Impact of Glyoxalase-I (Glo-I) and Advanced Glycation End Products (AGEs) in Chronic Liver Disease

Inflammation caused by oxidative stress (ROS) is a main driver for development of chronic inflammatory liver disease leading to fibrosis and cirrhosis. An important source of ROS constitutes methylglyoxal (MGO). MGO is formed as a by-product in glycolysis, threonine catabolism, and ketone bodies pathway leading to formation of advanced glycation end products (AGEs). AGEs bind to their receptor for AGEs (RAGE) and activate intracellular transcription factors, such as nuclear factor-κB (NF-κB), resulting in production of pro-inflammatory cytokines and ROS. The enzymes glyoxalase-I (Glo-I) and glyoxalase-II (Glo-II) form the glyoxalase system and are essential for the detoxification of methylglyoxal (MGO). This chapter highlights Glo-I and (R)AGE in chronic liver disease with focus on fibrosis and cirrhosis. AGEs and RAGE have been shown to be upregulated in fibrosis, and silencing of RAGE reduced the latter. In contrast, recent study highlighted reduced expression of Glo-I in cirrhosis with consecutive elevation of MGO and oxidative stress. Interestingly, modulation of Glo-I activity by ethyl pyruvate resulted in reduced activation of hepatic stellate cells and reduced fibrosis in CCl4 model of cirrhosis. In conclusion, Glo-I and R(AGE) are important components in development and progression of chronic liver disease and constitute interesting therapeutic target

Die immunmodulatorische Wirkung von Ethylpyruvat

In einer Vielzahl von Arbeiten konnten anti-inflammatorische Eigenschaften von Ethylpyruvat (EP) aufgezeigt werden. An verschiedenen Modellen der Sepsis, des hämorrhagischen Schocks, von Verbrennungsschäden, des Apoplex oder der Ischämie und Reperfusion wurde bei der Behandlung mit EP ein protektiver Effekt sowie eine verminderte Produktion von pro-inflammatorischen Zytokinen nachgewiesen. Als biochemische Grundlage wurde die Interaktion von EP mit dem Transkriptionsfaktor NF-κB identifiziert, die spezifischen Regulationsmechanismen konnten bisher allerdings nicht zufriedenstellend aufgeklärt werden. In dieser Arbeit wurde als eine neue mögliche Erklärung für die anti-inflammatorischen Eigenschaften des EP und weiterer α-oxo-Karbonsäureester die Inhibierung der Glyoxalase I (Glo-I) aufgezeigt. In vitro-Experimente zur Enzymaktivität belegten die Hemmung der Glo-I durch EP, während α-Hydroxy-Karbonsäureester wie L-Ethyllaktat (EL) keine inhibierenden Eigenschaften aufwiesen. Dennoch waren sowohl EP als auch EL und weitere Laktatester in der Lage, die LPS-induzierte Produktion von pro-inflammatorischen Zytokinen wie IL-1β, IL-6, IL-8 und TNF-α von humanen immunkompetenten Zellen zu supprimieren und die Expression von Immunrezeptoren wie HLA-DR, CD14 und CD91 zu modulieren. Somit konnten erstmals anti-inflammatorische Eigenschaften von Laktatestern nachgewiesen sowie eine Verbindung zwischen den Glyoxalase-Enzymen und dem Immunsystem etabliert werden. Diese und weitere Ergebnisse zur Einflussnahme der Karbonsäureester auf die Zellvitalität präsentieren das Glyoxalasesystem als mögliches Ziel neuer Therapiekonzepte für die Immunsuppression und bestätigen dessen Bedeutung für die Entwicklung von Anti-Tumor-Agenzien

Using The Barton Libraries Dataset As An RDF benchmark

This report describes the Barton Libraries RDF dataset and Longwell querybenchmark that we use for our recent VLDB paper on Scalable Semantic WebData Management Using Vertical Partitioning

Glyoxalase-I Is Upregulated in Acute Cerulein-Induced Pancreatitis: A New Mechanism in Pancreatic Inflammation?

