contenus dans les requêtes. Ces différences doivent être prises en considération au moment de l’élaboration des fonctionnalités de recherche proposées par les moteurs permettant la recherche d’images. En outre, la manière de chercher des images varie en fonction de la langue maternelle du chercheur d’images. Le défi de l’accès aux images, peu importe leur mode d’indexation, reste entier.

  17. Schisandrin B Ameliorates ICV-Infused Amyloid β Induced Oxidative Stress and Neuronal Dysfunction through Inhibiting RAGE/NF-κB/MAPK and Up-Regulating HSP/Beclin Expression.

    Science.gov (United States)

    Giridharan, Vijayasree V; Thandavarayan, Rajarajan A; Arumugam, Somasundaram; Mizuno, Makoto; Nawa, Hiroyuki; Suzuki, Kenji; Ko, Kam M; Krishnamurthy, Prasanna; Watanabe, Kenichi; Konishi, Tetsuya

    2015-01-01

    Amyloid β (Aβ)-induced neurotoxicity is a major pathological mechanism of Alzheimer's disease (AD). Our previous studies have demonstrated that schisandrin B (Sch B), an antioxidant lignan from Schisandra chinensis, could protect mouse brain against scopolamine- and cisplatin-induced neuronal dysfunction. In the present study, we examined the protective effect of Sch B against intracerebroventricular (ICV)-infused Aβ-induced neuronal dysfunction in rat cortex and explored the potential mechanism of its action. Our results showed that 26 days co-administration of Sch B significantly improved the behavioral performance of Aβ (1-40)-infused rats in step-through test. At the same time, Sch B attenuated Aβ-induced increases in oxidative and nitrosative stresses, inflammatory markers such as inducible nitric oxide syntheses, cyclooxygenase-2, interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, and DNA damage. Several proteins such as receptor for advanced glycation end products (RAGE), nuclear factor-κB, mitogen-activated protein kinases, and apoptosis markers were over expressed in Aβ-infused rats but were significantly inhibited by Sch B treatment. Furthermore, Sch B negatively modulated the Aβ level with simultaneous up-regulation of HSP70 and beclin, autophagy markers in Aβ-infused rats. The aforementioned effects of Sch B suggest its protective role against Aβ-induced neurotoxicity through intervention in the negative cycle of RAGE-mediated Aβ accumulation during AD patho-physiology.

  18. Schisandrin B Ameliorates ICV-Infused Amyloid β Induced Oxidative Stress and Neuronal Dysfunction through Inhibiting RAGE/NF-κB/MAPK and Up-Regulating HSP/Beclin Expression.

    Directory of Open Access Journals (Sweden)

    Vijayasree V Giridharan

    Full Text Available Amyloid β (Aβ-induced neurotoxicity is a major pathological mechanism of Alzheimer's disease (AD. Our previous studies have demonstrated that schisandrin B (Sch B, an antioxidant lignan from Schisandra chinensis, could protect mouse brain against scopolamine- and cisplatin-induced neuronal dysfunction. In the present study, we examined the protective effect of Sch B against intracerebroventricular (ICV-infused Aβ-induced neuronal dysfunction in rat cortex and explored the potential mechanism of its action. Our results showed that 26 days co-administration of Sch B significantly improved the behavioral performance of Aβ (1-40-infused rats in step-through test. At the same time, Sch B attenuated Aβ-induced increases in oxidative and nitrosative stresses, inflammatory markers such as inducible nitric oxide syntheses, cyclooxygenase-2, interleukin-1β (IL-1β, IL-6, and tumor necrosis factor-α, and DNA damage. Several proteins such as receptor for advanced glycation end products (RAGE, nuclear factor-κB, mitogen-activated protein kinases, and apoptosis markers were over expressed in Aβ-infused rats but were significantly inhibited by Sch B treatment. Furthermore, Sch B negatively modulated the Aβ level with simultaneous up-regulation of HSP70 and beclin, autophagy markers in Aβ-infused rats. The aforementioned effects of Sch B suggest its protective role against Aβ-induced neurotoxicity through intervention in the negative cycle of RAGE-mediated Aβ accumulation during AD patho-physiology.

  19. Survivin、RAGE和HMGB1在乳腺癌中表达及其临床意义%Expression of Survivin, RAGE and HMGB1 gene in human breast cancer and its clinical significance

    Institute of Scientific and Technical Information of China (English)

    鲁凯; 姚壮凯; 刘燕文; 叶红玲; 吕三云

    2012-01-01

    目的 探讨乳腺癌组织中Survivin、RAGE和HMGB1基因表达及其临床意义.方法 对50例早期(Ⅰ+Ⅱ期)、50例晚期(Ⅲ+Ⅳ期)乳腺癌及100例对照组蜡块标本,运用Real-time PCR和荧光原位杂交技术(FISH)技术检测Survivin、RAGE和HMGB1基因表达.并分析各基因表达与乳腺癌组织的分化程度、浸润深度、淋巴结转移、TNM分期之间的关系.结果 Survivin、RAGE和HMGB1基因表达荧光实时定量PCR法上调分别为62%、73%、79%,FISH法基因扩增阳性分别为78%、69%、72%.乳腺癌TNM分期、淋巴结转移与基因高表达有密切关系,Survivin基因表达与RAGE、HMGB1表达呈正相关.结论 Survivin、RAGE和HMGB1基因表达对乳腺癌早期诊断和预后分析有重要指导意义.%Objective To investigate the expression of Survivin,receptor for advanced glycation endproduct(RAGE) and high mobility group protein B1 (HMGB1) gene in human breast cancer and their clinical significance.Methods The expression of Survivin,RAGE and HMGB1 gene was detected by Real-time PCR technology and fluorescence in situ hybridization (FISH) technology in the following tissue samples:50 early breast cancers,50 advanced breast cancers,and the corresponding adjacent normal mammary tissues.The relationship of their expression and several factors such as differentiation degree,invasion,lymph node metastasis and TNM stage of cancer was explored.Results The positive expression rate of Survivin,RAGE and HMGB1 gene was 62%,73% and 79% detected by Real-time PCR technology,78%,69% and 72% detected by FISH technology in breast cancer tissues.The overexpression of these genes was positively correlated with TNM stage and lymph node metastasis.The expression of Survivin gene was positively correlated with the expression of RAGE and HMGB1.Conclusion Overexpression of Survivin,RAGE and HMGB1 gene is of great significance in early diagnosis and prognosis of human breast cancer.

  20. Repérages bibliographiques

    Directory of Open Access Journals (Sweden)

    Sabrina Mommolin

    2015-12-01

    Full Text Available Commerce électronique - E-commerce BURKHALTER J. N., WOOD N. T., (Eds. (2015, Maximizing Commerce and Marketing Strategies through Micro-Blogging, Hershey, PA, USA: IGI Global. 354 p. ISBN: 978-1-4666-8408-9 KHOSROW-POUR M. (Ed. (2015, Strategic E-Commerce Systems and Tools for Competing in the Digital Marketplace, Hershey, PA, USA: IGI Global, 263 p. ISBN: 978-1-4666-8133-0 LTIFI M., GHARBI J. (2015, « Impact de la qualité perçue du site web marchand sur le bonheur du cyberconsommateur ...

  1. Repérages bibliographiques

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    Sabrina Mommolin

    2015-10-01

    Full Text Available Commerce électronique - E-commerce AYDIN, E., SAVRUL, B. K. (2014, "The Relationship between Globalization and E-commerce: Turkish Case", Procedia - Social and Behavioral Sciences, vol. 150, pp. 1267-1276. BASTARD, I., BOURREAU, M., MOREAU, F. (2014, "L’impact du piratage sur l’achat et le téléchargement légal: Une comparaison de quatre filières culturelles", Revue économique, vol. 65, n°3, pp. 573-599. FEIZOLLAHI, S., SHIRMOHAMMADI, A., KAHREH, Z. S., et al. (2014, "Investigation the Effe...

  2. Repérages bibliographiques

    OpenAIRE

    Sabrina Mommolin

    2015-01-01

    Commerce électronique - E-commerce AYDIN, E., SAVRUL, B. K. (2014), "The Relationship between Globalization and E-commerce: Turkish Case", Procedia - Social and Behavioral Sciences, vol. 150, pp. 1267-1276. BASTARD, I., BOURREAU, M., MOREAU, F. (2014), "L’impact du piratage sur l’achat et le téléchargement légal: Une comparaison de quatre filières culturelles", Revue économique, vol. 65, n°3, pp. 573-599. FEIZOLLAHI, S., SHIRMOHAMMADI, A., KAHREH, Z. S., et al. (2014), "Investigation the Effe...

  3. Repérages bibliographiques

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    Sabrina Mommolin

    2013-11-01

    Full Text Available Gouvernance  - Governance AL AJEELI, Abid., AL-BASTAKI, Yousif A. Latif., Handbook of research on e-services in the public sector : e-government strategies and advancements, Hershey PA : Information Science Reference, 2010, ISBN-10: 1615207899, ISBN-13: 978-1615207893 CHADWICK, Andrew, HOWARD, Philip N. (Ed. By, Routledge handbook of Internet politics, Routledge, 2009, 512 pages, ISBN: 978-0-415-42914-6 COLEMAN, Stephen, BLUMLER, Jay G., The Internet and democratic citizenship : theory, prac...

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    Sabrina Mommolin

    2016-05-01

    Full Text Available Développement durable – Sustainable development APAK S., ATAY E. (2015, “Global Competitiveness in the EU through Green Innovation Technologies and Knowledge Production”, Procedia - Social and Behavioral Sciences, vol. 181, pp. 207-217. BORSDORF A., BENDER O., BRAUN F., HALLER A. (2015, Web-based instruments for strengthening sustainable regional development in the Alps, Geografski Zbornik / Acta Geographica Slovenica, vol. 55, N° 1, pp. 174-182. SIRSIKAR S.V., KAREMORE P. (2015, Design an...

  5. Repérages bibliographiques

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    Sabrina Mommolin

    2013-04-01

    Full Text Available Gouvernance – Governance AYANSO A., CHATTERJEE D., CHO D. I. (2011, “E-Government readiness index: A methodology and analysis”, Government Information Quarterly, vol. 28, n° 4, pp. 522-532. CHEN Y.-C., CHU P.-Y. (2011, Electronic Governance and Cross-Boundary Collaboration: Innovations and Advancing Tools, Hershey, PA: IGI Global, 422 p. ISBN: 9781609607548 CONCHA G., ASTUDILLO H., PORRÚA M. (et al. (2011, “E-Government procurement observatory, maturity model and early measurements”, Gove...

  6. Repérages bibliographiques

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    Sabrina Mommolin

    2013-06-01

    Full Text Available GOUVERNANCE – GOVERNANCE ARDUINI D., BELOTTI F., DENNI M. et al. (2010, Technology adoption and innovation in public services the case of e-government in Italy, Information Economics and Policy, Vol. 22, n° 3, pp. 257-275. BAQIR M. N., IYER L. (2010, E-government maturity over 10 years : A comparative analysis of E-government maturity in select countries around the world, In C. G. Reddick, Comparative E-Government, Integrated Series in Information Systems, Vol. 25, Springer New York, pp. 3-...

  7. Repérages bibliographiques

    OpenAIRE

    Sabrina Mommolin

    2013-01-01

    Gouvernance – Governance AYANSO A., CHATTERJEE D., CHO D. I. (2011), “E-Government readiness index: A methodology and analysis”, Government Information Quarterly, vol. 28, n° 4, pp. 522-532. CHEN Y.-C., CHU P.-Y. (2011), Electronic Governance and Cross-Boundary Collaboration: Innovations and Advancing Tools, Hershey, PA: IGI Global, 422 p. ISBN: 9781609607548 CONCHA G., ASTUDILLO H., PORRÚA M. (et al.) (2011), “E-Government procurement observatory, maturity model and early measurements”, Gove...

  8. Repérages bibliographiques

    OpenAIRE

    Mommolin, Sabrina

    2014-01-01

    Gouvernance – Governance AYANSO A., CHATTERJEE D., CHO D. I. (2011), “E-Government readiness index: A methodology and analysis”, Government Information Quarterly, vol. 28, n° 4, pp. 522-532. CHEN Y.-C., CHU P.-Y. (2011), Electronic Governance and Cross-Boundary Collaboration: Innovations and Advancing Tools, Hershey, PA: IGI Global, 422 p. ISBN: 9781609607548 CONCHA G., ASTUDILLO H., PORRÚA M. (et al.) (2011), “E-Government procurement observatory, maturity model and early measurements”, Gove...

  9. Repérages bibliographiques

    Directory of Open Access Journals (Sweden)

    Sabrina Mommolin

    2013-05-01

    Full Text Available Gouvernance – Governance AL AJEELI A., AL-BASTAKI Y. A. L. (2011, Handbook of research on e-services in the public sector: e-government strategies and advancements. Hershey, PA : Information Science Reference, 523 p. CHEN Y.-C., CHU P.-Y. (2011, Electronic governance and cross-boundary collaboration : innovations and advancing tools. Hershey, PA : IGI Global, 421 p. CROPF R. A., KRUMMENACHER W. S. (2011, Information Communication Technologies and the virtual public sphere: impacts of netwo...

  10. Repérages bibliographiques

    OpenAIRE

    2013-01-01

    Gouvernance – Governance AL AJEELI A., AL-BASTAKI Y. A. L. (2011), Handbook of research on e-services in the public sector: e-government strategies and advancements. Hershey, PA : Information Science Reference, 523 p. CHEN Y.-C., CHU P.-Y. (2011), Electronic governance and cross-boundary collaboration : innovations and advancing tools. Hershey, PA : IGI Global, 421 p. CROPF R. A., KRUMMENACHER W. S. (2011), Information Communication Technologies and the virtual public sphere: impacts of netwo...

  11. Repérages bibliographiques

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    Sabrina Mommolin

    2014-06-01

    Full Text Available Développement durable – Sustainable development CHIABAI, A., RÜBBELKE D., and MAURER L. (2013, "ICT applications in the research into environmental sustainability: a user preferences approach", Environment, Development and Sustainability, vol.15, n°1, pp. 81-100. MOLLA, A. (2013, "Identifying IT sustainability performance drivers: Instrument development and validation", Information Systems Frontiers, pp. 1-19. Developpement rural - Rural development ADHIKARY, M.M., S.K. ACHARYA, and D. BASU...

  12. Effect of penequinine hydrochloride on the expression of RAGE in rat hippocampal neurons after status epilepticus%盐酸戊乙奎醚对癫疒间持续状态大鼠海马神经元RAGE表达的影响

    Institute of Scientific and Technical Information of China (English)

    程伟; 朱建南; 孙秀媛; 齐敦益; 戴体俊; 刘功俭

    2012-01-01

    Objective To investigate the effect of penequinine hydrochloride on the expression of RAGE and NF -κB in rat hippocampal neurons after status epilepticus . Methods Male SD rats were randomly divided into three groups , ie. A control group, a status epilepticus group and a penequinine hydrochloride group (re = 8 each). The rats abdominal cavity of status epilepticus group were injected lithium - pilecarpine to establish status epilepticus model. The expression of RAGE and nuclear factor kappa B ( NF - κB) p65 in hippocampal was measured by Western blot. TUNEL assay was used merely to identify apoptotic cells. Results Compared with the control group , the expression of RAGE and NF - κB p65 was significantly higher in status epilepticus group and apoptotic cells were significant increased (P <0.01). Compared with the status epilepticus group , the expression of RAGE and NF - κB p65 was significantly lower and apoptotic cells were decreased in penequinine hydrochloride group ( P < 0. 01). Conclusion Penequinine hydrochloride shows a protective effects on rat hippocampal neurons after status epilepticus through inhibiting the expression of RAGE and NF -κB.%目的 探讨盐酸戊乙奎醚(长托宁)对癫(癎)持续状态(SE)后大鼠海马晚期糖基化终末产物受体(RAGE)和核因子κB(NF-κB)的影响.方法 SD大鼠随机分为A组(对照组)、B组(模型组)和C组(盐酸戊乙奎醚组),每组8只.应用氯化锂-匹罗卡品制备SE模型.TUNEL法检测大鼠海马细胞凋亡,Western blot法检测大鼠海马RAGE及NF-κB p65的表达改变情况.结果 与A组比较,B组大鼠海马RAGE、NF-κB p65水平明显增高,神经元凋亡增加(P<0.01);与B组比较,C组大鼠海马RAGE、NF-κB p65水平降低,神经元凋亡减少(P<0.01).结论 盐酸戊乙奎醚可抑制RAGE-NF-κB通路和减少神经元凋亡,对SE后大鼠海马神经元发挥保护作用.

  13. AGE-RAGE系统与糖尿病足综合征的发病机制及治疗进展%The relationship between AGE-RAGE system and pathogenesis of diabetic foot syndrome, and advance on treatment

    Institute of Scientific and Technical Information of China (English)

    孟庆元; 林炜栋; 陈向芳

    2009-01-01

    糖尿病足综合征(DFS)是糖尿病严重慢性并发症之一,其发病机制至今尚未完全阐明.晚期糖基化终末产物(AGEs)的形成参与DFS的发生、发展,AGEs与AGEs受体(RAGE)相互作用,并通过一系列分子机制导致糖尿病神经病变和外周血管病变.因此,抑制AGEs形成或阻断AGEs与其受体相互作用可以延缓糖尿病足的发生、发展.本文就AGEs形成、AGE-RAGE系统在DFS中的作用和DFS的治疗进展等作一综述.

  14. S100 A14与RAGE在子宫颈鳞癌组织中的表达及临床意义%The expression and significance of S100 A14 and RAGE in cervical squamous cell carci-noma

    Institute of Scientific and Technical Information of China (English)

    杨晶; 王翔宇; 王欣; 郝莉; 崔竹梅

    2015-01-01

    Objective:To investigate the expression and clinical significance of S100 A14 and the receptor of advanced glycation end products ( RAGE ) in cervical squamous cell carcinoma ( CSCC ) . Methods:Ⅰmmunohistochemical staining was conducted to detect the expression of S100A14 and RAGE in the following tissue samples:23 normal tissue,76 cervical intraepithelial neoplasias ( CⅠN) ,and 102 primary CSCC. Further analysis was made to explore the relationship between the S100 A14 and RAGE expression and various clinicopathological factors. Results:The expressions of S100A14 and RAGE increased during the normal to tumor transition of CSCC ( P<0 . 05 ) , and this increased expression was significantly associated with tumor FⅠGO stage,lymph node metastasis,deep stromal invasion and survival rate (P<0. 05). The expression of RAGE was associated with tumor size but not grade. The expression of S100A14 was associated with grade but not tumor size. There was a significant positive correla-tion between S100 A14 and RAGE in CSCC ( P<0 . 05 ) . Conclusion:S100 A14 and RAGE are both up-regulated expressed in CSCC. The high expression may be responsible for the process of carcinogenesis,progression invasion,and distant metastasis. S100A14 and RAGE may be useful targets for treatment of CSCC and a powerful index to estimate prognosis.%目的:探讨钙结合蛋白S100 A14与晚期糖基化终产物受体( RAGE )在宫颈鳞癌组织中的表达及临床意义。方法:免疫组化法检测S100 A14与RAGE在23例正常宫颈、76例宫颈上皮内瘤变( CⅠN )及102例宫颈鳞癌组织中的表达,探讨 S100 A14与RAGE表达与宫颈癌临床病理指标的关系。对102例宫颈鳞癌患者进行术后随访,分析S100 A14与RAGE表达与预后的关系。结果:S100 A14和RAGE在正常宫颈到宫颈鳞癌组织中的表达均呈递增趋势( P<0.05)。宫颈鳞癌中S100 A14和RAGE表达与FⅠGO分期、淋巴结转移和深层间质浸润有关( P<0.05);RAGE表

  15. Advanced Glycation End Products Affect Osteoblast Proliferation and Function by Modulating Autophagy Via the Receptor of Advanced Glycation End Products/Raf Protein/Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase/Extracellular Signal-regulated Kinase (RAGE/Raf/MEK/ERK) Pathway.

    Science.gov (United States)

    Meng, Hong-Zheng; Zhang, Wei-Lin; Liu, Fei; Yang, Mao-Wei

    2015-11-20

    The interaction between advanced glycation end products (AGEs) and receptor of AGEs (RAGE) is associated with the development and progression of diabetes-associated osteoporosis, but the mechanisms involved are still poorly understood. In this study, we found that AGE-modified bovine serum albumin (AGE-BSA) induced a biphasic effect on the viability of hFOB1.19 cells; cell proliferation was stimulated after exposure to low dose AGE-BSA, but cell apoptosis was stimulated after exposure to high dose AGE-BSA. The low dose AGE-BSA facilitates proliferation of hFOB1.19 cells by concomitantly promoting autophagy, RAGE production, and the Raf/MEK/ERK signaling pathway activation. Furthermore, we investigated the effects of AGE-BSA on the function of hFOB1.19 cells. Interestingly, the results suggest that the short term effects of low dose AGE-BSA increase osteogenic function and decrease osteoclastogenic function, which are likely mediated by autophagy and the RAGE/Raf/MEK/ERK signal pathway. In contrast, with increased treatment time, the opposite effects were observed. Collectively, AGE-BSA had a biphasic effect on the viability of hFOB1.19 cells in vitro, which was determined by the concentration of AGE-BSA and treatment time. A low concentration of AGE-BSA activated the Raf/MEK/ERK signal pathway through the interaction with RAGE, induced autophagy, and regulated the proliferation and function of hFOB1.19 cells.

  16. Novel CoQ10 antidiabetic mechanisms underlie its positive effect: modulation of insulin and adiponectine receptors, Tyrosine kinase, PI3K, glucose transporters, sRAGE and visfatin in insulin resistant/diabetic rats.

    Directory of Open Access Journals (Sweden)

    Mohamed M Amin

    Full Text Available As a nutritional supplement, coenzyme Q10 (CoQ10 was tested previously in several models of diabetes and/or insulin resistance (IR; however, its exact mechanisms have not been profoundly explicated. Hence, the objective of this work is to verify some of the possible mechanisms that underlie its therapeutic efficacy. Moreover, the study aimed to assess the potential modulatory effect of CoQ10 on the antidiabetic action of glimebiride. An insulin resistance/type 2 diabetic model was adopted, in which rats were fed high fat/high fructose diet (HFFD for 6 weeks followed by a single sub-diabetogenic dose of streptozotocin (35 mg/kg, i.p.. At the end of the 7(th week animals were treated with CoQ10 (20 mg/kg, p.o and/or glimebiride (0.5 mg/kg, p.o for 2 weeks. CoQ10 alone opposed the HFFD effect and increased the hepatic/muscular content/activity of tyrosine kinase (TK, phosphatidylinositol kinase (PI3K, and adiponectin receptors. Conversely, it decreased the content/activity of insulin receptor isoforms, myeloperoxidase and glucose transporters (GLUT4; 2. Besides, it lowered significantly the serum levels of glucose, insulin, fructosamine and HOMA index, improved the serum lipid panel and elevated the levels of glutathione, sRAGE and adiponectin. On the other hand, CoQ10 lowered the serum levels of malondialdehyde, visfatin, ALT and AST. Surprisingly, CoQ10 effect surpassed that of glimepiride in almost all the assessed parameters, except for glucose, fructosamine, TK, PI3K, and GLUT4. Combining CoQ10 with glimepiride enhanced the effect of the latter on the aforementioned parameters.These results provided a new insight into the possible mechanisms by which CoQ10 improves insulin sensitivity and adjusts type 2 diabetic disorder. These mechanisms involve modulation of insulin and adiponectin receptors, as well as TK, PI3K, glucose transporters, besides improving lipid profile, redox system, sRAGE, and adipocytokines. The study also points to the

  17. 转化生长因子β1对A549细胞晚期糖基化终产物受体与细胞外基质表达的影响%Expression of RAGE and extracellular matrix induced by transforming growth factor beta 1 in A549 cells

    Institute of Scientific and Technical Information of China (English)

    丁辉; 冯艳; 陈如华

    2013-01-01

    目的 研究转化生长因子β1 (transforming growth factor beta 1,TGF-β1)对人A549细胞的晚期糖基化终产物受体(receptor for advanced glycation end-products,RAGE)和胶原-Ⅰ、α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)表达的作用.方法 体外培养人A549细胞,以不加TGF-β1刺激为对照组,不同终浓度TGF-β1(2 μg/L、5 μg/L、10 μg/L)处理A549细胞为实验组,RT-PCR和Western blotting法检测TGF-β1刺激12 h、24 h、36 h后对照组和实验组RAGE mRNA和RAGE、胶原-Ⅰ及α-SMA的蛋白表达.结果 ①随着TGF-β1浓度的增加,刺激时间的延长,A549细胞的RAGE mRNA和蛋白的表达逐渐降低,呈时间-浓度依赖关系.②与对照组相比,A549在TGF-β1(5 μg/L)刺激24 h后,RAGE mRNA的表达明显降低(0.387±0.088 vs 1.345±0.132,P<0.01).RAGE蛋白表达较对照组明显降低(0.174±0.061 vs 1.229±0.112,P<0.01).③TGF-β1(5μg/L)刺激24 h后,A549的胶原-Ⅰ及α-SMA蛋白表达(0.916±0.071和0.899±0.022)分别较对照组(0.295±0.041和0.134±0.028)升高3.1和6.7倍,差异有统计学意义(P<0.01).④相关分析显示,A549的RAGE蛋白表达与胶原-Ⅰ(r=-0.843,P<0.05)、α-SMA蛋白的表达(r=-0.897,P<0.05)呈负相关.结论 TGF-β1下调A549细胞RAGE的mRNA和蛋白表达,与胶原-Ⅰ及α-SMA蛋白表达上调呈负相关,提示RAGE的表达下调可能与肺纤维化的发生和发展有关.%Objective To investigate the expressions of receptor for advanced glycation endproducts (RAGE),collagen-Ⅰ,and α-smooth muscle actin (α-SMA) in human A549 cells induced by transforming growth factor beta 1 (TGF-β1).Methods With no TGF-β1-stimulated cells for the control group,human A549 cells were cultured in vitro.Cultured cells were exposed to TGF-β1 with different final concentration (2 μg/L,5 μg/L,10 μg/L) for different time (12 h,24 h,36 h).RAGE mRNA and protein,collagen-Ⅰ and α-SMA in cells were detected at different points after the treatment of TGF

  18. 血管性认知障碍患者血清BACE1、sRAGE水平变化%Changes of serum BACE1 and sRAGE levels in patients with vascular cognitive impairment

    Institute of Scientific and Technical Information of China (English)

    陈雪梅; 方丽; 顾明霞

    2014-01-01

    目的 探讨血清淀粉蛋白前B位分解酶1(BACE1)、糖基化终末产物受体可溶性片段(sRAGE)在血管性认知障碍患者中的变化及其临床意义.方法 选取2012年1月至12月收治的89例缺血性脑卒中患者,其中无认知障碍的患者(脑卒中组)26例,血管性轻度认知障碍非痴呆组50例,血管性痴呆组13例.另选20例正常健康人作为对照组.检测并比较各组血清BACE1、sRAGE水平.结果 脑卒中组与对照组血清sRAGE、BACE1水平相近,差异均无统计学意义(P均>0.05).与脑卒中组和对照组相比,血管性轻度认知障碍组、血管性痴呆组血清sRAGE水平明显下降(P均<0.05),血清BACE1水平明显增高(P均<0.05).结论 BACE1、sRAGE在血管性认知障碍患者中早期就有变化,可作为卒中后认知障碍早期诊断的分子生物学标记物.

  19. 银杏叶提取物、α-硫辛酸对糖尿病大鼠肾组织中糖基化终产物及其受体RAGE表达的影响%Extract of Ginkgo biloba and α-lipoic Acid Attenuate Advanced Glycation End Products Accumulation and RAGE Expression in Diabetic Nephropathy Rats

    Institute of Scientific and Technical Information of China (English)

    李雪竹; 严海东; 王俊; 江薇

    2011-01-01

    Objective To investigate the accumulation of advanced glycation end products (AGEs) and expression of receptor for AGEs (RAGE) in streptozocin (STZ)-induced diabetic nephropathy in rats, and the role of antioxidants on the AGEs-RAGE signaling.Methods Diabetic rats were induced by once intraperitoneal injection of STZ at the dose of 60 mg/kg, and randomly divided into the DN group (n=12, treated with normal saline by intraperitoneal injection, once daily), the extract of Ginkgo biloba (EGb) group ( n =14, treated with EGb 300 mg/kg by oral administration, once every other day), and the α-lipoic add (ALA) group ( n =12, treated with ALA at the dose of 35 mg/kg by intraperitoneal injection, once every other day).Rats of the normal control group (n=10) were given vehicle dtrate buffer at the dose of 60 mg/kg.Rats were sacrificed at the 12th week and the 20th week of this study.The four groups were compared in terms of body weight, blood glucose, renal function, 24-h urine protein.Renal pathological changes were observed by PAS staining.Oxidative stress indices were detected using spectrophotometry.The concentrations of AGEs were measured using fluorospectrophotometry, and the expressions of RAGE were detected by Real-time PCR and Western blot.Results Compared with the normal control group, the 24-h urine protein quantitation was higher and the glomerular filtration rate increased in rats at the 12th week and the 20th week.The pathological tissue staining showed dilated glomerular mesangium, proliferated glomerular matrix, vacuolar degeneration of the renal tubular epithelium.Malonaldehyde (MDA) levels and 8-hydroxide radical guanine deoxyriboside (8-OHdG) levels increased, and catalase (CAT) and reduced glutathione hormone (GSH) levels decreased.The AGEs contents in serum and renal tissue homogenate increased.The expressions of RAGE mRNA and protein increased in the DN group at the 12th and the 20th week.The 24-h udne protein quantitation was reduced in the EGb group

  20. 羧甲基赖氨酸和可溶性糖基化终产物受体水平与2型糖尿病冠状动脉钙化相关性研究%Correlation of Nε-(carboxymethyl) lysine and sRAGE with Coronary Artery Calcification in Type 2 Diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    殷汉; 孙子林; 王尧

    2011-01-01

    目的 探讨羧甲基赖氨酸(CML)和可溶性糖基化终产物受体(sRAGE)水平与2型糖尿病冠状动脉钙化及其危险因素的关系.方法 101例2型糖尿病患者采用ELISA法检测sRAGE和CML水平;根据64排螺旋CT冠状动脉钙化积分(CACS)结果分为钙化组(CACS>0),无钙化组(CACS=0),并进一步分四个亚组;测定踝臂指数(ABI)、颈动脉内膜中层厚度(IMT)及糖脂指标等;所有资料均以SPSS 16.0软件进行统计分析.结果 二项分类Logistic回归分析发现年龄及ABI是冠状动脉钙化独立相关因素;CACS与年龄呈正相关,与ABI呈负相关;重度钙化组sRAGE水平较无钙化组明显降低,差异有统计学意义(P<0.05).结论 ABI可作为评估冠状动脉钙化的独立预测因子;年龄是冠状动脉钙化的独立危险因素;sRAGE是冠状动脉硬化、钙化进程中的预测指标和保护因子.%Objective To investigate the relationship between the levels of serum Ne - ( carboxymethyl ) lysine ( CML ) and soluble receptor for advanced glycation end products ( sRAGE ) and the coronary artery calcification ( CAC ), and analyze the risk factors of coronary artery calcification in type 2 diabetes mellitus. Methods The levels of CML and sRAGE were detected by ELISA for 101 patients with type 2 diabetes mellitus; according to CAC score ( CACS ) measured by 64 - detector computed tomography the patients were divided as CAC group ( CACS > 0 ) and non - CAC group ( CACS = 0 ), and further divided into 4 subgroups of different degrees of CAC. The clinical data of patients including intima - media thickness ( IMT ), ankle -brachial index ( ABI ), and the indexes of glucose and fat were collected. All data were analyzed by using SPSS 16.0 software. Results Binar Logistic regression analysis showed that the age and ABI were significantly and independently associated with CAC, and CACS was correlated positively with age and negatively with ABI. The serum sRAGE level was obviously decreased

  1. GHB acid: A rage or reprive

    Directory of Open Access Journals (Sweden)

    Prakhar Kapoor

    2013-01-01

    Full Text Available Gamma-hydroxybutyric acid (GHB is a naturally occurring analog of gamma-aminobutyric acid (GABA that has been used in research and clinical medicine for many years. GHB was used clinically as an anesthetic in the 1960s but was withdrawn due to side effects that included seizures and coma. GHB has been implicated in a number of crime types; most notably in drug-facilitated sexual assault. GHB is abused by three main groups of users: Body builders who use the substance believing that it stimulated the release of growth hormone; sexual predators who covertly administer the drug for its sedative and amnesic effects and club-goers (rave parties who take the drug for its euphoric effects. The short-lived hypnotic effects, relative safety and widespread availability of the drug have made it particularly well suited to this role. The drug has an addictive potential if used for long term. The primary effects of GHB use are those of a CNS depressant and therefore range from relaxation, to euphoria, confusion, amnesia, hallucinations, and coma. Despite the increased regulation, GHB remains widely available through the Internet where one can easily purchase the necessary reagents as well as recipes for home production. There are reports of patients being unresponsive to painful stimuli and cases of oral self-mutilations linked to the abuse of GHB, though quiet rare. Such cases should remind odontologists that intra-oral lesions may be the result of self-mutilation either due to mental illness or altered states caused by the use of prescription or non-prescription drugs.

  2. GHB acid: A rage or reprive.

    Science.gov (United States)

    Kapoor, Prakhar; Deshmukh, Revati; Kukreja, Ipsita

    2013-10-01

    Gamma-hydroxybutyric acid (GHB) is a naturally occurring analog of gamma-aminobutyric acid (GABA) that has been used in research and clinical medicine for many years. GHB was used clinically as an anesthetic in the 1960s but was withdrawn due to side effects that included seizures and coma. GHB has been implicated in a number of crime types; most notably in drug-facilitated sexual assault. GHB is abused by three main groups of users: Body builders who use the substance believing that it stimulated the release of growth hormone; sexual predators who covertly administer the drug for its sedative and amnesic effects and club-goers (rave parties) who take the drug for its euphoric effects. The short-lived hypnotic effects, relative safety and widespread availability of the drug have made it particularly well suited to this role. The drug has an addictive potential if used for long term. The primary effects of GHB use are those of a CNS depressant and therefore range from relaxation, to euphoria, confusion, amnesia, hallucinations, and coma. Despite the increased regulation, GHB remains widely available through the Internet where one can easily purchase the necessary reagents as well as recipes for home production. There are reports of patients being unresponsive to painful stimuli and cases of oral self-mutilations linked to the abuse of GHB, though quiet rare. Such cases should remind odontologists that intra-oral lesions may be the result of self-mutilation either due to mental illness or altered states caused by the use of prescription or non-prescription drugs.

  3. The Roots of Muslim Rage Revisited

    Science.gov (United States)

    2013-03-01

    famous political scientist Francis Fukuyama wrote in The Guardian: Modernity has a cultural basis. Liberal democracy and free markets do not work...L. Esposito and Dalia Mogahed, Who Speaks for Islam (New York: Gallup Press, 2007), 9. 44 Yoshihiro Francis Fukuyama , “The West has Won,” The

  4. PTW modeling in xRage

    Energy Technology Data Exchange (ETDEWEB)

    Long, Christopher Curtis [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Rauenzahn, Rick M. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-05-01

    Preston-Tonks-Wallace Model (PTW), is a viscoplastic material model for very high strain rates (~1011/s) and uses a Voce work hardening model. Strain rates above 109/s uses Wallace’s model of overdriven shocks in metals. PTW is applicable for broad range of strain rates (10-3) -1012).

