Meroterpenoids from the Brown Alga Cystoseira usneoides as Potential Anti-Inflammatory and Lung Anticancer Agents

The anti-inflammatory and anticancer properties of eight meroterpenoids isolated from the brown seaweed Cystoseira usneoides have been evaluated. The algal meroterpenoids (AMTs) 1-8 were tested for their inhibitory effects on the production of the pro-inflammatory cytokines tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta), and the expression of cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in LPS-stimulated THP-1 human macrophages. The anticancer effects were assessed by cytotoxicity assays against human lung adenocarcinoma A549 cells and normal lung fibroblastic MRC-5 cells, together with flow cytometry analysis of the effects of these AMTs on different phases of the cell cycle. The AMTs 1-8 significantly reduced the production of TNF-alpha, IL-6, and IL-1 beta, and suppressed the COX-2 and iNOS expression, in LPS-stimulated cells (p < 0.05). The AMTs 1-8 displayed higher cytotoxic activities against A549 cancer cells than against MRC-5 normal lung cells. Cell cycle analyses indicated that most of the AMTs caused the arrest of A549 cells at the G2/M and S phases. The AMTs 2 and 5 stand out by combining significant anti-inflammatory and anticancer activities, while 3 and 4 showed interesting selective anticancer effects. These findings suggest that the AMTs produced by C. usneoides may have therapeutic potential in inflammatory diseases and lung cancer

Biological Evaluation and Docking Studies of Synthetic Oleananetype Triterpenoids

Saponins are potential wide-spectrum antitumor drugs, and copper(I) catalyzed azide−alkyne 1,3-dipolar cycloaddition is a suitable approach to synthesizing saponinlike compounds by regioselective glycosylation of the C2/C3 hydroxyl and C28 carboxylic groups of triterpene aglycones maslinic acid (MA) and oleanolic acid (OA). Biological studies on the T-84 human colon carcinoma cell line support the role of the hydroxyl groups at C2/C3, the influence of the aglycone, and the bulky nature of the substituents in C28. OA bearing a α-D-mannose moiety at C28 (compound 18) focused our interest because the estimated inhibitory concentration 50 was similar to that reported for ginsenoside Rh2 against colon cancer cells and it inhibits the G1−S phase transition affecting the cell viability and apoptosis. Considering that triterpenoids from natural sources have been identified as inhibitors of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling, docking studies were conducted to evaluate whether NF-κB may be a potential target. Results are consistent with the biological study and predict a similar binding mode of MA and compound 18 to the p52 subunit from NF- κB but not for OA. The fact that the binding site is shared by the NF-κB inhibitor 6,6-dimethyl-2-(phenylimino)-6,7- dihydrobenzo[d][1,3]oxathiol-4(5H)-one supports the result and points to NF-κB as a potential target of both MA and compound 18.This work was supported by a grant from Ramón Areces Foundation (Madrid, Spain) and by grant CTQ2014-55474- C2-1-R from the Spanish Ministerio de Economia y Competitividad (MINECO) co-financed by FEDER funds

Mitochondrial Stress Links Environmental Triggers with Pro-Inflammatory Signaling in Crohn's Disease

Inflammatory Bowel Diseases (IBD) are a group of chronic, inflammatory disorders of the gut. The incidence and activity of IBD are determined by both genetic and environmental factors. Among these factors, polymorphisms in genes related to autophagy and the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have been consistently associated with IBD. We show that NSAIDs induce mitochondrial stress and mitophagy in intestinal epithelial cells. In an altered mitophagy context simulating that observed in IBD patients, NSAID-induced mitochondrial stress leads to the release of mitochondrial components, which act as Danger Associated Molecular Patterns with pro-inflammatory potential. Furthermore, colonic organoids from Crohn's disease patients and healthy donors show activation of the mitochondrial Unfolded Protein Response (UPRmt) upon treatment with ibuprofen. Finally, colon biopsies from Crohn's disease patients in remission or with low-to-moderate activity also show expression of genes involved in UPRmt, while patients with severe activity show no increase compared to healthy donors. Our results suggest the involvement of mitochondria in the mechanisms triggering inflammation in IBD after NSAID use. Moreover, our results highlight the clinical relevance of mitochondrial stress and activation of the UPRmt pathway in the pathophysiology of Crohn's disease

The unidentified TeV source (TeVJ2032+4130) and surrounding field: Final HEGRA IACT-System results