Inflammation caused by oxidative stress (ROS) demonstrates an essential mechanism in the pathogenesis of acute pancreatitis (AP). Important sources for ROS comprise the reactive compound methylglyoxal (MGO) itself and the MGO-derived formation of advanced glycation end-products (AGEs). AGEs bind to the transmembrane receptor RAGE and activate NF-κB, and lead to the production of pro-inflammatory cytokines. MGO is detoxified by glyoxalase-I (Glo-I). The importance of Glo-I was shown in different models of inflammation and carcinogenesis. Nevertheless, the role of Glo-I and MGO in AP has not been evaluated so far. This study analyzed Glo-I in cerulein-(CN)-induced AP and determined the effects of Glo-I knockdown, overexpression and pharmacological modulation. Methods: AP was induced in C57BL6/J mice by i.p. injection of CN. Glo-I was analyzed in explanted pancreata by Western Blot, qRT-PCR and immunohistochemistry. AR42J cells were differentiated by dexamethasone and stimulated with 100 nM of CN. Cells were simultaneously treated with ethyl pyruvate (EP) or S-p-bromobenzylglutathione-cyclopentyl-diester (BrBz), two Glo-I modulators. Knockdown and overexpression of Glo-I was achieved by transient transfection with Glo-I siRNA and pEGFP-N1-Glo-I-Vector. Amylase secretion, TNF-α production (ELISA) and expression of Glo-I, RAGE and NF-κB were measured. Results: Glo-I was significantly upregulated on protein and mRNA levels in CN-treated mice and AR42J cells. Dexamethasone-induced differentiation of AR42J cells increased the expression of Glo-I and RAGE. Treatment of AR42J cells with CN and EP or BrBz resulted in a significant reduction of CN-induced amylase secretion, NF-κB, RAGE and TNF-α. Overexpression of Glo-I led to a significant reduction of CN-induced amylase levels, NF-κB expression and TNF-α, whereas Glo-I knockdown revealed only slight alterations. Measurements of specific Glo-I activity and MGO levels indicated a complex regulation in the model of CN-induced AP. Conclusion: Glo-I is overexpressed in a model of CN-induced AP. Pharmacological modulation and overexpression of Glo-I reduced amylase secretion and the release of pro-inflammatory cytokines in AP in vitro. Targeting Glo-I in AP seems to be an interesting approach for future in vivo studies of AP

Validation of a consumer-grade activity monitor for continuous daily activity monitoring in individuals with multiple sclerosis.

Background:Technological advancements of remote-monitoring used in clinical-care and research require validation of model updates. Objectives:To compare the output of a newer consumer-grade accelerometer to a previous model in people with multiple sclerosis (MS) and to the ActiGraph, a waist-worn device widely used in MS research. Methods:Thirty-one individuals with MS participated in a 7-day validation by the Fitbit Flex (Flex), Fitbit Flex-2 (Flex2) and ActiGraph GT3X. Primary outcome was step count. Valid epochs of 5-min block increments, where there was overlap of ≥1 step/min for both devices were compared and summed to give a daily total for analysis. Results:Bland-Altman plots showed no systematic difference between the Flex and Flex2; mean step-count difference of 25 more steps-per-day more recorded by Flex2 (95% confidence intervals (CI) = 2, 48; p = 0.04),interclass correlation coefficient (ICC) = 1.00. Compared to the ActiGraph, Flex2 (and Flex) tended to record more steps (808 steps-per-day more than the ActiGraph (95% CI= -2380, 765; p < 0.01), although the ICC was high (0.98) indicating that the devices were likely measuring the same kind of activity. Conclusions:Steps from Flex and Flex2 can be used interchangeably. Differences in total step count between ActiGraph and Flex devices can make cross-device comparisons of numerical step-counts challenging particularly for faster walkers

Study Protocol of the ESAP Study: Endoscopic Papillectomy vs. Surgical Ampullectomy vs. Pancreaticoduodenectomy for Ampullary Neoplasm—A Pancreas2000/EPC Study

Background: Lesions of the Ampulla of Vater are a rare condition and represent <10% of peri-ampullary neoplasms. Nevertheless, ampullary adenomas have the potential for malignant transformation to ampullary carcinomas by an adenoma-to-carcinoma sequence. Thus, adequate patient selection and complete resection (R0) of non-invasive ampullary lesions either by endoscopic papillectomy (EP), surgical ampullectomy (SA), or pancreaticoduodenectomy (PD) is essential. Although PD was traditionally performed, recent studies reported considerable efficacy and fewer complications following EP and SA. Since consistent comparative data are lacking, the Endoscopic Papillectomy vs. Surgical Ampullectomy vs. Pancreaticoduodectomy (ESAP) study will provide evidence for a therapeutic standard and post procedure morbidity in ampullary lesions. Methods: International multicenter retrospective study. Adult patients (>18 years of age) who underwent SA or PD for ampullary neoplasm between 2004 and 2018 or EP between 2007 and 2018 will be evaluated. Main inclusion criteria are ampullary lesions strictly located to the ampulla. This includes adenoma, adenocarcinoma (T1 and T2), neuroendocrine tumors, gastrointestinal stroma tumors and other rare conditions. Exclusion criteria are peri-ampullary lesions, e.g., from the duodenal wall or the head of the pancreas, and interventions for tumor stages higher than T2. The main objective of this study is to analyze rates of complete resection (R0), recurrence and necessity for complementary interventions following EP, SA, and PD. Treatment-quality for each procedure will be defined by morbidity, mortality and complication rates and will be compared between EP, SA, and PD. Secondary objectives include outcome for patients with incomplete resection or initially understated tumors, lesions of the minor papilla, hereditary syndromes, neuroendocrine tumors, mesenchymal lesions, and other rare conditions. Additionally, we will analyze therapy by argon plasma coagulation and radiofrequency ablation. Furthermore, outcome in curative and palliative interventions can be distinguished. Conclusion: The ESAP study will provide evidence for therapeutic algorithms and data for the implementation of guidelines in the treatment of different types of ampullary tumors, including recurrent, or incomplete resected lesions