  5. Effect of Tanshinone ⅡA on RAGE Expression and Oxidative Stress Status in Human Mesangial Cells Induced by AGE%丹参酮ⅡA对人肾小球系膜细胞晚期糖化终产物受体表达及氧化应激水平的影响研究

    Institute of Scientific and Technical Information of China (English)

    蔡伟; 徐积兄; 朱凌燕; 肖钧仁; 李刚

    2014-01-01

    Objective To investigate the effect of Tanshinone ⅡA( TanⅡA)on the expression of receptor for ad-vanced glycated endproducts( RAGE)and the oxidative stress status of human mesangial cells induced by AGE. Methods Hu-man mesangial cells(HMCs)were cultured with various concentration of AGE-BSA(1. 0 μg/ml,10. 0 μg/ml,50. 0 μg/ml and 100. 0 μg/ml),and then were treated with Tan ⅡA(0. 1 μg/ml,1. 0 μg/ml,5. 0 μg/ml and 10. 0 μg/ml). The cul-tured HMCs were divided into AGE group,AGE+TanⅡA group and control group. By using GAPDH as reference,the protein and mRNA expression of RAGE were evaluated by Western blotting analysis and real-time PCR respectively. The activity of su-peroxide dismutase( SOD),glutathione peroxidase( GSH-Px)and malonaldehyde( MDA)levels in the supernatant of HMCs were measured. Results The expressions of RAGE and mRNA in HMCs between control group and different concentration of AGE groups all showed statistically significant differences(F=4. 428 and 5. 031,P<0. 05). Compared with the control group,the expressions of RAGE and mRNA in HMCs of 10. 0 μg/ml,50. 0 μg/ml and 100. 0 μg/ml AGE groups were significantly higher (P<0. 05). The expressions of RAGE and mRNA in HMCs between control group and AGE+different concentrations of TanⅡA groups all showed statistically significant differences(F=5. 002 and 5. 312,P<0. 05). Compared with AGE+0 μg/ml Tan ⅡA group,the expressions of RAGE and mRNA in HMCs of the control group,AGE+0. 1 μg/ml TanⅡA group,AGE+1. 0μg/ml TanⅡA group,AGE+5. 0 μg/ml TanⅡA group and AGE+10. 0 μg/ml TanⅡA group were significantly lower( P<0. 05). The SOD,GSH-Px and MDA levels in the supernantant of HMCs showed statistically significant differences between the control group,different concentrations of AGE group and AGE+TanⅡA group(P<0. 05). Conclusion TanⅡA could sig-nificantly reduce the RAGE and mRNA expression in HMCs induced by AGE,and the oxidative stress levels are also improved.%

  6. Breast-feeding in Buddhist Art:Concerning the Raging Controversy about Breasting-feeding in Public Places%漫谈佛教艺术中的哺乳图--从当代社会关于公共场所哺乳问题的争论谈起

    Institute of Scientific and Technical Information of China (English)

    胡同庆

    2016-01-01

    In recent years, many controversies have taken place on the internet about the legitimacy of breast-feeding in full view of the public.The heart of these controversies can be summarized as follows:what is beautiful and what is reprehensi-ble?In this age of diverse ideologies, why is there so much tolerance about ugly things and yet so little tolerance, or even zero tolerance, for truly beautiful things?Focusing on the raging controversy about breast-feeding in upblic places and mak-ing reference to breast-feeding scene s in the history of Buddhist art and their underlying aestheitc ideas, this paper attempts to reflect on this phenomenon.%近年来,关于妇女在公共场所无遮盖哺乳是否具有正当性的争议,在互联网上可谓此伏彼起。这一争论的实质在于:什么是美的?什么是不美的?在这个思想观念日益多元的时代,为什么人们有时候能够对丑陋的事物表现出极大的宽容,却对某些真正美好的事物如此苛责,甚至是“零容忍”?由此围绕当代社会关于公共场所哺乳问题的争论,结合宗教艺术史上的诸多艺术表现及其背后的审美观念进行反思。

  7. Engineering of blood vessel patterns by angio-morphogens [angiotropins]: non-mitogenic copper-ribonucleoprotein cytokins [CuRNP ribokines] with their metalloregulated constituents of RAGE-binding S100-EF-hand proteins and extracellular RNA bioaptamers in vascular remodeling of tissue and angiogenesis in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Wissler, J.H. [ARCONS Applied Research, Bad Nauheim (Germany)

    2001-12-01

    Tissue vascularization is requisite to successful cell-based therapies, biomaterial design and implant integration. Thus, known problems in ossointegration of avascular implants in connection with the generation of bone tissue reflect arrays of general problems of socio-economic relevance existing in reparative medicine still waiting for to be solved. For this purpose, morphogenesis and remodeling of endothelial angio-architectures in tissue and in vitro by isolated non-mitogenic angio-morphogens [angiotropins] are considered in terms of their structure, function and action mechanisms. Extracellular angiotropins are secreted by activated leukocytes/monocytes/macrophages. They are a family of cytokines with morphogen bioactivity selectively directed to endothelial cells. Their structure was deciphered as metalloregulated copper-ribonucleoproteins [CuRNP ribokines]. They are built up of angiotropin-related S100-EF-hand protein [ARP] and highly modified and edited 5'end-phosphorylated RNA [ARNA], complexed together by copper ions. Oxidant-sensitive ARNA and their precursors represent novel types in a RNA world: They are the first isolated and sequenced forms of extracellular RNA [eRNA], may act as cytokine and bioaptamer, contain isoguanosine [crotonoside] as modified nucleoside and show up copper as RNA-structuring transition metal ion. By metalloregulated bioaptamer functions, ARNA impart novel biofunctions to RAGE-binding S100-EF-hand proteins. Angiotropin morphogens were shown suitable for neointiation and remodeling of blood vessel patterns in different, adult, embryonal and artificial tissues. These neovascular patterns manifest regulated hemodynamics for preventing tissue necrosis, supporting tissue functions and promoting wound healing. As evaluated in skin and muscle vascularization, the neovascular patterns are integrated into homeostatic control mechanisms of tissue. Thus, the morphogens show up beneficial perspectives and are suggested useful tools

  8. 糖基化终产物通过其受体诱导小鼠足细胞表达单核细胞趋化因子1%Advanced glycation end products-induced MCP-1 expression via its receptor RAGE in mouse podocytes

    Institute of Scientific and Technical Information of China (English)

    顾乐怡; 倪兆慧; 钱家麒; Yasuhiko Tomino

    2006-01-01

    目的了解糖基化终产物(AGE)能否在体外诱导小鼠足细胞表达单核细胞趋化蛋白1(MCP-1)以及其受体RAGE在其中的作用.方法以RT-PCR和ELISA的方法检测AGE、羰甲基化白蛋白(CML)、S100蛋白和RAGE中和抗体对小鼠足细胞的MCP-1的基因和蛋白质表达的影响.结果 (1)未分化和已分化的足细胞都能表达RAGE.(2)AGE和CML以剂量依赖的方式诱导足细胞表达MCP-1mRNA.AGE和CML孵育8 h诱导足细胞产生MCP-1蛋白[分别为(7.44±1.01,8.06±0.96)ng/L],明显高于牛血清白蛋白(BSA)孵育的足细胞[(3.77±0.39)ng/L,均P<0.05],而孵育24 h MCP-1的浓度分别为(87.78±9.32,85.35±9.83和17.95±0.76)ng/L(均P<0.01).(3)RAGE的另外一个配体,S100蛋白,也能以剂量依赖的方式诱导足细胞表达MCP-1 mRNA.RAGE中和抗体完全阻断了AGE、CML和S100的作用.结论 AGE和CML通过RAGE使诱导分化的足细胞表达MCP-1.

  9. 晚期糖化终产物受体反义 RNA 腺相关病毒载体的构建及在肾脏系膜细胞中表达%Construction of recombinant RAGE antisense RNA adeno-associated virus vector and its expression in rat mesangial cell

    Institute of Scientific and Technical Information of China (English)

    游捷; 赵蓉; 刘礼斌; 林建银

    2007-01-01

    目的 构建晚期糖化终产物受体(RAGE)反义RNA腺相关病毒载体,并在大鼠肾脏系膜细胞中表达. 方法 构建腺相关病毒介导的RAGE反义RNA载体,3个质粒共转染293细胞,获得病毒原液,感染大鼠肾脏系膜细胞,流式细胞术、RT-PCR、ELISA检测重组病毒感染的细胞RAGE的表达和分泌细胞外基质的情况.结果 经酶切鉴定、序列分析显示RAGE基因片段正确完整反向插入pAAV-MCS.利用293细胞包装获得病毒原液的滴度为8.7×107VP/mL.感染重组病毒的细胞与正常细胞比较RAGE表达被抑制(48.2±6.1)%,分泌Ⅳ型胶原(ColⅣ)水平明显下降(P<0.05).结论 成功构建具有抑制功能的RAGE反义RNA腺相关病毒载体,为进一步研究RAGE的作用机制,以及基因治疗RAGE相关疾病提供一个重要工具.

  10. Generation of human endometrial knockout cell lines with the CRISPR/Cas9 system confirms the prostaglandin F2α synthase activity of aldo-ketoreductase 1B1.

    Science.gov (United States)

    Lacroix Pépin, Nicolas; Chapdelaine, Pierre; Rodriguez, Yoima; Tremblay, Jacques-P; Fortier, Michel A

    2014-07-01

    Prostaglandins (PGs) are important regulators of female reproductive function. The primary PGs produced in the endometrium are PGE2 and PGF2α. Relatively little is known about the biosynthetic pathways leading to the formation of PGF2α. We have described the role of aldo-ketoreductase (AKR)1B1 in increased PGF2α production by human endometrial cells following stimulation with interleukin-1β (IL-1β). However, alternate PGF synthases are expressed concurrently in endometrial cells. A definite proof of the role of AKR1B1 would require gene knockout; unfortunately, this gene has no direct equivalent in the mouse. Recently, an efficient genome-editing technology using RNA-guided DNase Cas9 and the clustered regularly interspaced short palindromic repeats (CRISPR) system has been developed. We have adapted this approach to knockout AKR1B1 gene expression in human endometrial cell lines. One clone (16-2) of stromal origin generated by the CRISPR/Cas9 system exhibited a complete loss of AKR1B1 protein and mRNA expression, whereas other clones presented with partial edition. The present report focuses on the characterization of clone 16-2 exhibiting deletion of 68 and 2 nucleotides, respectively, on each of the alleles. Cells from this clone lost their ability to produce PGF2α but maintained their original stromal cell (human endometrial stromal cells-2) phenotype including the capacity to decidualize in the presence of progesterone (medroxyprogesterone acetate) and 8-bromo-cAMP. Knockout cells also maintained their ability to increase PGE2 production in response to IL-1β. In summary, we demonstrate that the new genome editing CRISPR/Cas9 system can be used in human cells to generate stable knockout cell line models. Our results suggest that genome editing of human cell lines can be used to complement mouse KO models to validate the function of genes in differentiated tissues and cells. Our results also confirm that AKR1B1 is involved in the synthesis of PGF2α.

  11. Advanced glycosylation end products induce CTGF and FN expression via their receptor RAGE in human renal mesangial cells%糖基化终产物通过其受体诱导人肾小球系膜细胞表达CTGF和FN

    Institute of Scientific and Technical Information of China (English)

    冯敏; 黄国良; 李健榕; 钟林娜

    2010-01-01

    目的:探讨体外培养条件下糖基化终产物(AGEs)对人肾小球系膜细胞(HRMCs)中结缔组织生长因子(CTGF)及纤维连接蛋白(FN)基因表达的影响及其可能的作用机制.方法: 将HRMCs与不同浓度的糖化牛血清白蛋白(AGE-BSA)和牛血清白蛋白(BSA)共同培养,或与同一质量浓度的AGE-BSA和BSA共同培养不同时间,以中和性抗RAGE抗体封闭细胞膜上糖基化终末产物受体(RAGE);采用免疫印迹法(Western blotting)观察AGEs对HRMCs中RAGE表达的影响,半定量逆转录-聚合酶链反应(RT-PCR)法检测CTGF、FN mRNA的表达.结果: 在HRMCs中存在少量RAGE的表达,AGE-BSA能够诱导HRMCs中RAGE的表达增加,并以时间和剂量依赖方式促进HRMCs中CTGF和FN的表达上调;CTGF、FN的表达水平在加入不同浓度(50、100、200、400 mg/L)的AGE-BSA 作用48 h后以及加入质量浓度为200 mg/L的 AGE-BSA 作用不同时间(12、24、48、72h)后,较相应质量浓度或时间的BSA组和空白对照组均明显升高(P<0.05);抗RAGE抗体干预后能够部分抑制AGE-BSA诱导CTGF及FN的表达,而人IgG没有这种作用.结论: AGEs可能通过RAGE诱导CTGF及FN的表达上调,是糖尿病肾病肾脏纤维化的可能机制.

  12. AGE-RAGE interaction promotes the proliferation of human colon carcinoma SW-480 cells%晚期糖基化终产物与其受体相互作用对人结肠癌细胞SW-480增殖的影响

    Institute of Scientific and Technical Information of China (English)

    张圭; 薛耀明; 高方; 朱波

    2010-01-01

    目的 糖尿病患者结肠癌的发病率显著高于非糖尿病人群,晚期糖基化终产物(advanced glycation end products, AGEs)在糖尿病患者体内生成明显增多.文中观察AGEs对人结肠癌细胞SW-480增殖的影响及其机制.方法 体外培养人结肠癌细胞SW-480,以终浓度分别为100μg/ml、200μg/ml、500μg/ml的AGE-BSA处理细胞24h,并设正常对照组和BSA对照组进行比较.采用四甲基偶氮唑盐(MTT)法检测SW-480细胞活力,利用流式细胞术检测细胞周期的改变,实时荧光定量PCR测定晚期糖基化终产物受体(receptor for advanced glycation end products, RAGE)mRNA、细胞周期素D1(cyclin D1)mRNA的表达.结果 ①MTT结果示100μg/ml、200μg/ml、500μg/mlAGE-BSA作用SW-480细胞24h后可以显著促进细胞增殖(P<0.05),并呈浓度依赖性.②流式细胞术结果示200μg/mlAGE-BSA干预组24h后可以减少SW-480细胞G1期百分率,同时增加S期百分率,与正常对照组比较具有统计学差异(P<0.05).③实时荧光定量PCR结果示与正常对照组相比,200μg/mlAGE-BSA干预后可以上调RAGEmRNA和cyclin D1mRNA的表达(P<0.05).结论 AGEs能促进SW-480细胞的增殖,其机制可能与上调RAGEmRNA和cyclin D1mRNA的表达,加速细胞G1期向S期转换相关.

  13. Stress in children exposed to violence. Reenactment and rage.

    Science.gov (United States)

    Pfefferbaum, B; Allen, J R

    1998-01-01

    Violence is a major public health problem that increasingly involves children and adolescents as both victims and witnesses. Exposure to violence is now implicated in the development of stress conditions. This article uses Terr's typology to describe responses to various kinds of violence and suggests that the posttraumatic stress model adds a unique dimension to our understanding of the effects of violence on children and adolescents.

  14. Ritual, rage and revenge in 2 Maccabees 6 and 7

    Directory of Open Access Journals (Sweden)

    Pierre J. Jordaan

    2012-01-01

    Full Text Available The martyrs in 2 Maccabees 6 and 7 have been explored in various ways. In their commentaries on 2 Maccabees, Jan Willem van Henten and Daniel Schwartz proposed that the deaths of the martyrs should be seen as human sacrifices to please the deity. This idea has either been challenged or supported by scholars. This article supported the idea of human sacrifice, and applied the view of Richard DeMaris of the martyr’s deaths as exit rite to the above-mentioned texts. In essence this amounts to ritual critique. The results were surprising, and proved the model of DeMaris as a useful tool to examine rituals. The conclusion was reached that 2 Maccabees 6 and 7 is indeed an exit rite.

  15. Booktalking Wuthering Heights: Themes of Love, Ghosts, and Rage.

    Science.gov (United States)

    Rochman, Hazel

    1986-01-01

    Describes method of presenting theme booktalks to high school students to appeal to their various reading levels and interests. Excerpts from various forms of adult classics and young adult literature illustrate a technique to link the works by themes pertinent to teenage readers. (CD)

  16. Reducing Adolescent Rage Bullies: Study on Behavior Management Training Intervention

    Directory of Open Access Journals (Sweden)

    M Beirami

    2016-12-01

    Full Text Available Background and aim: Adverse effects inner anger and interpersonal relationships will follow on from the other parent behavior management training and promoting and improving relations between parent-child.در این راستا هدف پژوهش حاضر بررسی اثربخشی آموزش مدیریت رفتار براساس مدل بارکلی در کاهش خشم دانش آموزان دختر و پسر قلدر دوره اول متوسطه بود. Methods: The present Experimental research used a pretest– posttest and a control group. جامعه آماری شامل دانش آموزان دختر و پسر دوره اول متوسطه شهر تبریز که در سال تحصیلی 93-1392 مشغول به تحصیل بودند. The population consisted of male and female junior high school students in Tabriz who were enrolled in the 2012-2013 school year. به منظور اجرای پژوهش پس از انجام سرند توسط معلمان و اجرای پرسشنامه قلدر/قربانی الویوس، 30نفر از کودکانی که براساس نمرات کسب شده در پرسشنامه الویوس، به عنوان قلدر طبقه بندی شده بودند به صورت تصادفی در دو گروه 15 نفری آزمایش و کنترل جایگزین شدند؛ و پس از تکمیل پرسشنامه خشم نیلسون(2000 توسط دانش آموزان قلدر؛ والدین گروه آزمایش به مدت 9جلسه (45 دقیقه ای در برنامه آموزش مدیریت رفتار قرارگرفتند، ولی گروه کنترل هیچگونه آموزشی دریافت نکرد.Therefore, after screening by the teachers and the Nelson anger questionnaire, 30 children who, according to scores on the questionnaire were bullies, were classified randomly into two groups of 15 cases and controls were replaced and after completing the questionnaire anger Nilsson (2000 bullying by students, parents groups for 9 sessions (45 minutes each were treated in a management training program, while the control group received no training. آزمودنی ها پس پایان جلسات آموزش مدیریت رفتار والدین ، مورد بررسی مجدد قرار گرفتند. Parent Management Training participants after the end of the session, were reviewed and followed a month later. داده ها با استفاده از نرم افزار آماری18 SPSS و با استفاده از شاخص های توصیفی و آزمون تحلیل کوواریانس چند متغیری مورد تجزیه وتحلیل قرار گرفتند. نتایج حاکی از اثربخشی آموزش مدیریت رفتاری والدین بر کاهش خشم نوجوانان قلدر (05/0 P< بود. Data were analyzed by the SPSS version 18 statistical software using descriptive indicators and multivariate analysis. Results: The results indicated the effectiveness of Parent Management Training to Reduce Anger of the teen bullies (P <0.05, respectively.فقط در مولفه های ناکامی و پرخاشگری بدنی تفاوت معنی داری نبود و در مقایسه اثربخشی آموزش مدیریت رفتار به دختران و پسران گروه آزمایش، نتایج نشان داد که در بین دختران و پسران گروه آزمایش تفاوت معناداری وجود ندارد این نشانگر این است که آموزش مدیریت رفتار به والدین درکاهش خشم نوجوانان قلدر، هردوگروه تاثیر مثبت داشته است. . نتایج درمرحله پیگیری نیز تفاوت معناداری (05/0 P< را بین گروه آزمایش وکنترل نشان داد. The results of the follow-up phase difference (P <0.05 between the test and control groups, respectively. Conclusion: The findings revealed that the behavioral management training had been effective in reducing anger bullying teenagers that might have been due to the effect of education on their daily relations. کلید واژه‌ها: آموزش مدیریت رفتار، بهزیستی روانشناختی، قلدری Keywords: Anger, Bulling, Behavior management training

  17. Pathogen roid rage: cholesterol utilization by Mycobacterium tuberculosis.

    Science.gov (United States)

    Wipperman, Matthew F; Sampson, Nicole S; Thomas, Suzanne T

    2014-01-01

    The ability of science and medicine to control the pathogen Mycobacterium tuberculosis (Mtb) requires an understanding of the complex host environment within which it resides. Pathological and biological evidence overwhelmingly demonstrate how the mammalian steroid cholesterol is present throughout the course of infection. Better understanding Mtb requires a more complete understanding of how it utilizes molecules like cholesterol in this environment to sustain the infection of the host. Cholesterol uptake, catabolism and broader utilization are important for maintenance of the pathogen in the host and it has been experimentally validated to contribute to virulence and pathogenesis. Cholesterol is catabolized by at least three distinct sub-pathways, two for the ring system and one for the side chain, yielding dozens of steroid intermediates with varying biochemical properties. Our ability to control this worldwide infectious agent requires a greater knowledge of how Mtb uses cholesterol to its advantage throughout the course of infection. Herein, the current state of knowledge of cholesterol metabolism by Mtb is reviewed from a biochemical perspective with a focus on the metabolic genes and pathways responsible for cholesterol steroid catabolism.

  18. From Rage to Rap and Prison to Print:

    Directory of Open Access Journals (Sweden)

    Josephine Metcalf

    2009-11-01

    Full Text Available 1. IntroductionBy the late 1980s, while thousands of former gang members were either dead or incarcerated, their legacy and the gang subculture was being celebrated and commodified through gangsta rap music and videos, film and fashion. In the early 1990s this lucrative cultural trend sparked interest from potential authors and publishers. Such literary attention was partially fuelled by a public fascination with life in the ghettos following the 1992 Los Angeles (LA riots, resulting in a ne...

  19. Peru v. Yale: A Battle Rages over Machu Picchu

    Science.gov (United States)

    Glenn, David

    2009-01-01

    In early 1916, the legendary Yale University archaeologist Hiram Bingham III completed his third and final expedition in southern Peru. He shipped home 74 boxes of artifacts from Machu Picchu, a spectacular site in the Andes that is believed to have been the last major settlement of the Inca empire. Those boxes were supposed to be on temporary…

  20. New Rage on Campus: E-Commerce Degrees.

    Science.gov (United States)

    Dobbs, Kevin

    1999-01-01

    As electronic commerce expands, higher education attempts to keep up with the demand for instruction. Some universities have added a concentration in e-commerce to their master of business administration program and others are adding majors, certifications, or degrees. (JOW)

  1. Induction of IFNT-Stimulated Genes by Conceptus-Derived Exosomes during the Attachment Period.

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    Keigo Nakamura

    Full Text Available Biochemical and/or physical communication between the conceptus and the uterine endometrium is required for conceptus implantation to the maternal endometrium, leading to placentation and the establishment of pregnancy. We previously reported that in vitro co-culture system with bovine trophoblast CT-1 cells, primary uterine endometrial epithelial cells (EECs, and uterine flushings (UFs mimics in vivo conceptus attachment process. To identify molecules in UFs responsible for this change, we first characterized protein contents of UFs from day 17 cyclic (C17 and pregnant (P17 ewes through the use of two dimensional-Polyacrylamide Gel Electrophoresis (2D-PAGE, followed by Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS analysis. These analyses identified 266 proteins specific for P17 UFs, from which 172 proteins were identified as exosomal proteins. Among 172 exosomal proteins, 8 proteins that had been identified as exosomal proteins were chosen for further analysis, including macrophage-capping protein (CAPG, aldo-keto reductase family 1, member B1 protein (AKR1B1, bcl-2-like protein 15 (BCL2L15, carbonic anhydrase 2 (CA2, isocitrate dehydrogenase 2 (IDH2, eukaryotic translation elongation factor 2 (EEF2, moesin (MSN, and ezrin (EZR. CAPG and AKR1B1 were again confirmed in P15 and P17 UFs, and more importantly CAPG and AKR1B1, mRNA and protein, were found only in P15 and P17 conceptuses. Moreover, exosomes were isolated from C15, C17, P15, or P17 UFs. Only P15 and P17 exosomes, originated from the conceptus, contained interferon tau (IFNT as well as CAPG and AKR1B1, and up-regulated STAT1, STAT2, MX1, MX2, BST2, and ISG15 transcripts in EECs. These observations indicate that in addition to endometrial derived exosomes previously described, conceptus-derived exosomes are present in UFs and could function to modify endometrial response. These results suggest that exosomes secreted from conceptuses as well as endometria are involved in cell

  2. Correlation between activated NF-κB and synthetase regulating PGF in chorion before and after labor%临产前后绒毛膜中激活的 NF-κB 与 PGF 合成调节酶的相关性

    Institute of Scientific and Technical Information of China (English)

    丁晓颖; 黄鹰; 王晓波; 高青云; 储莉鸣

    2015-01-01

    Objective To study the changes and relationship between activation of NF-κB and the expression of PGF synthetase in chorion before and after labor in term pregnancy.Methods Fifteen cases of term labor ( TL) and 15 cases of term non-labor ( TNL) were selected as the objects of study.Western Blot test was used to observe the expression of activated NF-κB, COX-2 and AKR1B1 in their chorion, and the correlation between them was analyzed.Results Compared with the TNL group, the levels of COX-2 and AKR1B1 increased in TL group, there were significant differences between two groups (F value was 7.737 and 8.772, respectively, both P<0.01), and the level of activated NF-κB was also higher in TL group (F=38.563,P<0.05).Both the expressions of COX-2 and AKR1B1 were positively correlated with the activated NF-κB in chorion before and after labor (r value was 0.243 and 0.168, respectively, both P<0.05). Conclusion The levels of NF-κB, COX-2 and AKR1B1 protein increase in human chorion after labor, and the activated NF-κB can up-regulate the expression of PGF synthetase and lead to increased synthesis of PGF.It may be the mechanism of NF-κB participating in initiation of labor.%目的:分析足月妊娠妇女临产前后绒毛膜中核因子-κB( NF-κB)的激活与前列腺素F( PGF)合成调节酶的蛋白表达变化及其相关性。方法收集足月妊娠临产及未临产妇女各15例的绒毛膜组织,采用Western Blot方法检测其中NF-κB的激活水平以及环氧合酶( COX)-2、醛糖还原酶( AKR1B)1的蛋白水平,并分析NF-κB的激活水平与COX-2、AKR1B1表达的相关性。结果①临产组绒毛膜中COX-2、AKR1B1的蛋白水平均高于未临产组,差异均有极显著性( F值分别为7.737和8.772,均P<0.01);NF-κB的激活水平也高于未临产组,差异有显著性(F=38.563,P<0.05);②临产前后绒毛膜中NF-κB的激活水平与COX-2、AKR1B1的表

  3. Repérage Spatio-Temporel Dans Aurélia

    OpenAIRE

    KAZANOĞLU, Fatma

    2016-01-01

    Aurélia de Gérard de Nerval est une oeuvre autobiographique mais elle peut aussi être considérée comme une oeuvre onirique. Nerval y retransmet son expérience personnelle du rêve. Après avoir déterminé le caractère autobiographique de l’oeuvre à travers la représentation du narrateur, nous procéderons à une classification de l’espace en nous basant essentiellement sur la distinction fondamentale qui se pose d’elle-même d’après le titre complet de l’oeuvre : Aurélia ou le rêve et la vie. L’esp...

  4. Ruminations on the dark side: history of art as rage and denials

    Directory of Open Access Journals (Sweden)

    Branko Mitrović

    2009-12-01

    Full Text Available The holist view is that the creativity of an author is the manifestation of the creativity of the group he or she belongs to; the individualist view is that the creativity of the group is merely the sum of the creativities of the individuals who constitute that group. The holist understanding of human creativity was particularly widespread among Weimar-era historians and their almost unanimous tendency to adopt holist historical explanations constitutes a collective phenomenon in its own right. The paper explores the problems of providing an individualist explanation of this phenomenon.

  5. Amongst the unbelievable: Rage, faith and reason in selected writings by V.S. Naipaul

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    Robert J. Balfour

    2014-02-01

    Full Text Available This article focuses on the representation of faith as conveyed by Naipaul in the course of four travelogues. Drawing on historical scholarship pertaining to Islamic societies in transition, and comparing this to a selection of the literary critical reception that Naipaul’s writing about Islam has evoked, I argue for a revision of literary readings of Naipaul’s travelogues. My premise is that the author’s subject positioning influences both a self-critical as well as more compassionate perspective on the relationship between faith and political transition in developing societies.

  6. Amongst the unbelievable: Rage, faith and reason in selected writings by V.S. Naipaul

    Directory of Open Access Journals (Sweden)

    Robert J. Balfour

    2014-05-01

    Full Text Available This article focuses on the representation of faith as conveyed by Naipaul in the course of four travelogues. Drawing on historical scholarship pertaining to Islamic societies in transition, and comparing this to a selection of the literary critical reception that Naipaul’s writing about Islam has evoked, I argue for a revision of literary readings of Naipaul’s travelogues. My premise is that the author’s subject positioning influences both a self-critical as well as more compassionate perspective on the relationship between faith and political transition in developing societies.

  7. Amongst the unbelievable: Rage, faith and reason in selected writings by V.S. Naipaul

    OpenAIRE

    Balfour, Robert J

    2014-01-01

    This article focuses on the representation of faith as conveyed by Naipaul in the course of four travelogues. Drawing on historical scholarship pertaining to Islamic societies in transition, and comparing this to a selection of the literary critical reception that Naipaul’s writing about Islam has evoked, I argue for a revision of literary readings of Naipaul’s travelogues. My premise is that the author’s subject positioning influences both a self-critical as well as more compassionate perspe...

  8. Relatively Conscious: The Enduring Rage of Baldwin and the Education of a White Southern Baptist Queer

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    Jon-Marc McDonald

    2016-12-01

    Full Text Available Delivered in Paris at the 2016 International James Baldwin Conference just two weeks before the killing of 49 individuals at a LGBT nightclub in Orlando, Florida on 26 June 2016, “Relatively Conscious” explores, through the eyes of an LGBT American and the words of James Baldwin, how separate and unequal life remains for so many within the United States. Written in the tradition of memoir, it recounts how, just as Paris saved Baldwin from himself, the writer’s life was transformedupon the discovery of Baldwin.

  9. 'Go! Sterilise the fertile with thy rage' envy as embittered desire.

    Science.gov (United States)

    Meredith-Owen, William

    2008-09-01

    This paper is concerned with the operation of envy: it considers its origins and their repercussions, in particular its compulsion to sterilize the evidence of fertility, exemplified by Roger Money-Kyrle's evocation of 'the parental intercourse as the supremely creative act'. The inevitable impact on the analytic relationship is considered in the context of two clinical examples of impasse. It is argued that such fundamentally negative transferences, one full of overt aggression and enactment, the other more covertly sabotaging, derive from envious retaliatory impulses originating in experiences--whether phantasied or factual--of exclusion from the anticipated 'good'. Significant recent Jungian contributions to this area are considered and the absence of references to 'envy'--so characteristic of Kleinian discourse--is noted. The ongoing value of integrating Jungian and Kleinian approaches is affirmed.

  10. Possible Role of −374T/A Polymorphism of RAGE Gene in Longevity

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    Colomba Falcone

    2013-11-01

    Full Text Available Demographic and social changes in the last decades have resulted in improvements in health and longevity. The survival of elderly people has improved significantly and thus centenarians are becoming the fastest growing population group. Environmental, genetic, and accidental factors have influenced the human life span. Researchers have gained substantial evidence that advanced glycation end products may play an important role in the processes of physiological aging. The aim of the present study was to investigate any differences in the frequencies of −374T/A polymorphism in subjects aged >90 years and in middle-aged individuals. We observed association between the A allele and genotype homozygous for this allele (AA with a longer life expectancy in the male population. In particular, there was a prevalence of AA genotype and A allele in long-living subjects and a prevalence of the allele T in middle-aged subjects, indicating a possible protective role of the allele A to aging. In conclusion, our results support the hypothesis that longevity is the result of a good functioning of the immune system and a presumable hyper-expression of variants of anti-inflammatory genes of immunity. The differences in the genetic regulation of inflammatory processes may influence the presence of age-related disorders.

  11. Misplaced Populist Rage: Congressional Missteps With Executive Compensation Limitations In The Bailout Legislation

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    Joseph Filloy

    2009-04-01

    Full Text Available Starting in the summer of 2008, the United States and most other economies of the world began to feel the effects of the subprime mortgage crisis. In response, the federal government enacted The Emergency Economic Stabilization Act of 2008 (EESA and The American Recovery and Reinvestment Act of 2009 (ARRA to help restore stability to the U.S. economy. Ultimately this legislation, commonly referred to as “the bailout bill(s,” would result in substantial outlays of taxpayer money to financial institutions deemed systemically significant, or “too big to fail.”

  12. Rage against the Machine: Vincenzo Agnetti’s Critique of Industrial Alienation

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    Laura Moure Cecchini

    2012-12-01

    Full Text Available This essay analyzes the work of the Milanese artist Vincenzo Agnetti (1926-1981, in particular his pieces La macchina drogata (1968 and NEG (1970. Like other Italian artists and intellectuals of the 1960s and 1970s, Agnetti was concerned about the alienation caused by industrial development and consumer society, manifested in carefully designed objects of everyday use. To counteract the automatism of perception and thought that he considered the sign of alienated experience, Agnetti’s artworks employed several strategies that obliged the public to attend to its thinking processes. Thus, Agnetti put in practice forms of aesthetic estrangement similar to those evoked in the same period by Gillo Dorfles and Umberto Eco to counteract the widespread loss of awareness.

  13. The Wellcome Prize Lecture. Genetic imprinting: the battle of the sexes rages on.

    Science.gov (United States)

    Reik, W

    1996-03-01

    Genomic imprinting in mammals is an important genetic mechanism by which genes are expressed or repressed depending on which parent they have been inherited from. Some properties of the imprinting mechanism are already established; notably, some of the effects of imprinting on mammalian development can be explained by the phenotypic effects of a number of specific imprinted genes, which include major fetal growth factors. An evolutionary explanation of imprinting has also been suggested. Some of the molecular mechanisms of imprinting are known, and these include the modification of DNA and chromosomes in the form of DNA methylation and possibly heritable chromatin structures. Loss of imprinting or altered imprinting is implicated in a large number of genetic diseases and cancers. Many important issues remain to be resolved; these include the precise molecular mechanisms and, in particular, the nature of the primary imprints that are inherited from the parental gametes, and the genes that control the imprinting process. Isolation of the majority of imprinted genes and the elucidation of their phenotypic effects and physiology are major goals for the future. These studies will provide important insights into human genetics, and will connect evolutionary understanding with physiology, genetic disease and human behaviour.

  14. Prevention Immediate de la Rage chez L'homme Apres Morsure en Iran

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    M. Baltazard

    1962-01-01

    Full Text Available A new and efficient organization of the early preventron of rabies in man can be proposed thanks to the serum prepared by the Razi Insti~ute in the dried form. This serum, highly concentrated, has therefore an outstanding potency, but a complete innocuity; its dry state allows a perfect c~nservation without special precautions. All medical centers, e.ven the m?st re~ote m the parts Of,the country where rabies remains enzootic, WIll be provided WIth a reserve of this serum, so that eventlhe peasants of the most distant vmages can receive the saving injection .in time, i.e. during the seventy two hours after the inoculation of the virus by the biting animal. Under the protection of the serum the sending of the wounded tow~rds Teheran is 'not, as in the past, a dramatic emergency and would be avoided in many cases. ThLis paper gives then to the physicians the necessary hints, not only for the use of the serum and the wound treatment, but also for the observation of the wounded and of the biting animal.

  15. Etude structurale de la Nucléoprotéine du virus de la rage

    OpenAIRE

    2006-01-01

    Rabies virus, a member of the Mononegavirales family, constitutes a serious health problem in developingcountries lacking effective vaccination programs. The genome of negative-strand RNA viruses is compactedby the nucleoprotein (N) resulting in an N-RNA complex forming a tight helical nucleocapsid that ispackaged into enveloped virions. Transcription and replication in the cytoplasm upon virus infection requiresthe N-RNA as a template for the RNA dependent RNA-polymerase complex. When N is e...

  16. Qualidade de luz no cultivo in vitro de Dendranthema grandiflorum cv. Rage: características morfofisiológicas Quality of light on the in vitro culture of Dendranthema grandiflorum cv. Rage: morphophysiological characteristics

    Directory of Open Access Journals (Sweden)

    Francyane Tavares Braga

    2009-04-01

    Full Text Available Na micropropagação a manutenção das salas de crescimento torna a técnica onerosa, aumentando assim, a necessidade de conduzir estudos envolvendo a manipulação e o controle das condições de cultivo para otimizar o crescimento in vitro. A qualidade de luz pode alterar a morfogênese das plantas por meio de uma série de processos mediados por receptores, que absorvem a luz na região do vermelho e azul do espectro, sendo, portanto, uma maneira viável de aumentar a qualidade das mudas micropropagadas. Objetivou-se com o presente trabalho avaliar o efeito da qualidade de luz, na morfofisiologia de crisântemo [Dendranthema grandiflorum (Ramat. Kitam] micropropagadas. Os explantes constituíram-se de segmentos nodais cultivados in vitro contendo uma gema. Foi utilizado o meio MS acrescido de 15g.L-1 de sacarose e as condições de incubação foram: (SC sala de crescimento, sendo este o tratamento controle; (CV casa-de-vegetação luz natural e casa-de-vegetação com sombrite 50% nas cores: preto, vermelho e azul. A avaliação foi efetuada 60 dias após a implantação do ensaio. Para número de folhas, SC mostrou-se a forma mais efetiva de incubação, com maior número médio de folhas. O mesmo ocorreu com número de raízes, brotações e comprimento médio de raízes. Para comprimento de parte aérea, SC e CV com proteção de sombrite: azul, preto e vermelho foram mais eficientes. Quanto aos aspectos anatômicos, para densidade estomática o maior número de estômatos/mm² foi observado em CV sem sombrite e CV com sombrite vermelho. Para diâmetros polar e equatorial dos estômatos, CV sem sombrite, seguidos de CV azul, vermelho, apresentaram maiores diâmetros. Com os resultados apresentados, é possível recomendar a utilização de luz natural no cultivo in vitro de crisântemo, porém não é recomendado a manipulação da qualidade espectral.In micropropagation, the maintenance of the growth rooms is labor-consuming and expensive, which increases the necessity of studies involving the manipulation and control of the culture conditions to optimize the in vitro growth. The quality of light may modify the morphogenesis of the plants through many processes mediated by receivers, which absorb the light in the blue and red region of the spectrum, being therefore, a viable way to increase the quality of the micropopagated plants. This work aimed at evaluating the effect of the spectral alteration under conditions of natural light on the morphophysiology of micropropagated chrysanthemum [Dendranthema grandiflorum (Ramat. Kitam] plants. Nodal segments with one bud cultivated in vitro were used as explants. The medium used was MS with half of its salts concentration supplemented with 15g.L-1 sucrose. The incubation conditions were growth room (GR, this being the control treatment, greenhouse (GH without shadow protection and greenhouse with 50% shadow in the colors black, blue, and red. The evaluation was done 60 days after the implantation of the assay. For the leaf number, GR showed to be the most effective incubation form, with a higher number of leafs. The same occurred with the number of roots and shoots and the average length of roots. For the aerial part length, GR and GH with shadow protection in all three colors were more efficient. Considering the anatomical aspects for stomatal density, a greater number of stomatal/mm² was observed in GH without shadow protection and in GH with red shadow protection. For the polar and equatorial diameters of the stomata, GR without shadow protection, followed by GR with shadow protection in the colors blue and red, presented a bigger stomatal diameter. With the presented results, it is possible to recommend the use of natural light for the in vitro cultivation of chrysanthemum, however, the manipulation of the spectral quality is not recommended.

