Ivabradine Reduces Chemokine-Induced CD4-Positive Lymphocyte Migration

Aims. Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that ivabradine, a selective I(f)-channel blocker, reduces atherosclerotic plaque formation in apolipoprotein E-deficient mice, hitherto nothing is known about the mechanism by which ivabradine modulates plaque formation. Therefore, the present study investigated whether ivabradine regulates chemokine-induced migration of lymphocytes. Methods and results. Stimulation of CD4-positive lymphocytes with SDF-1 leads to a 2.0 ± 0.1 fold increase in cell migration (P < .01; n = 7). Pretreatment of cells with ivabradine reduces this effect to a maximal 1.2 ± 0.1 fold induction at 0.1 µmol/L ivabradine (P < .01 compared to SDF-1-treated cells, n = 7). The effect of ivabradine on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity as determined by PI-3 kinase activity assays. Downstream, ivabradine inhibits activation of the small GTPase Rac and phosphorylation of the Myosin Light Chain (MLC). Moreover, ivabradine treatment reduces f-actin formation as well as ICAM3 translocation to the uropod of the cell, thus interfering with two important steps in T cell migration. Conclusion. Ivabradine inhibits chemokine-induced migration of CD4-positive lymphocytes. Given the crucial importance of chemokine-induced T-cell migration in early atherogenesis, ivabradine may be a promising tool to modulate this effect

C12orf5 (chromosome 12 open reading frame 5)

Review on C12orf5, with data on DNA/RNA, on the protein encoded and where the gene is implicated

PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2)

Review on PFKFB2, with data on DNA/RNA, on the protein encoded and where the gene is implicated

The Expression of TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Can Be Controlled by the Antioxidant Orchestrator NRF2 in Human Carcinoma Cells

Hyperactivation of the KEAP1-NRF2 axis is a common molecular trait in carcinomas from different origin. The transcriptional program induced by NRF2 involves antioxidant and metabolic genes that render cancer cells more capable of dealing with oxidative stress. The TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) is an important regulator of glycolysis and the pentose phosphate pathway that was described as a p53 response gene, yet TIGAR expression is detected in p53-null tumors. In this study we investigated the role of NRF2 in the regulation of TIGAR in human carcinoma cell lines. Exposure of carcinoma cells to electrophilic molecules or overexpression of NRF2 significantly increased expression of TIGAR, in parallel to the known NRF2 target genes NQO1 and G6PD. The same was observed in TP53KO cells, indicating that NRF2-mediated regulation of TIGAR is p53-independent. Accordingly, downregulation of NRF2 decreased the expression of TIGAR in carcinoma cell lines from different origin. As NRF2 is essential in the bone, we used mouse primary osteoblasts to corroborate our findings. The antioxidant response elements for NRF2 binding to the promoter of human and mouse TIGAR were described. This study provides the first evidence that NRF2 controls the expression of TIGAR at the transcriptional level

Fructose 2,6-bisphosphate in cancer cell metabolism

For a long time, pioneers in the field of cancer cell metabolism, such as Otto Warburg, have focused on the idea that tumor cells maintain high glycolytic rates even with adequate oxygen supply, in what is known as aerobic glycolysis or the Warburg effect. Recent studies have reported a more complex situation, where the tumor ecosystem plays a more critical role in cancer progression. Cancer cells display extraordinary plasticity in adapting to changes in their tumor microenvironment, developing strategies to survive and proliferate. The proliferation of cancer cells needs a high rate of energy and metabolic substrates for biosynthesis of biomolecules. These requirements are met by the metabolic reprogramming of cancer cells and others present in the tumor microenvironment, which is essential for tumor survival and spread. Metabolic reprogramming involves a complex interplay between oncogenes, tumor suppressors, growth factors and local factors in the tumor microenvironment. These factors can induce overexpression and increased activity of glycolytic isoenzymes and proteins in stromal and cancer cells which are different from those expressed in normal cells. The fructose-6-phosphate/fructose-1,6-bisphosphate cycle, catalyzed by 6-phosphofructo-1-kinase/fructose 1,6-bisphosphatase (PFK1/FBPase1) isoenzymes, plays a key role in controlling glycolytic rates. PFK1/FBpase1 activities are allosterically regulated by fructose-2,6-bisphosphate, the product of the enzymatic activity of the dual kinase/phosphatase family of enzymes: 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFKFB1-4) and TP53-induced glycolysis and apoptosis regulator (TIGAR), which show increased expression in a significant number of tumor types. In this review, the function of these isoenzymes in the regulation of metabolism, as well as the regulatory factors modulating their expression and activity in the tumor ecosystem are discussed. Targeting these isoenzymes, either directly or by inhibiting their activating factors, could be a promising approach for treating cancers

Characterisation of archaeological waterlogged wood by pyrolytic and mass spectrometric techniques

