Sulodexide counteracts endothelial dysfunction induced by metabolic or non-metabolic stresses through activation of the autophagic program

OBJECTIVE: Endothelial dysfunction (ED) predisposes to venous thrombosis (VT) and post-thrombotic syndrome (PTS), a long-term VT-related complication. Sulodexide (SDX) is a highly purified glycosaminoglycan with antithrombotic, pro-fibrinolytic and anti-inflammatory activity used in the treatment of chronic venous disease (CVD), including patients with PTS. SDX has recently obtained clinical evidence in the “extension therapy” after initial-standard anticoagulant treatment for the secondary prevention of recurrent deep vein thrombosis (DVT). Herein, we investigated how SDX counteracts ED. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVEC) were used. Metabolic and non metabolic-induced ED was induced by treating with methylglyoxal (MGO) or irradiation (IR), respectively. Bafilomycin A1 was used to inhibit autophagy. The production of reactive oxygen species (ROS), tetrazolium bromide (MTT) assay for cell viability, terminal de-oxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay for cell apoptosis, Real-time PCR and Western blot analysis for gene and protein expression were used. RESULTS: SDX protected HUVEC from MGO- or IR-induced apoptosis by counteracting the activation of the intrinsic and extrinsic caspase cascades. The cytoprotective effects of SDX resulted from a reduction in a) ROS production, b) neo-synthesis and release of pro-inflammatory cytokines (TNFα, IL1, IL6, IL8), c) DNA damage induced by MGO or IR. These effects were reduced when autophagy was inhibited. CONCLUSIONS: Data herein collected indicate the ability of SDX to counteract ED induced by metabolic or non-metabolic stresses by involving the intracellular autophagy pathway. Our experience significantly increases the knowledge of the mechanisms of action of SDX against ED and supports the use of SDX in the treatment of CVD, PTS and in the secondary prevention of recurrent DVT

Hole dynamics in a quantum antiferromagnet beyond the retraceable path approximation

The one-hole spectral weight for two chains and two dimensional lattices is studied numerically using a new method of analysis of the spectral function within the Lanczos iteration scheme: the Lanczos spectra decoding method. This technique is applied to the $t-J_z$ model for $J_z \to 0$, directly in the infinite size lattice. By a careful investigation of the first 13 Lanczos steps and the first 26 ones for the two dimensional and the two chain cases respectively, we get several new features of the one-hole spectral weight. A sharp incoherent peak with a clear momentum dispersion is identified, together with a second broad peak at higher energy. The spectral weight is finite up to the Nagaoka energy where it vanishes in a non-analytic way. Thus the lowest energy of one hole in a quantum antiferromagnet is degenerate with the Nagaoka energy in the thermodynamic limit.Comment: RevTeX 3.0, SISSA preprint 156/93/CM/MB, 10 pages + postscript file appended, contains more accurate calculations in Fig.

The sequential price of anarchy for atomic congestion games

In situations without central coordination, the price of anarchy relates the quality of any Nash equilibrium to the quality of a global optimum. Instead of assuming that all players choose their actions simultaneously, here we consider games where players choose their actions sequentially. The sequential price of anarchy, recently introduced by Paes Leme, Syrgkanis, and Tardos then relates the quality of any subgame perfect equilibrium to the quality of a global optimum. The effect of sequential decision making on the quality of equilibria, however, depends on the specific game under consideration.\ud Here we analyze the sequential price of anarchy for atomic congestion games with affine cost functions. We derive several lower and upper bounds, showing that sequential decisions mitigate the worst case outcomes known for the classical price of anarchy. Next to tight bounds on the sequential price of anarchy, a methodological contribution of our work is, among other things, a "factor revealing" integer linear programming approach that we use to solve the case of three players

Quantum Monte Carlo simulations of infinitely strongly correlated fermions

Numerical simulations of the two-dimensional t-J model in the limit $J/t \ll 1$ are performed for rather large systems (up to $N = 12 \times 12$) using a world-line loop-algorithm. It is shown that in the one-hole case with J=0, where no minus signs appear, very low temperatures ($\beta t \sim 3000$) are necessary in order to reach Nagaoka's state. J/t \ltsim 0.05 leads to the formation of partially polarized systems, whereas J/t \gtsim 0.05 corresponds to minimal spin. The two-hole case shows enhanced total spin up to the lowest attainable temperatures ($\beta t = 150$).Comment: 6 pages, 5 figure

Iron-dependent trafficking of 5-lipoxygenase and impact on human macrophage activation

5-lipoxygenase (5-LOX) is a non-heme iron-containing dioxygenase expressed in immune cells that catalyzes the two initial steps in the biosynthesis of leukotrienes. It is well known that 5-LOX activation in innate immunity cells is related to different iron-associated proinflammatory disorders, including cancer, neurodegenerative diseases, and atherosclerosis. However, the molecular and cellular mechanism(s) underlying the interplay between iron and 5-LOX activation are largely unexplored. In this study, we investigated whether iron (in the form of Fe3+ and hemin) might modulate 5-LOX influencing its membrane binding, subcellular distribution, and functional activity. We proved by fluorescence resonance energy transfer approach that metal removal from the recombinant human 5-LOX, not only altered the catalytic activity of the enzyme, but also impaired its membrane-binding. To ascertain whether iron can modulate the subcellular distribution of 5-LOX in immune cells, we exposed THP-1 macrophages and human primary macrophages to exogenous iron. Cells exposed to increasing amounts of Fe3+ showed a redistribution (ranging from ~45 to 75%) of the cytosolic 5-LOX to the nuclear fraction. Accordingly, confocal microscopy revealed that acute exposure to extracellular Fe3+, as well as hemin, caused an overt increase in the nuclear fluorescence of 5-LOX, accompanied by a co-localization with the 5-LOX activating protein (FLAP) both in THP-1 macrophages and human macrophages. The functional relevance of iron overloading was demonstrated by a marked induction of the expression of interleukin-6 in iron-treated macrophages. Importantly, pre-treatment of cells with the iron-chelating agent deferoxamine completely abolished the hemin-dependent translocation of 5-LOX to the nuclear fraction, and significantly reverted its effect on interleukin-6 overexpression. These results suggest that exogenous iron modulates the biological activity of 5-LOX in macrophages by increasing its ability to bind to nuclear membranes, further supporting a role for iron in inflammation-based diseases where its homeostasis is altered and suggesting further evidence of risks related to iron overload