  17. Railways, Rebellions and Rage Against The Machine: Adolescents' Interests and Meaning-Making in the Creation of Multimodal Identity Texts

    Science.gov (United States)

    Nagle, Joelle; Stooke, Rosamund

    2016-01-01

    This paper draws on a Canadian qualitative case study grounded in multiliteracies theory to describe the meaning-making processes of four students aged 13-14 years as they created history projects. Students were invited to explore curriculum content in self-chosen ways and to produce presentations in a range of formats. The data we present and…

  18. MicroRNAs in chronic lymphocytic leukemia: miRacle or miRage for prognosis and targeted therapies?

    Science.gov (United States)

    Van Roosbroeck, Katrien; Calin, George A

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is a heterogeneous disease and has a highly variable clinical course with survival ranging from a couple of months to several decades. MicroRNAs (miRNAs), small non-coding RNAs that regulate transcription and translation of genes, have been found to be involved in CLL initiation, progression, and resistance to therapy. In addition, they can be used as prognostic biomarkers and as targets for novel therapies. In this review, we describe the association between miRNAs and the cytogenetic aberrations commonly found in CLL, as well as with other prognostic factors. We describe the presence of miRNAs as extracellular entities in the plasma and serum of CLL patients and discuss their role in resistance to therapy. Finally, we will explore the potential of targeted miRNA therapy for the treatment of CLL, with a special emphasis on MRX34, the first miRNA mimic that is currently being evaluated for clinical use.

  19. Receptor for Advanced Glycation End Products (RAGE) as a Novel Target for Inhibiting Breast Cancer Bone Metastasis

    Science.gov (United States)

    2013-04-01

    generated for studying the role of mS100a7a15 in psoriasis (26). To determine the role of mS100a7a15 in tumor- igenesis, we generated an inducible...been proposed for hS100A7, its biologic role particularly in breast cancer remains to be defined. In this study, we characterized the tumor-enhancing...mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer 2006;95: 272–81. 22. Webb

  20. Raging Hormones and Powerful Cars: The Construction of Men's Sexuality in School Sex Education and Popular Adolescent Films.

    Science.gov (United States)

    Whatley, Mariamne H.

    1988-01-01

    Discusses issues of men's sexuality in the context of school sex education, and analyzes units on human reproduction in secondary biology textbooks. Compares official school knowledge about men's sexuality with alternative sources, including progressive books and the films of John Hughes, to explore the overlapping and contradictory discourses…

  1. Gartley and Pesavento’s harmonic patterns: the corner of stability in the rage sea of technical analysis

    Directory of Open Access Journals (Sweden)

    Ruslan R. Rakhmangulov

    2013-01-01

    Full Text Available Rapid development of financial sector has been attracting many people who want to try themselves as investors during last decades. As statistics says, 9 out of 10 traders lose their money. They fly by the seat of their pants and this is the main reason of failures. Trading system, described in this work, promotes to order investment process and to make it profitable.

  2. Enzymes of the AKR1B and AKR1C subfamilies and uterine diseases

    Directory of Open Access Journals (Sweden)

    Tea eLanisnik Rizner

    2012-03-01

    Full Text Available Endometrial and cervical cancers, uterine myoma, and endometriosis are very common uterine diseases. Worldwide, more than 800,000 women are affected annually by gynecological cancers, as a result of which, more than 360,000 die. During their reproductive age, about 70% of women develop uterine myomas, 10% to 15% suffer from endometriosis, and 35% to 50% from infertility associated with endometriosis. Uterine diseases are associated with aberrant inflammatory responses and concomitant increased production of prostaglandins (PG. They are also related to decreased differentiation, due to low levels of protective progesterone and retinoic acid, and to enhanced proliferation, due to high local concentrations of estrogens. The pathogenesis of these diseases can thus be attributed to disturbed PG, estrogen and retinoid metabolism and actions. Five human members of the aldo-keto reductase 1B (AKR1B and 1C (AKR1C superfamilies, i.e., AKR1B1, AKR1B10, AKR1C1, AKR1C2 and AKR1C3, have roles in these processes and can thus be implicated in uterine diseases. AKR1B1 and AKR1C3 catalyze the formation of PGF2alpha which stimulates cell proliferation. AKR1C3 converts PGD2 to 9alpha,11beta-PGF2, and thus counteracts the formation of 15deoxy-PGJ2, which can activate pro-apoptotic peroxisome-proliferator-activated receptor beta. AKR1B10 catalyzes the reduction of retinal to retinol, and in thus lessens the formation of retinoic acid, with potential pro-differentiating actions. The AKR1C1-AKR1C3 enzymes also act as 17-keto- and 20-ketosteroid reductases to varying extents, and are implicated in increased estradiol and decreased progesterone levels. This review comprises a short introduction to uterine diseases, followed by an overview of the current literature on the AKR1B and AKR1C expression in the uterus and in uterine diseases. The potential implications of the AKR1B and AKR1C enzymes and their pathophysiologies are then discussed, followed by conclusions and

  3. Soluble receptor for advanced glycation end products and risk of liver cancer

    OpenAIRE

    2013-01-01

    Binding of advanced glycation end products (AGEs) to their receptor (RAGE) increases oxidative stress and inflammation, and may be involved in liver injury and subsequent carcinogenesis. Soluble RAGE (sRAGE) may neutralize the effects mediated by AGEs/RAGE complex. Epidemiologic studies examining sRAGE or AGEs in association with liver cancer are lacking. We examined the associations between prediagnostic serum concentrations of sRAGE or Nε-(carboxymethyl)-lysine (CML)-AGE and hepatocellular ...

  4. Screening system of blocking agents of the receptor for advanced glycation endproducts in cells using fluorescence.

    Science.gov (United States)

    Jung, Dong Ho; Kim, Young Sook; Kim, Jin Sook

    2012-01-01

    Activation of the receptor for advanced glycation endproducts (RAGE) triggers cellular responses implicated in the pathogenesis of diabetic complications; blockade of RAGE has been shown to inhibit the development of diabetic complications. To develop a screening system to identify novel disruptors of advanced glycation endproducts (AGE)-RAGE binding, we used an AGE-RAGE binding system in RAGE-overexpressing cells; test compounds were screened using this system. To construct human RAGE-overexpressing cells, mouse mesangial cells (MMCs) were stably transfected with the pcDNA-human RAGE (hRAGE) vector and selected under 1 mg/mL gentamicin (G418). RAGE expression in hRAGE-overexpressing MMCs was analyzed by Western blotting with specific RAGE antibody. To identify novel disruptors of AGE-RAGE binding, 50 single compounds and AGE-bovine serum albumin (BSA)-Alexa 488 (AGE-BSA labeled with Alexa 488) were treated to the hRAGE-overexpressing MMCs. Nonbinding AGE-BSA-Alexa 488 was washed and fluorescence measured by microtiter plate reader (excitation wavelength, 485 nm; emission wavelength, 528 nm). In hRAGE-overexpressing cells, only treatment with AGE-BSA-Alexa 488 significantly increased fluorescence intensity in a dose-dependent manner. Of 50 compounds tested, genistein disrupted AGE-RAGE binding in a dose-dependent manner. This AGE-RAGE binding system using AGE-BSA-Alexa 488 in hRAGE-overexpressing cells was suitable for screening of agents that disrupt AGE-hRAGE binding.

  5. Role of carbonyl reducing enzymes in the phase I biotransformation of the non-steroidal anti-inflammatory drug nabumetone in vitro.

    Science.gov (United States)

    Skarydova, Lucie; Nobilis, Milan; Wsól, Vladimir

    2013-04-01

    1. Nabumetone is a clinically used non-steroidal anti-inflammatory drug, its biotransformation includes major active metabolite 6-methoxy-2-naphtylacetic acid and another three phase I as well as corresponding phase II metabolites which are regarded as inactive. One important biotransformation pathway is carbonyl reduction, which leads to the phase I metabolite, reduced nabumetone. 2. The aim of this study is the determination of the role of a particular human liver subcellular fraction in the nabumetone reduction and the identification of participating carbonyl reducing enzymes along with their stereospecificities. 3. Both subcellular fractions take part in the carbonyl reduction of nabumetone and the reduction is at least in vitro the main biotransformation pathway. The activities of eight cytosolic carbonyl reducing enzymes--CBR1, CBR3, AKR1B1, AKR1B10, AKR1C1-4--toward nabumetone were tested. Except for CBR3, all tested reductases transform nabumetone to its reduced metabolite. AKR1C4 and AKR1C3 have the highest intrinsic clearances. 4. The stereospecificity of the majority of the tested enzymes is shifted to the production of an (+)-enantiomer of reduced nabumetone; only AKR1C1 and AKR1C4 produce predominantly an (-)-enantiomer. This project provides for the first time evidence that seven specific carbonyl reducing enzymes participate in nabumetone metabolism.

  6. Detoxifying enzymes at the cross-roads of inflammation, oxidative stress and drug hypersensitivity: role of glutathione transferase P1-1 and aldose reductase

    Directory of Open Access Journals (Sweden)

    Francisco J Sánchez-Gómez

    2016-08-01

    Full Text Available Phase I and II enzymes are involved in the metabolism of endogenous reactive compounds as well as xenobiotics, including toxicants and drugs. Genotyping studies have established several drug metabolizing enzymes as markers for risk of drug hypersensitivity. However, other candidates are emerging that are involved in drug metabolism but also in the generation of danger or costimulatory signals. Enzymes such as aldo-keto reductases (AKR and glutathione transferases (GST metabolize prostaglandins and reactive aldehydes with proinflammatory activity, as well as drugs and/or their reactive metabolites. In addition, their metabolic activity can have important consequences for the cellular redox status, and impacts the inflammatory response as well as the balance of inflammatory mediators, which can modulate epigenetic factors and cooperate or interfere with drug-adduct formation. These enzymes are, in turn, targets for covalent modification and regulation by oxidative stress, inflammatory mediators and drugs. Therefore, they constitute a platform for a complex set of interactions involving drug metabolism, protein haptenation, modulation of the inflammatory response and/or generation of danger signals with implications in drug hypersensitivity reactions. Moreover, increasing evidence supports their involvement in allergic processes. Here, we will focus on GSTP1-1 and AKR1B1 and provide a perspective for their involvement in drug hypersensitivity.

  7. Detoxifying Enzymes at the Cross-Roads of Inflammation, Oxidative Stress, and Drug Hypersensitivity: Role of Glutathione Transferase P1-1 and Aldose Reductase

    Science.gov (United States)

    Sánchez-Gómez, Francisco J.; Díez-Dacal, Beatriz; García-Martín, Elena; Agúndez, José A. G.; Pajares, María A.; Pérez-Sala, Dolores

    2016-01-01

    Phase I and II enzymes are involved in the metabolism of endogenous reactive compounds as well as xenobiotics, including toxicants and drugs. Genotyping studies have established several drug metabolizing enzymes as markers for risk of drug hypersensitivity. However, other candidates are emerging that are involved in drug metabolism but also in the generation of danger or costimulatory signals. Enzymes such as aldo-keto reductases (AKR) and glutathione transferases (GST) metabolize prostaglandins and reactive aldehydes with proinflammatory activity, as well as drugs and/or their reactive metabolites. In addition, their metabolic activity can have important consequences for the cellular redox status, and impacts the inflammatory response as well as the balance of inflammatory mediators, which can modulate epigenetic factors and cooperate or interfere with drug-adduct formation. These enzymes are, in turn, targets for covalent modification and regulation by oxidative stress, inflammatory mediators, and drugs. Therefore, they constitute a platform for a complex set of interactions involving drug metabolism, protein haptenation, modulation of the inflammatory response, and/or generation of danger signals with implications in drug hypersensitivity reactions. Moreover, increasing evidence supports their involvement in allergic processes. Here, we will focus on GSTP1-1 and aldose reductase (AKR1B1) and provide a perspective for their involvement in drug hypersensitivity. PMID:27540362

  8. 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.

  9. The association between the -374T/A polymorphism of the receptor for advanced glycation endproducts gene and blood pressure and arterial stiffness is modified by glucose metabolism status: the Hoorn and CoDAM studies

    NARCIS (Netherlands)

    Engelen, L.; Ferreira, I.; Gaens, K.H.; Henry, R.; Dekker, J.M.; Nijpels, G.; Heine, R.J.; Hart, t L.M.; Greevenboek, van M.M.; Kallen, C.J.; Blaak, E.E.; Feskens, E.J.M.; Cate, ten H.; Stehouwer, C.D.; Schalkwijk, C.G.

    2010-01-01

    Objectives: Receptor for advanced glycation endproducts (RAGE)–ligand interaction may lead to vascular complications. Genetic variation in RAGE has been shown to alter expression, activity of RAGE or both. We, therefore, investigated whether RAGE single-nucleotide polymorphisms (SNPs) and haplotypes

  10. Trientine Reduces BACE1 Activity and Mitigates Amyloidosis via the AGE/RAGE/NF-κB Pathway in a Transgenic Mouse Model of Alzheimer's Disease

    OpenAIRE

    Wang, Chun-yan; Xie, Jing-Wei; Xu, Ye; WANG Tao; Cai, Jian-Hui; Wang,Xu; Zhao, Bao-Lu; AN Li; Wang, Zhan-You

    2013-01-01

    Aims: There is mounting evidence that the transition metal copper may play an important role in the pathophysiology of Alzheimer's disease (AD). Triethylene tetramine dihydrochloride (trientine), a CuII-selective chelator, is a commonly used treatment for Wilson's disease to decrease accumulated copper, and thereby decreases oxidative stress. In the present study, we evaluated the effects of a 3-month treatment course of trientine (Trien) on amyloidosis in 7-month-old β-amyloid (Aβ) precursor...

  11. De la terminologie musicale pour la didactique du français langue étrangère: ouvertures et repérages

    OpenAIRE

    Aubin, Sophie

    2010-01-01

    La terminología musical actual de la didáctica del francés como lengua extranjera se limita a una serie de términos que proceden generalmente y directamente de la fonética aplicada. El nivel de integración didáctica de esta terminología, por presentar cierta complejidad, sigue siendo muy relativo dando lugar a cierto vacío. Sin embargo y teniendo en cuenta la naturaleza profundamente musical de una lengua viva y moderna, la necesidad de nombrar los elementos musicales así como las técnicas qu...

  12. RAGE介导S100蛋白的细胞外信号效应%RAGE mediates the extracellular effects of S100 protein

    Institute of Scientific and Technical Information of China (English)

    杨井金; 曹仁贤; 文芳

    2009-01-01

    S100蛋白家族至少由25个成员组成,参与多种细胞内功能活动的调节.最近研究表明,一些S100蛋白经过非经典途径释放到细胞外,并与晚期糖基化终末产物受体结合发挥生物学效应.S100蛋白与晚期糖基化终末产物受体的相互作用在炎症、肿瘤的发生发展中可能起重要的作用.

  13. Transient and Prolonged Response of Chicken Cecum Mucosa to Colonization with Different Gut Microbiota

    Science.gov (United States)

    Volf, Jiri; Polansky, Ondrej; Varmuzova, Karolina; Gerzova, Lenka; Sekelova, Zuzana; Faldynova, Marcela; Babak, Vladimir; Medvecky, Matej; Smith, Adrian L.; Kaspers, Bernd; Velge, Philippe; Rychlik, Ivan

    2016-01-01

    In this study we determined protein and gene expression in the caeca of newly hatched chickens inoculated with cecal contents sourced from hens of different ages. Over 250 proteins exhibited modified expression levels in response to microbiota inoculation. The most significant inductions were observed for ISG12-2, OASL, ES1, LYG2, DMBT1-L, CDD, ANGPTL6, B2M, CUZD1, IgM and Ig lambda chain. Of these, ISG12-2, ES1 and both immunoglobulins were expressed at lower levels in germ-free chickens compared to conventional chickens. In contrast, CELA2A, BRT-2, ALDH1A1, ADH1C, AKR1B1L, HEXB, ALDH2, ALDOB, CALB1 and TTR were expressed at lower levels following inoculation of microbiota. When chicks were given microbiota preparations from different age donors, the recipients mounted differential responses to the inoculation which also differed from the response profile in naturally colonised birds. For example, B2M, CUZD1 and CELA2A responded differently to the inoculation with microbiota of 4- or 40-week-old hens. The increased or decreased gene expression could be recorded 6 weeks after the inoculation of newly hatched chickens. To characterise the proteins that may directly interact with the microbiota we characterised chicken proteins that co-purified with the microbiota and identified a range of host proteins including CDD, ANGPTL6, DMBT1-L, MEP1A and Ig lambda. We propose that induction of ISG12-2 results in reduced apoptosis of host cells exposed to the colonizing commensal microbiota and that CDD, ANGPTL6, DMBT1-L, MEP1A and Ig lambda reduce contact of luminal microbiota with the gut epithelium thereby reducing the inflammatory response. PMID:27685470

  14. Aldo-Keto Reductases 1B in Endocrinology and Metabolism.

    Science.gov (United States)

    Pastel, Emilie; Pointud, Jean-Christophe; Volat, Fanny; Martinez, Antoine; Lefrançois-Martinez, Anne-Marie

    2012-01-01

    The aldose reductase (AR; human AKR1B1/mouse Akr1b3) has been the focus of many research because of its role in diabetic complications. The starting point of these alterations is the massive entry of glucose in polyol pathway where it is converted into sorbitol by this enzyme. However, the issue of AR function in non-diabetic condition remains unresolved. AR-like enzymes (AKR1B10, Akr1b7, and Akr1b8) are highly related isoforms often co-expressed with bona fide AR, making functional analysis of one or the other isoform a challenging task. AKR1B/Akr1b members share at least 65% protein identity and the general ability to reduce many redundant substrates such as aldehydes provided from lipid peroxidation, steroids and their by-products, and xenobiotics in vitro. Based on these properties, AKR1B/Akr1b are generally considered as detoxifying enzymes. Considering that divergences should be more informative than similarities to help understanding their physiological functions, we chose to review specific hallmarks of each human/mouse isoforms by focusing on tissue distribution and specific mechanisms of gene regulation. Indeed, although the AR shows ubiquitous expression, AR-like proteins exhibit tissue-specific patterns of expression. We focused on three organs where certain isoforms are enriched, the adrenal gland, enterohepatic, and adipose tissues and tried to connect recent enzymatic and regulation data with endocrine and metabolic functions of these organs. We presented recent mouse models showing unsuspected physiological functions in the regulation of glucido-lipidic metabolism and adipose tissue homeostasis. Beyond the widely accepted idea that AKR1B/Akr1b are detoxification enzymes, these recent reports provide growing evidences that they are able to modify or generate signal molecules. This conceptually shifts this class of enzymes from unenviable status of scavenger to upper class of messengers.

  15. Aldose reductases influence prostaglandin F2α levels and adipocyte differentiation in male mouse and human species.

    Science.gov (United States)

    Pastel, Emilie; Pointud, Jean-Christophe; Loubeau, Gaëlle; Dani, Christian; Slim, Karem; Martin, Gwenaëlle; Volat, Fanny; Sahut-Barnola, Isabelle; Val, Pierre; Martinez, Antoine; Lefrançois-Martinez, Anne-Marie

    2015-05-01

    Aldose reductases (AKR1B) are widely expressed oxidoreductases whose physiological function remains elusive. Some isoforms are genuine prostaglandin F2α (PGF2α) synthases, suggesting they might influence adipose homeostasis because PGF2α inhibits adipogenesis. This was shown by Akr1b7 gene ablation in the mouse, which resulted in increased adiposity related to a lower PGF2α content in fat. Yet humans have no ortholog gene for Akr1b7, so the role of aldose reductases in human adipose homeostasis remains to be explored. We analyzed expression of genes encoding human and mouse aldose reductase isoforms in adipose tissues and differentiating adipocytes to assess conserved mechanisms regulating PGF2α synthesis and adipogenesis. The Akr1b3 gene encoded the most abundant isoform in mouse adipose tissue, whereas Akr1b7 encoded the only isoform enriched in the stromal vascular fraction. Most mouse aldose reductase gene expression peaked in early adipogenesis of 3T3-L1 cells and diminished with differentiation. In contrast with its mouse ortholog Akr1b3, AKR1B1 expression increased throughout differentiation of human multipotent adipose-derived stem cells, paralleling PGF2α release, whereas PGF2α receptor (FP) levels collapsed in early differentiation. Pharmacological inhibition of aldose reductase using Statil altered PGF2α production and enhanced human multipotent adipose-derived stem adipocyte differentiation. As expected, the adipogenic effects of Statil were counteracted by an FP agonist (cloprostenol). Thus, in both species aldose reductase-dependent PGF2α production could be important in early differentiation to restrict adipogenesis. PGF2α antiadipogenic signaling could then be toned down through the FP receptor or aldose reductases down-regulation in human and mouse cells, respectively. Our data suggest that aldose reductase inhibitors could have obesogenic potential.

  16. Aldo-keto reductases 1B in adrenal cortex physiology

    Directory of Open Access Journals (Sweden)

    Emilie PASTEL

    2016-07-01

    Full Text Available Aldose reductase proteins are cytosolic monomeric enzymes, belonging to the aldo-keto reductase (AKR superfamily. They perform oxidoreduction of carbonyl groups from a wide variety of substrates such as aliphatic and aromatic aldehydes or ketones. The Aldose reductase subgroup (AKR1B is one of the most characterized because of its involvement in human diseases such as diabetic complications resulting from the ability of its human archetype AKR1B1 to reduce glucose into sorbitol. However the issue of AKR1B function in non pathologic condition remains poorly resolved. Adrenal steroidogenesis is strongly associated with high production of endogenous harmful lipid aldehyde by-products including isocaproaldehyde (4-methylpentanal derived from cholesterol side chain cleavage (the first step of steroid synthesis and 4-hydroxynonenal (4- HNE that can both be reduced by AKR1B proteins. More recently, some AKR1B isoforms have been shown to be endowed with prostaglandin F synthase activity, suggesting that in addition to possible scavenger function, they could instigate paracrine signals. Interestingly, previous studies have established that the adrenal gland is one of the major site for human and murine AKR1B expression suggesting that their detoxifying/signaling activity could be specifically required for the correct handling of adrenal function. Moreover chronic effects of ACTH result in a coordinated regulation of genes encoding the steroidogenic enzymes and some AKR1B isoforms.This review presents the molecular mechanisms accounting for the adrenal specific expression of some AKR1B genes. Using data from recent mouse genetic models, we will try to connect their enzymatic properties and regulation with adrenal functions.

  17. Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: structure determination of both ternary complexes and implications for drug design.

    Science.gov (United States)

    Cousido-Siah, Alexandra; Ruiz, Francesc X; Mitschler, André; Porté, Sergio; de Lera, Ángel R; Martín, María J; Manzanaro, Sonia; de la Fuente, Jesús A; Terwesten, Felix; Betz, Michael; Klebe, Gerhard; Farrés, Jaume; Parés, Xavier; Podjarny, Alberto

    2014-03-01

    Aldo-keto reductases (AKRs) are mostly monomeric enzymes which fold into a highly conserved (α/β)8 barrel, while their substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable external loops. The closely related human enzymes aldose reductase (AR or AKR1B1) and AKR1B10 are of biomedical interest because of their involvement in secondary diabetic complications (AR) and in cancer, e.g. hepatocellular carcinoma and smoking-related lung cancer (AKR1B10). After characterization of the IC50 values of both AKRs with a series of polyhalogenated compounds, 2,2',3,3',5,5',6,6'-octafluoro-4,4'-biphenyldiol (JF0064) was identified as a lead inhibitor of both enzymes with a new scaffold (a 1,1'-biphenyl-4,4'-diol). An ultrahigh-resolution X-ray structure of the AR-NADP(+)-JF0064 complex has been determined at 0.85 Å resolution, allowing it to be observed that JF0064 interacts with the catalytic residue Tyr48 through a negatively charged hydroxyl group (i.e. the acidic phenol). The non-competitive inhibition pattern observed for JF0064 with both enzymes suggests that this acidic hydroxyl group is also present in the case of AKR1B10. Moreover, the combination of surface lysine methylation and the introduction of K125R and V301L mutations enabled the determination of the X-ray crystallographic structure of the corresponding AKR1B10-NADP(+)-JF0064 complex. Comparison of the two structures has unveiled some important hints for subsequent structure-based drug-design efforts.

  18. Structural analysis of sulindac as an inhibitor of aldose reductase and AKR1B10.

    Science.gov (United States)

    Cousido-Siah, Alexandra; Ruiz, Francesc X; Crespo, Isidro; Porté, Sergio; Mitschler, André; Parés, Xavier; Podjarny, Alberto; Farrés, Jaume

    2015-06-05

    Aldose reductase (AR, AKR1B1) and AKR1B10 are enzymes implicated in important pathologies (diabetes and cancer) and therefore they have been proposed as suitable targets for drug development. Sulindac is the metabolic precursor of the potent non-steroidal anti-inflammatory drug (NSAID) sulindac sulfide, which suppresses prostaglandin production by inhibition of cyclooxygenases (COX). In addition, sulindac has been found to be one of the NSAIDs with higher antitumoral activity, presumably through COX inhibition. However, sulindac anticancer activity could be partially mediated through COX-independent mechanisms, including the participation of AR and AKR1B10. Previously, it had been shown that sulindac and sulindac sulfone were good AR inhibitors and the structure of the ternary complex with NADP(+) and sulindac was described (PDB ID 3U2C). In this work, we determined the three-dimensional structure of AKR1B10 with sulindac and established structure-activity relationships (SAR) of sulindac and their derivatives with AR and AKR1B10. The difference in the IC50 values for sulindac between AR (0.36 μM) and AKR1B10 (2.7 μM) might be explained by the different positioning and stacking interaction given by Phe122/Phe123, and by the presence of two buried and ordered water molecules in AKR1B10 but not in AR. Moreover, SAR analysis shows that the substitution of the sulfinyl group is structurally allowed in sulindac derivatives. Hence, sulindac and its derivatives emerge as lead compounds for the design of more potent and selective AR and AKR1B10 inhibitors.

  19. Screening of potential pseudo att sites of Streptomyces phage ΦC31 integrase in the human genome

    Institute of Scientific and Technical Information of China (English)

    Zhi-peng HU; Lu-sheng CHEN; Cai-yan JIA; Huan-zhang ZHU; Wei WANG; Jiang ZHONG

    2013-01-01

    Aim:ΦC31 integrase mediates site-specific recombination between two short sequences,attP and attB,in phage and bacterial genomes,which is a promising tool in gene regulation-based therapy since the zinc finger structure is probably the DNA recognizing domain that can further be engineered.The aim of this study was to screen potential pseudo att sites of ΦC31 integrase in the human genome,and evaluate the risks of its application in human gene therapy.Methods:TFBS (transcription factor binding sites) were found on the basis of reported pseudo att sites using multiple motif-finding tools,including AlignACE,BioProspector,Consensus,MEME,and Weeder.The human genome with the proposed motif was scanned tc find the potential pseudo att sites of ΦC31 integrase.Results:The possible recognition motif of ΦC31 integrase was identified,which was composed of two co-occurrence conserved elements that were reverse complement to each other flanking the core sequence TTG.In the human genome,a total of 27924 potential pseudo att sites of ΦC31 integrase were found,which were distributed in each human chromosome with high-risk specificity values in the chromosomes 16,17,and 19.When the risks of the sites were evaluate more rigorously,53 hits were discovered,and some of them were just the vital functional genes or regulatory regions,such as ACYP2,AKR1B1,DUSP4,etc.Conclusion:The results provide clues for more comprehensive evaluation of the risks of using ΦC31 integrase in human gene therapy and for drug discovery.

  20. The isolation and characterization of β-glucogallin as a novel aldose reductase inhibitor from Emblica officinalis.

    Directory of Open Access Journals (Sweden)

    Muthenna Puppala

    Full Text Available Diabetes mellitus is recognized as a leading cause of new cases of blindness. The prevalence of diabetic eye disease is expected to continue to increase worldwide as a result of the dramatic increase in the number of people with diabetes. At present, there is no medical treatment to delay or prevent the onset and progression of cataract or retinopathy, the most common causes of vision loss in diabetics. The plant Emblica officinalis (gooseberry has been used for thousands of years as a traditional Indian Ayurvedic preparation for the treatment of diabetes in humans. Extracts from this plant have been shown to be efficacious against the progression of cataract in a diabetic rat model. Aldose reductase (ALR2 is implicated in the development of secondary complications of diabetes including cataract and, therefore, has been a major drug target for the development of therapies to treat diabetic disease. Herein, we present the bioassay-guided isolation and structure elucidation of 1-O-galloyl-β-D-glucose (β-glucogallin, a major component from the fruit of the gooseberry that displays selective as well as relatively potent inhibition (IC(50 = 17 µM of AKR1B1 in vitro. Molecular modeling demonstrates that this inhibitor is able to favorably bind in the active site. Further, we show that β-glucogallin effectively inhibits sorbitol accumulation by 73% at 30 µM under hyperglycemic conditions in an ex-vivo organ culture model of lenses excised from transgenic mice overexpressing human ALR2 in the lens. This study supports the continued development of natural products such as β-glucogallin as therapeutic leads in the development of novel therapies to treat diabetic complications such as cataract.

  1. Proteome analysis of early lineage specification in bovine embryos.

    Science.gov (United States)

    Demant, Myriam; Deutsch, Daniela R; Fröhlich, Thomas; Wolf, Eckhard; Arnold, Georg J

    2015-02-01

    During mammalian embryo development, the zygote undergoes embryonic cleavage in the oviduct and reaches the uterus at the morula stage, when compaction and early lineage specification take place. To increase knowledge about the associated changes of the embryonic protein repertoire, we performed a comprehensive proteomic analysis of in vitro produced bovine morulae and blastocysts (six biological replicates), using an iTRAQ-based approach. A total of 560 proteins were identified of which 502 were quantified. The abundance of 140 proteins was significantly different between morulae and blastocysts, among them nucleophosmin (NPM1), eukaryotic translation initiation factor 5A-1 (EIF5A), receptor of activated protein kinase C 1 (GNB2L1/RACK1), and annexin A6 (ANXA6) with increased, and glutathione S-transferase mu 3 (GSTM3), peroxiredoxin 2 (PRDX2), and aldo-keto reductase family 1 member B1 (AKR1B1) with decreased abundance in blastocysts. Seventy-three percent of abundance altered proteins increased, reflecting an increase of translation activity in this period. This is further supported by an increase in the abundance of proteins involved in the translation machinery and the synthesis of ATP. Additionally, a complementary 2D saturation DIGE analysis led to the detection of protein isoforms, e.g. of GSTM3 and PRDX2, relevant for this period of mammalian development, and exemplarily verified the results of the iTRAQ approach. In summary, our systematic differential proteome analysis of bovine morulae and blastocysts revealed new molecular correlates of early lineage specification and differentiation events during bovine embryogenesis.

  2. STAR and AKR1B10 are down-regulated in high-grade endometrial cancer.

    Science.gov (United States)

    Sinreih, Maša; Štupar, Saša; Čemažar, Luka; Verdenik, Ivan; Grazio-Frković, Snježana; Smrkolj, Špela; Rižner, Tea Lanišnik

    2017-02-20

    Endometrial cancer is the most frequent gynecological malignancy in the developed world. The majority of cases are estrogen dependent, and are associated with diminished protective effects of progesterone. Endometrial cancer is also related to enhanced inflammation and decreased differentiation. In our previous studies, we examined the expression of genes involved in estrogen and progesterone actions, in inflammation and tumor differentiation, in tissue samples from endometrial cancer and adjacent control endometrium. The aims of the current study were to examine correlations between gene expression and several demographic characteristics, and to evaluate changes in gene expression with regard to histopathological and clinical characteristics of 51 patients. We studied correlations and differences in expression of 38 genes involved in five pathophysiological processes: (i) estrogen-stimulated proliferation; (ii) estrogen-dependent carcinogenesis; (iii) diminished biosynthesis of progesterone: (iv) enhanced formation of progesterone metabolites; and (v) increased inflammation and decreased differentiation. Spearman correlation coefficient analysis shows that expression of PAQR7 correlates with age, expression of SRD5A1, AKR1B1 and AKR1B10 correlate with body mass, while expression of SRD5A1 and AKR1B10 correlate with body mass index. When patients with endometrial cancer were stratified based on menopausal status, histological grade, myometrial invasion, lymphovascular invasion, and FIGO stage, Mann-Whitney U tests revealed significantly decreased expression of STAR (4.4-fold; adjusted p=0.009) and AKR1B10 (9-fold; adjusted p=0.003) in high grade versus low grade tumors. Lower levels of STAR might lead to decreased de-novo steroid hormone synthesis and tumor differentiation, and lower levels of AKR1B10 to diminished elimination of toxic electrophilic carbonyl compounds in high-grade endometrial cancer. These data thus reveal the potential STAR and AKR1B10 as

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Vessel Ultrasound Sonographic Assessment of Soluble Receptor for Advanced Glycation End Products Efficacy in a Rat Balloon Injury Model

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Soluble Forms and Ligands of the Receptor for Advanced Glycation End-Products in Patients with Acute Respiratory Distress Syndrome: An Observational Prospective Study.

    Directory of Open Access Journals (Sweden)

    Matthieu Jabaudon

    Full Text Available The main soluble form of the receptor for advanced glycation end-products (sRAGE is elevated during acute respiratory distress syndrome (ARDS. However other RAGE isoforms and multiple ligands have been poorly reported in the clinical setting, and their respective contribution to RAGE activation during ARDS remains unclear. Our goal was therefore to describe main RAGE isoforms and ligands levels during ARDS.30 ARDS patients and 30 mechanically ventilated controls were prospectively included in this monocenter observational study. Arterial, superior vena cava and alveolar fluid levels of sRAGE, endogenous-secretory RAGE (esRAGE, high mobility group box-1 protein (HMGB1, S100A12 and advanced glycation end-products (AGEs were measured in duplicate ELISA on day 0, day 3 and day 6. In patients with ARDS, baseline lung morphology was assessed with computed tomography.ARDS patients had higher arterial, central venous and alveolar levels of sRAGE, HMGB1 and S100A12, but lower levels of esRAGE and AGEs, than controls. Baseline arterial sRAGE, HMGB1 and S100A12 were correlated with nonfocal ARDS (AUC 0.79, 0.65 and 0.63, respectively. Baseline arterial sRAGE, esRAGE, S100A12 and AGEs were associated with severity as assessed by PaO2/FiO2.This is the first kinetics study of levels of RAGE main isoforms and ligands during ARDS. Elevated sRAGE, HMGB1 and S100A12, with decreased esRAGE and AGEs, were found to distinguish patients with ARDS from those without. Our findings should prompt future studies aimed at elucidating RAGE/HMGB1/S100A12 axis involvement in ARDS.clinicaltrials.gov Identifier: NCT01270295.

  7. Receptor for advanced glycation end products Glycine 82 Serine polymorphism and risk of cardiovascular events in rheumatoid arthritis

    OpenAIRE

    Carroll, Lisa; Frazer, Ian H; Turner, Malcolm; Marwick, Thomas H.; Thomas, Ranjeny

    2007-01-01

    Patients with rheumatoid arthritis (RA) are at risk of excess mortality, predominantly owing to cardiovascular (CV) events. The receptor for advanced glycation end products (RAGE) has been implicated in the perpetuation of the chronic inflammatory response in vascular disease. A Gly82→Ser polymorphism in the RAGE gene, which is associated with enhanced RAGE signaling, is present more frequently in patients with RA than the general population. To investigate whether RAGE Gly82→Ser polymorphism...

  8. 全程健康教育在全脑血管造影术中的应用研究%Application of full rage health education in aortocranial angiography

    Institute of Scientific and Technical Information of China (English)

    张芬; 张贵清; 苏晓梅

    2012-01-01

    目的 探讨全程健康教育在全脑血管造影术中的应用效果.方法 选择未开展全程健康教育的72例患者为对照组,实施全程健康教育的78例患者为实验组.对照组采用常规护理干预,实验组实施全程健康教育,即术前、术中和术后由专职健康教育护士给予个体化的全程健康教育和护理干预.观察并比较2组患者手术依从性、术后舒适度及不良反应的发生情况.结果 实验组患者手术依从性和术后舒适度明显高于对照组(P<0.05),不良反应则低于对照组(P<0.05).结论 实施全程健康教育可以提高患者的手术依从性,改善患者的舒适度,减少术后不良反应的发生.%Objective To explore the effect of full range health education on aortocranial angiography. Methods 72 patients without any health education were selected as control group, while 78 patients with full range health education were selected as experimental group. Control group received conventional nursing intervention, and experimental group received full range health education, which was preoperative, intraoperative, postoperative individualized full range health education and nursing intervention given by special health education nurses. Operation compliance, postoperative comfort degree and adverse reaction were observed and compared between two groups. Results Operation compliance and postoperative comfort degree of experimental group were significantly higher than that of control group(P<0. 05), while the adverse action in experimental group was lower than control group (P < 0. 05). Conclusion Implementation of full range health education can improve the patients' operation compliance and postoperative comfort as well as reduce incidence of adverse reactions.