Systematic Review with Meta-Analysis: Endoscopic and Surgical Resection for Ampullary Lesions

Ampullary lesions (ALs) can be treated by endoscopic (EA) or surgical ampullectomy (SA) or pancreaticoduodenectomy (PD). However, EA carries significant risk of incomplete resection while surgical interventions can lead to substantial morbidity. We performed a systematic review and meta-analysis for R0, adverse-events (AEs) and recurrence between EA, SA and PD. Electronic databases were searched from 1990 to 2018. Outcomes were calculated as pooled means using fixed and random-effects models and the Freeman-Tukey-Double-Arcsine-Proportion-model. We identified 59 independent studies. The pooled R0 rate was 76.6% (71.8–81.4%, I2 = 91.38%) for EA, 96.4% (93.6–99.2%, I2 = 37.8%) for SA and 98.9% (98.0–99.7%, I2 = 0%) for PD. AEs were 24.7% (19.8–29.6%, I2 = 86.4%), 28.3% (19.0–37.7%, I2 = 76.8%) and 44.7% (37.9–51.4%, I2 = 0%), respectively. Recurrences were registered in 13.0% (10.2–15.6%, I2 = 91.3%), 9.4% (4.8–14%, I2 = 57.3%) and 14.2% (9.5–18.9%, I2 = 0%). Differences between proportions were significant in R0 for EA compared to SA (p = 0.007) and PD (p = 0.022). AEs were statistically different only between EA and PD (p = 0.049) and recurrence showed no significance for EA/SA or EA/PD. Our data indicate an increased rate of complete resection in surgical interventions accompanied with a higher risk of complications. However, studies showed various sources of bias, limited quality of data and a significant heterogeneity, particularly in EA studies

Electronic properties of curved few-layers graphene: a geometrical approach

We show the presence of non-relativistic L\'evy-Leblond fermions in flat three- and four-layers graphene with AB stacking, extending the results obtained in [Curvatronics2017] for bilayer graphene. When the layer is curved we obtain a set of equations for Galilean fermions that are a variation of those of L\'evy-Leblond with a well defined combination of pseudospin, and that admit L\'evy-Leblond spinors as solutions in an approriate limit. The local energy of such Galilean fermions is sensitive to the intrinsic curvature of the surface. We discuss the relationship between two-dimensional pseudospin, labelling layer degrees of freedom, and the different energy bands. For L\'evy-Leblond fermions an interpretation is given in terms of massless fermions in an effective 4D spacetime, and in this case the pseudospin is related to four dimensional chirality. A non-zero energy band gap between conduction and valence electronic bands is obtained for surfaces with positive curvature.Comment: 16 pages, 4 figures. Matches the published version. Refined theory that describes the unique combination of isospin states ocurring in curved bilayer graphene sheet

Enoxaparin does not ameliorate liver fibrosis or portal hypertension in rats with advanced cirrhosis

Background & Aims Recent studies suggest that heparins reduce liver fibrosis and the risk of decompensation of liver disease. Here, we evaluated the effects of enoxaparin in several experimental models of advanced cirrhosis. Methods Cirrhosis was induced in male Sprague‐Dawley (SD) rats by: (i) Oral gavage with carbon tetrachloride (CCl4ORAL), (ii) Bile duct ligation (BDL) and (iii) CCl4 inhalation (CCl4INH). Rats received saline or enoxaparin s.c. (40 IU/Kg/d or 180 IU/Kg/d) following various protocols. Blood biochemical parameters, liver fibrosis, endothelium‐ and fibrosis‐related genes, portal pressure, splenomegaly, bacterial translocation, systemic inflammation and survival were evaluated. Endothelial dysfunction was assessed by in situ bivascular liver perfusions. Results Enoxaparin did not ameliorate liver function, liver fibrosis, profibrogenic gene expression, portal hypertension, splenomegaly, ascites development and infection, serum IL‐6 levels or survival in rats with CCl4ORAL or BDL‐induced cirrhosis. Contrarily, enoxaparin worsened portal pressure in BDL rats and decreased survival in CCl4ORAL rats. In CCl4INH rats, enoxaparin had no effects on hepatic endothelial dysfunction, except for correcting the hepatic arterial dysfunction when enoxaparin was started with the CCl4 exposure. In these rats, however, enoxaparin increased liver fibrosis and the absolute values of portal venous and sinusoidal resistance. Conclusions Our results do not support a role of enoxaparin for improving liver fibrosis, portal hypertension or endothelial dysfunction in active disease at advanced stages of cirrhosis. These disease‐related factors and the possibility of a limited therapeutic window should be considered in future studies evaluating the use of anticoagulants in cirrhosis