The unidentified TeV source in Cygnus is now confirmed by follow-up observations from 2002 with the HEGRA stereoscopic system of Cherenkov Telescopes. Using all data (1999 to 2002) we confirm this new source as steady in flux over the four years of data taking, extended with radius 6.2 arcmin (+-1.2 arcmin (stat) +-0.9 arcmin (sys)) and exhibiting a hard spectrum with photon index -1.9. It is located in the direction of the dense OB stellar association, Cygnus OB2. Its integral flux above energies E>1 TeV amounts to \~5% of the Crab assuming a Gaussian profile for the intrinsic source morphology. There is no obvious counterpart at radio, optical nor X-ray energies, leaving TeVJ2032+4130 presently unidentified. Observational parameters of this source are updated here and some astrophysical discussion is provided. Also included are upper limits for a number of other interesting sources in the FoV, including the famous microquasar Cygnus X-3.Comment: 7 pages, 3 figures. Accepted for publication in Astronomy & Astrophysic

First bounds on the high-energy emission from isolated Wolf-Rayet binary systems

High-energy gamma-ray emission is theoretically expected to arise in tight binary star systems (with high mass loss and high velocity winds), although the evidence of this relationship has proven to be elusive so far. Here we present the first bounds on this putative emission from isolated Wolf-Rayet (WR) star binaries, WR 147 and WR 146, obtained from observations with the MAGIC telescope.Comment: (Authors are the MAGIC Collaboration.) Manuscript in press at The Astrophysical Journal Letter

Unfolding of differential energy spectra in the MAGIC experiment

The paper describes the different methods, used in the MAGIC experiment, to unfold experimental energy distributions of cosmic ray particles (gamma-rays). Questions and problems related to the unfolding are discussed. Various procedures are proposed which can help to make the unfolding robust and reliable. The different methods and procedures are implemented in the MAGIC software and are used in most of the analyses.Comment: Submitted to NIM

Implementation of the Random Forest Method for the Imaging Atmospheric Cherenkov Telescope MAGIC

The paper describes an application of the tree classification method Random Forest (RF), as used in the analysis of data from the ground-based gamma telescope MAGIC. In such telescopes, cosmic gamma-rays are observed and have to be discriminated against a dominating background of hadronic cosmic-ray particles. We describe the application of RF for this gamma/hadron separation. The RF method often shows superior performance in comparison with traditional semi-empirical techniques. Critical issues of the method and its implementation are discussed. An application of the RF method for estimation of a continuous parameter from related variables, rather than discrete classes, is also discussed.Comment: 16 pages, 8 figure

Upper limit for gamma-ray emission above 140 GeV from the dwarf spheroidal galaxy Draco

The nearby dwarf spheroidal galaxy Draco with its high mass to light ratio is one of the most auspicious targets for indirect dark matter searches. Annihilation of hypothetical DM particles can result in high-energy gamma-rays, e.g. from neutralino annihilation in the supersymmetric framework. With the MAGIC telescope a search for a possible DM signal originating from Draco was performed during 2007. The analysis of the data results in a flux upper limit of 1.1x10^-11 photons cm^-2 sec^-1 for photon energies above 140 GeV, assuming a point like source. Furthermore, a comparison with predictions from supersymmetric models is given. While our results do not constrain the mSUGRA phase parameter space, a very high flux enhancement can be ruled out.Comment: Accepted for publication by Astrophysical Journa

Discovery of Very High Energy gamma-rays from 1ES 1011+496 at z=0.212

We report on the discovery of Very High Energy (VHE) gamma-ray emission from the BL Lacertae object 1ES1011+496. The observation was triggered by an optical outburst in March 2007 and the source was observed with the MAGIC telescope from March to May 2007. Observing for 18.7 hr we find an excess of 6.2 sigma with an integrated flux above 200 GeV of (1.58$\pm0.32) 10^{-11}$ photons cm$^{-2}$ s$^{-1}$. The VHE gamma-ray flux is >40% higher than in March-April 2006 (reported elsewhere), indicating that the VHE emission state may be related to the optical emission state. We have also determined the redshift of 1ES1011+496 based on an optical spectrum that reveals the absorption lines of the host galaxy. The redshift of z=0.212 makes 1ES1011+496 the most distant source observed to emit VHE gamma-rays up to date.Comment: 4 pages, 6 figures, minor changes to fit the ApJ versio

MAGIC observations of very high energy gamma-rays from HESS J1813-178

Recently, the HESS collaboration has reported the detection of gamma-ray emission above a few hundred GeV from eight new sources located close to the Galactic Plane. The source HESS J1813-178 has sparked particular interest, as subsequent radio observations imply an association with SNR G12.82-0.02. Triggered by the detection in VHE gamma-rays, a positionally coincident source has also been found in INTEGRAL and ASCA data. In this Letter we present MAGIC observations of HESS J1813-178, resulting in the detection of a differential gamma-ray flux consistent with a hard-slope power law, described as dN/(dA dt dE) = (3.3+/-0.5)*10^{-12} (E/TeV)^{-2.1+/-0.2} cm^(-2)s^(-1)TeV^(-1). We briefly discuss the observational technique used, the procedure implemented for the data analysis, and put this detection in the perspective of multifrequency observations.Comment: Accepted by ApJ Letter