  9. 血脑屏障RAGE/LRP1转运体及神经血管单元与阿尔茨海默病关系的研究进展

    Institute of Scientific and Technical Information of China (English)

    王浩[1; 杜贯涛[2; 刘广军[2; 洪浩[1

    2015-01-01

    血脑屏障(blood-brain barrier,BBB)是介于外周和中枢神经系统之间的一道生理屏障,对维持中枢神经系统的稳态起着重要作用。研究表明,血脑屏障与阿尔茨海默病(Alzheimer’s disease,AD)的发生发展密切相关。该文重点论述血脑屏障晚期糖基化终产物受体(receptor for advanced glycation end products,RAGE)/低密度脂蛋白受体相关蛋白1(low density lipoprotein receptor-related protein 1,LRP1)受体转运系统及以血脑屏障为核心组分的神经血管单元(neurovascular unit,NVU)介导的中枢β-淀粉样蛋白(β-amyloid protein,Aβ)水平调控与AD发病机制的关系,为AD防治提供新思路。

  10. Endogenous secretory receptor for advanced glycation end-products inhibits amyloid-β1-42 uptake into mouse brain.

    Science.gov (United States)

    Sugihara, Takahiro; Munesue, Seiichi; Yamamoto, Yasuhiko; Sakurai, Shigeru; Akhter, Nasima; Kitamura, Yoji; Shiba, Kazuhiro; Watanabe, Takuo; Yonekura, Hideto; Hayashi, Yasuhiko; Hamada, Jun-Ichiro; Yamamoto, Hiroshi

    2012-01-01

    The cell-surface receptor for advanced glycation end-products (RAGE) has been implicated in the development of diabetic vascular complications and Alzheimer's disease. RAGE has been considered to be involved in amyloid-β1-42 (Aβ1-42) uptake into brain. In the present study, we demonstrate that endogenous secretory RAGE (esRAGE), a decoy form of RAGE generated by alternative RNA processing, is able to inhibit Aβ1-42 influx into mouse brain. Surface plasmon resonance and competitive binding assays revealed that human Aβ1-42 interacted with human esRAGE within the immunoglobulin V type region. We next examined the uptake and distribution of 125I-labeled human Aβ1-42 in various organs and body fluids of newly created mice overexpressing human esRAGE as well as RAGE-null and wild-type (WT) mice. The transition of the 125I-labeled Aβ1-42 from circulation to brain parenchyma peaked at 30 min after the injection into WT mice, but this was significantly blunted in esRAGE-overexpressing and RAGE-null mice. Significant reduction in 125I-labeled Aβ1-42-derived photo-stimulated luminescence were marked in ventricles, cerebral cortex, hippocampus, especially CA1 and CA3 regions, putamen, and thalamus. The results thus suggest the potential of esRAGE in protection against the development of Alzheimer's disease.

  11. Levels of Soluble Receptor for Advanced Glycation End Products in Bronchoalveolar Lavage Fluid in Patients with Various Inflammatory Lung Diseases

    Science.gov (United States)

    Kamo, Tetsuro; Tasaka, Sadatomo; Tokuda, Yuriko; Suzuki, Shoji; Asakura, Takanori; Yagi, Kazuma; Namkoong, Ho; Ishii, Makoto; Hasegawa, Naoki; Betsuyaku, Tomoko

    2015-01-01

    Receptor for advanced glycation end products (RAGE) is a multiligand receptor of S100/calgranulins, high-mobility group box 1, and others, and it is associated with the pathogenesis of various inflammatory and circulatory diseases. The soluble form of RAGE (sRAGE) is a decoy receptor and competitively inhibits membrane-bound RAGE activation. In this study, we measured sRAGE levels in bronchoalveolar lavage fluid (BALF) of 78 patients, including 41 with interstitial pneumonia, 11 with sarcoidosis, 9 with respiratory infection, 7 with ARDS, 5 with lung cancer, and 5 with vasculitis. Among them, sRAGE was detectable in BALF of 73 patients (94%). In patients with ARDS and vasculitis, the sRAGE levels were significantly higher than in the control subjects and those with interstitial pneumonia. The sRAGE levels were positively correlated with total cell counts in BALF and serum levels of surfactant protein-D, lactate dehydrogenase, and C-reactive protein. There was an inverse correlation between PaO2/FIO2 ratio and sRAGE levels. These results indicate that sRAGE in BALF might be considered as a biomarker of lung inflammatory disorders, especially ARDS and vasculitis. PMID:27147899

  12. Role of the receptor for advanced glycation end products in hepatic fibrosis

    Institute of Scientific and Technical Information of China (English)

    Christina Lohwasser; Daniel Neureiter; Yury Popov; Michael Bauer; Detlef Schuppan

    2009-01-01

    AIM: To study the role of advanced glycation end products (AGE) and their specific receptor (RAGE) in the pathogenesis of liver fibrogenesis. METHODS: In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells (HSC) were measured after stimulation with the two RAGE ligands, advanced glycation end product-bovine serum albumin (AGEBSA) and Nε-(carboxymethyl) lysine (CML)-BSA, or with tumor necrosis factor-α (TNF-α). In vivo RAGE expression was examined in models of hepatic fibrosis induced by bile duct ligation or thioacetamide. The effects of AGE-BSA and CML-BSA on HSC proliferation, signal transduction and profibrogenic gene expression were studied in vitro. RESULTS: In hepatic fibrosis, RAGE expression was enhanced in activated HSC, and also in endothelial cells, inflammatory cells and activated bile duct epithelia. HSC expressed RAGE which was upregulated after stimulation with AGE-BSA, CML-BSA, and TNF-α. RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation, apoptosis, fibrogenic signal transduction and fibrosis- or fibrolysis-related gene expression, except for marginal upregulation of procollagen α1(Ⅰ) mRNA by AGE-BSA. CONCLUSION: Despite upregulation of RAGE in activated HSC, RAGE stimulation by AGE does not alter their fibrogenic activation. Therefore, RAGE does not contribute directly to hepatic fibrogenesis.

  13. Receptor for advanced glycation end products is detrimental during influenza A virus pneumonia☆

    OpenAIRE

    2009-01-01

    Pneumonia caused by influenza A virus (IAV) can have devastating effects, resulting in respiratory failure and death. The idea that a new influenza pandemic might occur in the near future has triggered renewed interests in IAV infection. The receptor for advanced glycation end products (RAGE) is expressed on different cell types and plays a key role in diverse inflammatory processes. We here investigated the role of RAGE in the host response to IAV pneumonia using wild-type (wt) and RAGE defi...

  14. Pop / Tõnis Kahu

    Index Scriptorium Estoniae

    Kahu, Tõnis, 1962-

    2008-01-01

    Heliplaatidest: Chemical Brothers "Brotherhood", Plutonium 74 "Peittoalueen ulkopuolella", Disturbed "Indestructible", Thomas Feiner & Anywhen "The Opiates Revised", DefRage "Save Us from Religion", Kago "Mopskassi maja"

  15. 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...

  16. The role of the receptor for advanced glycation end-products in a murine model of silicosis.

    Directory of Open Access Journals (Sweden)

    Lasse Ramsgaard

    Full Text Available BACKGROUND: The role of the receptor for advanced glycation end-products (RAGE has been shown to differ in two different mouse models of asbestos and bleomycin induced pulmonary fibrosis. RAGE knockout (KO mice get worse fibrosis when challenged with asbestos, whereas in the bleomycin model they are largely protected against fibrosis. In the current study the role of RAGE in a mouse model of silica induced pulmonary fibrosis was investigated. METHODOLOGY/PRINCIPAL FINDINGS: Wild type (WT and RAGE KO mice received a single intratracheal (i.t. instillation of silica in saline or saline alone as vehicle control. Fourteen days after treatment mice were subjected to a lung mechanistic study and the lungs were lavaged and inflammatory cells, protein and TGF-beta levels in lavage fluid determined. Lungs were subsequently either fixed for histology or excised for biochemical assessment of fibrosis and determination of RAGE protein- and mRNA levels. There was no difference in the inflammatory response or degree of fibrosis (hydroxyproline levels in the lungs between WT and RAGE KO mice after silica injury. However, histologically the fibrotic lesions in the RAGE KO mice had a more diffuse alveolar septal fibrosis compared to the nodular fibrosis in WT mice. Furthermore, RAGE KO mice had a significantly higher histologic score, a measure of affected areas of the lung, compared to WT silica treated mice. A lung mechanistic study revealed a significant decrease in lung function after silica compared to control, but no difference between WT and RAGE KO. While a dose response study showed similar degrees of fibrosis after silica treatment in the two strains, the RAGE KO mice had some differences in the inflammatory response compared to WT mice. CONCLUSIONS/SIGNIFICANCE: Aside from the difference in the fibrotic pattern, these studies showed no indicators of RAGE having an effect on the severity of pulmonary fibrosis following silica injury.

  17. Decreased level of endogenous secretory receptor for advanced glycation end-products in diabetes with concomitant hyperlipidemia.

    Science.gov (United States)

    Turk, Z; Ljubić, S; Boras, J

    2014-01-01

    Endogenous secretory receptor (esRAGE) for advanced glycation end-product (AGE) acts as decoy for AGEs. The AGE-to-esRAGE ratio was hypothesized to be implicated in diabetic vasculopathy. We investigated an association of esRAGE and methylglyoxal-adducts serum level, as well as AGE-to-esRAGE ratio in subpopulation of diabetic patients with or without concomitant hyperlipidemia and macrovascular disease in history. In diabetes with concomitant hyperlipidemia esRAGE was significantly decreased compared to hyperlipidemia with normal glucose metabolism (0.306+/-0.2 vs. 0.367+/-0.1; p=0.019) or diabetes alone (0.306+/-0.2 vs. 0.404+/-0.1; p=0.004). High AGE/esRAGE ratio, found in diabetic patients with hyperlipidemia, pointed to increased production of AGEs and low expression of esRAGE. In multivariable analysis adjusted for several confounding factors, increased AGE/esRAGE ratio was recognized as a high risk for vascular disease outcomes.

  18. Receptor for advanced glycation end products plays a more important role in cellular survival than in neurite outgrowth during retinoic acid-induced differentiation of neuroblastoma cells.

    Science.gov (United States)

    Sajithlal, Gangadharan; Huttunen, Henri; Rauvala, Heikki; Munch, Gerald

    2002-03-01

    The receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, is known to interact with amphoterin. This interaction has been proposed to play a role in neurite outgrowth and process elongation during neurodifferentiation. However, there is as yet no direct evidence of the relevance of this pathway to neurodifferentiation under physiological conditions. In this study we have investigated a possible role of RAGE and amphoterin in the retinoic acid-induced differentiation of neuroblastoma cells. The functional inactivation of RAGE by dominant negative and antisense strategies showed that RAGE is not required for process outgrowth or differentiation, although overexpression of RAGE accelerates the elongation of neuritic processes. Using the antisense strategy, amphoterin was shown to be essential for process outgrowth and differentiation, suggesting that amphoterin may interact with other molecules to exert its effect in this context. Interestingly, the survival of the neuroblastoma cells treated with retinoic acid was partly dependent on the expression of RAGE, and inhibition of RAGE function partially blocked the increase in anti-apoptotic protein Bcl-2 following retinoic acid treatment. Based on these results we propose that a combination therapy using RAGE blockers and retinoic acid may prove as a useful approach for chemotherapy for the treatment of neuroblastoma.

  19. Healing from Racism: Cross Cultural Leadership Teachings for the Multicultural Future.

    Science.gov (United States)

    Rose, Lillian Roybal

    1995-01-01

    In her presentation at the 1994 American Indian Science and Engineering Society Annual Conference, Lillian Roybal Rose describes how racism results in internalized oppression and internalized rage among minority groups. Rose, who is Mexican American and American Indian, healed from racism by letting go of her rage and allowing herself to relate to…

  20. Do Not Go Gentle into That Good Night

    Institute of Scientific and Technical Information of China (English)

    Dylan; Thomas

    2008-01-01

    Do not go gentle into that good night,Old age should burn and rave at close of day;Rage, rage against the dying of the light.Though wise men at their end know dark is right,Because their words had forked no lightning theyDo not go gentle into that good night.

  1. Advanced glycation end product ligands for the receptor for advanced glycation end products: Biochemical characterization and formation kinetics

    NARCIS (Netherlands)

    Valencia, J.V.; Weldon, S.C.; Quinn, D.; Kiers, G.H.; Groot, J. de; TeKoppele, J.M.; Hughes, T.E.

    2004-01-01

    Advanced glycation end products (AGEs) accumulate with age and at an accelerated rate in diabetes. AGEs bind cell-surface receptors including the receptor for advanced glycation end products (RAGE). The dependence of RAGE binding on specific biochemical characteristics of AGEs is currently unknown.

  2. Status of LANL Efforts to Effectively Use Sequoia

    Energy Technology Data Exchange (ETDEWEB)

    Nystrom, William David [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-05-14

    Los Alamos National Laboratory (LANL) is currently working on 3 new production applications, VPC, xRage, and Pagosa. VPIC was designed to be a 3D relativist, electromagnetic Particle-In-Cell code for plasma simulation. xRage, a 3D AMR mesh amd multi physics hydro code. Pagosa, is a 3D structured mesh and multi physics hydro code.

  3. Receptor for advanced glycation end product expression in experimental diabetic retinopathy

    NARCIS (Netherlands)

    Wang, Yumei; Hagen, Filanziska Vom; Pfister, Frederick; Bierhaus, Angelika; Feng, Yuxi; Gans, Reinhold; Hammes, Hans-Peter; Schleicher, E; Somoza,; Shieberle, P

    2008-01-01

    The advanced glycation end product (AGE)-receptor for AGE (RAGE) pathway is involved in the pathogenesis of diabetic microvascular damage. The special distribution of RAGE and its engagement has an impact on the development of diabetic retinopathy. In the present study, we used immunofluorescence an

  4. Early expression of the receptor for advanced glycation end products in a toxic model produced by 6-hydroxydopamine in the rat striatum.

    Science.gov (United States)

    Serratos, Iris N; Castellanos, Pilar; Pastor, Nina; Millán-Pacheco, César; Colín-González, Ana Laura; Rembao, Daniel; Pérez-Montfort, Ruy; Cabrera, Nallely; Sánchez-García, Aurora; Gómez, Isabel; Rangel-López, Edgar; Santamaria, Abel

    2016-04-05

    The receptor for advanced glycation end products (RAGE) is commonly involved in different neurodegenerative and inflammatory disorders. The cellular signaling associated to RAGE activation may occur upon binding to different ligands. In this study we investigated whether the toxic model produced by 6-hydroxydopamine (6-OHDA) in rats comprises early noxious responses related to RAGE-mediated signaling cascades. In order to explore a possible interaction between 6-OHDA and RAGE, affinity parameters of RAGE with 6-OHDA were estimated by different means. The possible binding sites of 6-OHDA with the VC1 homodimer for both rat and human RAGE were also modeled. Our results show that the striatal infusion of 6-OHDA recruits RAGE upregulation, as evidenced by an early expression of the receptor. 6-OHDA was also found to bind the VC1 homodimer, although its affinity was moderate when compared to other ligands. This work contributes to the understanding of the role of RAGE activation for 6-OHDA-induced neurotoxicity.

  5. Soluble receptor for advanced glycation end products as an indicator of pulmonary vascular injury after cardiac surgery

    NARCIS (Netherlands)

    S. Tuinman (Sietske); A.D. Cornet (Alexander); M.T. Kuipers (Maria); A.P.J. Vlaar (Alexander); M.J. Schultz (Marcus); A. Beishuizen (Auke); A.B.J. Groeneveld (Johan); N.P. Juffermans (Nicole)

    2013-01-01

    textabstractBackground: Cardiac surgery is frequently complicated by an acute vascular lung injury and this may be mediated, at least in part, by the (soluble) receptor for advanced glycation end products (sRAGE).Methods: In two university hospital intensive care units, circulating sRAGE was measure

  6. Opposing roles of membrane and soluble forms of the receptor for advanced glycation end products in primary respiratory syncytial virus infection.

    Science.gov (United States)

    Miller, Allison L; Sims, Gary P; Brewah, Yambasu A; Rebelatto, Marlon C; Kearley, Jennifer; Benjamin, Ebony; Keller, Ashley E; Brohawn, Philip; Herbst, Ronald; Coyle, Anthony J; Humbles, Alison A; Kolbeck, Roland

    2012-04-15

    Respiratory syncytial virus (RSV), a common respiratory pathogen in infants and the older population, causes pulmonary inflammation and airway occlusion that leads to impairment of lung function. Here, we have established a role for receptor for advanced glycation end products (RAGE) in RSV infection. RAGE-deficient (ager(-/-)) mice were protected from RSV-induced weight loss and inflammation. This protection correlated with an early increase in type I interferons, later decreases in proinflammatory cytokines, and a reduction in viral load. To assess the contribution of soluble RAGE (sRAGE) to RSV-induced disease, wild-type and ager(-/-) mice were given doses of sRAGE following RSV infection. Of interest, sRAGE treatment prevented RSV-induced weight loss and neutrophilic inflammation to a degree similar to that observed in ager(-/-) mice. Our work further elucidates the roles of RAGE in the pathogenesis of respiratory infections and highlights the opposing roles of membrane and sRAGE in modulating the host response to RSV infection.

  7. Soluble Form of Receptor for Advanced Glycation End Products Is Associated with Obesity and Metabolic Syndrome in Adolescents

    Directory of Open Access Journals (Sweden)

    Chih-Tsueng He

    2014-01-01

    Full Text Available The aim of this cross-sectional study was to investigate the relationship between soluble form of receptor for advanced glycation end products (sRAGE, obesity, and metabolic syndrome (MetS in adolescents. A total of 522 male and 561 female adolescents were enrolled into the final analyses. Anthropometric parameters, blood pressure, blood biochemistry, fasting insulin, and plasma sRAGE levels were measured. In males, sRAGE was significantly and inversely correlated with waist circumference (WC, body mass index (BMI, systolic blood pressure, triglyceride (TG, low density lipoprotein cholesterol (LDL-C, and homeostasis model assessment-insulin resistance (HOMA-IR. Only WC and BMI were significantly and inversely correlated with sRAGE in females. Using linear regression analysis adjusting for age and gender, significant association was found between sRAGE and WC, BMI, TG, LDL-C, and HOMA-IR in adolescents of either gender (P<0.05. This association was abolished when further adjusting BMI. In addition, sRAGE was significantly and inversely correlated with the increasing number of components of MetS in males (P for trend = 0.006 but not in females (P for trend = 0.422. In conclusion, plasma sRAGE is associated with obesity and MetS among adolescents. BMI may be the most important determinant of sRAGE levels in adolescents.

  8. St Columban's Nursing Home, Magheramore, Wicklow.

    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.

  9. 媒体报道的公司治理促进作用机制研究--基于上市公司信息披露质量改善的视角%Research in ot the Actoin Mechanism of Media Coev rage on Corporate Governanc e---From the Perspective of Improvement in Information Quality of Listed Company

    Institute of Scientific and Technical Information of China (English)

    尹飘扬; 江俊龙

    2016-01-01

    以我国深圳证券交易所主板上市公司为样本,实证分析检验了媒体报道总量和媒体负面报道量对上市公司信息披露质量的监督促进效果。实证结果表明,总体来说媒体报道对改善上市公司信息披露质量产生显著的正向作用;但在中西部地区,媒体报道对上市公司信息披露质量的改善没有起到应有的作用,而媒体负面报道与东部地区上市公司信息披露质量的改善呈现显著的正相关关系;实证结果也证明媒体报道对国有上市公司信息披露质量的改善相关性很小,但媒体负面报道对非国有上市公司信息质量的改善却有很强的监督效应。%Based on the sampling of listed companies on the main board of Shenzhen Stock Exchange , the paper empirically tests the supervision effect of media coverage on information disclosure quality of listed companies . The results show that there exists a positive relation between media coverage and the improvement in information quality of listed companies .However , media coverage has no expected effect on information quality of listed companies in the west of China; negative media coverage has a positive effect on information quality of listed companies in the east of China .Furthermore, the findings show that though media coverage has little effect on information quality in state -owned enterprises ,negative media coverage has a strong supervising effect on infor -mation quality in non-state-owned enterprises .

  10. Soluble and Endogenous Secretory Receptors for Advanced Glycation End Products in Threatened Preterm Labor and Preterm Premature Rupture of Fetal Membranes

    Directory of Open Access Journals (Sweden)

    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.

  11. Plasma Levels of Soluble Receptor for Advanced Glycation End Products and Coronary Atherosclerosis: Possible Correlation with Clinical Presentation

    Directory of Open Access Journals (Sweden)

    Colomba Falcone

    2013-01-01

    Full Text Available Receptor for Advanced Glycation End-products (RAGE is a multi-ligand receptor ubiquitous present on epithelial, neuronal, vascular and inflammatory cells, usually expressed at low levels in homeostasis and to increased degrees at sites of stress or injury. The aim of the present study was to evaluate sRAGE plasma levels in patients with Acute Coronary Syndrome (ACS and to assess its diagnostic efficacy in identification of patients with acute events. Plasma levels of sRAGE were determined in 860 patients with Coronary Artery Disease (CAD: 530 patients presented stable angina and 330 were observed during acute ischemic event (147 with unstable angina and 183 with myocardial infarction. sRAGE plasma levels were significantly lower in patients with ACS than in patients with stable angina: [median 584 pg/mL (IQR: 266–851 pg/mL in MI patients, median 769 pg/mL (IQR: 394–987 pg/mL in patients with unstable angina, median 834 pg/mL (IQR 630–1005 pg/mL in patients with stable angina; P<0.001]. sRAGE levels did not differ among ACS patients stratified by the extent of coronary artery disease. In conclusion, this study confirm the role of sRAGE in activation and progression of inflammatory process and suggests the possibility that sRAGE can be considered an indicator of destabilization of vulnerable plaque.

  12. Receptor for advanced glycation end products is detrimental during influenza A virus pneumonia.

    Science.gov (United States)

    van Zoelen, Marieke A D; van der Sluijs, Koenraad F; Achouiti, Ahmed; Florquin, Sandrine; Braun-Pater, Jennie M; Yang, Huan; Nawroth, Peter P; Tracey, Kevin J; Bierhaus, Angelika; van der Poll, Tom

    2009-09-01

    Pneumonia caused by influenza A virus (IAV) can have devastating effects, resulting in respiratory failure and death. The idea that a new influenza pandemic might occur in the near future has triggered renewed interests in IAV infection. The receptor for advanced glycation end products (RAGE) is expressed on different cell types and plays a key role in diverse inflammatory processes. We here investigated the role of RAGE in the host response to IAV pneumonia using wild-type (wt) and RAGE deficient ((-/-)) mice. Whereas strong RAGE was constitutively expressed in the lungs of uninfected wt mice, in particular on endothelium, IAV pneumonia was associated with enhanced expression on endothelium and de novo expression on bronchial epithelium. Additionally, the high-affinity RAGE ligand high mobility group box 1 was upregulated during IAV pneumonia. RAGE(-/-) mice were relatively protected from IAV induced mortality and showed an improved viral clearance and enhanced cellular T cell response and activation of neutrophils. These data suggest that RAGE is detrimental during IAV pneumonia.

  13. Metformin inhibits advanced glycation end products (AGEs)-induced growth and VEGF expression in MCF-7 breast cancer cells by suppressing AGEs receptor expression via AMP-activated protein kinase.

    Science.gov (United States)

    Ishibashi, Y; Matsui, T; Takeuchi, M; Yamagishi, S

    2013-05-01

    Metformin use has been reported to decrease breast cancer incidence and mortality in diabetic patients. We have previously shown that advanced glycation end products (AGEs) and their receptor (RAGE) interaction stimulate growth and/or migration of pancreatic cancer and melanoma cells. However, effects of metformin on AGEs-RAGE axis in breast cancers remain unknown. We examined here whether and how metformin could block the AGEs-induced growth and vascular endothelial growth factor (VEGF) expression in MCF-7 breast cancer cells. Cell proliferation was measured with an electron coupling reagent WST-1 based colorimetric assay. Gene expression level was evaluated by real-time reverse-transcription polymerase chain reactions. AGEs significantly increased cell proliferation of MCF-7 cells, which was completely prevented by the treatment with 0.01 or 0.1 mM metformin or anti-RAGE antibodies. Furthermore, metformin at 0.01 mM completely suppressed the AGEs-induced upregulation of RAGE and VEGF mRNA levels in MCF-7 cells. An inhibitor of AMP-activated protein kinase, compound C significantly blocked the growth-inhibitory and RAGE and VEGF suppressing effects of metformin in AGEs-exposed MCF-7 cells. Our present study suggests that metformin could inhibit the AGEs-induced growth and VEGF expression in MCF-7 breast cancer cells by suppressing RAGE gene expression via AMP-activated protein kinase pathway. Metformin may protect against breast cancer expansion in diabetic patients by blocking the AGEs-RAGE axis.

  14. Receptor for Advanced Glycation End Products and its Inflammatory Ligands are Upregulated in Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Judyta eJuranek

    2015-12-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal motor neuron disorder of largely unknown pathogenesis. Recent studies suggest that enhanced oxidative stress and neuroinflammation contribute to the progression of the disease. Mounting evidence implicates the receptor for advanced glycation end-products (RAGE as a significant contributor to the pathogenesis of certain neurodegenerative diseases and chronic conditions. It is hypothesized that detrimental actions of RAGE are triggered upon binding to its ligands, such as AGEs (advanced glycation end products, S100/calgranulin family members, and High Mobility Group Box-1 (HMGB1 proteins. Here, we examined the expression of RAGE and its ligands in human ALS spinal cord. Tissue samples from age-matched human control and ALS spinal cords were tested for the expression of RAGE, carboxymethyllysine (CML AGE, S100B and HMGB1, and intensity of the immunofluorescent and immunoblotting signals was assessed. We found that the expression of both RAGE and its ligands was significantly increased in the spinal cords of ALS patients versus age-matched control subjects. Our study is the first report describing co-expression of both RAGE and its ligands in human ALS spinal cords. These findings suggest that further probing of RAGE as a mechanism of neurodegeneration in human ALS is rational.

  15. C-reactive protein, advanced glycation end products and their receptor in type 2 diabetic, elderly patients with mild cognitive impairment

    Directory of Open Access Journals (Sweden)

    Malgorzata eGorska-Ciebiada

    2015-10-01

    Full Text Available Objective: The aim of the study was to evaluate serum levels of AGEs (advanced glycation end products, RAGE (receptor for advanced glycation end products and CRP (C-reactive protein in elderly patients with T2DM with and without mild cognitive impairment (MCI and to determine the predictors (including AGEs, RAGE and CRP levels of having MCI in elderly patients with type 2 diabetes.Methods: 276 diabetics elders were screened for MCI (using the Montreal Cognitive Assessment: MoCA score. Data of biochemical parameters and biomarkers were collected. Results: Serum AGEs, RAGE and CRP levels were significantly increased in MCI patients compared to controls. In group of patients with MCI serum RAGE level was positively correlated with AGEs level and with CRP level. RAGE, AGEs and CRP concentrations were positively correlated with HbA1c levels and negatively correlated with MoCA score. The univariate logistic regression models revealed that variables which increased the likelihood of diagnosis of MCI in elderly patients with type 2 diabetes were: higher levels of HbA1c, RAGE, AGEs, CRP, TG, lower level of HDL cholesterol, previous CVD, HA or use of HA drugs, hiperlipidaemia, retinopathy, nephropathy, increased number of co-morbidities, older age and less years of formal education. HA or use of HA drugs, previous CVD, higher level of RAGE and CRP, older age and less years of formal education are the factors increasing the likelihood of having MCI in elderly patients with type 2 diabetes in multivariable model. Conclusions: In summary, serum AGEs, RAGE and CRP are increased in the circulation of MCI elderly diabetic patients compared to controls. A larger population-based prospective study needs to be performed to further confirm the relationship between AGEs, RAGE and the cognitive decline or progress to dementia.

  16. Intra-coronary administration of soluble receptor for advanced glycation end-products attenuates cardiac remodeling with decreased myocardial transforming growth factor-β1 expression and fibrosis in minipigs with ischemia-reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    LU Lin; SHEN Wei-feng; ZHANG Qi; XU Yan; ZHU Zheng-bin; GENG Liang; WANG Ling-jie; JIN Cao; CHEN Qiu-jing; Ann Marie Schmidt

    2010-01-01

    Background The cardioprotective effects of soluble receptor for advanced glycation end-products (sRAGE) have not been evaluated in large animals and the underlying mechanisms are not fully understood. This study aimed to evaluate the effects of intra-coronary administration of sRAGE on left ventricular function and myocardial remodeling in a porcine model of ischemia-reperfusion (I/R) injury. Methods Ten male minipigs with I/R injury were randomly allocated to receive intra-coronary administration of sRAGE (sRAGE group, n=5) or saline (control group, n=5). Echocardiography was performed before and 2 months after infarction. Myocardial expression of transforming growth factor (TGF)-β1was determined by immunohistochemistry and fibrosis was evaluated by Sirius red staining. Results As compared with the baseline values in the control animals, left ventricular end-diastolic volume (from (19.5 5.1) to (32.3 5.6) ml, P <0.05) and end-systolic volume (from (8.3 3.2) to (15.2 4.1) ml, P <0.05) were significantly increased, whereas ejection fraction was decreased (from (61.6 13.3)% to (50.2 11.9)%, P<0.05). No obvious change in these parameters was observed in the sRAGE group. Myocardial expression of TGF-β1 was significantly elevated in the infarct and non-infarct regions in the control group, as compared with sRAGE group (both P<0.01). Fibrotic lesions were consistently more prominent in the infarct region of the myocardium in the control animals (P<0.05). Conclusion Intra-coronary sRAGE administration attenuates RAGE-mediated myocardial fibrosis and I/R injury through a TGF-β1-dependent mechanism, suggesting a clinical potential in treating RAGE/ligand-associated cardiovascular diseases.

  17. 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......: 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...... end products; Receptor for advanced glycation end products...

  18. Development of a Single-Frequency Narrow Linewidth 1.5mm Semiconductor Laser Suitable for Spaceflight Operation Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Many space applications rely on the utilization of Light Detection and Raging (LIDAR) techniques. A key component of any LIDAR system is the laser source. Single...

  19. Young Adult Books.

    Science.gov (United States)

    Rochman, Hazel

    1986-01-01

    Applies the idea of the theme booktalk to "Wuthering Heights," which serves as a springboard for talking about themes of family rage, confrontation, quarrel and rebellion in other works of literature with relevance to contemporary young people. (JK)

  20. Uusi plaate / Marko T. Lepp

    Index Scriptorium Estoniae

    Lepp, Marko T.

    1999-01-01

    Uutest plaatidest Enrique Iglesias "Enrique", Will Smith "Willennium", Celine Dion "All The Way... A Decade Of Song". Korn "Issues", Rage Agains The Machine "The Battle Of Los Angeles", Sevendust "Home"

  1. Fandango and the Rhetoric of Resistance in Flamenco

    Directory of Open Access Journals (Sweden)

    Tony Dumas

    2015-01-01

    socioeconómico. Como dice una de las bailaoras des Flo6x8,flamenco captures perfectly how we feel about the crisis. You can use it to express desperation, rage, pain, and the desire to change things.

  2. 英文摘要

    Institute of Scientific and Technical Information of China (English)

    2013-01-01

    COVER STORY EXHAUSTED WITH SMOG The cottony smog of toxic pollution that has covered some of China's largest cities has spurred a raging debate over the most effective methods to reduce the bad air quality.

  3. Serum soluble receptor for advanced glycation end products correlates inversely with measures of adiposity in young adults.

    Science.gov (United States)

    Davis, Kathleen E; Prasad, Chandan; Vijayagopal, Parakat; Juma, Shanil; Imrhan, Victorine

    2014-06-01

    Advanced glycation end products (AGEs) may promote inflammation by interacting with the receptor for advanced glycation end products. Serum soluble receptor for advanced glycation end products (sRAGE), a form of receptor for advanced glycation end products thought to mediate AGE's inflammatory properties, is decreased in diabetes mellitus and coronary artery disease. Evidence in older adults suggests that sRAGE is depressed in individuals without current disease who are obese; however, 2 studies have failed to find this correlation. We hypothesized that sRAGE would be inversely correlated with adiposity and positively correlated with inflammation, even in apparently healthy, young adults. By considering adults of body mass index (BMI) varying from normal weight to overweight and obese, we aimed to define how closely AGEs and sRAGE correlate with adiposity and other indicators of metabolic stress. Anthropometric measurements and fasting blood samples were obtained from participants (n = 69). Sera were analyzed for sRAGE, n-epsilon carboxy-methyl-lysine, a measure of AGEs, and high sensitivity C-reactive protein. High molecular weight adiponectin, glucose, insulin, total cholesterol, high-density lipoprotein, and triacylglycerol were also assessed (n = 32). Spearman rank correlations were used to evaluate the relationship among indicators of adiposity and biochemical indicators of metabolic health and inflammation. Factors inversely correlated with sRAGE include weight (Rs = -0.397; P = .001), waist circumference (-0.291; P = .015), and BMI (-0.3338; P = .004). High molecular weight adiponectin was positively correlated with sRAGE, and predictors of sRAGE included BMI and total cholesterol. This is the first time these associations have been found in a diverse population of young adults.

  4. Opposing Roles of Membrane and Soluble Forms of the Receptor for Advanced Glycation End Products in Primary Respiratory Syncytial Virus Infection

    OpenAIRE

    2012-01-01

    Respiratory syncytial virus (RSV), a common respiratory pathogen in infants and the older population, causes pulmonary inflammation and airway occlusion that leads to impairment of lung function. Here, we have established a role for receptor for advanced glycation end products (RAGE) in RSV infection. RAGE-deficient (ager−/− ) mice were protected from RSV-induced weight loss and inflammation. This protection correlated with an early increase in type I interferons, later decreases in proinflam...

  5. Advanced glycation end products: A link between metabolic and endothelial dysfunction in polycystic ovary syndrome?

    Science.gov (United States)

    Pertynska-Marczewska, Magdalena; Diamanti-Kandarakis, Evanthia; Zhang, John; Merhi, Zaher

    2015-11-01

    Polycystic ovary syndrome (PCOS), a heterogeneous syndrome of reproductive and metabolic alterations, is associated with increased long-term risk of cardiovascular complications. This phenomenon has been linked to an increase in oxidative stress and inflammatory markers. Advanced glycation end products (AGEs) are pro-inflammatory molecules that trigger a state of intracellular oxidative stress and inflammation after binding to their cell membrane receptors RAGE. The activation of the AGE-RAGE axis has been well known to play a role in atherosclerosis in both men and women. Women with PCOS have systemic chronic inflammatory condition even at the ovarian level as represented by elevated levels of serum/ovarian AGEs and increased expression of the pro-inflammatory RAGE in ovarian tissue. Data also showed the presence of sRAGE in the follicular fluid and its potential protective role against the harmful effect of AGEs on ovarian function. Thus, whether AGE-RAGE axis constitutes a link between metabolic and endothelial dysfunction in women with PCOS is addressed in this review. Additionally, we discuss the role of hormonal changes observed in PCOS and how they are linked with the AGE-RAGE axis in order to better understand the nature of this complex syndrome whose consequences extend well beyond reproduction.

  6. Receptor for Advanced Glycation End Products and Its Involvement in Inflammatory Diseases

    Directory of Open Access Journals (Sweden)

    Yaw Kuang Chuah

    2013-01-01

    Full Text Available The receptor for advanced glycation end products (RAGE is a transmembrane receptor of the immunoglobulin superfamily, capable of binding a broad repertoire of ligands. RAGE-ligands interaction induces a series of signal transduction cascades and lead to the activation of transcription factor NF-κB as well as increased expression of cytokines, chemokines, and adhesion molecules. These effects endow RAGE with the role in the signal transduction from pathogen substrates to cell activation during the onset and perpetuation of inflammation. RAGE signaling and downstream pathways have been implicated in a wide spectrum of inflammatory-related pathologic conditions such as arteriosclerosis, Alzheimer's disease, arthritis, acute respiratory failure, and sepsis. Despite the significant progress in other RAGE studies, the functional importance of the receptor in clinical situations and inflammatory diseases still remains to be fully realized. In this review, we will summarize current understandings and lines of evidence on the molecular mechanisms through which RAGE signaling contributes to the pathogenesis of the aforementioned inflammation-associated conditions.

