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

The Pictet-Spengler reaction updates its habits

The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydroisoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011–2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations

Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors

Hedgehog signaling is essential for tissue development and stemness, and its deregulation has been observed in many tumors. Aberrant activation of Hedgehog signaling is the result of genetic mutations of pathway components or other Smo-dependent or independent mechanisms, all triggering the downstream effector Gli1. For this reason, understanding the poorly elucidated mechanism of Gli1-mediated transcription allows to identify novel molecules blocking the pathway at a downstream level, representing a critical goal in tumor biology. Here, we clarify the structural requirements of the pathway effector Gli1 for binding to DNA and identify Glabrescione B as the first small molecule binding to Gli1 zinc finger and impairing Gli1 activity by interfering with its interaction with DNA. Remarkably, as a consequence of its robust inhibitory effect on Gli1 activity, Glabrescione B inhibited the growth of Hedgehog-dependent tumor cells in vitro and in vivo as well as the self-renewal ability and clonogenicity of tumor-derived stem cells. The identification of the structural requirements of Gli1/DNA interaction highlights their relevance for pharmacologic interference of Gli signaling

COMPONENTES QUÍMICOS E ATIVIDADE ANTIMICROBIANA DE

Ptychopetalum olacoides Bentham, popularly known as marapuama or muirapuama is an Olacaceae native of North Brazil, known and used for its stimulating and aphrodisiac properties for a long time. The phytochemical study of the stems of this tree revealed the presence of several fatty acids, sterols and xanthines, including palmitic and stearic acids, - sitosterol, stigmasterol, lupeol, glutinol, -amirin, caffeine, theobromine and adenine. Antimicrobial assays showed that the alcoholic extract of the plant has inhibitory action on the growth of strains of Colletotrichum acutatum and Fusarium oxysporum. On the other hand, the extracts have no effect against strains of Staphylococcus aureus, Staphylococcus epidermidis and Escherichia coli. Keywords: muirapuama; muirapuamine; caffeine; antimicrobial.Ptychopetalum olacoides Bentham, popularmente conhecida como marapuama ou muirapuama, é uma olacaceae nativa na região norte do Brasil, conhecida e utilizada há longo tempo por suas propriedades estimulantes e afrodisíacas. O estudo fitoquímico das cascas dos galhos desta árvore de pequeno porte revelou a presença de vários ácidos graxos, esteróides e xantinas, incluindo os ácidos palmítico e esteárico, -sitosterol, estigmasterol, lupeol, glutinol, -amirina, cafeína, teobromine e adenina. Os ensaios antimicrobianos mostraram que o extrato alcoólico tem ação inibitória no crescimento de cepas de Colletotrichum acutatum e Fusarium oxysporum. Por outro lado, os extratos não apresentaram efeitos contra cepas de Staphylococcus aureus, Staphylococcus epidermidis e Escherichia coli. Palavras-chave: muirapuama; muirapuamina; cafeíne; antimicrobiano

LARES/WEBER-SAT and the equivalence principle

It has often been claimed that the proposed Earth artificial satellite LARES/WEBER-SAT-whose primary goal is, in fact, the measurement of the general relativistic Lense-Thirring effect at a some percent level-would allow to greatly improve, among (many) other things, the present-day (10^-13) level of accuracy in testing the equivalence principle as well. Recent claims point towards even two orders of magnitude better, i.e. 10^-15. In this note we show that such a goal is, in fact, unattainable by many orders of magnitude being, instead, the achievable level of the order of 10^-9.Comment: LaTex, 4 pages, no figures, no tables, 26 references. Proofs corrections included. To appear in EPL (Europhysics Letters

Particle acoustic detection in gravitational wave aluminum resonant antennas

The results on cosmic rays detected by the gravitational antenna NAUTILUS have motivated an experiment (RAP) based on a suspended cylindrical bar, which is made of the same aluminum alloy as NAUTILUS and is exposed to a high energy electron beam. Mechanical vibrations originate from the local thermal expansion caused by warming up due to the energy lost by particles crossing the material. The aim of the experiment is to measure the amplitude of the fundamental longitudinal vibration at different temperatures. We report on the results obtained down to a temperature of about 4 K, which agree at the level of about 10% with the predictions of the model describing the underlying physical process.Comment: RAP experiment, 16 pages, 7 figure

Modeling the impact of sea-spray on particle concentrations in a coastal city

An atmospheric chemistry-transport model is used to assess the impacts of sea-spray chemistry on the particle composition in and downwind of a coastal city--Vancouver, British Columbia. Reactions in/on sea-spray affect the entire particle ensemble and particularly the size distribution of particle nitrate. Urban air quality, and particularly airborne particles, is a major concern in terms of human health impacts. Sea-spray is known to be a major component of the particle ensemble at coastal sites yet relatively few air quality models include the interaction of gases with sea-spray and the fate of the particles produced. Sea-spray is not an inert addition to the particle ensemble because heterogeneous chemistry in/on sea-spray droplets changes the droplets composition and the particle size distribution, which impacts deposition and the ion balance in different particle size fractions. It is shown that the ISOPART model is capable of simulating gas and particle concentrations in the coastal metropolis of Vancouver and the surrounding valley. It is also demonstrated that to accurately simulate ambient concentrations of particles and reactive/soluble gases in a coastal valley it is absolutely critical to include heterogeneous chemistry in/on sea-spray. Partitioning of total particle-NO{sub 3}{sup -} between sea-spray and NH{sub 4}NO{sub 3} is highly sensitive to the amount of sea-spray present, and hence the initial vertical profile, sea-spray source functions [48] and the wind speed. When a fixed wind speed is used to initialize the sea-spray vertical profiles, as expected, the sea-spray concentration decays with distance inland, but the particle-NO{sub 3}{sup -} concentration decays more slowly because it is also a function of the uptake rate for HNO{sub 3}. The simulation results imply model analyses of air quality in coastal cities conducted without inclusion of sea-spray interactions may yield highly misleading results in terms of emission sensitivities of the PM size distribution. The sensitivity of the model results to the initial sea spray profile further suggests there would be great benefit in better definition of the vertical profile of size resolved sea-spray for use in such model studies