Effects of Rare Phytocannabinoids on the Endocannabinoid System of Human Keratinocytes

The decriminalization and legalization of cannabis has paved the way for investigations into the potential of the use of phytocannabinoids (pCBs) as natural therapeutics for the treatment of human diseases. This growing interest has recently focused on rare (less abundant) pCBs that are non-psychotropic compounds, such as cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). Notably, pCBs can act via the endocannabinoid system (ECS), which is involved in the regulation of key pathophysiological processes, and also in the skin. In this study, we used human keratinocytes (HaCaT cells) as an in vitro model that expresses all major ECS elements in order to systematically investigate the effects of CBG, CBC, THCV and CBGA. To this end, we analyzed the gene and protein expression of ECS components (receptors: CB1, CB2, GPR55, TRPV1 and PPARα/γ/δ; enzymes: NAPE-PLD, FAAH, DAGLα/β and MAGL) using qRT-PCR and Western blotting, along with assessments of their functionality using radioligand binding and activity assays. In addition, we quantified the content of endocannabinoid(-like) compounds (AEA, 2-AG, PEA, etc.) using UHPLC-MS/MS. Our results demonstrated that rare pCBs modulate the gene and protein expression of distinct ECS elements differently, as well as the content of endocannabinoid(-like) compounds. Notably, they all increased CB1/2 binding, TRPV1 channel stimulation and FAAH and MAGL catalytic activity. These unprecedented observations should be considered when exploring the therapeutic potential of cannabis extracts for the treatment of human skin diseases

Language of CTO interventions – Focus on hardware

AbstractThe knowledge of variety of chronic total occlusion (CTO) hardware and the ability to use them represents the key to success of any CTO interventions. However, the multiplicity of CTO hardware and their physical character and the terminology used by experts create confusion in the mind of an average interventional cardiologist, particularly a beginner in this field. This knowledge is available but is scattered. We aim to classify and compare the currently used devices based on their properties focusing on how physical character of each device can be utilized in a specific situation, thus clarifying and simplifying the technical discourse

Understanding structure-activity relationships in highly active La promoted Ni catalysts for CO₂ methanation

Ni-based catalysts are selective in the hydrogenation of CO_{2} to CH_{4} but their activity and stability need improvement. Herein, we propose a hydrotalcite-derived high loaded Ni-Al_{2}O_{3} catalyst promoted by La. The effect of La on the catalyst properties is investigated and compared with that of Y and Ce. The NiO_{x} rystallite size and basic properties (rather than the nickel reducibility) as well as the catalytic activity depend on the rare-earth element. The La-catalyst achieves a more relevant activity enhancement at low temperature and high space velocity (480 L g^{-1} h^{-1}, CO_{2}/H_{2}/N_{2} = 1/4/1 v/v), high CH_{4} productivity (101 L_{CH4} gNi^{-1} h^{-1}) and stability, even under undiluted feeds. In situ DRIFTS and the characterization of spent catalysts confirm that this enhanced performance is related to the combination of dissociative and associative CO_{2} activation on more reduced, highly dispersed and stable Ni nanoparticles and basic sites in the La_{2}O_{3}-Al_{2}O_{3} matrix, respectively

Tofacitinib May Inhibit Myofibroblast Differentiation from Rheumatoid-Fibroblast-like Synoviocytes Induced by TGF-β and IL-6

During rheumatoid arthritis (RA), the pathogenic role of resident cells within the synovial membrane is suggested, especially for a population frequently referred to as fibroblast-like synoviocytes (FLSs). In this study, we assess the markers of myofibroblast differentiation of RA-FLSs by ex vivo observations and in vitro evaluations following the stimulation with both TGF-β and IL-6. Furthermore, we investigated the possible inhibiting role of tofacitinib, a JAK inhibitor, in this context. Myofibroblast differentiation markers were evaluated on RA synovial tissues by immune-fluorescence or immune-histochemistry. RA-FLSs, stimulated with transforming growth factor (TGF-β) and interleukin-6 (IL-6) with/without tofacitinib, were assessed for myofibroblast differentiation markers expression by qRT-PCR and Western blot. The same markers were evaluated following JAK-1 silencing by siRNA assay. The presence of myofibroblast differentiation markers in RA synovial tissue was significantly higher than healthy controls. Ex vivo, α-SMA was increased, whereas E-Cadherin decreased. In vitro, TGF-β and IL-6 stimulation of RA-FLSs promoted a significant increased mRNA expression of collagen I and α-SMA, whereas E-Cadherin mRNA expression was decreased. In the same conditions, the stimulation with tofacitinib significantly reduced the mRNA expression of collagen I and α-SMA, even if the Western blot did not confirm this finding. JAK-1 gene silencing did not fully prevent the effects of stimulation with TGF-β and IL-6 on these features. TGF-β and IL-6 stimulation may play a role in mediating myofibroblast differentiation from RA-FLSs, promoting collagen I and α-SMA while decreasing E-Cadherin. Following the same stimulation, tofacitinib reduced the increases of both collagen I and α-SMA on RA-FLSs, although further studies are needed to fully evaluate this issue and confirm our results