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

    Directory of Open Access Journals (Sweden)

    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

  8. Role of abnormal expression of receptor for advanced glycosylation end products in carcinogenesis,tumor invasion, and metastasis%晚期糖基化终产物受体异常表达对肿瘤发生和侵袭转移的影响

    Institute of Scientific and Technical Information of China (English)

    岳志强; 王颖钰; 刘玉萍; 郑仕中; 陆茵

    2011-01-01

    以往人们将晚期糖基化终产物受体(receptor for advanced glycosylation end products,RAGE)的研究重点放在糖尿病血管病变中.近年来的临床研究发现,RAGE在人肝癌、胃癌、胰腺癌和前列腺癌等多种肿瘤组织中均高表达,而在横纹肌肉瘤和肺癌组织中低表达.RAGE的异常表达与肿瘤的发生、血管生成和侵袭转移等恶性化程度密切相关.本文对不同肿瘤组织中RAGE的异常表达及其与肿瘤发生、发展的相关性进行简要综述.%Receptor for advanced glycosylation end products (RACE) has long been a focus in studies of diabetic vascular diseases. Recently, clinical evidence has shown that the expression level of RAGE is high in liver, stomach, pancreas and prostate cancer tissues whereas the expression level of RAGE is lower in chondrosarcoma and lung cancer tissues. The abnormal expression of RAGE is closely associated with tumorgenesis, angiogenesis, tumor invasion and metastasis. This review summarizes the abnormal expression of RAGE in different tumors and its role in carcinogenesis and development of tumor.

  9. Exploring of protein - protein interactions at the solid - aqueous interface by means of contact angle measurements.

    Science.gov (United States)

    Grabowska, I; Dehaen, W; Radecka, H; Radecki, J

    2016-05-01

    In this article we present the results of the studies on interactions between the VC1 domain of the Receptor for Advanced Glycation End Products (RAGE) and its ligand, the S100B protein, performed by contact angle measurements. Histidine-tagged (His6) VC1-RAGE domain was covalently bonded to Cu(II) or Ni(II) complexes with dipyrromethene (DPM) self-assembled on gold surface. The method based on the theory of van Oss was used for the purpose of determining the Lifshitz-van der Waals (γ(LW)) component as well as the electron acceptor-electron donor (the Lewis acid-base, γ(+)-γ(-)) parameters of the VC1-RAGE-S100B complex. Moreover, the surface free energies of the interactions between the VC1 domain attached to the surface and the ligand present in the aqueous phase were determined. The specificity of the VC1- RAGE interactions with the ligand studied was also proved.

  10. Analysis Of Wetted-Foam ICF Capsule Perormance

    Science.gov (United States)

    Peterson, R.; Olson, R.; Zylstra, A.; Haines, B.; Yi, A.; Bradley, P.; Yin, L.; Leeper, R.; Kline, J.

    2016-10-01

    The performance of wetted-foam ICF capsules is investigated with the RAGE Eulerian radiation-hydrodynamics computer code. We are developing an experimental platform on NIF that employs a wetted foam liquid DT fuel layer ICF capsules. By varying the capsule temperature, the vapor density in the capsule can be prescribed, and the hot spot convergence ratio (CR) of the capsule implosion can be controlled. This allows us to investigate the fidelity of RAGE in modeling of capsule implosions as the value of CR is varied. In the NIF experiments, CR can be varied from 12 to 25. This presentation will cover simulations with RAGE of three NIF shots performed in 2016; a DD and a DT liquid fuel shot with CR =14 and a DT shot with CR =16. It will also discuss analysis of future experiments. This work was performed under auspices of the U. S. DOE by LANL.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Skin autofluorescence relates to soluble receptor for advanced glycation end-products and albuminuria in diabetes mellitus.

    Science.gov (United States)

    Skrha, J; Soupal, J; Loni Ekali, G; Prázný, M; Kalousová, M; Kvasnička, J; Landová, L; Zima, T; Skrha, J

    2013-01-01

    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 (R (2) = 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.

  13. 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.

    Science.gov (United States)

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

    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.

  14. Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease

    Science.gov (United States)

    Leung, Christopher; Herath, Chandana B; Jia, Zhiyuan; Andrikopoulos, Sof; Brown, Bronwyn E; Davies, Michael J; Rivera, Leni R; Furness, John B; Forbes, Josephine M; Angus, Peter W

    2016-01-01

    AIM To determine if manipulation of dietary advanced glycation end product (AGE), intake affects non-alcoholic fatty liver disease (NAFLD) progression and whether these effects are mediated via RAGE. METHODS Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol (HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mRNA were determined. RESULTS Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content (a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE-/- animals developed NASH of similar severity to RAGE+/+ animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury. CONCLUSION In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD. PMID:27672297

  15. Modélisation de la morphodynamique fluviale pour la recherche des relations habitat/faune aquatique

    Directory of Open Access Journals (Sweden)

    LE COARER Y.

    1995-04-01

    Full Text Available Un matériel de topographie électronique et des méthodes adaptées nous procurent rapidité, précision et souplesse dans le repérage spatial des éléments morphodynamiques et biologiques. Le traitement informatique des données fait appel à des techniques de repérage curviligne d'interpolation et de maillage. La structure numérique et topologique de cet outil de recherche offre de nombreuses possibilités de calculs et permet des visualisations conviviales des résultats.

  16. Receptor for Advanced Glycation End Products Regulates Leukotriene B4 Receptor 1 Signaling.

    Science.gov (United States)

    Ichiki, Takako; Koga, Tomoaki; Yokomizo, Takehiko

    2016-12-01

    Leukotriene B4 receptor 1 (BLT1), a high-affinity G protein-coupled receptor (GPCR) for leukotriene B4 (LTB4), plays important roles in inflammatory and immune reactions. Although the LTB4-BLT1 axis is known to promote inflammation, the binding proteins that modulate LTB4-BLT1 signaling have not been identified. Recently, we discovered that receptor for advanced glycation end products (RAGE) interacts with BLT1 and modulates LTB4-BLT1 signaling. We propose RAGE as a new class of GPCR modulator and a new target of future GPCR studies.

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

    OpenAIRE

    Šoupal, J.; G. Loni Ekali; Prázný, M.; Kalousová, M.; Kvasnička, J.; Landová, L.; Zima, T.; Škrha, J.

    2013-01-01

    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 (2.3...

  18. C-reactive protein, advanced glycation end products and their receptor in type 2 diabetic, elderly patients with mild cognitive impairment

    OpenAIRE

    2015-01-01

    Objective: The aim of the study was to evaluate serum levels of AGEs (advanced glycation end products), RAGE (receptor for advanced glycation end products) and CRP (C-reactive protein) in elderly patients with T2DM with and without mild cognitive impairment (MCI) and to determine the predictors (including AGEs, RAGE and CRP levels) of having MCI in elderly patients with type 2 diabetes.Methods: 276 diabetics elders were screened for MCI (using the Montreal Cognitive Assessment: MoCA score). D...

  19. Flaubert's Madame Bovary: a study in envy and revenge.

    Science.gov (United States)

    Arlow, Jacob A; Baudry, Francis D

    2002-04-01

    Flaubert's Emma Bovary is one of the most convincingly realized characters in modern literature. Her husband, Charles, a rural doctor, loves her dearly, but he is dull, ineffectual, and boring. Emma seems to hate him with a fury that knows no bounds. She betrays him sexually, ruins him financially, and ultimately destroys his very life. What drives her to such unmitigated rage? The authors identify evidence in the novel suggestive of a dynamic thrust for revenge along the lines described by Freud (1918) in "The Taboo of Virginity." Elements of narcissistic rage and a sense of entitlement intensify Emma's anger and vengefulness.

  20. Psychogenic seizures--why women?

    Science.gov (United States)

    Rosenbaum, M

    2000-01-01

    The only consistent finding in studies of psychogenic seizures is the approximately threefold higher incidence in women. Therefore, why women? Charcot and Freud emphasized the sexual aspects of the seizure as has the current interest in childhood sexual abuse. From case studies and review of the literature the author believes that psychogenic seizures in women express rage, fear, and helplessness against the dominant and abusive male rather than sexual conflicts. Emphasizing the aggressive component of seizures does not minimize the traumatic effects of sexual abuse but rather includes it as leading to rage and helplessness.

  1. Poly (3-Hydroxyalkanoates): Biodegradable Plastics

    OpenAIRE

    2013-01-01

    During the 1920’s, a polyester called poly (3-hydroxybutyrate) was discovered in bacterial cells. This compound, otherwise known as PHB, is part of a polyester family called polyhydroxyalkanoates (PHAs). Polyhydroxyalkanoates are used as an energy and carbon sto rage compound within certain bacterial cells. Polyhydroxyalkanoates (PHAs) are thermoplastic, biodegradable polyesters synthesized by some bacteria from rene...

  2. JPRS Report, East Asia, Southeast Asia.

    Science.gov (United States)

    2007-11-02

    people. Every year there is more and more of the deadly malaria and right now a dengue fever epidemic is raging, to which mostly children and...skilled personnel is felt not only by Perumtel and the PLN but also by the automotive, electronics, basic metals, financial, tourism , construc- tion

  3. The Feud over Food: The Truth about the School Lunch Wars

    Science.gov (United States)

    Johns, Stephanie

    2010-01-01

    Serving meals and snacks at school is fraught with politics and pitfalls. While the battle rages in school cafeterias over menu choices, beverage sales, vending foods, and outright bans on what students can buy or even bring to school, there is some good news. More school districts are reducing the number of fried foods, increasing the levels of…

  4. 肠润通对糖尿病大鼠结肠糖基化终末产物及其受体表达的干预作用

    DEFF Research Database (Denmark)

    Zhao, Dong; Sha, Hong; Liao, Donghua

    2016-01-01

    groups received gavage administration with CRT daily,and the modeling process lasted for 60 days.Blood glucose level and body weight of rats were measured termly.The expression of AGEs and RAGE in colon bowel layers was detected by using immunohistochemistry and analyzed quantificationally by using...

  5. Benzodiazepine Administration Induces Exogenic Psychosis: A Case of Child Abuse.

    Science.gov (United States)

    Marcus, Alexander; And Others

    1995-01-01

    An 11-year-old boy with psychiatric symptoms (anxiety, panic reactions, rage, and disorientation) was brought to the pediatric clinic by his father. Purposeful administration by his mother of benzodiazepine, a prescription drug available in the household, was suspected as responsible for the psychotic symptoms. (DB)

  6. United Nations Day (联合国成立纪念日)

    Institute of Scientific and Technical Information of China (English)

    胡亚萍

    2002-01-01

    As World War Ⅱ raged on with no end in sight, the United Nations was conceived as a way to help prevent future world wars. As early as 1943, government officials from the United States, Great Britain, and the Soviet Union agreed to meet to discuss plans for an international peacekeeping organization.

  7. Build Your Own Board: Brightboards Offer a Cost-Effective Alternative to Interactive Whiteboards

    Science.gov (United States)

    Vallis, Keith; Williamson, Peter

    2009-01-01

    Interactive whiteboards are all the rage in classrooms across the world these days, and for good reason. Like most technology, they hold students' attention much better than a traditional lecture-and-blackboard lesson ever could. They also solve the problem of having only one classroom computer for 30 students by projecting the screen at the front…

  8. JPRS Report, Political Affairs.

    Science.gov (United States)

    2007-11-02

    republic opportunities for the normal reproduction and enjoyment of their own culture and maximum opportunities for the satisfaction of their cultural...worker A. Kozhokar, born in 1948, beat his wife while he was drunk and she died in the hospital from her injuries. Just what a man in a drunk rage

  9. Putting Big Data to Work: Community Colleges Use Detailed Reports to Design Smarter Workforce Training and Education Programs

    Science.gov (United States)

    Woods, Bob

    2013-01-01

    In this article, Bob Woods reports that "Big data" is all the rage on college campuses, and it makes sense that administrators would use what they know to boost student outcomes. Woods points out that community colleges around the country are using the data: (1) to guide the systematic expansion of its curriculum, providing targeted…

  10. Peace Education in Societies Involved in Intractable Conflicts: Direct and Indirect Models

    Science.gov (United States)

    Bar-Tal, Daniel; Rosen, Yigal

    2009-01-01

    The present article deals with the crucial question: Can peace education facilitate change in the sociopsychological infrastructure that feeds continued intractable conflict and then how the change can be carried? Intractable conflicts still rage in various parts of the globe, and they not only cause local misery and suffering but also threaten…

  11. Multiculturalism Swedish Style: Shifts and Sediments in Educational Policies and Textbooks

    Science.gov (United States)

    Gruber, Sabine; Rabo, Annika

    2014-01-01

    In the almost two decades that have passed since the Swedish parliament declared that Sweden is a multicultural society, debates about immigrants, about multiculturalism and about different ways of being a citizen have raged. So far there has been no stepping away from the declaration. In the rhetorical arena multiculturalism is still a word with…

  12. A Mediating Model of Relational Aggression, Narcissistic Orientations, Guilt Feelings, and Perceived Classroom Norms

    Science.gov (United States)

    Onishi, Ayako; Kawabata, Yoshito; Kurokawa, Masayuki; Yoshida, Toshikazu

    2012-01-01

    The purpose of the present study was to examine the relation between narcissistic orientations (grandiose sense of self-importance, interpersonal exploitation, and narcissistic rage) and relational aggression (self-satisfactory and punishment type) and the mediating effects of guilt feelings toward and perceived classroom norms against relational…

  13. Comparative effects of pioglitazone and rosiglitazone on plasma levels of soluble receptor for advanced glycation end products in type 2 diabetes mellitus patients.

    Science.gov (United States)

    Oz Gul, Ozen; Tuncel, Ercan; Yilmaz, Yusuf; Ulukaya, Engin; Gul, Cuma Bulent; Kiyici, Sinem; Oral, Arzu Yilmaztepe; Guclu, Metin; Ersoy, Canan; Imamoglu, Sazi

    2010-01-01

    Low levels of soluble receptor for advanced glycation end products (sRAGE) have been associated with the occurrence of vascular complications in patients with type 2 diabetes mellitus. Preliminary evidence has suggested that thiazolidinediones have the ability to modulate circulating levels of this molecule in the hyperglycemic milieu. The aim of this pilot study was to assess the differential effect of 2 different thiazolidinediones-pioglitazone and rosiglitazone-on plasma levels of sRAGE in type 2 diabetes mellitus patients. Sixty type 2 diabetes mellitus subjects were randomly assigned to receive pioglitazone (30 mg/d, n = 19), rosiglitazone (4 mg/d, n = 20), or placebo (medical nutrition therapy, n = 21) for 12 weeks. Changes in plasma glucose, glycosylated hemoglobin, insulin resistance (homeostasis model assessment), total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and sRAGE were evaluated at baseline and after 12 weeks. At 12 weeks, the pioglitazone (P diabetes mellitus patients, pioglitazone-but not rosiglitazone-significantly raised sRAGE, which may contribute to its antiatherogenic effects.

  14. Dublini festival II : Külalised. Muust / Jaak Rähesoo

    Index Scriptorium Estoniae

    Rähesoo, Jaak, 1941-

    2002-01-01

    Ka Kopenhaageni Betty Nanseni Teatri näidatud Robert Wilsoni tehtud Georg Büchneri "Woyzecki" tõlgenduse ning noore inglise trupi näidatud Edward Halli lavastatud William Shakespeare "Rose Rage" ("Henry VI") etenduse lavakujundusest ja -kostüümidest.

  15. Oriana Fallaci viha ja raev / Urmas Kiil

    Index Scriptorium Estoniae

    Kiil, Urmas

    2006-01-01

    Ajakirjanik ja kirjanik Oriana Fallaci, kelle artikkel New Yorgis toimunud terrorirünnaku muljetest avaldati 29. sept. 2001. a. Itaalia juhtivas ajalehes Corriere della sera, avaldas peagi raamatu "Raev ja uhkus" (The Rage and Pride). Raamatus mõistab ta islamimaailma mööndusteta tervikuna hukka

  16. 阿里斯蒂德黯然离去

    Institute of Scientific and Technical Information of China (English)

    朱晓超; sipa

    2005-01-01

    February 28 2004, dead bodies have been left in front of the General Hospital all over Haiti as chaos,looting and violence rage in Port Au Prince, Haiti. The next day, President Jean-Bertrand Aristide left Haiti and exiled to Dominica seeking political asylum.

  17. The politics of civil society building: European private aid agencies and democratic transitions in Central America

    NARCIS (Netherlands)

    Biekart, C.H.

    1999-01-01

    Strengthening civil society may be all the rage in the international donor community, but what does it mean in practice? This seminal work critically examines the political aspects of civil society building and the role of non-governmental development aid agencies during recent democratic transition

  18. The politics of civil society building : European private aid agencies and democratic transitions in Central America

    NARCIS (Netherlands)

    K. Biekart (Kees)

    1999-01-01

    textabstractStrengthening civil society may be all the rage in the international donor community, but what does it mean in practice? This seminal work critically examines the political aspects of civil society building and the role of non-governmental development aid agencies during recent democrati

  19. Nuclear Power on Energy Agenda

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The big debate on whether or not to use nuclear power as an energy option has raged among countries like the U.S., Britain, and Germany for decades, with not even the advent and threat of global warming forcing a conclusion. China, however, has always stressed energy diversity and been determined to develop and use this alternative energy source.

  20. Innate immune responses to Chlamydia pneumoniae infection: role of TLRs, NLRs, and the inflammasome.

    Science.gov (United States)

    Shimada, Kenichi; Crother, Timothy R; Arditi, Moshe

    2012-11-01

    Chlamydiae are important human pathogens that are responsible for a wide rage of diseases with a significant impact on public health. In this review article we highlight how recent studies have increased our knowledge of Chlamydia pneumoniae pathogenesis and mechanisms of innate immunity directed host defense against C. pneumoniae infection.

  1. "If I Knew Where the Enemy, or Even Germany Was, We Could Have Fired in that Direction": Bion's Experience of War

    Science.gov (United States)

    Likierman, Meira

    2012-01-01

    During the First World War, Bion fought in three major battles over a period of two years. He left ample writings both honest and soul searching. Travelling to The Front under raging pressure from his father, he enlisted in a state of mind, which fluctuated wildly between wanting to be a "hero" and sudden fears that made him join the Tank Corps…

  2. Girl's Schooling in War-Torn Somalia

    Science.gov (United States)

    Moyi, Peter

    2012-01-01

    A civil war has raged in Somalia since 1991. The civil war was the final blow to an already collapsed education system. Somalia has received little research and policy attention yet children, especially girls, are very vulnerable during times of conflict. The different gender roles, activities, and status in society create gender differentiated…

  3. In skeletal muscle advanced glycation end products (AGEs) inhibit insulin action and induce the formation of multimolecular complexes including the receptor for AGEs.

    Science.gov (United States)

    Cassese, Angela; Esposito, Iolanda; Fiory, Francesca; Barbagallo, Alessia P M; Paturzo, Flora; Mirra, Paola; Ulianich, Luca; Giacco, Ferdinando; Iadicicco, Claudia; Lombardi, Angela; Oriente, Francesco; Van Obberghen, Emmanuel; Beguinot, Francesco; Formisano, Pietro; Miele, Claudia

    2008-12-26

    Chronic hyperglycemia promotes insulin resistance at least in part by increasing the formation of advanced glycation end products (AGEs). We have previously shown that in L6 myotubes human glycated albumin (HGA) induces insulin resistance by activating protein kinase Calpha (PKCalpha). Here we show that HGA-induced PKCalpha activation is mediated by Src. Coprecipitation experiments showed that Src interacts with both the receptor for AGE (RAGE) and PKCalpha in HGA-treated L6 cells. A direct interaction of PKCalpha with Src and insulin receptor substrate-1 (IRS-1) has also been detected. In addition, silencing of IRS-1 expression abolished HGA-induced RAGE-PKCalpha co-precipitation. AGEs were able to induce insulin resistance also in vivo, as insulin tolerance tests revealed a significant impairment of insulin sensitivity in C57/BL6 mice fed a high AGEs diet (HAD). In tibialis muscle of HAD-fed mice, insulin-induced glucose uptake and protein kinase B phosphorylation were reduced. This was paralleled by a 2.5-fold increase in PKCalpha activity. Similarly to in vitro observations, Src phosphorylation was increased in tibialis muscle of HAD-fed mice, and co-precipitation experiments showed that Src interacts with both RAGE and PKCalpha. These results indicate that AGEs impairment of insulin action in the muscle might be mediated by the formation of a multimolecular complex including RAGE/IRS-1/Src and PKCalpha.

  4. Inspiring Hybridity: A Call to Engage with(in) Global Flows of the Multicultural Classroom

    Science.gov (United States)

    Gallagher-Geurtsen, Tricia

    2009-01-01

    I propose that educators construct pedagogical responses to youth in schools in ways that consider classrooms to be the result of and the boardroom for complex global flows. Youth's production of individual and collective identities wherein flows are apprehended, discarded, combined, and recombined, rages against purifying processes of neocolonial…

  5. Mechanisms of Coagulation Abnormalities and Trauma

    Science.gov (United States)

    2013-11-01

    activated protein C, tissue plasminogen activator, and D-Dimers. Base deficit (BD) was used as a measure of tissue hypoperfusion. Our results show...of the alveolar -capillary barrier. This is further associated with activation of inflammatory DAMPs including HMGB1 and sRAGE and associated with the

  6. The First Amendment and the Web: The Internet Porn Panic and Restricting Indecency in Cyberspace.

    Science.gov (United States)

    Mullin, Dorothy Imrich

    In the wake of the Communications Decency Act of 1996, discussions have raged both online and in the press about free speech, online pornography, and the protection of children. This paper discusses the legal and social science issues surrounding content regulation of the World Wide Web and the Internet as a whole, with an emphasis on the…

  7. Dairy Sector Profit Squeeze

    Institute of Scientific and Technical Information of China (English)

    WANG PEI

    2006-01-01

    @@ Like any other industries in China,the potential in the dairy industry is huge but competition is tough,The big players such as Mengniu and Yili are happy to stay engaged in a price war that has raged for the last year,seemingly not affected by rising raw material prices.

  8. Intrapsychic dynamics, behavioral manifestations, and related interventions with youthful fire setters.

    Science.gov (United States)

    Williams, Dian L; Clements, Paul T

    2007-01-01

    Fire setting in youth has often been overlooked and misunderstood as a coping skill for expressing rage. The act of deliberate fire setting, if uninterrupted, may continue throughout an individual's lifetime. Forensic examiners, mental health care providers, and criminal justice professionals can help guide referral and treatment through better understanding of behaviors and intrapsychic dynamics.

  9. Beyond the Bravado: Sex Roles and the Exploitive Male.

    Science.gov (United States)

    Taubman, Stan

    1986-01-01

    Examines the tendency of men to engage in domestic violence and sexual exploitation and presents male sex-role acquisition as a process of psychosocial violence against young boys, which creates a sense of shame, powerlessness, self-alienation, isolation from others, and retaliatory rage and inhibits capacities for intimacy and mutuality.…

  10. Teaching the Arts of Public Theology

    Science.gov (United States)

    Casey, Shaun

    2006-01-01

    While intense discussions are raging over the definition and status of public theology, within graduate theological education relatively little attention is being paid to the teaching of the practices of public theology. This article explores one venue in graduate theological education that attempts to equip seminary and divinity school students…

  11. Bone marrow stromal cells inhibits HMGB1-mediated inflammation after stroke in type 2 diabetic rats.

    Science.gov (United States)

    Hu, J; Liu, B; Zhao, Q; Jin, P; Hua, F; Zhang, Z; Liu, Y; Zan, K; Cui, G; Ye, X

    2016-06-02

    High-mobility group box 1 (HMGB1), a ligand of receptor for advanced glycation endproducts (RAGE), functions as a proinflammatory factor. It is mainly involved in inflammatory activation and contributes to the initiation and progression of stroke. By using a model of transient middle cerebral artery occlusion (MCAo) in type 2 diabetic rats, we investigated the changes of pro-inflammation mediators, blood-brain barrier (BBB) leakage and functional outcome after stroke. Type 2 diabetic rats did not show an increased lesion volume, but exhibited significantly increased expression of HMGB1 and RAGE, BBB leakage, as well as decreased functional outcome after stroke compared with control rats. Injection of bone marrow stromal cells (BMSCs) into type 2 diabetic rats significantly reduced the expression of HMGB1 and RAGE, attenuated BBB leakage, and improved functional outcome after stroke. BMSCs-treated type 2 diabetic rats inhibited inflammation and improved functional outcome after stroke. Furthermore, in vitro data support the hypothesis that BMSCs-induced reduction of HMGB1 and RAGE in T2DM-MCAo rats contributed to attenuated inflammatory response in the ischemic brain, which may lead to the beneficial effects of BMSCs treatment. Further investigation of BMSCs treatment in type 2 diabetic stroke is warranted.

  12. The Role of the Blood-Brain Barrier in the Pathogenesis of Senile Plaques in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    J. Provias

    2014-01-01

    Full Text Available The accumulation of beta-amyloid [Aβ] within senile plaques [SP] is characteristic of these lesions in Alzheimer’s disease. The accumulation of Aβ42, in particular, in the superior temporal [ST] cortex may result from an inability of the blood brain barrier (BBB to regulate the trans-endothelial transport and clearance of the amyloid. Lipoprotein receptor-related protein [LRP] and P-glycoprotein [P-gp] facilitate the efflux of Aβ out of the brain, whereas receptor for advanced glycation end products [RAGE] facilitates Aβ influx. Additionally, vascular endothelial growth factor [VEGF] and endothelial nitric oxide synthase [eNOS] may influence the trans-BBB transport of Aβ. In this study we examined ST samples and compared SP burden of all types with the capillary expression of LRP, p-gp, RAGE, VEGF, and e-NOS in samples from 15 control and 15 Alzheimer brains. LRP, P-gp, RAGE, VEGF, and eNOS positive capillaries and Aβ42 plaques were quantified and statistical analysis of the nonparametric data was performed using the Mann-Whitney and Kruskal-Wallis tests. In the Alzheimer condition P-gp, VEGF, and eNOS positive capillaries were negatively correlated with SP burden, but LRP and RAGE were positively correlated with SP burden. These results indicate altered BBB function in the pathogenesis of SPs in Alzheimer brains.

  13. Negative Experiences as Learning Trigger: A Play Experience Empirical Research on a Game for Social Change Case Study

    Science.gov (United States)

    Mariani, Ilaria; Gandolfi, Enrico

    2016-01-01

    This study shows the results gathered from 141 subjects playing the persuasive urban game "A Hostile World" via a post-game-experience quantitative questionnaire. The aim is to problematize and deepen the role of negative emotions (e.g., frustration, rage)--explicitly fostered by "A Hostile World" to increase empathy toward…

  14. The Navy of Brazil: An Emerging Power at Sea (Marinha do Brasil: Um Poder Emergente no Mar),

    Science.gov (United States)

    1983-01-01

    Proceedings, February 1978, p. 62. Chapter I 1. Prado Mala, J.D.N.O.G. Uma Pqgfina Esquecida da Historia do Marinha Brasileira (A Forgotten rage of...1976), p. 27. 2. Brasil , Escola Superior de Guerra, Fundamentos da Doutrina (Fundamentals of Doctrine). Rio de Janeiro, 1981, p. 205. 3. Albert

  15. Danish Municipal planning in Change

    DEFF Research Database (Denmark)

    Møller, Jørgen

    2003-01-01

    are breaking up, that the fight for planning competence in the open country is raging and that the protection og nature-friendly legislation, for which the previous gouvernment was responsible, is under quick phasing-out, at the same time as the traditional professional urban planner standards are challenged...

  16. Spatial atmospheric ALD of functional layers for CIGS Solar Cells

    NARCIS (Netherlands)

    Illiberi, A.; Frijters, C.; Balder, J.E.; Poodt, P.W.G.; Roozeboom, F.

    2015-01-01

    Spatial Atmosperic Atomic Layer Depositon combines the advantages of temporal ALD, i.e. excellent control of film composition and uniformity over large area substrates, with high growth rages (up tot nm/s). In this paper we present a short overview of our research acctivity carried out on S-ALD of f

  17. Beginning to Think Critically about Culturally Responsive Pedagogy in Practice: An Elementary Education Book Study in Student Teaching

    Science.gov (United States)

    Eick, Charles J.; McCormick, Theresa M.

    2010-01-01

    In this study student teachers in an elementary education program took part in a book study, "From Rage to Hope", on culturally responsive teaching. Interns critically reflected on their practice and began making changes based on practical strategies from the book. Four themes of learning and change emerged in intern written reflections: Project…

  18. Between green and grey

    NARCIS (Netherlands)

    Jeanet Kullberg

    2016-01-01

    Taking cuttings is cool. Growing vegetables is all the rage. Green oases can now be found scattered throughout Dutch towns and cities: community gardens and roof gardens where residents can go to relax and enjoy themselves, improve the appearance of their neighbourhood and meet their fellow resident

  19. Advocacy in Action: Annual 2006 DPI/NGO Conference at the United Nations

    Science.gov (United States)

    Brown, Nancy

    2007-01-01

    The Association for Childhood Education International (ACEI) was again represented at the annual 2006 DPI/NGO conference, along with 1,600 participants from around the world. The mood this year was somber and quite serious, possibly in response to the uncertainty created by the Middle East crisis that was raging while the conference was taking…

  20. A Case Study of a "Collaborative Organizational Innovation" Intervention, Combining Action Research and Design-Thinking Methodologies

    Science.gov (United States)

    Wetzler, Jeffrey Richard

    2013-01-01

    For decades, debates have raged about performance management in education. While it is essential to understand the degree of student learning and the nature of teacher impact in education systems, when attempts at managing outcomes go wrong, the consequences can be problematic. National Education Organization (a pseudonym for the organization…

  1. Problematising the Intellectual Gaze of the Educational Administration Scholar

    Science.gov (United States)

    Eacott, Scott

    2015-01-01

    Whereas epistemological debates raged in educational administration during the Theory Movement, or inspired by intervention from Thom Greenfield, Richard Bates or Colin Evers and Gabriele Lakomski, epistemology and the quest for the scientific study of educational administration has somewhat diminished in the era of managerialism and the pursuit…

  2. The Effects of Disturbed Adolescents on Their Teachers.

    Science.gov (United States)

    Bloom, Robert B.

    1983-01-01

    The author first reviews emotional hazards and conflicts of teachers of the emotionally disturbed, then describes, with frequent anecdotes, nine examples of the "interpersonal underworld of special education" such as helplessness rage, anger at teammates, and implementation despair. Suggests recognizing feelings to disengage from unproductive…

  3. A Delinquent Discipline: The Rise and Fall of Criminology

    Science.gov (United States)

    Adams, Mike S.

    2009-01-01

    What is the cause of crime? One can find answers in many places: in Genesis, in the plays of Sophocles and Shakespeare, in Dostoyevsky's "Crime and Punishment" and "Brothers Karamazov." The many answers include impiety, appetite, rage, and even the lure of transgression itself. For many, religious and poetic insights still offer the most…

  4. How Should the Financial Crisis Change How We Teach Economics?

    Science.gov (United States)

    Shiller, Robert J.

    2010-01-01

    Student dissatisfaction with teaching of economics--particularly with macroeconomics--during the current financial crisis mirrors dissatisfaction that was expressed during the last big crisis, the Great Depression. Then and now, a good number of students have felt that their lectures bear little relation to the economic crisis raging outside the…

  5. Follow the Leaders? An Analysis of Convergence and Innovation of Faculty Recruiting Practices in US Business Schools

    Science.gov (United States)

    Finch, David; Deephouse, David L.; O'Reilly, Norm; Massie, Tyler; Hillenbrand, Carola

    2016-01-01

    The debate associated with the qualifications of business school faculty has raged since the 1959 release of the Gordon-Howell and Pierson reports, which encouraged business schools in the USA to enhance their legitimacy by increasing their faculties' doctoral qualifications and scholarly rigor. Today, the legitimacy of specific faculty…

  6. Criminal Psychological Profiling

    Science.gov (United States)

    1993-10-18

    the medical sciences have attempted to explain and classify human behavior, such as hate, love , fear, and rage, as well as abnormal characteristics...usually the third person called," he joked, "after the psychic and the astrologer ." 󈧪 As mentioned early, in his book Serial Murder, Dr. Holmes called

  7. Experimental and clinical studies of fast three-dimensional MR imaging of the heart

    Energy Technology Data Exchange (ETDEWEB)

    Sato, Shuhei [Okayama Univ. (Japan). School of Medicine

    1999-07-01

    MRI has been utilized since its inception to study the anatomy and physiology of the heart. However, the sensitivity of MRI to motion has always posed a major challenge in imaging this organ. The purpose of this study was to develop a 3D MP-RAGE technique for the heart, and to apply it clinically. In the experimental study, data acquisition timing was discussed by normal volunteers. Changes in magnetization recovery time affected imaging contrast very little in the phantom study. Fourteen adults and 21 children were examined. In the adults, MP-RAGE images were rated as high in quality in the visual estimation. In the quantitative estimation, the images provided almost the same anatomical information as those of cine MRI. In the children, MP-RAGE was useful for cases of partial anomalous pulmonary venous drainage, particularly in the evaluation of abnormal pulmonary veins. The 3D MP-RAGE technique was useful in imaging the heart because it was possible to obtain continuous views in the same cardiac cycle and to reconstruct views from any direction after the examination. (author)

  8. Disabling Emotion in Young Children with Particular Reference to Depression and Suicide: An Overview of Current Research. Unit for Child Studies Selected Papers Number 12.

    Science.gov (United States)

    Phillips, Shelley

    A review of the literature and a survey of texts show a remarkable absence of concern and reference to depression and suicidal behavior in young children. The meaning of death, the depressive and suicidal consequences of the agony of aloneness, and the fear of parental hostility, rage and abandonment are elements of early and middle childhood…

  9. Laser Induced Chemistry for Production of Decaborane, B10H14, from Diborane, B2H6.

    Science.gov (United States)

    1977-10-01

    properties suitable for solid propellants and I bat list Ic burn moderators. Decaborane is presently produced by pyrolysis of ii ibora,ie , R211(, at...resu l ted in a calculated beam iumperat tire of ~00°l< and au av e rage v ibrat ional excitation (n) of .06 .07 above Liii’ gr~ und ii = I

  10. Religious Dialogue, World Peace and Social Harmony

    Institute of Scientific and Technical Information of China (English)

    YE XIAOWEN

    2007-01-01

    @@ Ⅰ. The World Peace Requires Religious Dialogues Peace, development and cooperation are the mainstay of the times in the present world, but there are unseen tricky and atrocious flows. The increasing opposition and conflicts are raging between different countries, nations and religions, which are challenging the wisdom and civilization of mankind.

  11. Divining Victory: Airpower in the 2006 Israel-Hezbollah War

    Science.gov (United States)

    2007-08-01

    fishermen’s Co-op offices, the cafe , the steel repair ga- rage, carpentry workshop, net repair workshop and market—as well as a three- storey [sic] Lebanese...implementing an immediate cease-fire. In a live address beamed to the Organization of the Islamic Conference (OIC) in Malaysia , PM Siniora calls on the OIC

  12. Draadloze ondergang van een bedrijf

    NARCIS (Netherlands)

    Degen, A.J.G.

    2003-01-01

    Draadloze netwerken zijn meer dan een rage. Ze bieden netwerktoegang onafhankelijk van kabelaansluitingen, wat bijvoorbeeld zorgt voor flexibiliteit qua werkplekken. Bedrijven kunnen zodoende heel wat besparen op de aanlegkosten voor hun intranet en interne verhuiskosten. Maar hoe zit het met de bev

  13. USA Stratified Monopoly: A Simulation Game about Social Class Stratification

    Science.gov (United States)

    Fisher, Edith M.

