Apigenin, by activating p53 and inhibiting STAT3, modulates the balance between pro-apoptotic and pro-survival pathways to induce PEL cell death

BACKGROUND: Apigenin is a flavonoid widely distributed in plant kingdom that exerts cytotoxic effects against a variety of solid and haematological cancers. In this study, we investigated the effect of apigenin against primary effusion lymphoma (PEL), a KSHV-associated B cell lymphoma characterized by a very aggressive behavior, displaying constitutive activation of STAT3 as well as of other oncogenic pathways and harboring wtp53. METHODS: Cell death was assessed by trypan blue exclusion assay, FACS analysis as well as by biochemical studies. The latter were also utilized to detect the occurrence of autophagy and the molecular mechanisms leading to the activation of both processes by apigenin. FACS analysis was used to measure the intracellular ROS utilizing DCFDA. RESULTS: We show that apigenin induced PEL cell death and autophagy along with reduction of intracellular ROS. Mechanistically, apigenin activated p53 that induced catalase, a ROS scavenger enzyme, and inhibited STAT3, the most important pro-survival pathway in PEL, as assessed by p53 silencing. On the other hand, STAT3 inhibition by apigenin resulted in p53 activation, since STAT3 negatively influences p53 activity, highlighting a regulatory loop between these two pathways that modulates PEL cell death/survival. CONCLUSION: The findings of this study demonstrate that apigenin may modulate pro-apoptotic and pro-survival pathways representing a valid therapeutic strategy against PEL

Lithium abundances in red giants of M4: evidence for asymptotic giant branch star pollution in globular clusters?

The determination of Li and proton-capture element abundances in globular cluster (GC) giants allows us to constrain several key questions on the multiple population scenarios in GCs, from formation and early evolution, to pollution and dilution mechanisms. In this Letter, we present our results on Li abundances for a large sample of giants in the intermediate-metallicity GC NGC 6121 (M4), for which Na and O have been already determined by Marino et al. The stars analyzed are both below and above the red giant branch bump luminosity. We found that the first and second generation stars share the same Li content, suggesting that a Li production must have occurred. This is a strong observational evidence providing support for the scenario in which asymptotic giant branch stars are GC polluters.Comment: updated version after proo

Cytotoxic drugs activate KSHV lytic cycle in latently infected PEL cells by inducing a moderate ROS increase controlled by HSF1, NRF2 and p62/SQSTM1

Previous studies have indicated that cytotoxic treatments may induce or not activate viral lytic cycle activation in cancer cells latently infected by Kaposi’s sarcoma-associated herpesvirus (KSHV). To investigate the molecular mechanisms responsible for such an effect, we compared two cytotoxic treatments able to induce the viral lytic cycle, named 12-O-tetradecanoylphorbol 13-acetate (TPA) (T) in combination with sodium butyrate (B) and bortezomib (BZ), with two cytotoxic treatments that did not activate this process, named metformin (MET) and quercetin (Q). Our results indicated that TB and bortezomib increased levels of oxygen reactive species (ROS) while metformin and quercetin reduced them. The finding that N-acetylcysteine (NAC), a reactive oxigen species (ROS) scavenger, counteracted K-bZIP expression induced by TB or bortezomib, confirmed that an ROS increase played a role in KSHV lytic cycle activation. Moreover, we found that TB and bortezomib up-regulated p62/Sequestosome1(p62/SQSTM1) protein, while metformin and quercetin down-regulated it. p62/SQSTM1 silencing or the inhibition of NF-E2-related factor 2 (NRF2) or Heat Shock Factor 1 (HSF1), that mediate p62/SQSTM1 transcription, also reduced KSHV lytic antigen expression induced by TB or bortezomib. Interestingly, such combination treatments further increased intracellular ROS and cytotoxicity induced by the single TB or bortezomib treatment, suggesting that NRF2, HSF1 and p62/SQSTM1 keep the ROS level under control, allowing primary effusion lymphoma (PEL) cells to continue to survive and KSHV to replicate

The chemical composition of nearby young associations: s-process element abundances in AB Doradus, Carina-Near, and Ursa Major