1) Department of Chemistry and Industrial Chemistry, University of Pisa, via Risorgimento 35. 56126 Pisa, Italy ; 2) IRNAS-CSIC, Seville, Spain; E-mail address: [email protected] combination of two techniques based on analytical pyrolysis and mass spectrometry, including direct exposure-MS (DE-MS) and pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS), was used to study the chemical composition of waterlogged archaeological wood. In particular, the two techniques were used to chemically characterise samples of archaeological wood from the excavation of the Site of the Ancient Ships of Pisa San Rossore in Pisa (Italy). The data were compared to those of native sound wood of the same species. The results highlight that DE-MS is a valuable technique for the characterisation of archaeological wood. DE-MS allows us to use a minimal sample size and to perform the analysis in a few minutes, thus avoiding the long wet-chemical procedures that are commonly used to characterise wood. The results also confirm the importance of Py-GC/MS as a tool for shedding light on the chemical modifications of wood in archaeological objects. The analyses demonstrated that waterlogged wood from the site of Pisa San Rossore have undergone an extensive loss of polysaccharides together with partial demethylation of lignin units, both guaiacyl and syringyl monomers. In fact, catechols and methoxy catechols were identified among the pyrolysis products of the waterlogged wood samples.The authors wish to thank Dott.ssa G. Giachi (Restoration Laboratories of the Archaeological Superintendence of Tuscany, Florence, Italy) for providing archaeological wood samples and for her valuable support and collaboration. Funding was provided by the Archaeological Superintendence of Tuscany and by the Italian MIUR (PRIN Cofin05).Peer reviewe

Efectivitat de l'aprenentatge basat en problemes (ABP) en l'assignatura de Teràpia Gènica i Molecular d'Odontologia

Podeu consultar la Vuitena trobada de professorat de Ciències de la Salut completa a: http://hdl.handle.net/2445/66524L’aprenentatge basat en problemes (ABP) és una estratègia didàctica innovadora centrada en l’estudiant, que facilita l’adquisició d’unes habilitats i competències indispensables en l’entorn professional i que proporciona el context adequat per afavorir el treball en grup i l’aprenentatge significatiu. L’experiència que aquí descrivim neix de la necessitat de motivar i implicar els estudiants d’Odontologia (2n-4t curs) en l’aprenentatge i assoliment de les competències transversals i les específiques definides en el pla docent de l’assignatura optativa de 3 ECTS Teràpia gènica i molecular durant el curs 2013-2014. Han participat un total de 32 estudiants distribuïts en 4 grups La dinàmica de l’ABP consisteix en la resolució d’un cas entre 6 dissenyats prèviament per l'equip de profesors, que cada grup d'estudiants ha de solucionar aplicant conceptes de Teràpia Gènica per a dissenyar una estratègia terapèutica innovadora aplicada a un desordre de la salut. En aquesta comunicació es descriu l’experiència realitzada, tenint en compte aspectes metodològics, descripció de les dinàmiques de grup, avaluació de l’experiència per part dels estudiants i dels tutors, així com la seva incidència en els resultats globals de l’assignatura. Tambè se ha fet una anàlisi comparativa dels resultats d'aquest curs amb els dels cursos previs. Aquest projecte ha constituït la primera experiència amb l

Тактика тушения пожара на открытом распределительном устройстве объекта энергетики

Работа посвящена изучению тактики и особенносткй тушения пожара на открытом распределительном устройстве объекта энергетики. Рассмотрены особенности развития пожара на энергетических объектах, проведен анализ пожарной опасности открытого распределительного устройства, а также произведен расчет сил и средств для ликвидации пожара на открытом распределительном устройстве.The work is devoted to studying the tactics and features of extinguishing a fire in an open switchgear of an energy facility. The features of the development of a fire at power facilities are analyzed, the fire hazard of an open switchgear is analyzed, and the forces and means for eliminating a fire in an open switchgear are calculated

TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Is Upregulated in Lymphocytes Stimulated with Concanavalin A

The glycolytic modulator TP53-Inducible Glycolysis and Apoptosis Regulator (TIGAR) is overexpressed in several types of cancer and has a role in metabolic rewiring during tumor development. However, little is known about the role of this enzyme in proliferative tissues under physiological conditions. In the current work, we analysed the role of TIGAR in primary human lymphocytes stimulated with the mitotic agent Concanavalin A (ConA). We found that TIGAR expression was induced in stimulated lymphocytes through the PI3K/AKT pathway, since Akti-1/2 and LY294002 inhibitors prevented the upregulation of TIGAR in response to ConA. In addition, suppression of TIGAR expression by siRNA decreased the levels of the proliferative marker PCNA and increased cellular ROS levels. In this model, TIGAR was found to support the activity of glucose 6-phosphate dehydrogenase (G6PDH), the first enzyme of the pentose phosphate pathway (PPP), since the inhibition of TIGAR reduced G6PDH activity and increased autophagy. In conclusion, we demonstrate here that TIGAR is upregulated in stimulated human lymphocytes through the PI3K/AKT signaling pathway, which contributes to the redirection of the carbon flux to the PPP

TIGAR (chromosome 12 open reading frame 5)

Human TIGAR protein consists of 270 arninoacids, with a molecular weight of 30063 Da. It is cornposed of a bisphosphatase active site in which two histidines, His-11 and His-198, and one glutamic acid, Glu-1 02, are key residues for its function TIGAR catalytic domain belongs to the histidine phosphatase superfamily of proteins, a conserved group of proteins which contain a domain with a histidine forming a phosphoenzyme transiently during the catalysis (Rigden, 2008). This domain shares similarity with enzymes ofthe phosphoglycerate rrutase fumily (PGAM) and with the bisphosphatase domain of6-phosphofructo-2-kinase/:6:uctose-2,6-bisphosphatase (PFK-2/FBPase- 2.), in which the three aminoacids in the catalytic domain are conserved. More infurmation about TIGAR protein can be found in Uniprot 0 9N088. Human TIGAR structure contains different motifs as represented in the image below (PDB reference 3DCY). The crystallized structure of Danio rerio TIGAR is available inPDB (3E9D rererence) and was published by Li and Jogl, 2009