    2008-01-01

    Effectively teaching college students about social class stratification is a difficult challenge. Explanations for this difficulty tend to focus on the students who often react with resistance, paralysis, or rage. Sociologists have been using games and simulations as alternative methods for several decades to teach about these sensitive subjects.…

  14. The Harmon Memorial Lectures in Military History 1959-1987

    Science.gov (United States)

    1988-01-01

    years at the Academy. Harmon fell ill with cancer soon after launching the Air Force Acad- emy at Lowry Air Force Base, Denver, Colorado, in 1954, and...such perfectly childish rage that they trample tunder fool every sinigle rule of’ w~i-Flare. Without placing any considecrable force to guard the road

  15. Academic Superheroes? A Critical Analysis of Academic Job Descriptions

    Science.gov (United States)

    Pitt, Rachael; Mewburn, Inger

    2016-01-01

    For over a decade, debate has raged about the nature and purpose of the PhD, including its role as preparation for working in academia. Academic work has changed a great deal in the last 60 years, yet our doctoral curriculum has remained relatively static. While there is increasing interest in matching PhD programmes to "real world"…

  16. Misophonia: physiological investigations and case descriptions

    NARCIS (Netherlands)

    M. Edelstein; D. Brang; R. Rouw; V.S. Ramachandran

    2013-01-01

    Misophonia is a relatively unexplored chronic condition in which a person experiences autonomic arousal (analogous to an involuntary "fight-or-flight" response) to certain innocuous or repetitive sounds such as chewing, pen clicking, and lip smacking. Misophonics report anxiety, panic, and rage when

  17. Massive and Open

    Science.gov (United States)

    Fasimpaur, Karen

    2013-01-01

    MOOCs--massive open online courses--are all the rage these days, with hundreds of thousands of participants signing up and investors plunking down millions to get a piece of the pie. Why is there so much excitement about this new disruptive form of online learning, and how does this model apply to professional learning for teachers? Traditional…

  18. Green Science: Wildfires

    Science.gov (United States)

    Palliser, Janna

    2012-01-01

    Every summer, fires rage in different areas of the western United States. They are often massive, out of control, and extremely destructive. How do these fires begin and how are they controlled? What are the overall impacts of a wildfire? Are there any benefits of a wildfire? These questions will be addressed in this article. (Contains 3 online…

  19. Fiddling while the ice melts? How organizational scholars can take a more active role in the climate change debate

    NARCIS (Netherlands)

    S.M. Ansari (Shahzad); B. Gray (Barbara); F.H. Wijen (Frank)

    2011-01-01

    textabstractThe debate over anthropogenic climate change or the idea that human activities are altering the physical climate of the planet continues to rage amid seemingly irreconcilable differences, both within the developed world and between developed and less developed countries. With high uncert

  20. Massive Open Online Librarianship: Emerging Practices in Response to MOOCs

    Science.gov (United States)

    Mune, Christina

    2015-01-01

    Massive Open Online Courses, or MOOCs, have recently emerged as a disruptive pedagogy gaining rapid momentum in higher education. In some states, proposed legislations would accredit MOOCs to provide college-credit courses in the name of cost saving, efficiency and access. While debates rage regarding the place of MOOCs in higher education, some…

  1. Undocumented to Hyperdocumented: A "Jornada" of Protection, Papers, and PhD Status

    Science.gov (United States)

    Chang, Aurora

    2011-01-01

    In this personal essay, Aurora Chang describes her experience of "hyperdocumentation"--the effort to accrue awards, accolades, and eventually academic degrees to compensate for her undocumented status. In spite of her visible successes and naturalization, Chang still confronts the rage and intolerance of American "commonsense" beliefs about…

  2. Dispositional and Situational Autonomy as Moderators of Mood and Creativity

    Science.gov (United States)

    Xiao, Fengqiu; Wang, Ling; Chen, Yinghe; Zheng, Zhiwei; Chen, Wenjun

    2015-01-01

    Although previous research suggests that mood can influence creativity, the controversy about the effects of positive and negative moods has raged for years. This study investigated how the relationship between induced mood and creativity is moderated by dispositional and situational autonomy. It contrasted the different moderating effects of the…

  3. Between green and grey

    NARCIS (Netherlands)

    Jeanet Kullberg

    2016-01-01

    Original title: Tussen groen en grijs Taking cuttings is cool. Growing vegetables is all the rage. Green oases can now be found scattered throughout Dutch towns and cities: community gardens and roof gardens where residents can go to relax and enjoy themselves, improve the appearance of their neigh

  4. Army Sustainment. Volume 42, Issue 4, July-August 2010

    Science.gov (United States)

    2010-08-01

    47-foot motor lifeboat speeds through raging surf off the coast of Washington during a training exercise. This exercise is per formed on a regu- lar...food table. Chief Petty Officer Derrick Davenport and Petty Officer First Class Michael Edwards, representing Team Navy, won the Nutritional Hot Food

  5. Complete Genome Sequence of a Rabies Virus Strain Isolated from a Brown Bear (Ursus arctos) in Primorsky Krai, Russia (November 2014).

    Science.gov (United States)

    Shchelkanov, Michael Y; Deviatkin, Andrei A; Ananiev, Vasily Y; Dedkov, Vladimir G; Shipulin, German A; Sokol, Nataliya N; Dombrovskaya, Irina E; Galkina, Irina V; Shmelev, Mikhail E; Gorelikov, Vladimir N; Kozhan, Valentina N; Prosyannikova, Marina N; Aramilev, Sergei V; Fomenko, Pavel V

    2016-07-07

    We report here the complete genome sequence (GenBank KP997032) of rabies virus strain RABV/Ursus arctos/Russia/Primorye/PO-01/2014, isolated in November 2014 from a brown bear (Ursus arctos) that attacked a person in Primorsky Krai (Russian Federation). This strain was clustered into the Eurasian genetic subgroup of genotype 1 (street rage).

  6. Neurofeedback, Affect Regulation and Attachment: A Case Study and Analysis of Anti-Social Personality

    Science.gov (United States)

    Fisher, Sebern F.

    2007-01-01

    This case study examines the effects of neurofeedback (EEG biofeedback) training on affect regulation in a fifty-five year-old man with a history marked by fear, rage, alcoholism, chronic unemployment and multiple failed treatments. He had been diagnosed with ADHD and attachment disorder and met criteria for anti-social personality disorder. The…

  7. An overview of the Los Alamos Crestone Project : uses for astrophysical problems

    Energy Technology Data Exchange (ETDEWEB)

    Weaver, R. P. (Robert P.); Gittings, M. L. (Michael L.); Gisler, Galen R.; Coker, R. F. (Robert F.); New, K. C. (Kimberly C.); Hueckstaedt, R. M. (Robert M.)

    2004-01-01

    The Los Alamos Crestone Project is part of the Department of Energy's (DoE) Advanced Simulation and Computing (ASC) program. The main goal of this project is to investigate the use of continuous adaptive mesh refinement (CAMR) techniques for application to problems of interest to the Laboratory. An overview of the astrophysical simulations performed with the SAGE/RAGE codes will be shown here, including asteroid impacts in the deep-ocean, asteroid impacts on the continental shelf (e.g. - Chicxulub - the dinosaur killer), calculations of massive black holes at the galactic center, and calculations of supernova explosions. Examples of these simulations will be shown. We have shown that the SAGE and RAGE codes of the Crestone Project have been very successful products of the DoE's Advanced Simulation and Computing program. It is clear to those performing massively-parallel computations, that the use of thousands of processors in parallel is fundamentally changing the way we think about computer simulations. The Crestone Project codes are fully utilizing each new ASC supercomputer as they become available. The SAGE and RAGE codes are sophisticated Continuous Adaptive Mesh Refinement hydrodynamics codes for large parallel simulations. SAGE and RAGE are becoming useful tools for astrophysical applications. Further research is starting in a wider variety of areas, including cosmological studies with Mike Norman's group at UCSD.

  8. Attachment Disorder: An Emerging Concern for School Counselors.

    Science.gov (United States)

    Parker, Kandis Cooke; Forrest, Donald

    1993-01-01

    Explains attachment theory and posits that, if proper bonding and subsequent attachment, usually between mother and child, does not occur, the child develops mistrust and deep-seated rage. Presents evidence of the problem of attachment disorders, lists symptoms of unattached children, examines treatment of attachment disorders, and discusses…

  9. "I Asked My Parents Why a Wall Was so Important": Teaching about the GDR and Post-Reunification Germany

    Science.gov (United States)

    Streitwieser, Bernhard; Lys, Franziska

    2008-01-01

    Fifteen years after the "peaceful revolutions" brought about the collapse of communism and the reunification of East and West Germany, a heated debate rages over the legacy of communism and the continuing impact of 1989. This paper describes a new course that explores the contentious issues in this debate through the innovative use of the course…

  10. Revision de la famille des Alcyoniidae: les genres Sarcophytum et Lobophytum

    NARCIS (Netherlands)

    Tixier-Durivault, A.

    1958-01-01

    TABLE DES MATIÈ RES rages Introduction ..............1 1. — Genre Sarcophytum Lesson..........2 Généralités..............2 Classification.............7 Description des espèces...........10 2. — Genre Lobophytum Marenzeller.........88 Généralités..............88 Classification.............91 Descript

  11. Open access: the changing face of scientific publishing.

    Science.gov (United States)

    Chatterjee, Pranab; Biswas, Tamoghna; Mishra, Vishala

    2013-04-01

    The debate on open access to scientific literature that has been raging in scholarly circles for quite some time now has been fueled further by the recent developments in the realm of the open access movement. This article is a short commentary on the current scenario, challenges, and the future of the open access movement.

  12. EST Table: CK511111 [KAIKOcDNA[Archive

    Lifescience Database Archive (English)

    Full Text Available CK511111 rswdd0_007120.y1 10/09/29 99 %/222 aa ref|NP_001106747.2| sex-specific sto...rage-protein 1 precursor [Bombyx mori] 10/08/30 37 %/178 aa FBpp0240255|DwilGK11112-PA 10/08/28 n.h 10/09/10

  13. “Entre a cólera e o ódio”: justiça popular e assassinatos no Sudoeste do Paraná (1920-1930 - 10.4025/dialogos.v13i2.414 “Between rage and hatred”: street justice and murders in southwestern Paraná (1920-1930 - doi: 10.4025/dialogos.v13i2.414 “Entre la cólera y el odio”: justicia popular y asesinatos en el sureste del estado de Paraná (1920-1930

    Directory of Open Access Journals (Sweden)

    Aruanã Antônio dos Passos

    2010-08-01

    Full Text Available O artigo discute a relação entre a justiça e a violência na Região Sudoeste do Paraná nos anos anteriores à “efetiva” colonização da região (1920-1930. Buscamos compreender as relações estabelecidas em um sistema punitivo-repressivo (aparelho judiciário que conviveu com a violência popular, bem como a forma e as condições dessas relações. Para tanto, a análise do processo contra um habitante da região e seu filho transcorrido em 1920 na Comarca de Clevelândia é capaz de demonstrar as dificuldades que o aparelho judiciário encontrou diante da violência no Interior do Paraná, onde a justiça e a violência mantinham uma relação ambivalente.The article discusses the relationship between justice and violence in the southwestern region of Paraná in the years prior to the “effective” colonization of the region (1920-1930. We sought to comprehend how, under what conditions and which relationships were established by a punitive-repressive system (the judiciary apparatus that dealt with street justice. To that end, an analysis of the 1920 case against an inhabitant of the region and his son in Clevelândia County demonstrates the difficulties the judiciary apparatus faced against violence in the Paraná countryside, where justice and violence had an ambiguous relationship.El artículo discute la relación entre la justicia y la violencia en el sureste del Estado de Paraná (Brasil durante los años anteriores a la “efectiva” colonización de la región (1920-1930. Buscamos comprender de qué forma y cuáles fueron las condiciones y relaciones que se establecieron entre un sistema punitivo/represivo (aparato judicial y la violencia popular. Para ello, el análisis del proceso judicial contra un habitante y su hijo, ocurrido en la comarca de Clevelândia en 1920, permite demostrar las dificultades con las que tropezó el aparato judicial frente a la violencia en el interior del Estado de Paraná, donde justicia y violencia mantenían una relación ambivalente.

  14. The effect of valsartan on the expression of the receptor for advanced glycation end products in human glomerular mesangial cells%缬沙坦对人肾小球系膜细胞糖基化终产物受体表达的影响

    Institute of Scientific and Technical Information of China (English)

    钟林娜; 黄国良; 冯敏; 张莹

    2011-01-01

    目的:本实验探讨缬沙坦对糖基化终产物诱导的人肾小球系膜细胞氧化应激水平及糖基化终产物受体(RAGE)表达的影响.方法:体外常规培养人肾小球系膜细胞,运用糖基化修饰的牛血清白蛋白(AGE-BSA)和缬沙坦进行干预,流式细胞术检测细胞内活性氧(ROS),RT-PCR法检测NADPH氧化酶的亚基p47phox的mRNA表达,RT-PCR和细胞免疫化学法检测RAGE的表达量.结果:缬沙坦干预组人肾小球系膜细胞的ROS产生量、NADPH氧化酶的亚基p47phox mRNA表达量、RAGE表达量均低于AGE-BSA组(P<0.05),且缬沙坦的抑制作用呈浓度和时间依赖性.结论:缬沙坦可能通过降低氧化应激水平来抑制RAGE的表达.%Objective: To elucidate the effect of valsartan on human glomerular mesangial cells oxidative stress and the expression of the receptor for advanced glycation end products (RAGE) induced by the advanced glycation end-products (AGEs). Methods: Human glomerular mesangial cells were treated with advanced glycation end-product-bovine serum albumin (AGE-BSA) in the presence of valsartan. The reactive oxygen species( ROS) in cells were measured by Flow cytomeuy, and the mRNA of p47 phox, which was the primary subunits of NADPH oxi-dase, was detected by semi-quantitative reberse transcription polymerase chain reaction (RT-PCR). The mRNA of RAGE was detected by RT-PCR and the RAGE protein was assayed by immunocytochemistry. Results: The product of ROS, and the expression of p47 phox and RAGE in mesangial cells , which were treated with AGE-BSA in the presence of valsartan, were down-regulated compared with the groups treated with AGE-BSA(P < 0.05). Valsartan dose-dependently and ume-dependently inhibited the AGE-elicited overexpression of RAGE, ROS and p47phox in mesangial cells. Conclusion: Valsartan could inhibit RAGE expression through downregularion of oxidative stress.

  15. 糖基化终末产物及其受体在胃肠道中的分布%Distribution of advanced glycation end products and their receptor in the gastrointestinal tract

    Institute of Scientific and Technical Information of China (English)

    陈朋民; 赵静波; Hans Gregersen

    2012-01-01

    目的:研究糖基化终末产物(advanced glycation end products,AGE)及其受体(receptor for advanced glycation end products,RAGE)在胃肠道中的分布,为进一步探索其在慢性糖尿病胃肠功能紊乱中的作用奠定基础.方法:分别对成年Wistar大鼠食管、胃、十二指肠、空肠、回肠、结肠及直肠组织进行AGE及RAGE免疫组织化学染色.结果:(1)食管:AGE及RAGE主要分布在横纹肌的肌细胞及黏膜的鳞状上皮细胞;(2)胃:AGE在壁细胞为强阳性.RAGE在主细胞、肥大细胞、神经细胞为强阳性,在壁细胞为中等强度阳性,在表面黏液细胞为弱阳性;(3)小肠:AGE及RAGE在绒毛及固有层上皮细胞为阳性或强阳性.RAGE在肠道的神经细胞亦为强阳性;(4)结肠及直肠:AGE及RAGE在黏膜上皮细胞为弱阳性,RAGE在神经细胞为强阳性.结论:AGE及RAGE广泛分布于肠道上皮细胞及食管的横纹肌细胞,AGE亦分布于胃的壁细胞,RAGE亦分布于胃的壁细胞、主细胞、表面黏液细胞、肥大细胞及胃肠道的神经细胞.%AIM: 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-(c arboxymethyl) 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 and squamous epithelial cells. In the stomach, AGEs were mainly distributed in parietal cells, and RAGE was strongly expressed in chief cells, mast cells and neurons in ganglia, moderately in parietal cells, and mildly in surface mucous cells. In the intestine, colon and rectum, AGEs and RAGE were distributed in mucosal

  16. Efek Kortikosteroid Dosis Rendah terhadap Kadar Soluble Receptor for Advanced Glycation End Products Mencit Balb/C Model Sepsis

    Directory of Open Access Journals (Sweden)

    Diding Heri Prasetyo

    2015-03-01

    Full Text Available The use of low-dose corticosteroids in the management of early sepsis is still under debate. Soluble receptor for advanced glycation end products (sRAGE is a biomarker of severity and poor outcome of sepsis. This study aimed to analyze the effects of the use of low-dose corticosteroids on sRAGE serum levels in Balb/C mice model of early sepsis. This study was an experimental research laboratory study with 30 male Balb/C mice which divided into control, sepsis and sepsis+low-dose corticosteroids groups. The study was conducted at Histology and Biomedical Laboratory, Faculty of Medicine, Sebelas Maret University, Surakarta, from June to December 2013. Sepsis was induced in the male Balb/C mice by inoculation with an intraperitoneally (i.p. injection of lipopoly-saccharide/LPS (E. coli with a dose of 0.1 mg/mice/i.p.for sepsis mice model. Control mice were not inoculated during the study. Low-dose corticosteroids used was methyl prednisolone at a dose of 0.05 mg/mice/day/i.p. Levels of sRAGE 54.29±16.28 pg/mL in control group, 78.12±13.38 pg/mL in sepsis group, and 63.39±11.07 pg/mL in low-dose corticosteroids group. Low-dose corticosteroids significantly decreased sRAGE level (p=0.044 compared to the sepsis group. In conclusion, the use of low-dose corticosteroids reduces levels of sRAGE in early sepsis.

  17. Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression.

    Science.gov (United States)

    Ojima, Ayako; Ishibashi, Yuji; Matsui, Takanori; Maeda, Sayaka; Nishino, Yuri; Takeuchi, Masayoshi; Fukami, Kei; Yamagishi, Sho-ichi

    2013-01-01

    Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells. However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic rats received continuous i.p. infusion of 0.3 μg of vehicle or 1.5 μg of the GLP-1 analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS, and ADMA generation in tubular cells, which were blocked by small-interfering RNAs raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of Rage, Prmt-1, Icam-1, and Mcp-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2'-deoxyguanosine and albumin; and improved histopathologic changes of the kidney in diabetic rats. Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE-mediated ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation, thereby protecting against the development and progression of diabetic nephropathy.

  18. High-mobility group box 1 inhibits gastric ulcer healing through Toll-like receptor 4 and receptor for advanced glycation end products.

    Science.gov (United States)

    Nadatani, Yuji; Watanabe, Toshio; Tanigawa, Tetsuya; Ohkawa, Fumikazu; Takeda, Shogo; Higashimori, Akira; Sogawa, Mitsue; Yamagami, Hirokazu; Shiba, Masatsugu; Watanabe, Kenji; Tominaga, Kazunari; Fujiwara, Yasuhiro; Takeuchi, Koji; Arakawa, Tetsuo

    2013-01-01

    High-mobility group box 1 (HMGB1) was initially discovered as a nuclear protein that interacts with DNA as a chromatin-associated non-histone protein to stabilize nucleosomes and to regulate the transcription of many genes in the nucleus. Once leaked or actively secreted into the extracellular environment, HMGB1 activates inflammatory pathways by stimulating multiple receptors, including Toll-like receptor (TLR) 2, TLR4, and receptor for advanced glycation end products (RAGE), leading to tissue injury. Although HMGB1's ability to induce inflammation has been well documented, no studies have examined the role of HMGB1 in wound healing in the gastrointestinal field. The aim of this study was to evaluate the role of HMGB1 and its receptors in the healing of gastric ulcers. We also investigated which receptor among TLR2, TLR4, or RAGE mediates HMGB1's effects on ulcer healing. Gastric ulcers were induced by serosal application of acetic acid in mice, and gastric tissues were processed for further evaluation. The induction of ulcer increased the immunohistochemical staining of cytoplasmic HMGB1 and elevated serum HMGB1 levels. Ulcer size, myeloperoxidase (MPO) activity, and the expression of tumor necrosis factor α (TNFα) mRNA peaked on day 4. Intraperitoneal administration of HMGB1 delayed ulcer healing and elevated MPO activity and TNFα expression. In contrast, administration of anti-HMGB1 antibody promoted ulcer healing and reduced MPO activity and TNFα expression. TLR4 and RAGE deficiency enhanced ulcer healing and reduced the level of TNFα, whereas ulcer healing in TLR2 knockout (KO) mice was similar to that in wild-type mice. In TLR4 KO and RAGE KO mice, exogenous HMGB1 did not affect ulcer healing and TNFα expression. Thus, we showed that HMGB1 is a complicating factor in the gastric ulcer healing process, which acts through TLR4 and RAGE to induce excessive inflammatory responses.

  19. High-mobility group box 1 inhibits gastric ulcer healing through Toll-like receptor 4 and receptor for advanced glycation end products.

    Directory of Open Access Journals (Sweden)

    Yuji Nadatani

    Full Text Available High-mobility group box 1 (HMGB1 was initially discovered as a nuclear protein that interacts with DNA as a chromatin-associated non-histone protein to stabilize nucleosomes and to regulate the transcription of many genes in the nucleus. Once leaked or actively secreted into the extracellular environment, HMGB1 activates inflammatory pathways by stimulating multiple receptors, including Toll-like receptor (TLR 2, TLR4, and receptor for advanced glycation end products (RAGE, leading to tissue injury. Although HMGB1's ability to induce inflammation has been well documented, no studies have examined the role of HMGB1 in wound healing in the gastrointestinal field. The aim of this study was to evaluate the role of HMGB1 and its receptors in the healing of gastric ulcers. We also investigated which receptor among TLR2, TLR4, or RAGE mediates HMGB1's effects on ulcer healing. Gastric ulcers were induced by serosal application of acetic acid in mice, and gastric tissues were processed for further evaluation. The induction of ulcer increased the immunohistochemical staining of cytoplasmic HMGB1 and elevated serum HMGB1 levels. Ulcer size, myeloperoxidase (MPO activity, and the expression of tumor necrosis factor α (TNFα mRNA peaked on day 4. Intraperitoneal administration of HMGB1 delayed ulcer healing and elevated MPO activity and TNFα expression. In contrast, administration of anti-HMGB1 antibody promoted ulcer healing and reduced MPO activity and TNFα expression. TLR4 and RAGE deficiency enhanced ulcer healing and reduced the level of TNFα, whereas ulcer healing in TLR2 knockout (KO mice was similar to that in wild-type mice. In TLR4 KO and RAGE KO mice, exogenous HMGB1 did not affect ulcer healing and TNFα expression. Thus, we showed that HMGB1 is a complicating factor in the gastric ulcer healing process, which acts through TLR4 and RAGE to induce excessive inflammatory responses.

  20. HMGB1 binds to activated platelets via the receptor for advanced glycation end products and is present in platelet rich human coronary artery thrombi.

    Science.gov (United States)

    Ahrens, Ingo; Chen, Yung-Chih; Topcic, Danijal; Bode, Michael; Haenel, David; Hagemeyer, Christoph E; Seeba, Hannah; Duerschmied, Daniel; Bassler, Nicole; Jandeleit-Dahm, Karin A; Sweet, Matthew J; Agrotis, Alex; Bobik, Alex; Peter, Karlheinz

    2015-11-01

    High mobility group box 1 (HMGB1) acts as both a nuclear protein that regulates gene expression, as well as a pro-inflammatory alarmin that is released from necrotic or activated cells. Recently, HMGB1-expression in human atherosclerotic plaques was identified. Therapeutic blockade of HMGB1 reduced the development of diet-induced atherosclerosis in ApoE knockout mice. Thus, we hypothesised an interaction between HMGB1 and activated platelets. Binding of recombinant HMGB1 to platelets was assessed by flow cytometry. HMGB1 bound to thrombin-activated human platelets (MFI 2.49 vs 25.01, p=0.0079). Blood from wild-type, TLR4 and RAGE knockout mice was used to determine potential HMGB1 receptors on platelets. HMGB1 bound to platelets from wild type C57Bl6 (MFI 2.64 vs 20.3, p 0.05). RAGE expression on human platelets was detected by RT-PCR with mRNA extracted from highly purified platelets and confirmed by Western blot and immunofluorescence microscopy. Platelet activation increased RAGE surface expression (MFI 4.85 vs 6.74, p< 0.05). Expression of HMGB1 in human coronary artery thrombi was demonstrated by immunohistochemistry and revealed high expression levels. Platelets bind HMGB1 upon thrombin-induced activation. Platelet specific expression of RAGE could be detected at the mRNA and protein level and is involved in the binding of HMGB1. Furthermore, platelet activation up-regulates platelet surface expression of RAGE. HMGB1 is highly expressed in platelet-rich human coronary artery thrombi pointing towards a central role for HMGB1 in atherothrombosis, thereby suggesting the possibility of platelet targeted anti-inflammatory therapies for atherothrombosis.

  1. 可溶性晚期糖基化终末产物受体在急性呼吸窘迫综合征患者诊断及预后评估中的应用价值%Application Value of Soluble Receptor of Advanced Glycation End products in the Diagnostic and prognostic Assessment of patients With Acute Respiratory Distress Syndrome

    Institute of Scientific and Technical Information of China (English)

    胡占升

    2014-01-01

    目的:探讨可溶性晚期糖基化终末产物受体(sRAGE)在急性呼吸窘迫综合征(ARDS)患者诊断及预后预测中的价值。方法选取2012年3月-2013年3月入住辽宁医学院附属第一医院重症监护病房的 ARDS 患者60例为 ARDS 组,根据氧合指数(PaO2/ FiO2)将 ARDS 组分为轻度 ARDS 组(23例)、中度 ARDS 组(23例)及重度ARDS 组(14例),根据预后分为死亡组(18例)及存活组(42例);另选择同时期入住重症监护病房的非 ARDS 患者60例为非 ARDS 组。采用酶联免疫吸附试验(ELISA)法检测患者血浆 sRAGE 水平,记录患者PaO2/ FiO2。结果ARDS 组较非 ARDS 组患者 sRAGE 水平升高,PaO2/ FiO2降低,差异有统计学意义(P é0.05)。不同严重程度 ARDS 组患者 sRAGE 水平及PaO2/ FiO2比较,差异均有统计学意义(P é0.05);其中中度 ARDS 组、重度 ARDS 组较轻度 ARDS组,重度 ARDS 组较中度 ARDS 组患者 sRAGE 水平升高,PaO2/ FiO2降低,差异有统计学意义(P é0.05)。死亡组较存活组 ARDS 患者 sRAGE 水平升高,PaO2/ FiO2降低,差异有统计学意义( P é0.05)。直线相关性分析显示,ARDS组患者 sRAGE 水平与PaO2/ FiO2呈负相关(r =-0.949,P =0.0002)。结论 sRAGE 在 ARDS 患者预后预测方面存在价值,可作为评价 ARDS 预后的一个生化标记物;在诊断方面可能存在一定价值,有待于进一步研究验证。%Objective To discuss the application value about soluble receptor for advanced glycation end products (sRAGE)in the diagnostic and prognostic assessment of patients with acute respiratory distress syndrome(ARDS)in the inten-sive care unit(ICU). Methods 60 ARDS patients admitted to the First Affiliated Hospital of Liaoning Medical University from March 2012 to March 2013 were selected. The patients were divided into mild group(23 cases),moderate group(23 cases)and severe group(14 cases)based on o

  2. 糖基化终产物受体在大鼠牙周膜成纤维细胞中的表达%Expression of receptor for advanced glycation end-product in rat periodontal ligament fibroblasts

    Institute of Scientific and Technical Information of China (English)

    邓天政; 吕晶; 冯岩; 李冬霞; 刘冰; 逄键梁; 柯杰

    2012-01-01

    Objective To detect expression of receptor for advanced glycation end products (RAGE) produced by human periodontal ligament fibroblasts ( PDL) cultured in vitro. Methods To collect rat periodontal ligament firbroblast induced by 50, 100, 200 mg/L advanced glycation end products-bovine serum albumin ( AGE-BSA) 200 mg/L BSA and blank control in DMEM in vitro, which were group A, B, C, D, E respectively. Detect mRNA of RAGE using RT-PCR and protein expression using immunohistochemistry. Results Immunohistochemistry showed the protein expression ofRAGE in group A, B, C, and the expression level elevated with the increase of AGE-BSA concentration. Group D and E did not express RAGE protein. RT-PCR proved the gene of RAGE expresses in group A, B, C. Group D expressed a little, group E did not express. Conclusion RAGE can be produced by PDL cultured in vitro induced by AGE-BSA.%目的 研究体外培养大鼠牙周膜成纤维细胞在糖基化终产物诱导下糖基化终产物受体( receptor for advanced glycation end-product,RAGE)的表达情况.方法 收集第三代体外培养的大鼠牙周膜成纤维细胞,在含有终浓度为50、100、200 mg/L的糖基化牛血清白蛋白、200 ms/L的牛血清白蛋白以及不含上述蛋白成分培养基内孵育48h,分别设为A组、B组、C组、D组、E组.免疫组织化学法、反转录-聚合酶链反应(reverse transcription-polymerase chain reaction,RT-PCR)检测细胞内RAGE蛋白及mRNA表达.结果 免疫组织化学结果显示A、B、C组中牙周膜成纤维细胞内RAGE蛋白表达均为阳性,且随浓度增高,表达强度略有增强,而D及E组无表达;RT-PCR检测发现A、B、C组RAGE mRNA均表达且表达强度随浓度增高而增强,D组有少量表达,E组不表达.结论 体外培养的牙周膜成纤维细胞在糖基化终产物诱导下能够表达RAGE.

  3. Vagus nerve electrical stimulation inhibits serum levels of S100A8 protein in septic shock rats.

    Science.gov (United States)

    Lei, Ming; Liu, Xin-Xin

    2016-05-01

    The vagus nerve and the released acetylcholine exert anti-inflammatory effects and inhibit septic shock. However, their detailed mechanisms remain to be elucidated. The present study aimed to investigate the effects of vagus nerve electrical stimulation on serum S100A8 levels in septic shock rats. A total of 36 male Sprague-Dawley rats were randomly divided into six equal groups: i) Sham group, receiving sham operation; ii) CLP group, subjected to cecal ligation and puncture (CLP) to establish a model of polymicrobial sepsis; iii) VGX group, subjected to CLP and bilateral cervical vagotomy; iv) STM group, subjected to CLP, bilateral cervical vagotomy and electrical stimulation on the left vagus nerve trunk; v) α‑bungarotoxin (BGT) group was administered α‑BGT prior to electrical stimulation; vi) Anti‑receptor for advanced glycation end products (RAGE) group, administered intraperitoneal injection of anti‑RAGE antibody prior to electrical stimulation. The right carotid artery was cannulated to monitor mean artery pressure (MAP). The serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured to assess the liver function. Serum S100A8 and advanced glycation end product (AGE) levels were measured using enzyme‑linked immunosorbent assays. The expression of hepatic RAGE was determined by western blotting. The present study revealed that Sprague‑Dawley rats exhibited progressive hypotension and significantly increased serum AST and ALT levels following CLP challenge compared with the sham group. The levels of S100A8 and AGEs, and the protein expression of hepatic RAGE were significantly increased following CLP compared with the sham group. Vagus nerve electrical stimulation significantly prevented the development of CLP‑induced hypotension, alleviated the hepatic damage, reduced serum S100A8 and AGEs production, and reduced the expression of hepatic RAGE. The inhibitory effect of vagus nerve electrical

  4. Anti-atherosclerotic effects of sitagliptin in patients with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Omoto S

    2015-07-01

    Full Text Available Seitaro Omoto,1 Takehito Taniura,2 Tohru Nishizawa,3 Takeshi Tamaki,3 Akira Shouzu,4 Shosaku Nomura3 1Division of Internal Medicine, Korigaoka Yukeikai Hospital, 2Division of Internal Medicine, Daiwa Hospital, 3First Department of Internal Medicine, Kansai Medical University, 4Division of Internal Medicine, Saiseikai Izuo Hospital, Osaka, Japan Background: Advanced glycation end products, selectins, and adiponectin play important roles in the development of atherosclerosis in individuals with diabetes. Sitagliptin has been shown to reduce the concentration of glycated hemoglobin in diabetic patients. However, its effects on soluble receptor for advanced glycation end products (sRAGEs, selectins, and adiponectin in these patients are poorly understood. This study was conducted to assess the effects of sitagliptin on the circulating levels of sRAGEs, monocyte chemoattractant protein-1 (MCP-1, selectins, and adiponectin in patients with type 2 diabetes. Methods: Diabetic patients eligible for sitagliptin monotherapy or combination therapy (eg, sitagliptin plus a sulfonylurea were administered sitagliptin (50 mg/day for 6 months. Levels of soluble P-selectin (sP-selectin, soluble E-selectin (sE-selectin, soluble vascular cell adhesion molecule-1 (sVCAM-1, MCP-1, sRAGEs, and adiponectin were measured by ELISA at baseline and after 3 and 6 months of treatment. Results: At baseline, the levels of MCP-1, sP-selectin, sE-selectin, and sVCAM-1 were higher and the level of adiponectin was lower in diabetic patients than in nondiabetic patients. Sitagliptin therapy for 3 and 6 months significantly reduced plasma levels of sP-selectin, sE-selectin, sVCAM-1, and MCP-1 relative to baseline, while significantly increasing adiponectin levels. sRAGEs did not exhibit a statistical significance, although there was an increasing tendency. Furthermore, the reductions in sP-selectin, sE-selectin, sVCAM-1, and MCP-1 during sitagliptin therapy were significantly greater

  5. Co-morbid disorders in Tourette syndrome

    DEFF Research Database (Denmark)

    Debes, Nanette Marinette Monique

    2013-01-01

    Tourette syndrome (TS) is often accompanied by other symptoms and syndromes. The two best-known co-morbidities are Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD), but also other conditions like rage-attacks, depression, and sleeping disturbances are frequent......-morbid disorders, like rage, anxiety, and conduct disorders. The symptoms of a co-morbid disorder might appear prior to the time that tics reach clinical attention. The TS phenotype probably changes during the course of the disease. The exact aetiology of the co-occurrence of co-morbid disorders and TS...... is not known, but they probably all are neurotransmitter disorders. European guidelines recommend first-choice pharmacological treatment, but randomised double-blinded trials are needed. Professionals need to be aware of the close relationship between TS and co-morbidities in order to give the patients...

  6. The Effect of Chang Run Tong on Biomechanical Colon Remodeling in STZ-Induced Type I Diabetic Rats - Is It Related to Advanced Glycation End Product Formation?

    DEFF Research Database (Denmark)

    Zhao, Jingbo; Gregersen, Hans

    2015-01-01

    BACKGROUND AND AIM: The Chinese medicine Chang Run Tong (CRT) effectively improved senile constipation in the clinics. The aims of the present study were to investigate the effect of CRT on colonic remodeling in streptozotocin (STZ) induced diabetic rats and to explore the mechanisms of the CRT...... regression analysis was done to study association between AGE/RAGE expression with the histomorphometric and biomechanical parameters. RESULTS: The wet weight per unit length to body weight ratio, wall thickness, the cross-sectional wall area,opening angle and absolute values of inner and outer residual...... and biomechanical remodeling parameters. The AGE/RAGE expressions were significantly decreased in the T1 group (P0.05). CONCLUSIONS:CRT (high dose) treatment could partly restore the morphometric and biomechanical remodeling of colon in diabetic rats. One mechanism for CRT...

  7. Simulation and Analysis of Converging Shock Wave Test Problems

    Energy Technology Data Exchange (ETDEWEB)

    Ramsey, Scott D. [Los Alamos National Laboratory; Shashkov, Mikhail J. [Los Alamos National Laboratory

    2012-06-21

    Results and analysis pertaining to the simulation of the Guderley converging shock wave test problem (and associated code verification hydrodynamics test problems involving converging shock waves) in the LANL ASC radiation-hydrodynamics code xRAGE are presented. One-dimensional (1D) spherical and two-dimensional (2D) axi-symmetric geometric setups are utilized and evaluated in this study, as is an instantiation of the xRAGE adaptive mesh refinement capability. For the 2D simulations, a 'Surrogate Guderley' test problem is developed and used to obviate subtleties inherent to the true Guderley solution's initialization on a square grid, while still maintaining a high degree of fidelity to the original problem, and minimally straining the general credibility of associated analysis and conclusions.

  8. 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......-regulated in the GI tract of GK diabetic rats and may contribute to GI dysfunction in type 2 diabetic patients....

  9. Development and Implementation of Radiation-Hydrodynamics Verification Test Problems

    Energy Technology Data Exchange (ETDEWEB)

    Marcath, Matthew J. [Los Alamos National Laboratory; Wang, Matthew Y. [Los Alamos National Laboratory; Ramsey, Scott D. [Los Alamos National Laboratory

    2012-08-22

    Analytic solutions to the radiation-hydrodynamic equations are useful for verifying any large-scale numerical simulation software that solves the same set of equations. The one-dimensional, spherically symmetric Coggeshall No.9 and No.11 analytic solutions, cell-averaged over a uniform-grid have been developed to analyze the corresponding solutions from the Los Alamos National Laboratory Eulerian Applications Project radiation-hydrodynamics code xRAGE. These Coggeshall solutions have been shown to be independent of heat conduction, providing a unique opportunity for comparison with xRAGE solutions with and without the heat conduction module. Solution convergence was analyzed based on radial step size. Since no shocks are involved in either problem and the solutions are smooth, second-order convergence was expected for both cases. The global L1 errors were used to estimate the convergence rates with and without the heat conduction module implemented.

  10. Los Alamos Radiation Hydrocode Models of Asteroid Destruction by an Internal Explosion

    Science.gov (United States)

    Weaver, R.; Plesko, C. S.

    2009-12-01

    Disruption of a potentially hazardous object (PHO) by a conventional or nuclear subsurface burst is considered has been popularized in media presentations and is considered as one possible method of impact-hazard mitigation. We present RAGE radiation hydrocode models of the shock-generated disruption of PHOs by subsurface nuclear bursts using scenario-specific models from authentic RADAR shape models. We will show 2D and 3D models for the disruption by a large energy source at the center of such PHO models (10 Mton TNT equivalent) , specifically for Itokawa and Golevka. If possible, our RAGE model calculations will be compared to M. Boslough’s (Sandia National Laboratory) results from his similar simulations with a different code. As time permits, parametric studies will be done on source energy (from 1 Mton to 10 Mton) and on the parameters in the Steinberg-Guinan strength model used.