Recently, several studies have shown that young, open clusters are characterised by a considerable over-abundance in their barium content. In particular, D'Orazi et al. (2009) reported that in some younger clusters [Ba/Fe] can reach values as high as ~0.6 dex. The work also identified the presence of an anti-correlation between [Ba/Fe] and cluster age. For clusters in the age range ~4.5 Gyr-500 Myr, this is best explained by assuming a higher contribution from low-mass asymptotic giant branch stars to the Galactic chemical enrichment. The purpose of this work is to investigate the ubiquity of the barium over-abundance in young stellar clusters. We analysed high-resolution spectroscopic data, focusing on the s-process elemental abundance for three nearby young associations, i.e. AB Doradus, Carina-Near, and Ursa Major. The clusters have been chosen such that their age spread would complement the D'Orazi et al. (2009) study. We find that while the s-process elements Y, Zr, La, and Ce exhibit solar ratios in all three associations, Ba is over-abundant by ~0.2 dex. Current theoretical models can not reproduce this abundance pattern, thus we investigate whether this unusually large Ba content might be related to chromospheric effects. Although no correlation between [Ba/Fe] and several activity indicators seems to be present, we conclude that different effects could be at work which may (directly or indirectly) be related to the presence of hot stellar chromospheres.Comment: Accepted for publication in MNRA

Elemental abundances of low-mass stars in the young clusters 25 Ori and lambda Ori

Aims. We aim to derive the chemical pattern of the young clusters 25 Orionis and lambda Orionis through homogeneous and accurate measurements of elemental abundances. Methods. We present FLAMES/UVES observations of a sample of 14 K-type targets in the 25 Ori and lambda Ori clusters; we measure their radial velocities, in order to confirm cluster membership. We derive stellar parameters and abundances of Fe, Na, Al, Si, Ca, Ti, and Ni using the code MOOG. Results. All the 25 Ori stars are confirmed cluster members without evidence of binarity; in lambda Ori we identify one non-member and one candidate single-lined binary star. We find an average metallicity [Fe/H]=-0.05+/-0.05 for 25 Ori, where the error is the 1sigma standard deviation from the average. lambda Ori members have a mean iron abundance value of 0.01+/-0.01. The other elements show close-to-solar ratios and no star-to-star dispersion. Conclusions. Our results, along with previous metallicity determinations in the Orion complex, evidence a small but detectable dispersion in the [Fe/H] distribution of the complex. This appears to be compatible with large-scale star formation episodes and initial non-uniformity in the pre-cloud medium. We show that, as expected, the abundance distribution of star forming regions is consistent with the chemical pattern of the Galactic thin disk.Comment: Accepted by Astronomy and Astrophysics. 14 pages, 10 figures, 7 table

The Complex Behaviour of s-Process Element Abundances at Young Ages

Open clusters appear as simple objects in many respects, with a high degree of homogeneity in their (initial) chemical composition, and the typical solar-scaled abundance pattern that they exhibit for the majority of the chemical species. The striking singularity is represented by heavy elements produced from the slow process of the neutron-capture reactions. In particular, young open clusters (ages less than a few hundred Myr) give rise to the so-called barium puzzle: that is an extreme enhancement in their [Be/Fe] ratios, up to a factor of four of the solar value, which is not followed by other nearby s-process elements (e.g., lanthanum and cerium). The definite explanation for such a peculiar trend is still wanting, as many different solutions have been envisaged. We review the status of this field and present our new results on young open clusters and the pre-main sequence star RZ Piscium

Li - O anti-correlation in NGC 6752: evidence for Li-enriched polluting gas

Elemental correlations and anti-correlations are known to be present in globular clusters (GCs) owing to pollution by CNO cycled gas. Because of its fragility Li is destroyed at the temperature at which the CNO cycling occurs, and this makes Li a crucial study for the nature of the contaminating stars. We observed 112 un-evolved stars at the Turnoff of the NGC6752 cluster with FLAMES at the VLT to investigate the presence and the extent of a Li-O correlation. This correlation is expected if there is a simple pollution scenario. Li (670.8 nm) and O triplet (771 nm) abundances are derived in NLTE. All stars belong to a very narrow region of the color-magnitude diagram, so they have similar stellar parameters (Teff, log g). We find that O and Li correlate, with a high statistical significance that confirms the early results for this cluster. At first glance this is what is expected if a simple pollution of pristine gas with CNO cycled gas (O-poor, Li-poor) occurred. The slope of the relationship, however, is about 0.4, and differs from unity by over 7 Sigma. A slope of one is the value predicted for a pure contamination model. We confirm an extended Li-O correlation in non evolved stars of NGC 6752. At the same time the characteristic of the correlation shows that a simple pollution scenario is not sufficient to explain the observations. Within this scenario the contaminant gas must have been enriched in Li. This would rule out massive stars as main polluters, and favor the hypothesis that the polluting gas was enriched by intermediate or high-mass AGB stars, unless the former can be shown to be able to produce Li. According to our observations, the fraction of polluting gas contained in the stars observed is a considerable fraction of the stellar mass of the cluster.Comment: 8pages, 2 figures, accepted by A&A Lette

The debris disk host star HD 61005: a member of the Argus Association?