KLASH Conceptual Design Report

The axion, a pseudoscalar particle originally introduced by Peccei, Quinn [1, 2], Weinberg [3], and Wilczek [4] to solve the "strong CP problem", is a well motivated dark-matter (DM) candidate with a mass lying in a broad range from peV to few meV [5]. The last decade witnessed an increasing interest in axions and axion-like particles with many theoretical works published and many new experimental proposals [6] that started a real race towards their discovery. Driven by this new challenge and stimulated by the availability, at the Laboratori Nazionali di Frascati (LNF), of large superconducting magnets previously used for particle detectors [7, 8] at the DAFNE collider, we proposed to build a large haloscope [9] to observe galactic axions in the mass window between 0.2 and 1 µeV [10]. This paper is the Conceptual Design Report (CDR) of the KLASH (KLoe magnet for Axion SearcH) experiment, designed having in mind the performance and dimensions of the KLOE magnet, a large volume superconducting magnet with a moderate magnetic field of 0.6 T. In the first part of this Report we discuss the physics case of KLASH, the theoretical motivation for an axion in the mass window 0.1÷1µeV based on a review of standard and non-standard axion-cosmology (Sec. 1), and the physics reach of the KLASH experiment (Sec. 2), including both the sensitivity to QCD axions and to Dark-Photon DM. The sensitivity plots are based on the detector performance discussed in the second part of the CDR. Here, we summarize the results obtained with calculations and simulations of several aspects of the experiment: the mechanical construction of cryostat and cavity based on the study commissioned to the mechanical engineers of the Fantini-Sud company [11] (Sec. 3); the cryogenics plant (Sec. 4); the RF cavity design and tuning based on detailed simulations with code Ansys-HFSS (Sec. 5); the signal amplification, in particular the first stage based on a Microstrip SQUID Amplifier (Sec. 6). Finally, in Sec. 7, mainly based on the experience of existing experiments [12–14], we discuss the data taking, analysis procedure and computing requirements. The main conclusion we draw from this report is the possibility to build and put in operation at LNF in 2-3 years a large haloscope with the sensitivity to KSVZ axions in the low mass range between 0.2 and 1µeV in a region complementary to that of other experiments with a cost of about 3 MAC. Timeline and cost are competitive with respect to other proposals in the same mass region [15, 16] thanks to the availability of most of the infrastructure, in particular the superconducting magnet and the cryogenics plant. During the writing of this CDR, in July 2019, we were informed about the decision of INFN management to devote the KLOE magnet to the DUNE experiment at Fermilab. The KLOE magnet has always been the preferred choice for several reasons: it was in operation until 2018; its mechanical structure is able to support the several-tons weight of the cryostat and cavity; it is placed in the KLOE assembly-hall that can be used as the experimental area of KLASH. However, another option is given by the FINUDA magnet. The are few aspects to be explored (mechanical strength, move to experimental area, put in operation after more than 10 years), but it has a higher nominal field of 1.1 T in a large volume with an inner radius 1385 mm and length 3800 mm. A preliminary estimate of sensitivity to axions of FLASH, the haloscope built with the FINUDA magnet, gives results similar to those obtained for KLASH. This option will be eventually investigated in another document

Proposal for taking data with the KLOE-2 detector at the DAΦ\PhiNE collider upgraded in energy

This document reviews the physics program of the KLOE-2 detector at DA$\Phi$NE upgraded in energy and provides a simple solution to run the collider above the $\phi$-peak (up to 2, possibly 2.5 GeV). It is shown how a precise measurement of the multihadronic cross section in the energy region up to 2 (possibly 2.5) GeV would have a major impact on the tests of the Standard Model through a precise determination of the anomalous magnetic moment of the muon and the effective fine-structure constant at the $M_Z$ scale. With a luminosity of about $10^{32}$cm$^{-2}$s$^{-1}$, DA$\Phi$NE upgraded in energy can perform a scan in the region from 1 to 2.5 GeV in one year by collecting an integrated luminosity of 20 pb$^{-1}$ (corresponding to a few days of data taking) for single point, assuming an energy step of 25 MeV. A few years of data taking in this region would provide important tests of QCD and effective theories by $\gamma\gamma$ physics with open thresholds for pseudo-scalar (like the $\eta'$), scalar ($f_0,f'_0$, etc...) and axial-vector ($a_1$, etc...) mesons; vector-mesons spectroscopy and baryon form factors; tests of CVC and searches for exotics. In the final part of the document a technical solution for the energy upgrade of DA$\Phi$NE is proposed.Comment: 19 pages, 8 figure

In vitro cytotoxic screening of coumarins

This study reports the cytotoxicity screening of 33 coumarins in a panel of human tumor cell lines (Caco-2: human colorectal adenocarcinoma, HCT-8: human ileocecal adenocarcinoma, and HEp-2: human larynx epidermoid carcinoma). The classic MTT assay was employed to evaluate the influence of samples on cellular viability. Following continuous incubation with cells for 72 h, all tested coumarins exhibited CC50 values ≥ 0.34 mM for all three cell lines. These findings indicate that all samples were not able to reduce the viability of tumor cell lines used in this study in clinically relevant concentrations. Some structure-activity relationships were established and could be used for the synthesis of derivatives with improved cytotoxic potential.Colegio de Farmacéuticos de la Provincia de Buenos Aire