  11. A Psychoanalytic Study of Sylvia Plath.

    Science.gov (United States)

    Feirstein, Frederick

    2016-02-01

    Sylvia Plath's rage at her abandoning husband and at her late beloved father was partly a displacement of anger toward her loving but smothering mother. Her schizoid pathology resulting from the symbiosis (along with her bipolarity) helped prompt her suicide. At the same time her rage at the men represented a struggle to prevent it. The focus of this paper is to explore in the context of her life how the style as well as the content of her last book, Ariel, made for one long suicide note-albeit a beautifully written work of art. In the most accessible of her poems, such as "Daddy," "Lady Lazarus," and "Edge," her health overcomes her pathology. In others her pathology dominates. In Ariel Plath attempted and succeeded in turning herself into a tragic, mythic heroine, eventually drowning herself in a gas oven as she would have in the ocean-a key metaphor for her mother.

  12. 子痫前期患者胎盘组织中晚期糖基化终产物受体和P-选择素的表达%Expression of receptor of advanced glycation end products and P-selectin in placenta of preeclampsia patients

    Institute of Scientific and Technical Information of China (English)

    杨玲竹; 李亚敏

    2011-01-01

    Aim :To explore the role of receptor of advanced glycation end products (RAGE) and P-selectin in the development of preeclampsia (PE). Methods:SP method and RT-PCR analysis were used to detect the expression of RAGE and P-selectin protein and mRNA in placenta tissue from 40 cases of PE (20 cases of mild PE, 20 cases of severe PE) and 30 cases of normal term pregnant. Results: All groups showed RAGE and P-selectin positive pigmentation in the placenta.RAGE protein was mainly expressed in trophoblast cells, but there was a small amount in the vascular endothelial cells.P-selectin was mainly expressed in syncytiotrophoblast cells, vascular endothelial cells,and interstitial cells. There were significant differences among three groups on the expression of RAGE and P-selectin protein( F = 250.152 and 274. 044,P <0. 001 ) and mRNA( F =624. 550 and 708. 351 ,P <0. 001 ). Expression of RAGE and P-selectin mRNA was significantly higher in placenta tissue of PE group compared with that of control group ( P < 0.05 ), the levels of severe PE group were higher than those of mild PE group ( P < 0.05) , and there was a positive correlation between them of protein and mRNA expression ( r =0. 814 and 0. 796 ,P <0. 001 ). Conclusion:The high levels of RAGE and P-selectin in placenta tiusse in PE may be associated with the occurrence and development of PE, and both of them have synergies in the development of PE.%目的:探讨晚期糖基化终产物受体(RAGE)和P-选择素(P-selectin)在子痫前期(PE)发生发展中的作用.方法:采用免疫组织化学SP法和RT-PCR法检测30例正常孕妇(对照组)和40例PE患者(轻度20例、重度20例)胎盘组织中RAGE和P-selectin蛋白及mRNA的表达情况.结果:对照组与PE组胎盘组织内均有RAGE和P-selectin阳性表达,RAGE主要表达于滋养细胞.血管内皮细胞巾也有少量表达;P-seleetin主要表达于合体滋养细胞、血管内皮细胞及间质细胞.3组RAGE和P-seleetin蛋白(F=250.152

  13. On the Significance of New Biochemical Markers for the Diagnosis of Premature Labour

    Directory of Open Access Journals (Sweden)

    Rafał Rzepka

    2014-01-01

    Full Text Available Preterm labour is defined as a birth taking place between 22nd and 37th weeks of gestation. Despite numerous studies on the aetiology and pathogenesis of preterm labour, its very cause still remains unclear. The importance of the cytokines and acute inflammation in preterm labour aetiology is nowadays well-proven. However, chronic inflammation as an element of the pathogenesis of premature labour is still unclear. This paper presents a literature review on the damage-associated molecular patterns (DAMPs, receptors for advanced glycation end products (RAGE, negative soluble isoforms of RAGE, chemokine-stromal cell-derived factor-1 (SDF-1 and one of the adipokines, resistin, in the pathogenesis of preterm labour. We conclude that the chronic inflammatory response can play a much more important role in the pathogenesis of preterm delivery than the acute one.

  14. Psychohistory and Family Among Antebellum Slaveholders.

    Science.gov (United States)

    Adams, Kenneth Alan

    2016-01-01

    This article examines the macroscopic reasons for maternal rage and its injection into slaveholder children in the antebellum South. It is argued that the misogyny that infected antebellum life metastasized in southern mistresses and affected the way they felt about themselves and their children. As mothers, they were casual parents, concerned with molding the character of their charges, rearing warriors and proper ladies, but uninterested in caring for them and helping them realize their own aspirations. It is argued that the misanthropic rage that they injected into their children constituted the poison that each generation of slaveholders had to ventilate into poison containers, slaves, as a homeostatic means of psycho-emotional survival. This intergenerational process of poison injection--from father to mother, from mother to child, from child to slave, constituted the process that insured the perpetuation of the psychic structure necessary for the continuation of slavery from generation to generation.

  15. Aggressive Behaviour in Huntington’s Disease: A Cross-Sectional Study in a Nursing Home Population

    Directory of Open Access Journals (Sweden)

    R. S. Shiwach

    1993-01-01

    Full Text Available We describe a cross-sectional study of aggressive behaviour in a sample of patients suffering from Huntington's disease in a residential nursing home. Data were obtained using the RAGE, a behaviourally oriented rating scale for measuring aggressive behaviour in cognitively impaired patients. Nursing staff rated 27 patients after a 3 day observation period. A third of the sample were rated to be at least mildly aggressive; the frequencies of some specific types of aggressive behaviour were high. In contrast, the frequency of injuries sustained and the use of restraints and medication for aggressive behaviour were low. Aggressive behaviour was found to be significantly related to the degree of functional impairment. These data are compared with those reported in a study using the RAGE to assess aggressive behaviour in a sample of elderly patients with dementia.

  16. Large eddy simulation of a shocked gas cylinder instability induced turbulence

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The Navier-Stokes equations for compressible fluid are solved with the operator splitting technique and LES (large eddy simulation) with the Smagorinsky model. A computational code MVFT (multi-viscosity-fluid and turbulence) is developed to study hydrodynamic instability and the induced turbulent mixing for multi compressible fluid. In order to validate the code MVFT,the LANL’s shock tube experiment of shocked SF6 gas cylinder is simulated with the initial state of SF6 gas cylinder described by dissipative ITL (interface transition layer). It is shown that the width and height of gas cylinder calculated with MVFT are closer to the experimental results than RAGE,and that the velocities of upstream edge,downstream edge and vortex edge agree with the experimental results,and are appreciably smaller than the RAGE results. The code MVFT has been pre-liminarily validated.

  17. The danger signal S100B integrates pathogen- and danger-sensing pathways to restrain inflammation.

    Science.gov (United States)

    Sorci, Guglielmo; Giovannini, Gloria; Riuzzi, Francesca; Bonifazi, Pierluigi; Zelante, Teresa; Zagarella, Silvia; Bistoni, Francesco; Donato, Rosario; Romani, Luigina

    2011-03-01

    Humans inhale hundreds of Aspergillus conidia without adverse consequences. Powerful protective mechanisms may ensure prompt control of the pathogen and inflammation. Here we reveal a previously unknown mechanism by which the danger molecule S100B integrates pathogen- and danger-sensing pathways to restrain inflammation. Upon forming complexes with TLR2 ligands, S100B inhibited TLR2 via RAGE, through a paracrine epithelial cells/neutrophil circuit that restrained pathogen-induced inflammation. However, upon binding to nucleic acids, S100B activated intracellular TLRs eventually resolve danger-induced inflammation via transcriptional inhibition of S100B. Thus, the spatiotemporal regulation of TLRs and RAGE by S100B provides evidence for an evolving braking circuit in infection whereby an endogenous danger protects against pathogen-induced inflammation and a pathogen-sensing mechanism resolves danger-induced inflammation.

  18. Cell signaling and receptors in toxicity of advanced glycation end products (AGEs): α-dicarbonyls, radicals, oxidative stress and antioxidants.

    Science.gov (United States)

    Kovacic, Peter; Somanathan, Ratnasamy

    2011-10-01

    Considerable attention has been paid to the toxicity of advanced glycation end products (AGEs), including relation to various illnesses. AGEs, generated nonenzymatically from carbohydrates and proteins, comprises large numbers of simple and more complicated compounds. Many reports deal with a role for receptors (RAGE) and cell signaling, including illnesses and aging. Reactive oxygen species appear to participate in signaling. RAGE include angiotensin II type 1 receptors. Many signaling pathways are involved, such as kinases, p38, p21, TGF-β, NF-κβ, TNF-α, JNK and STAT. A recent review puts focus on α-dicarbonyl metabolites, formed by carbohydrate oxidation, and imine derivatives from protein condensation, as a source via electron transfer (ET) of ROS and oxidative stress (OS). The toxic species have been related to illnesses and aging. Antioxidants alleviate the adverse effects.

  19. An FPGA-based reconfigurable DDC algorithm

    Science.gov (United States)

    Juszczyk, B.; Kasprowicz, G.

    2016-09-01

    This paper describes implementation of reconfigurable digital down converter in an FPGA structure. System is designed to work with quadrature signals. One of the main criteria of the project was to provied wide range of reconfiguration in order to fulfill various application rage. Potential applications include: software defined radio receiver, passive noise radars and measurement data compression. This document contains general system overview, short description of hardware used in the project and gateware implementation.

  20. Tragedies by Life--A slight analysis of the main characters in Sons and Lovers

    Institute of Scientific and Technical Information of China (English)

    孙灵

    2003-01-01

    @@ Ⅰ.Introduction Traditionally, tragedies refer to those calamitous events with unhappy endings, which occur on a violent and vigorous scale. However, D. H. Lawrence expresses his own understanding of tragedy from a new angle, which adds a fresh color to its original definition. Frederick J. Hoffman notes in his Freudianism and the Literary Mind: ...Tragedy for him (Lawrence)consists not in sentimental or significant dying, but in ‘ the inner war which is raged between people who love each other...'.

  1. Electron Mobility of Doped Strained Si1-x Gex Alloys Grown on Si(100) Substrate①②

    Institute of Scientific and Technical Information of China (English)

    1997-01-01

    The electron mobility for strained Si1-xGex alloy layer grown on Si(100) substrate has been calculated for doping rage of 1017 cm-3 to 1020 cm-3with Ge contents of 0.0≤x≤1.0.The results show a decrease in the mobility with increasing of Ge content and doping concentration.The electron mobility in-plane is foud to be smaller than the perpendicular component.

  2. Rabies.

    Science.gov (United States)

    Burnett, Nark

    2013-01-01

    Rabies has been a scourge of mankind since antiquity. The name itself, ?rabies? is derived from the ancient Sanskrit rabhas meaning ?to do violence? and has been found described in medical writings several thousand years old. The rabies virus is an RNA virus of the family Rhabdoviridae (Greek for ?rod-shaped virus?), genus Lyssavirus (Lyssa being the Greek God of frenzy and rage). Rabies infections have a worldwide spread, with only a few, mostly island nations laying claim to being ?rabies free.?

  3. China Relief to Pakistan

    Institute of Scientific and Technical Information of China (English)

    Audrey GUO

    2010-01-01

    @@ In Pakistan the rains and floods that started around July 22 have raged through Khyber Pakhtunkhwa,Balochistan,Punjab,Azad Kashmir and Gilgit Baltistan.The rain and floods are now headed towards the Southern Province of Sindh.The provincial governments are bracing for huge flood waters."These are the most massive and heaviest floods in Pakistan territory since 1929,"said the ambassador of Pakistan Masood Khan at a press conference on August 6 in Beijing.

  4. Feruidus Ille Canis: the Lore and Poetry of the Dog Star in Antiquity

    Science.gov (United States)

    Ceragioli, Roger Charles

    1992-01-01

    The Dog Star, Sirius, appears in many important works of classical poetry. It also appears in numerous myths and several religious rituals. A complex body of folklore surrounds it and it had a paramount importance in agriculture. Yet no one has attempted a systematic analysis of Sirius' place in Greco-Roman art and thought. This thesis begins that analysis. The introductory chapter discusses the methodology and approach that the thesis takes to the evidence, and supplies essential background information on Sirius' place among the constellations and its relation to the physical environment of the Mediterranean. Chapter one explores Sirius' role in ancient warrior traditions. Sirius embodied the principle of cosmic heat, and through heat it was thought to cause rabies in dogs. The Greek word for rabies is lussa. But lussa also named the madness of warriors such as Achilles in the Iliad. Etymologically, lussa meant "wolfishness." Rabid dogs, wolves, and raging warriors all exhibit fiery heat as an integral part of their natures. It is argued that raging warriors, wolves, and rabid dogs were largely interchangeable entities for the Greeks. Thus when Hector and Achilles in their raging are compared to Sirius, the comparison reflects more than the likeness of their surface brilliance. Chapter two explores Sirius' connection to erotic themes in ancient poetry. Because erotic experience could be represented as a conflagration that might burn the lover into a frenzy, the fiery raging Dog Star was an appropriate symbolic accompaniment. Sirius itself experienced erotic frenzy when it became passionate for Opora (the ripe fruits of summer). Chapter three turns to Sirius' involvement in viticulture. Sirius was said to ripen the grapes, but was also conceived to have once been the faithful dog of Icarius, who first introduced wine-drinking among humans. The chapter explores Sirius' role in the myth of Icarius, and the relation of that myth to the erotic and martial sides of

  5. Does Environmental Enrichment Exposure Prior to Injury Influence Biomarkers Associated with Chronic Stage TBI?

    Science.gov (United States)

    2012-12-01

    subjected to TBI via a controlled cortical impact (CCI) device. Animals were anesthetized with isoflurane (5% induction , 2% maintenance) and...BDNF mRNA expression in the rat hippocampus after traumatic brain injury. Molecular Neuroscience. 11(15): 3381-3384 Hamm, R.J., Temple , M.D...Factors. RR Donnelly Willard. Pg. 96-99 Marmigere, F., Givalois, L., Rage, F., Arancibia, S., Tapia-Arancibia, L. (2003). Rapid induction of

  6. Proprietary software versus Open Source Software for Education

    OpenAIRE

    N. Pankaja

    2013-01-01

    The Internet has brought learning "online" and offers many advantages. It is convenient, available at any time of the day, and can be accessed nearly anywhere in the world. Recently, Cloud computing is all the rage. E-Learning offers tremendous potential to increase the availability and convenience of education. Today, online content is varied and can include: text on a website, digital audio, digital video, animated images, and virtual reality environments. This content can be created in a v...

  7. Juicios morales y fronteras biológicas: más allá de la frontera razón / emoción

    OpenAIRE

    Cabezas, Mar

    2013-01-01

    We build boundaries that are theoretically based on biological grounds and we derive moral judgments from them. Likewise, we take for granted that emotions such as fear, disgust or rage were the element that led us to this mistake, especially when we realise the logical inconsistency of deriving moral judgments in this way. Consequently, we often associate emotions with prejudices, beliefs or fallacies, which we ought to free ourselves from. However, emotions are not the cause of the pro...

  8. Design and Calibration of a Flowfield Survey Rake for Inlet Flight Research

    Science.gov (United States)

    Flynn, Darin C.; Ratnayake, Nalin A.; Frederick, Michael

    2009-01-01

    Flowfield rake was designed to quantify the flowfield for inlet research underneath NASA DFRC s F-15B airplane. Detailed loads and stress analysis performed using CFD and empirical methods to assure structural integrity. Calibration data were generated through wind tunnel testing of the rake. Calibration algorithm was developed to determine the local Mach and flow angularity at each probe. RAGE was flown November, 2008. Data is currently being analyzed.

  9. The politics of civil society building: European private aid agencies and democratic transitions in Central America

    OpenAIRE

    Biekart, C.H.

    1999-01-01

    textabstractStrengthening civil society may be all the rage in the international donor community, but what does it mean in practice? This seminal work critically examines the political aspects of civil society building and the role of non-governmental development aid agencies during recent democratic transitions in Central America. ‘The Politics of Civil Society Building’ is the first comparative study of the policies, practices and political impact of European NGO aid interventions. Drawing ...

  10. The Effects of Low-Power Laser Irradiation on Inflammation and Apoptosis in Submandibular Glands of Diabetes-Induced Rats

    Science.gov (United States)

    Simões, Alyne; Uchiyama, Toshikazu; Arana-Chavez, Victor Elias; Abiko, Yoshimitsu; Kuboyama, Noboru

    2017-01-01

    Diabetes can lead to dysfunction of the secretory capacity in salivary glands. Activation of the receptor for advanced glycation end products (RAGE) and its ligands has been suggested to participate in chronic disorders such as diabetes and its complications. In this study, the expression of RAGE, high mobility group box 1 (HMGB1) and advanced glycation end products (AGE), as well as the effects of low-power laser irradiation (LPLI) in salivary glands of diabetic rats were evaluated, and the mechanisms involved were characterized. The expression of RAGE and HMGB1 at the protein and mRNA levels was observed in submandibular glands (SMGs) of streptozotocin-induced diabetic rats. A diode laser was applied at 660 nm, 70 mW, 20 J/cm2, 0.56 J/point, with a spot area of 0.028 cm2 and its in vivo effects and the pathways involved were evaluated. Immunohistochemistry and western blotting analysis were performed for inflammatory and apoptosis markers. Diabetes up-regulates HMGB1/AGE/RAGE axis gene expression in SMGs that is associated with activation of the nuclear factor kappa B (NF-κB) pathway. Interestingly, LPLI suppresses NF-κB activation induced by inflammation. LPLI also reduces diabetes-induced apoptosis. That effect was accompanied by decreased levels of Bax, and cleaved caspase 3, which were up-regulated in diabetes. Taken together, our data suggest that LPLI reduces diabetes-induced inflammation by reducing the induction of HMGB1, ultimately leading to inhibition of apoptosis in submandibular glands of diabetic rats. PMID:28099448

  11. A Simple Model of Endogenous Agricultural Commodity Price Fluctuations with Storage

    OpenAIRE

    Sophie Mitra; Jean-Marc Boussard

    2011-01-01

    A debate has been raging for centuries regarding the effects of inter-annual storage on commodity prices. Most analysts consider storage to function as a price stabilizer, while others place it at the core of an explanation of intriguing features of commodity price series, such as skewed distributions. Most studies have been developed in the context of the theory of competitive storage where random shocks affect supply or demand. Recently, the endogenous chaotic behavior of markets has become...

  12. How absolute is zero? An evaluation of historical and current definitions of malaria elimination

    OpenAIRE

    Snow Robert W; Moonen Bruno; Cohen Justin M; Smith David L

    2010-01-01

    Abstract Decisions to eliminate malaria from all or part of a country involve a complex set of factors, and this complexity is compounded by ambiguity surrounding some of the key terminology, most notably "control" and "elimination." It is impossible to forecast resource and operational requirements accurately if endpoints have not been defined clearly, yet even during the Global Malaria Eradication Program, debate raged over the precise definition of "eradication." Analogous deliberations re...

  13. Nye patologier i selvdannelsens tidsalder

    DEFF Research Database (Denmark)

    Hammershøj, Lars Geer

    2004-01-01

    The aim of this article is to inquire into today's social pathologies, i.e. the negative consequences of the developmental processes of society. In a dialogue with Axel Honneth, the article asserts that a shift has occurred in individualization, a shift that implies a fundamental change in social...... in self-Bildung', which is conceived as a ‘refusal to transcend oneself into sociality', and offers interpretations of present pathologies such as depression, anorexia, populist freedom of speech, and demonic rage....

  14. Transport of Gas and Solutes in Permeable Estuarine Sediments

    Science.gov (United States)

    2011-09-30

    shallow sand sediments colonized by photosynthetizing diatoms and cyanobacteria . Photosynthetically active radiation at the water surface raged from... space and time. 6 Fig. 3. Acoustic scans conducted at St. Joseph Bay, Florida. The three left panes represent Site 1 upper pane: shortly after...expanding and gas moves into the pore space . This results in rough bubble surfaces that eventually form extrusions that penetrate further into the sediment

  15. The National Nanotechnology Initiative: Potential Impact on DoD

    Science.gov (United States)

    2016-07-13

    number. 1. REPORT DATE 19 MAR 2007 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE The National Nanotechnology Initiative...THIS PAGE unclassified Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 The National Nanotechnology Initiative: Potential Impact on...that may be technologically exploitable. Why is nanotechnology the current rage? First, beginning in 1980, the discovery and development of

  16. Sadism linked to loneliness: psychodynamic dimensions of the sadistic serial killer Jeffrey Dahmer.

    Science.gov (United States)

    Martens, Willem H J

    2011-08-01

    In this article the psychodynamic link between loneliness and sadism is examined on basis of a case report of the sadistic and cannibalistic serial killer Jeffery Dahmer. Envy, shame/rage mechanism, a disturbed oral-sadistic development, castration fear and severe feelings of inferiority, the conviction of being unlovable and unacceptable, need to diminish tension, powerful and sadistic fantasies as a consequence of inadequate and frustrated parenting, and reality distortion appear to be involved in sadistic etiology.

  17. Serum Amyloid A Receptor Blockade and Incorporation into High-Density Lipoprotein Modulates Its Pro-Inflammatory and Pro-Thrombotic Activities on Vascular Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Belal Chami

    2015-05-01

    Full Text Available The acute phase protein serum amyloid A (SAA, a marker of inflammation, induces expression of pro-inflammatory and pro-thrombotic mediators including ICAM-1, VCAM-1, IL-6, IL-8, MCP-1 and tissue factor (TF in both monocytes/macrophages and endothelial cells, and induces endothelial dysfunction—a precursor to atherosclerosis. In this study, we determined the effect of pharmacological inhibition of known SAA receptors on pro-inflammatory and pro-thrombotic activities of SAA in human carotid artery endothelial cells (HCtAEC. HCtAEC were pre-treated with inhibitors of formyl peptide receptor-like-1 (FPRL-1, WRW4; receptor for advanced glycation-endproducts (RAGE, (endogenous secretory RAGE; esRAGE and toll-like receptors-2/4 (TLR2/4 (OxPapC, before stimulation by added SAA. Inhibitor activity was also compared to high-density lipoprotein (HDL, a known inhibitor of SAA-induced effects on endothelial cells. SAA significantly increased gene expression of TF, NFκB and TNF and protein levels of TF and VEGF in HCtAEC. These effects were inhibited to variable extents by WRW4, esRAGE and OxPapC either alone or in combination, suggesting involvement of endothelial cell SAA receptors in pro-atherogenic gene expression. In contrast, HDL consistently showed the greatest inhibitory action, and often abrogated SAA-mediated responses. Increasing HDL levels relative to circulating free SAA may prevent SAA-mediated endothelial dysfunction and ameliorate atherogenesis.

  18. Manhunts: A Policy Maker’s Guide to High-Value Targeting

    Science.gov (United States)

    2013-06-01

    international political risks. In the Eichmann scenario, the endstate desired was one were the emotional wounds of the Holocaust that affected an entire...the emotional rage that consumed Israeli social and political life after the Munich massacre, which the BSO had carried out. The endstate envisioned...operations. 8 Simon Reeve , One Day in September: The Full Story of the 1972 Munich Olympics Massacre and The

  19. Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products

    Directory of Open Access Journals (Sweden)

    Greten Johannes

    2006-03-01

    Full Text Available Summary Background Atherosclerosis is an inflammatory disease in which a perpetuated activation of NFkappaB via the RAGE (receptor for advanced glycation end products-MAPK signalling pathway may play an important pathogenetic role. As recently S100 proteins have been identified as ligands of RAGE, we sought to determine the effects of the proinflammatory heterodimer of S100A8/S100A9 on the RAGE-NFkappaB mediated induction of proinflammatory gene expression. Methods Human umbilical vein endothelial cells (HUVEC were preincubated for 72 h with AGE-albumin or unmodified albumin for control, whereas AGE-albumin induction resulted in an upregulation of RAGE. Following this preactivation, cells were stimulated for 48 h with heterodimeric human recombinant S100A8/S100A9. Results Heterodimeric S100A8/S100A9 enhanced secretion of IL-6, ICAM-1, VCAM-1 and MCP1 in AGE-albumin pretreated HUVEC in a dose dependent manner. These effects could not be detected after stimulation with the homodimeric proteins S100A8, S100A9, S100A1 and S100B. The effects of heterodimeric S100A8/S100A9 were reduced by inhibition of the MAP-kinase pathways ERK1/2 and p38 by PD 98059 and SB 203580, respectively. Conclusion The heterodimeric S100A8/S100A9 might therefore play a hitherto unknown role in triggering atherosclerosis in diabetes and renal failure, pathophysiological entities associated with a high AGE burden. Thus, blocking heterodimeric S100A8/S100A9 might represent a novel therapeutic modality in treating atherosclerosis.

  20. Functional characterization of S100A8 and S100A9 in altering monolayer permeability of human umbilical endothelial cells.

    Directory of Open Access Journals (Sweden)

    Liqun Wang

    Full Text Available S100A8, S100A9 and S100A8/A9 complexes have been known as important endogenous damage-associated molecular pattern (DAMP proteins. But the pathophysiological roles of S100A8, S100A9 and S100A8/A9 in cardiovascular diseases are incompletely explained. In this present study, the effects of homo S100A8, S100A9 and their hetero-complex S100A8/A9 on endothelial barrier function were tested respectively in cultured human umbilical venous endothelial cells (HUVECs. The involvement of TLR4 and RAGE were observed by using inhibitor of TLR4 and blocking antibody of RAGE. The clarification of different MAPK subtypes in S100A8/A9-induced endothelial response was implemented by using specific inhibitors. The calcium-dependency was detected in the absence of Ca2+ or in the presence of gradient-dose Ca2+. The results showed that S100A8, S100A9 and S100A8/A9 could induce F-actin and ZO-1 disorganization in HUVECs and evoked the increases of HUVEC monolayer permeability in a dose- and time-dependent manner. The effects of S100A8, S100A9 and S100A8/A9 on endothelial barrier function depended on the activation of p38 and ERK1/2 signal pathways through receptors TLR4 and RAGE. Most importantly, we revealed the preference of S100A8 on TLR4 and S100A9 on RAGE in HUVECs. The results also showed the calcium dependency in S100A8- and S100A9-evoked endothelial response, indicating that calcium dependency on formation of S100A8 or A9 dimmers might be the prerequisite for this endothelial functional alteration.

  1. Diagnosing Autism Spectrum Disorder through Brain Functional Magnetic Resonance Imaging

    Science.gov (United States)

    2016-03-01

    Diagnosing Autism Spectrum Disorder through Brain Functional Magnetic Resonance Imaging THESIS MARCH 2016 Kyle A. Palko, Second Lieutenant, USAF AFIT...DISORDER THROUGH BRAIN FUNCTIONAL MAGNETIC RESONANCE IMAGING THESIS Presented to the Faculty Department of Operational Sciences Graduate School of...available data includes raw fMRI as well as processed MP RAGE1 images . All data within the ABIDE database was compiled through studies on autism. All

  2. SUBJECT INDEX

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    2, 4, 6-trinitrobenzenesulphonic acid, zinc sulfate, experimental colitis, 2003328AC133 antigen, hematopoietic stem cells, fetal blood, immunophe-notyping, 2003138ALR2 gene, eNOS gene, PON1 gene, RAGE gene, 2003179 ATN-ISI, prognosis, acute renal failure, acute tubular necrosis-individual severity index, acute physiology and chronic health evaluation, 2003118 Alzheimer disease, interleukin-1 beta, tumor necrosis factor alpha,

  3. TRADE PROTECTIONISM, Better Cooperate than Fight?

    Institute of Scientific and Technical Information of China (English)

    Guo Liqin

    2009-01-01

    @@ In 2009,China witnesses a rage of trade protectionism wave.According to the Ministry of Commerce,currently,35% of anti-dumping and71% of anti-subsidy cases are against Chinese products.In the first three quarters this year,there are 19 countries launching a total of 88 anti-dumping ("AD")and countervailing("CVD")investigations against China.

  4. Displaced murder.

    Science.gov (United States)

    Brand, Stewart

    1981-10-01

    Most suicide attempts appear to be impulsive and motivated by rage against another person. The author believes that publications of pro-suicide groups like EXIT or Hemlock serve a useful purpose for some terminally ill persons, although hospice care is a better approach for most dying patients. Potential suicides who are suffering from emotional stresses rather than terminal illnesses are best deterred by a personalized approach.

  5. A commentary on the positive discrimination policy of India

    OpenAIRE

    2009-01-01

    Affirmative action and discriminatory measures are complex and controversial issues. The goal of affirmative action is to speed up the creation of a representative and equitable workforce and to assist those who were historically disadvantaged by unfair discrimination to fulfil their maximum potential. The term invokes emotions that range from fear and rage to satisfaction. Affirmative action has encouraged an ongoing debate regarding the legal, moral and economic questions arising from the p...

  6. Simultaneous involvement of third and sixth cranial nerve in a patient with Lyme disease

    Energy Technology Data Exchange (ETDEWEB)

    Lell, M.; Schmid, A.; Tomandl, B.F. [Division of Neuroradiology, Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen (Germany); Stemper, B.; Maihoefner, C.; Heckmann, J.G. [Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen (Germany)

    2003-02-01

    We report a 57-year-old woman with neuroborreliosis presenting with headache, shoulder muscle pain and double vision. MRI demonstrated enhancement of the right third and sixth cranial nerves. A 3D MP-RAGE sequence was used to perform multiplanar reformations to show this more graphically. The patient was free of symptoms 1 month after completion of therapy, when thickening and contrast enhancement of the nerves were less pronounced. (orig.)

  7. Living it Up Mid-Air

    Institute of Scientific and Technical Information of China (English)

    GREGGWYCHERLEY

    2004-01-01

    There's something surreal about boarding a plane. Apart from the fact that you are defying gravity, the feeling of being enclosed in a large flying tube for up to 12 hours, far removed from earth and surrounded by strangers in. a strange environment can induce all kinds of behavioural changes, from air-rage to irrational fear, through to out of character flirting with aircrew or other passengers.

  8. Influence of glycated low density lipoprotein on the proliferation,expression of intercellular adhesion molecule-1,von Willebrand factor of human umbilical endothelial cells

    Institute of Scientific and Technical Information of China (English)

    LU Jun; LIU Hui-ying; ZHANG Xiu-zhen; LEI Tao

    2009-01-01

    @@ Diabetes mellitus known as its macro-and microangiopathy has caused thousands of mortality per year.Recent researches showed that hyperglycemia,advanced glycation end products(AGEs)and some other factors acted on the process of atherogenesis.AGEs can combine with receptors of AGEs(RAGEs),which exist on the vascular endothelium,smooth muscle cells,macrophage,lymphocyte and so on.

  9. Effects of Environmental Factors on Death Rate of Pigs in South Korea

    OpenAIRE

    Lee, Seung-Joo; Oh, Taek-Kuen; Kim, Suk; Min, Won-Gi; Gutierrez, Winson-Montanez; Chang, Hong-Hee; Chikushi, Jiro

    2012-01-01

    Reducing the mortality rate among pigs for a swine industry is very important. In this study, environmental factors such as average air temperature, average daily temperature rage and average relative humidity were determined on its effects of on mortality rate of pigs and its optimum ranges to influence pigs health that were correlated with the pigs periodic growth. Data were collected from 10 pig farms in South Korea during the Summer, Fall and Winter seasons. Correlation and regression equ...

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

    Science.gov (United States)

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

    2015-06-01

    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 IC50 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.

  11. The Soviet-Finnish War, 1939-1940 Getting the Doctrine Right

    Science.gov (United States)

    1993-05-21

    active debate raged on its proper role, organization, and strategy. One group, headed by Leon Trotsky , recommended the development of a large...development of the Red Army and its doctrine was also significant. Trotsky brought in many of these officers to serve as military specialists to train new...officers and serve as unit commanders. Trotsky believed the experience of officers of the former regime was important in the training of a new

  12. The Role of Hyperglycemia in Mechanisms of Exacerbated Inflammatory Responses within the Oral Cavity

    OpenAIRE

    Amir, Jamie; Waite, Matthew; Tobler, Jeffrey; Catalfamo, Dana L.; Koutouzis, Theofilos; Katz, Joseph; Wallet, Shannon M.

    2011-01-01

    Immune modulating factors are necessary for pathogen clearance, but also contribute to host tissues damage, as those seen in periodontal diseases. Many of these responses can be exacerbated by host conditions including type 2 diabetes [T2D], where toll-like receptor 4 [TLR4] and the receptor for advanced glycated end products [RAGE] play a significant role. Here we investigate causality associated with the increase in inflammatory markers observed in periodontally diseased patients with T2D u...

  13. Advanced glycation end products inhibit both infection and transmission in trans of HIV-1 from monocyte-derived dendritic cells to autologous T cells.

    Science.gov (United States)

    Nasreddine, Nadine; Borde, Chloé; Gozlan, Joël; Bélec, Laurent; Maréchal, Vincent; Hocini, Hakim

    2011-05-15

    Highly active antiretroviral therapy is associated with carbohydrate metabolic alterations that may lead to diabetes. One consequence of hyperglycemia is the formation of advanced glycation end products (AGEs) that are involved in diabetes complications. We investigated the impact of AGEs on the infection of monocyte-derived dendritic cells (MDDCs) by HIV-1 and the ability of MDDCs to transmit the virus to T cells. We showed that AGEs could inhibit infection of MDDCs with primary R5-tropic HIV-1(Ba-L) by up to 85 ± 9.2% and with primary X4-tropic HIV-1(VN44) by up to 60 ± 8.5%. This inhibitory effect of AGEs was not prevented by a neutralizing anti-receptor for advanced glycation end products (anti-RAGE) Ab, demonstrating a RAGE-independent mechanism. Moreover, AGEs inhibited by 70-80% the transmission in trans of the virus to CD4 T cells. Despite the inhibitory effect of AGEs on both MDDC infection and virus transmission in trans, no inhibition of virus attachment to cell membrane was observed, confirming that attachment and transmission of the virus involve independent mechanisms. The inhibitory effect of AGEs on infection was associated with a RAGE-independent downregulation of CD4 at the cell membrane and by a RAGE-dependent repression of the CXCR4 and CCR5 HIV-1 receptors. AGEs induce the secretion of proinflammatory cytokines IL-6, TNF-α, and IL-12, but not RANTES or MIP-1α, and did not lead to MDDC maturation as demonstrated by the lack of expression of the CD83 molecule. Taken together, our results suggest that AGEs can play an inhibiting role in HIV-1 infection in patients who accumulate circulating AGEs, including patients treated with protease inhibitors that developed diabetes.

  14. Genome-wide RNAi screen reveals the E3 SUMO-protein ligase gene SIZ1 as a novel determinant of furfural tolerance in Saccharomyces cerevisiae

    OpenAIRE

    Xiao, Han; Zhao, Huimin

    2014-01-01

    Background Furfural is a major growth inhibitor in lignocellulosic hydrolysates and improving furfural tolerance of microorganisms is critical for rapid and efficient fermentation of lignocellulosic biomass. In this study, we used the RNAi-Assisted Genome Evolution (RAGE) method to select for furfural resistant mutants of Saccharomyces cerevisiae, and identified a new determinant of furfural tolerance. Results By using a genome-wide RNAi (RNA-interference) screen in S. cerevisiae for genes in...

  15. Flight Test Results from the Rake Airflow Gage Experiment on the F-15B

    Science.gov (United States)

    Frederick, Michael; Ratnayake, Nalin

    2011-01-01

    The results are described of the Rake Airflow Gage Experiment (RAGE), which was designed and fabricated to support the flight test of a new supersonic inlet design using Dryden's Propulsion Flight Test Fixture (PFTF) and F-15B testbed airplane (see figure). The PFTF is a unique pylon that was developed for flight-testing propulsion-related experiments such as inlets, nozzles, and combustors over a range of subsonic and supersonic flight conditions. The objective of the RAGE program was to quantify the local flowfield at the aerodynamic interface plane of the Channeled Centerbody Inlet Experiment (CCIE). The CCIE is a fixed representation of a conceptual mixed-compression supersonic inlet with a translating biconic centerbody. The primary goal of RAGE was to identify the relationship between free-stream and local Mach number in the low supersonic regime, with emphasis on the identification of the particular free-stream Mach number that produced a local Mach number of 1.5. Measurements of the local flow angularity, total pressure distortion, and dynamic pressure over the interface plane were also desired. The experimental data for the RAGE program were obtained during two separate research flights. During both flights, local flowfield data were obtained during straight and level acceleration segments out to steady-state test points. The data obtained from the two flights showed small variations in Mach number, flow angularity, and dynamic pressure across the interface plane at all flight conditions. The data show that a free-stream Mach number of 1.65 will produce the desired local Mach number of 1.5 for CCIE. The local total pressure distortion over the interface plane at this condition was approximately 1.5%. At this condition, there was an average of nearly 2 of downwash over the interface plane. This small amount of downwash is not expected to adversely affect the performance of the CCIE inlet.

  16. Curcumin eliminates the effect of advanced glycation end-products (AGEs) on the divergent regulation of gene expression of receptors of AGEs by interrupting leptin signaling.