HD 61005 is a nearby young solar type star that shows a large infrared excess due to a debris disk. The disk has been recently imaged from ground and space, with indications of several components. Some characteristics of the disk suggest the presence of planetary companions around the star, that remain undetected in deep adaptive optics imaging. For a better understanding of the system we aim to refine the determination of the stellar parameters, with emphasis on the stellar age and system orientation. We used ASAS and Hipparcos photometry and FEROS spectra to determine the rotation period, radial and rotational velocity, chromospheric emission, effective temperature, and chemical composition. We find no indication of any misalignment between the star rotation axis and the disk. The standard age calibrations applied to several indicators yield an age close to that of the Pleiades (120 Myr); however the kinematic properties strongly support its membership in the younger (40 Myr) Argus association, which also includes the IC 2391 open cluster. Detailed comparison of the properties of HD 61005 and IC 2391 members shows that the characteristics of HD 61005 are compatible with membership to the Argus association, once its rather slow rotation is taken into account, because lithium and other age indicators are somewhat correlated with stellar rotation at a fixed age. We also identify systematic differences between the field and cluster population of the Argus association, which are probably selection effects, so we suggest that additional members with slower rotation and lower activity level are waiting to be identified.Comment: A&A, in press, 13 pages, 11 figure

Chemical composition of the Taurus-Auriga association

The Taurus-Auriga association is perhaps the most famous prototype of a low-mass star forming region, surveyed at almost all wavelengths. Unfortunately, like several other young clusters/associations, this T association lacks an extensive abundance analysis determination. We present a high-resolution spectroscopic study of seven low-mass members of Taurus-Auriga, including both weak-lined and classical T Tauri stars designed to help robustly determine their metallicity. After correcting for spectral veiling, we performed equivalent width and spectral synthesis analyses using the GAIA set of model atmospheres and the 2002 version of the code MOOG. We find a solar metallicity, obtaining a mean value of [Fe/H]=$-0.01\pm$0.05. The $\alpha$-element Si and the Fe-peak one Ni confirm a solar composition. Our work shows that the dispersion among members is well within the observational errors at variance with previous claims. As in other star forming regions, no metal-rich members are found, reinforcing the idea that old planet-host stars form in the inner part of the Galactic disc and subsequently migrate.Comment: In press on A\&

Chemical pattern across the young associations ONC and OB1b

Context. Abundances of iron-peak and alpha-elements are poorly known in Orion, and the available measurements yield contradictory results. Aims. We measure accurate and homogeneous elemental abundances of the Orion subgroups ONC and OB1b, and search for abundance differences across the Orion complex. Methods. We present FLAMES/UVES spectroscopic observations of 20 members of the ONC and OB1b. We measured radial velocity, veiling, effective temperature using two spectroscopic methods, and determined the chemical abundances of Fe, Na, Al, Si, Ca, Ti, and Ni using the code MOOG. We also performed a new consistent analysis of spectra previously analyzed by our group. Results. We find three new binaries in the ONC, two in OB1b, and three non-members in OB1b (two of them most likely being OB1a/25 Ori members). Veiling only affects one target in the ONC, and the effective temperatures derived using two spectroscopic techniques agree within the errors. The ONC and OB1b are characterized by a small scatter in iron abundance, with mean [Fe/H] values of -0.11+/-0.08 and -0.05+/-0.05, respectively. We find a small scatter in all the other elemental abundances. We confirm that P1455 is a metal-rich star in the ONC. Conclusions. We conclude that the Orion metallicity is not above the solar value. The OB1b group might be slightly more metal-rich than the ONC; on the other hand, the two subgroups have similar almost solar abundances of iron-peak and alpha-elements with a high degree of homogeneity.Comment: Accepted by Astronomy and Astrophysics. 16 figures, 8 table