    Science.gov (United States)

    Tang, Youcai; Chen, Anping

    2014-05-01

    Non-alcoholic steatohepatitis (NASH) is a major risk factor for hepatic fibrogenesis. NASH is often found in diabetic patients with hyperglycemia. Hyperglycemia induces non-enzymatic glycation of proteins, yielding advanced glycation end-products (AGEs). Effects of AGEs are mainly mediated by two categories of cytoplasmic membrane receptors. Receptor for AGEs (RAGE) is associated with increased oxidative stress and inflammation, whereas AGE receptor-1 (AGE-R1) is involved in detoxification and clearance of AGEs. Activation of hepatic stellate cells (HSC) is crucial to the development of hepatic fibrosis. We recently reported that AGEs stimulated HSC activation likely by inhibiting gene expression of AGE-R1 and inducing gene expression of RAGE in HSC, which were eliminated by the antioxidant curcumin. This study is to test our hypothesis that curcumin eliminates the effects of AGEs on the divergent regulation of the two receptors of AGEs in HSC by interrupting the AGE-caused activation of leptin signaling, leading to the inhibition of HSC activation. We observed herein that AGEs activated leptin signaling by inducing gene expression of leptin and its receptor in HSC. Like AGEs, leptin differentially regulated gene expression of RAGE and AGE-R1. Curcumin eliminated the effects of AGEs in HSC by interrupting leptin signaling and activating transcription factor NF-E2 p45-related factor 2 (Nrf2), leading to the elevation of cellular glutathione and the attenuation of oxidative stress. In conclusions, curcumin eliminated the effects of AGEs on the divergent regulation of gene expression of RAGE and AGE-R1 in HSC by interrupting the AGE-caused activation of leptin signaling, leading to the inhibition of HSC activation.

  17. Defining Victory: Three Case Studies of Strategic Guidance and Decision Making

    Science.gov (United States)

    2007-11-02

    causing massive destruction and starting a raging inferno below decks, even though its warhead failed to detonate (Levinson and Edwards 1997). In a...toppled and replaced by a less vile, more malleable military officer. They cite Schwarzkopf’s political advisor, Gordon Brown , in claiming that...Little, Brown and Co. Hamilton, Alexander, James Madison, and John Jay. 1937. The Federalist. New York: Tudor. Harris, John F. 1998. Aides

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  19. The Genetics of Cancer Risk

    OpenAIRE

    Pomerantz, Mark M.; Freedman, Matthew L.

    2011-01-01

    One hundred years ago, decades prior to the discovery of the structure of DNA, debate raged regarding how human traits were passed from one generation to the next. Phenotypes, including risk of disease, had long been recognized as having a familial component. Yet it was difficult to reconcile genetic segregation as described by Mendel with observations exhaustively documented by Karl Pearson and others regarding the normal distribution of human characteristics. In 1918, RA Fisher published hi...

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

    Science.gov (United States)

    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.

  1. Expression of high mobility group box 1 in inflamed dental pulp and its chemotactic effect on dental pulp cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Xufang, E-mail: xufang.zhang@student.qut.edu.au [Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055 (China); Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059 (Australia); Jiang, Hongwei, E-mail: jianghw@163.com [Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055 (China); Gong, Qimei, E-mail: gongqmei@gmail.com [Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055 (China); Fan, Chen, E-mail: c3.fan@student.qut.edu.au [Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059 (Australia); Huang, Yihua, E-mail: enu0701@163.com [Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055 (China); Ling, Junqi, E-mail: lingjq@mail.sysu.edu.cn [Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055 (China)

    2014-08-08

    Highlights: • HMGB1 translocated from nucleus to cytoplasm during dental pulp inflammation. • HMGB1and its receptor RAGE were up-regulated in hDPCs under LPS stimulation. • HMGB1 enhanced hDPCs migration and induces cytoskeleton reorganization. • HMGB1 may play a critical role in dental pulp repair during inflamed state. - Abstract: High mobility group box 1 protein (HMGB1) is a chromatin protein which can be released extracellularly, eliciting a pro-inflammatory response and promoting tissue repair process. This study aimed to examine the expression and distribution of HMGB1 and its receptor RAGE in inflamed dental pulp tissues, and to assess its effects on proliferation, migration and cytoskeleton of cultured human dental pulp cells (DPCs). Our data demonstrated that cytoplasmic expression of HMGB1 was observed in inflamed pulp tissues, while HMGB1 expression was confined in the nuclei in healthy dental pulp. The mRNA expression of HMGB1 and RAGE were significantly increased in inflamed pulps. In in vitro cultured DPCs, expression of HMGB1 in both protein and mRNA level was up-regulated after treated with lipopolysaccharide (LPS). Exogenous HMGB1 enhanced DPCs migration in a dose-dependent manner and induced the reorganization of f-actin in DPCs. Our results suggests that HMGB1 are not only involved in the process of dental pulp inflammation, but also play an important role in the recruitment of dental pulp stem cells, promoting pulp repair and regeneration.

  2. Targeting AGEs Signaling Ameliorates Central Nervous System Diabetic Complications in Rats

    Directory of Open Access Journals (Sweden)

    Mohamed Naguib Zakaria

    2015-01-01

    Full Text Available Diabetes is a chronic endocrine disorder associated with several complications as hypertension, advanced brain aging, and cognitive decline. Accumulation of advanced glycation end products (AGEs is an important mechanism that mediates diabetic complications. Upon binding to their receptor (RAGE, AGEs mediate oxidative stress and/or cause cross-linking with proteins in blood vessels and brain tissues. The current investigation was designed to investigate the effect of agents that decrease AGEs signaling, perindopril which increases soluble RAGE (sRAGE and alagebrium which cleaves AGEs cross-links, compared to the standard antidiabetic drug, gliclazide, on the vascular and central nervous system (CNS complications in STZ-induced (50 mg/kg, IP diabetes in rats. Perindopril ameliorated the elevation in blood pressure seen in diabetic animals. In addition, both perindopril and alagebrium significantly inhibited memory decline (performance in the Y-maze, neuronal degeneration (Fluoro-Jade staining, AGEs accumulation in serum and brain, and brain oxidative stress (level of reduced glutathione and activities of catalase and malondialdehyde. These results suggest that blockade of AGEs signaling after diabetes induction in rats is effective in reducing diabetic CNS complications.

  3. Contribution of the toxic advanced glycation end-productsreceptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jun-ichi; Takino; Kentaro; Nagamine; Takamitsu; Hori; Akiko; Sakasai-Sakai; Masayoshi; Takeuchi

    2015-01-01

    Hepatocellular carcinoma(HCC) is one of the most common malignancies worldwide. The main etiologies of HCC are hepatitis B virus and hepatitis C virus(HCV), and non-hepatitis B/non-hepatitis C HCC(NBNCHCC) has also been identified as an etiological factor. Although the incidence of HCV-related HCC in Japan has decreased slightly in recent years, that of NBNC-HCC has increased. The onset mechanism of NBNC-HCC, which has various etiologies, remains unclear; however, nonalcoholic steatohepatitis(NASH), a severe form of nonalcoholic fatty liver disease, is known to be an important risk factor for NBNC-HCC. Among the different advanced glycation end-products(AGEs) formed by the Maillard reaction, glyceraldehyde-derived AGEs, the predominant components of toxic AGEs(TAGE), have been associated with NASH and NBNC-HCC, including NASH-related HCC. Furthermore, the expression of the receptor for AGEs(RAGE) has been correlated with the malignant progression of HCC. Therefore, TAGE induce oxidative stress by binding with RAGE may, in turn, lead to adverse effects, such as fibrosis and malignant transformation, in hepatic stellate cells and tumor cells during NASH or NASH-related HCC progression. The aim of this review was to examine the contribution of the TAGE-RAGE axis in NASH-related HCC.

  4. AGEs and chronic subclinical inflammation in diabetes: disorders of immune system.

    Science.gov (United States)

    Hu, Hang; Jiang, Hongfei; Ren, Haitao; Hu, Xinlei; Wang, Xingang; Han, Chunmao

    2015-02-01

    Chronic subclinical inflammation represents a risk factor of type 2 diabetes and several diabetes complications, including neuropathy and atherosclerosis including macro-vasculopathy and micro-vasculopathy. However, the inflammatory response in the diabetic wound was shown to be remarkably hypocellular, unregulated and ineffective. Advanced glycation end products (AGEs) and one of its receptors, RAGE, were involved in inducing chronic immune imbalance in diabetic patients. Such interactions attracts immune cell into diffused glycated tissue and activates these cells to induce inflammatory damage, but disturbs the normal immune rhythm in diabetic wound. Traditional measurements of AGEs are high-performance liquid chromatography and immunohistochemistry staining, but their application faces the limitations including complexity, cost and lack of reproducibility. A new noninvasive method emerged in 2004, using skin autofluorescence as indicator for AGEs accumulation. It had been reported to be informative in evaluating the chronic risk of diabetic patients. Studies have indicated therapeutic potentials of anti-AGE recipes. These recipes can reduce AGE absorption/de novo formation, block AGE-RAGE interaction and arrest downstream signaling after RAGE activation.

  5. Advanced glycation end products induce human corneal epithelial cells apoptosis through generation of reactive oxygen species and activation of JNK and p38 MAPK pathways.

    Directory of Open Access Journals (Sweden)

    Long Shi

    Full Text Available Advanced Glycation End Products (AGEs has been implicated in the progression of diabetic keratopathy. However, details regarding their function are not well understood. In the present study, we investigated the effects of intracellular reactive oxygen species (ROS and JNK, p38 MAPK on AGE-modified bovine serum albumin (BSA induced Human telomerase-immortalized corneal epithelial cells (HUCLs apoptosis. We found that AGE-BSA induced HUCLs apoptosis and increased Bax protein expression, decreased Bcl-2 protein expression. AGE-BSA also induced the expression of receptor for advanced glycation end product (RAGE. AGE-BSA-RAGE interaction induced intracellular ROS generation through activated NADPH oxidase and increased the phosphorylation of p47phox. AGE-BSA induced HUCLs apoptosis was inhibited by pretreatment with NADPH oxidase inhibitors, ROS quencher N-acetylcysteine (NAC or neutralizing anti-RAGE antibodies. We also found that AGE-BSA induced JNK and p38 MAPK phosphorylation. JNK and p38 MAPK inhibitor effectively blocked AGE-BSA-induced HUCLs apoptosis. In addition, NAC completely blocked phosphorylation of JNK and p38 MAPK induced by AGE-BSA. Our results indicate that AGE-BSA induced HUCLs apoptosis through generation of intracellular ROS and activation of JNK and p38 MAPK pathways.

  6. Blockade of PKC-beta protects HUVEC from advanced glycation end products induced inflammation.

    Science.gov (United States)

    Xu, Youhua; Wang, Shanshan; Feng, Liang; Zhu, Quan; Xiang, Ping; He, Bao

    2010-12-01

    Advanced glycation end products (AGEs) have been recognized as a pivotal inducer in diabetes and kinds of aging-related vasculopathy. Endothelial dysfunction and inflammatory cells adhesion to endothelium have been regarded as important and early factors in the pathogenesis of vascular complications in diabetic patients. Owing to the key role of PKC-beta in AGEs-induced vascular dysfunction, we investigated effects of blocking PKC-beta by LY333531 on macrophage adhesion to HUVEC and the related mechanism. Transwell HUVEC-macrophage co-culture system was established to evaluate macrophage migration and adhesion ability. Immunocytochemistry was applied to examine TGF-beta1, ICAM-1 and RAGE protein expressions by SABC or SABC-AP method; mRNA expression of TGF-beta1, ICAM-1 and RAGE was determined by real-time RT-PCR. SOD and MDA levels in culture supernatant were detected. We found that LY333531 significantly reduced AGEs-induced macrophage adhesion to HUVEC. Blockade of PKC-beta strikingly decreased HUVEC TGF-beta1 and ICAM-1 expression in both protein and mRNA levels, RAGE protein level was also down-regulated. Furthermore, the anti-oxidative stress index, SOD/MDA was dramatically elevated on LY333531 application. Therefore we conclude that LY333531 can reduce AGEs-induced macrophage adhesion to endothelial cells and relieve the local inflammation, this was realized by its effect on decreasing inflammatory cytokines' expression and increasing cell anti-oxidative ability.

  7. The Association between Fibroblast Growth Factor-23 and Vascular Calcification Is Mitigated by Inflammation Markers

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    Mohamed M. NasrAllah

    2013-11-01

    Full Text Available Background: Fibroblast growth factor-23 (FGF-23 has been linked to vascular calcification, ventricular hypertrophy and mortality in chronic kidney disease (CKD, although these links may not be direct and independent. Similar grave outcomes are associated with inflammation and oxidative stress in CKD. Recently, accumulating evidence has linked components of phosphate homeostasis to inflammation and oxidative stress. The interaction between the triad of inflammation, FGF-23 and cardiovascular outcomes is underinvestigated. Methods: We studied 65 patients with stage 5 CKD on hemodialysis. Serum levels of FGF-23, high-sensitivity C-reactive protein (hsCRP, endogenous soluble receptor of advanced glycation end products (esRAGE, advanced oxidation protein products (AOPP, parathormone, lipids, calcium and phosphorous were measured. The aortic calcification index (ACI was determined using non-contrast CT scans of the abdominal aorta. Results: FGF-23 was elevated (mean: 4,681 pg/ml, SD: 3,906 and correlated with hsCRP, esRAGE, AOPP, dialysis vintage and phosphorus in univariate analysis. In multiple regression analysis, hsCRP, AOPP and phosphorus but not esRAGE were all significantly correlated to FGF-23 (R2 = 0.7, p 2 = 0.65, p Conclusion: FGF-23 is strongly correlated to various markers of inflammation and oxidative stress in hemodialysis patients. The association between FGF-23 and vascular calcification was mitigated when corrected for inflammation markers.

  8. Short-term effects of dietary advanced glycation end products in rats.

    Science.gov (United States)

    Poulsen, Malene W; Andersen, Jeanette M; Hedegaard, Rikke V; Madsen, Andreas N; Krath, Britta N; Monošík, Rastislav; Bak, Monika J; Nielsen, John; Holst, Birgitte; Skibsted, Leif H; Larsen, Lesli H; Dragsted, Lars O

    2016-02-28

    Dietary advanced glycation end products (AGE) formed during heating of food have gained interest as potential nutritional toxins with adverse effects on inflammation and glucose metabolism. In the present study, we investigated the short-term effects of high and low molecular weight (HMW and LMW) dietary AGE on insulin sensitivity, expression of the receptor for AGE (RAGE), the AGE receptor 1 (AGER1) and TNF-α, F2-isoprostaglandins, body composition and food intake. For 2 weeks, thirty-six Sprague-Dawley rats were fed a diet containing 20% milk powder with different proportions of this being given as heated milk powder (0, 40 or 100%), either native (HMW) or hydrolysed (LMW). Gene expression of RAGE and AGER1 in whole blood increased in the group receiving a high AGE LMW diet, which also had the highest urinary excretion of the AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1). Urinary excretion of N ε-carboxymethyl-lysine increased with increasing proportion of heat-treated milk powder in the HMW and LMW diets but was unrelated to gene expression. There was no difference in insulin sensitivity, F2-isoprostaglandins, food intake, water intake, body weight or body composition between the groups. In conclusion, RAGE and AGER1 expression can be influenced by a high AGE diet after only 2 weeks in proportion to MG-H1 excretion. No other short-term effects were observed.

  9. Contribution of the toxic advanced glycation end-products-receptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma.

    Science.gov (United States)

    Takino, Jun-Ichi; Nagamine, Kentaro; Hori, Takamitsu; Sakasai-Sakai, Akiko; Takeuchi, Masayoshi

    2015-10-18

    Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The main etiologies of HCC are hepatitis B virus and hepatitis C virus (HCV), and non-hepatitis B/non-hepatitis C HCC (NBNC-HCC) has also been identified as an etiological factor. Although the incidence of HCV-related HCC in Japan has decreased slightly in recent years, that of NBNC-HCC has increased. The onset mechanism of NBNC-HCC, which has various etiologies, remains unclear; however, nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is known to be an important risk factor for NBNC-HCC. Among the different advanced glycation end-products (AGEs) formed by the Maillard reaction, glyceraldehyde-derived AGEs, the predominant components of toxic AGEs (TAGE), have been associated with NASH and NBNC-HCC, including NASH-related HCC. Furthermore, the expression of the receptor for AGEs (RAGE) has been correlated with the malignant progression of HCC. Therefore, TAGE induce oxidative stress by binding with RAGE may, in turn, lead to adverse effects, such as fibrosis and malignant transformation, in hepatic stellate cells and tumor cells during NASH or NASH-related HCC progression. The aim of this review was to examine the contribution of the TAGE-RAGE axis in NASH-related HCC.

  10. Mangiferin suppressed advanced glycation end products (AGEs) through NF-κB deactivation and displayed anti-inflammatory effects in streptozotocin and high fat diet-diabetic cardiomyopathy rats.

    Science.gov (United States)

    Hou, Jun; Zheng, Dezhi; Fung, Gabriel; Deng, Haoyu; Chen, Lin; Liang, Jiali; Jiang, Yan; Hu, Yonghe

    2016-03-01

    Given the importance of the aggregation of advanced glycation end products (AGEs) and cardiac inflammation in the onset and progression of diabetic cardiomyopathy (DCM), our objective in this study was to demonstrate the cardioprotective effect of mangiferin, an antidiabetic and anti-inflammatory agent, on diabetic rat model. The DCM model was established by a high-fat diet and a low dose of streptozotocin. DCM rats were treated orally with mangiferin (20 mg/kg) for 16 weeks. Serum and left ventricular myocardium were collected for determination of inflammatory cytokines. AGEs mRNA and protein expression of nuclear factor kappa B (NF-κB) and receptor for AGEs (RAGE) in myocardium were assayed by real-time PCR and Western blot. ROS levels were measured by dihydroethidium fluorescence staining. NF-κB binding activity was assayed by TransAM NF-κB p65 ELISA kit. Chronic treatment with mangiferin decreased the levels of myocardial enzymes (CK-MB, LDH) and inflammatory mediators (TNF-α, IL-1β). Meanwhile, NF-κB is inhibited by the reduction of nuclear translocation of p65 subunit, and mangiferin reduced AGE production and decreased the mRNA and protein expression of RAGE in DCM rats. Our data indicated that mangiferin could significantly ameliorate DCM by preventing the release of inflammatory cytokines, and inhibiting ROS accumulation, AGE/RAGE production, and NF-κB nuclear translocation, suggesting that mangiferin treatment might be beneficial in DCM.

  11. Effect of PKC-β Signaling Pathway on Expression of MCP-1 and VCAM-1 in Different Cell Models in Response to Advanced Glycation End Products (AGEs).

    Science.gov (United States)

    Rempel, Lisienny C T; Finco, Alessandra B; Maciel, Rayana A P; Bosquetti, Bruna; Alvarenga, Larissa M; Souza, Wesley M; Pecoits-Filho, Roberto; Stinghen, Andréa E M

    2015-05-14

    Advanced glycation end products (AGEs) are compounds classified as uremic toxins in patients with chronic kidney disease that have several pro-inflammatory effects and are implicated in the development of cardiovascular diseases. To explore the mechanisms of AGEs-endothelium interactions through the receptor for AGEs (RAGE) in the PKC-β pathway, we evaluated the production of MCP-1 and VCAM-1 in human endothelial cells (HUVECs), monocytes, and a coculture of both. AGEs were prepared by albumin glycation and characterized by absorbance and electrophoresis. The effect of AGEs on cell viability was assessed with an MTT assay. The cells were also treated with AGEs with and without a PKC-β inhibitor. MCP-1 and VCAM-1 in the cell supernatants were estimated by ELISA, and RAGE was evaluated by immunocytochemistry. AGEs exposure did not affect cell viability, but AGEs induced RAGE, MCP-1, and VCAM-1 expression in HUVECs. When HUVECs or monocytes were incubated with AGEs and a PKC-β inhibitor, MCP-1 and VCAM-1 expression significantly decreased. However, in the coculture, exposure to AGEs and a PKC-β inhibitor produced no significant effect. This study demonstrates, in vitro, the regulatory mechanisms involved in MCP-1 production in three cellular models and VCAM-1 production in HUVECs, and thus mimics the endothelial dysfunction caused by AGEs in early atherosclerosis. Such mechanisms could serve as therapeutic targets to reduce the harmful effects of AGEs in patients with chronic kidney disease.

  12. [Glycotoxins and cellular dysfunction. A new mechanism for understanding the preventive effects of lifestyle modifications].

    Science.gov (United States)

    Michalsen, A; Bierhaus, A; Nawroth, P P; Dobos, G J

    2006-08-01

    Recently the AGE-RAGE interaction was identified as a potential mechanism underlying chronic and inflammatory diseases like atherosclerosis, diabetes mellitus and kidney disease. Advanced glycation end products (AGEs) are the derivatives of glucose-protein or glucose-lipid reactions and are mainly generated from the diet (depending on intensity of heating, cooking time and oxygenation). Binding of AGEs or other ligands to the AGE receptor (RAGE) results in cellular activation, i.e. increased expression of inflammatory mediators and oxidative stress. Diet-derived AGEs thus induce deleterious effects on tissues and the cardiovascular system. Recent research also found that other lifestyle factors are associated with pronounced inflammatory activation, e.g. psychosocial stress and smoking. In addition, each intake of meals is associated with proinflammatory cellular changes. The AGE-RAGE model and investigations of the underlying cellular mechanisms thus may lead to a better understanding of the health benefits of diets (Mediterranean diet, uncooked vegetarian diets), caloric restriction and intermittent fasting. The clinical impact of low-AGE diets and fasting and the interaction between stress and food intake should be further investigated in controlled trials.

  13. Advanced glycation endproducts in horses with insulin-induced laminitis.

    Science.gov (United States)

    de Laat, M A; Kyaw-Tanner, M T; Sillence, M N; McGowan, C M; Pollitt, C C

    2012-01-15

    Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of cancer, inflammatory conditions and diabetic complications. An interaction of AGEs with their receptor (RAGE) results in increased release of pro-inflammatory cytokines and reactive oxygen species (ROS), causing damage to susceptible tissues. Laminitis, a debilitating foot condition of horses, occurs in association with endocrine dysfunction and the potential involvement of AGE and RAGE in the pathogenesis of the disease has not been previously investigated. Glucose transport in lamellar tissue is thought to be largely insulin-independent (GLUT-1), which may make the lamellae susceptible to protein glycosylation and oxidative stress during periods of increased glucose metabolism. Archived lamellar tissue from horses with insulin-induced laminitis (n=4), normal control horses (n=4) and horses in the developmental stages (6h, 12h and 24h) of the disease (n=12) was assessed for AGE accumulation and the presence of oxidative protein damage and cellular lipid peroxidation. The equine-specific RAGE gene was identified in lamellar tissue, sequenced and is now available on GenBank. Lamellar glucose transporter (GLUT-1 and GLUT-4) gene expression was assessed quantitatively with qRT-PCR in laminitic and control horses and horses in the mid-developmental time-point (24 h) of the disease. Significant AGE accumulation had occurred by the onset of insulin-induced laminitis (48 h) but not at earlier time-points, or in control horses. Evidence of oxidative stress was not found in any group. The equine-specific RAGE gene was not expressed differently in treated and control animals, nor was the insulin-dependent glucose transporter GLUT-4. However, the glucose transporter GLUT-1 was increased in lamellar tissue in the developmental stages of insulin-induced laminitis compared to control horses and the insulin-independent nature of the lamellae may facilitate AGE formation. However, due to the lack of

  14. Advanced glycation end products promote differentiation of CD4(+) T helper cells toward pro-inflammatory response.

    Science.gov (United States)

    Han, Xiao-qun; Gong, Zuo-jiong; Xu, San-qing; Li, Xun; Wang, Li-kun; Wu, Shi-min; Wu, Jian-hong; Yang, Hua-fen

    2014-02-01

    This study investigated the effect of advanced glycation end products (AGEs) on differentiation of naïve CD4(+) T cells and the role of the receptor of AGEs (RAGE) and peroxisome proliferator-activated receptors (PPARs) activity in the process in order to gain insight into the mechanism of immunological disorders in diabetes. AGEs were prepared by the reaction of bovine serum albumin (BSA) with glucose. Human naïve CD4(+) T cells, enriched from blood of healthy adult volunteers with negative selection assay, were cultured in vitro and treated with various agents including AGEs, BSA, high glucose, PGJ2 and PD68235 for indicated time. In short hairpin (sh) RNA knock-down experiment, naïve CD4(+) T cells were transduced with media containing shRNA-lentivirus generated from lentiviral packaging cell line, Lent-X(TM) 293 T cells. Surface and intracellular cytokine stainings were used for examination of CD4(+) T cell phenotypes, and real-time PCR and Western blotting for detection of transcription factor mRNA and protein expression, respectively. The suppressive function of regulatory T (Treg) cells was determined by a [(3)H]-thymidine incorporation assay. The results showed that AGEs induced higher pro-inflammatory Th1/Th17 cells differentiated from naïve CD4(+) T cells than the controls, whereas did not affect anti-inflammatory Treg cells. However, AGEs eliminated suppressive function of Treg cells. In addition, AGEs increased RAGE mRNA expression in naïve CD4(+) T cells, and RAGE knock-down by shRNA eliminated the effect of AGEs on the differentiation of CD4(+) T cells and the reduction of suppressive function of Treg cells. Furthermore, AGEs inhibited the mRNA expression of PPARγ, not PPARα PPARγ agonist, PGJ2, inhibited the effect of AGEs on naïve CD4(+) T cell differentiation and reversed the AGE-reduced suppressive function of Treg cells; on the other hand, PPARγ antagonist, PD68235, attenuated the blocking effect of RAGE shRNA on the role of AGEs. It

  15. 晚期糖基化终产物对C57小鼠耳蜗螺旋神经节细胞凋亡及其受体表达的影响%Effect of advanced glycation end products on apoptosis of C57 mouse spiral ganglion cells and mRNA expression of advanced glycation end products receptor

    Institute of Scientific and Technical Information of China (English)

    龚麒麟; 左文静; 吴小波; 林昶

    2016-01-01

    目的:研究晚期糖基化终产物(advanced glycation end products,AGEs)对体外培养的小鼠耳蜗螺旋神经节细胞(spiral ganglion cells,SGCs)凋亡及晚期糖基化终产物受体(receptor for advanced glycation end products,RAGE)表达的影响,探讨AGEs诱导SGCs凋亡的可能作用途径,分析神经型老年性聋的可能致病机制。方法运用Tunel法,采用荧光显微镜观察不同浓度、不同时间AGEs对培养的SGCs凋亡的影响,同时用Real time RT-PCR方法检测RAGEmRNA表达。结果AGEs加入细胞培养中,可明显诱导SGCs凋亡,凋亡率与剂量、时间呈正相关。发生凋亡的同时有RAGEmRNA表达增强。结论AGEs对SGCs有诱导凋亡的作用,该作用可能通过RAGE介导。AGEs促使SGCs凋亡可能是神经型老年性聋的发病机制之一。%OBJECTIVE To analyze the effect of advanced glycation end products(AGEs) on apoptosis of cultured mouse spiral ganglion cells(SGCs) and expression of receptor of AGEs(RAGE). To explore the pathway of AGEs in promoting apoptosis of SGCs. And to explore the possible mechanism of neural presbycusis. METHODS The effect of AGEs on apoptosis of SGCs was studied by Tunel technique and fluorescence microscope. The expression of RAGE mRNA was assayed by Real time RT-PCR. RESULTS AGEs induced apoptosis of cultured SGCs. The effects were dose-dependent and time-dependent. Meanwhile RAGE mRNA expression was enhanced in apoptosis cells. CONCLUSION AGEs induced apoptosis in SGCs,which may be mediated by RAGE. And this may be one of the mechanisms of neural presbycusis.

  16. Effect of glycyrrhizin on traumatic brain injury in rats and its mechanism

    Directory of Open Access Journals (Sweden)

    Gu Xiangjin

    2014-02-01

    Full Text Available 【Abstract】Objective: To investigate the neuroprotective effects of glycyrrhizin (Gly as well as its effect on expression of high-mobility group box 1 (HMGB1 in rats after traumatic brain injury (TBI. Methods: Male Sprague-Dawley rats were randomly divided into three groups: sham group, TBI group, and TBI+Gly group (n=36 per group. Rat TBI model was made by using the modified Feeney’s method. In TBI+Gly group, Gly was administered intravenously at a dosage of 10 mg/kg 30 min after TBI. At 24 h after TBI, motor function and brain water content were evaluated. Meanwhile, HMGB1/HMGB1 receptors including toll-like receptor 4 (TLR4 and receptor for advanced glycation end products (RAGE/nuclear factor- κB(NF- κB signaling pathway and inflammatory cytokines in the injured brain tissues were detected using quantitative real-time polymerase chain reaction, western blot, electrophoretic mobility shift assay and enzyme-linked immunosorbent assay. Furthermore, HMGB1, RAGE and TLR4 immunohistochemistry and apoptosis were analyzed. Results: Beam walking performance impairment and brain edema were significantly reduced in TBI+Gly group compared with TBI group; meanwhile, the over-expressions of HMGB1/HMGB1 receptors (TLR4 and RAGE/NF-κB DNA-binding activity and inflammatory cytokines were inhibited. The percentages of HMGB1, RAGE and TLR4- positive cells and apoptotic cells were respectively 58.37%±5.06%, 54.15%±4.65%, 65.50%± 4.83%, 52.02%± 4.63% in TBI group and 39.99%±4.99%, 34.87%±5.02%, 43.33%±4.54%, 37.84%±5.16% in TBI+Gly group (all P<0.01 compared with TBI group. Conclusion: Gly can reduce secondary brain injury and improve outcomes in rat following TBI by down-regulation of HMGB1/HMGB1 receptors (TLR4 and RAGE/NF-κB - mediated inflammatory responses in the injured rat brain.

  17. Low levels of amyloid-beta and its transporters in neonatal rats with and without hydrocephalus

    Directory of Open Access Journals (Sweden)

    Silverberg Gerald D

    2009-05-01

    Full Text Available Abstract Background Previous studies in aging animals have shown that amyloid-beta protein (Aβ accumulates and its transporters, low-density lipoprotein receptor-related protein-1 (LRP-1 and the receptor for advanced glycation end products (RAGE are impaired during hydrocephalus. Furthermore, correlations between astrocytes and Aβ have been found in human cases of normal pressure hydrocephalus (NPH and Alzheimer's disease (AD. Because hydrocephalus occurs frequently in children, we evaluated the expression of Aβ and its transporters and reactive astrocytosis in animals with neonatal hydrocephalus. Methods Hydrocephalus was induced in neonatal rats by intracisternal kaolin injections on post-natal day one, and severe ventriculomegaly developed over a three week period. MRI was performed on post-kaolin days 10 and 21 to document ventriculomegaly. Animals were sacrificed on post-kaolin day 21. For an age-related comparison, tissue was used from previous studies when hydrocephalus was induced in a group of adult animals at either 6 months or 12 months of age. Tissue was processed for immunohistochemistry to visualize LRP-1, RAGE, Aβ, and glial fibrillary acidic protein (GFAP and with quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR to quantify expression of LRP-1, RAGE, and GFAP. Results When 21-day post-kaolin neonatal hydrocephalic animals were compared to adult (6–12 month old hydrocephalic animals, immunohistochemistry demonstrated levels of Aβ, RAGE, and LRP-1 that were substantially lower in the younger animals; in contrast, GFAP levels were elevated in both young and old hydrocephalic animals. When the neonatal hydrocephalic animals were compared to age-matched controls, qRT-PCR demonstrated no significant changes in Aβ, LRP-1 and RAGE. However, immunohistochemistry showed very small increases or decreases in individual proteins. Furthermore, qRT-PCR indicated statistically significant increases in GFAP

  18. Effect of glycyrrhizin on traumatic brain injury in rats and its mechanism

    Institute of Scientific and Technical Information of China (English)

    Gu Xiangjin; Xu Jin; Ma Banyou; Chen Gong; Gu Peiyuan; Wei Dong; Hu Weixing

    2014-01-01

    Objective:To investigate the neuroprotective effects of glycyrrhizin (Gly) as well as its effect on expression of high-mobility group box 1 (HMGB 1) in rats after traumatic brain injury (TBI).Methods:Male Sprague-Dawley rats were randomly divided into three groups:sham group,TBI group,and TBI+Gly group (n=36 per group).Rat TBI model was made by using the modified Feeney's method.In TBI+Gly group,Gly was administered intravenously at a dosage of 10 mg/kg 30 min after TBI.At 24 h after TBI,motor function and brain water content were evaluated.Meanwhile,HMGB 1/HMGB 1 receptors including toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE)/nuclear factor-κ B(NF-κ B) signaling pathway and inflammatory cytokines in the injured brain tissues were detected using quantitative real-time polymerase chain reaction,western blot,electrophoretic mobility shift assay and enzyme-linked immunosorbent assay.Furthermore,HMGB 1,RAGE and TLR4 immunohistochemistry and apoptosis were analyzed.Results:Beam walking performance impairment and brain edema were significantly reduced in TBI+Gly group compared with TBI group; meanwhile,the over-expressions of HMGB 1/HMGB 1 receptors (TLR4 and RAGE)/NF-κB DNA-binding activity and inflammatory cytokines were inhibited.The percentages of HMGB 1,RAGE and TLR4positive cells and apoptotic cells were respectively 58.37%±5.06%,54.15%±4.65%,65.50%± 4.83%,52.02%± 4.63% in TBI group and 39.99%±4.99%,34.87%±5.02%,43.33%±4.54%,37.84%±5.16% in TBI+Gly group (all P<0.01 compared with TBI group).Conclusion:Gly can reduce secondary brain injury and improve outcomes in rat following TBI by down-regulation of HMGB 1/HMGB 1 receptors (TLR4 and RAGE)/NF-κ B-mediated inflammatory responses in the injured rat brain.

  19. Advancements in web-database applications for rabies surveillance

    Directory of Open Access Journals (Sweden)

    Bélanger Denise

    2011-08-01

    Full Text Available Abstract Background Protection of public health from rabies is informed by the analysis of surveillance data from human and animal populations. In Canada, public health, agricultural and wildlife agencies at the provincial and federal level are responsible for rabies disease control, and this has led to multiple agency-specific data repositories. Aggregation of agency-specific data into one database application would enable more comprehensive data analyses and effective communication among participating agencies. In Québec, RageDB was developed to house surveillance data for the raccoon rabies variant, representing the next generation in web-based database applications that provide a key resource for the protection of public health. Results RageDB incorporates data from, and grants access to, all agencies responsible for the surveillance of raccoon rabies in Québec. Technological advancements of RageDB to rabies surveillance databases include 1 automatic integration of multi-agency data and diagnostic results on a daily basis; 2 a web-based data editing interface that enables authorized users to add, edit and extract data; and 3 an interactive dashboard to help visualize data simply and efficiently, in table, chart, and cartographic formats. Furthermore, RageDB stores data from citizens who voluntarily report sightings of rabies suspect animals. We also discuss how sightings data can indicate public perception to the risk of racoon rabies and thus aid in directing the allocation of disease control resources for protecting public health. Conclusions RageDB provides an example in the evolution of spatio-temporal database applications for the storage, analysis and communication of disease surveillance data. The database was fast and inexpensive to develop by using open-source technologies, simple and efficient design strategies, and shared web hosting. The database increases communication among agencies collaborating to protect human health from

  20. COPD纤维支气管镜肺泡灌洗液中可溶性晚期糖基化终末产物受体水平的临床意义%The Clinical Significances of Soluble Receptor for Advanced Glycation Endproducts in Bronchoscopy Alveolus Lavage Fluid among Patients with COPD

    Institute of Scientific and Technical Information of China (English)

    杨兴官; 雷超; 胡占升

    2014-01-01

    Objective To discuss the clinical significances of soluble receptor for advanced glycation end-products ( sRAGE)in bronchoscopy alveolus lavage fluid( BALF)in patients with COPD. Methods A total of 40 patients with COPD who were admitted to the department of intensive care unit of the First Hospital Affiliated to Liaoning Medical University from Oc-tober 2012 to May 2013,were selected as the COPD group,meanwhile 40 patients with non-COPD were selected as the non-COPD group,and these COPD patients were divided into mild group(12 cases),moderate group(10 cases),severe group (10 cases),very severe group(8 cases). The sRAGE concentrations in BALF were detected by enzyme-linked immunosor-bent assay(ELISA). Results The concentration of sRAGE in BALF of patients in the COPD group(191 ±71)ng/L was sig-nificantly higher than that in the non-COPD group(55 ±56)ng/L(t=9. 44,P<0. 001). The concentration of sRAGE in BALF of COPD patients in the mild group,moderate group,severe group and very severe group was(111 ± 44) ng/L,(184 ±45)ng/L,(226 ±34)ng/L,and(273 ±30)ng/L,respectively,there were significant differences in concentration of sRAGE among these groups(F=30. 48,P<0. 001),and the concentration of sRAGE in very severe COPD group was signifi-cantly higher than that in severe COPD group,the concentration of sRAGE in severe COPD group was significantly higher than that in moderate group,the concentration of sRAGE in moderate group was significantly higher than that in mild group( P <0. 05 ) . Linear correlation analysis results showed that the concentration of sRAGE in BALF of COPD patients were negatively cor-related with FEV1%(r= -0. 738,P <0. 05). Conclusion The concentration of sRAGE in BALF of COPD patients was higher than that of non-COPD patients;The concentration of sRAGE in BALF is related to severity of COPD,it could be used as an index of the prognosis evaluation of COPD.%目的:探讨纤维支气管镜肺泡灌洗液中可溶性晚期