Proapoptotic activity of Ukrain is based on Chelidonium majus L. alkaloids and mediated via a mitochondrial death pathway

BACKGROUND: The anticancer drug Ukrain (NSC-631570) which has been specified by the manufacturer as semisynthetic derivative of the Chelidonium majus L. alkaloid chelidonine and the alkylans thiotepa was reported to exert selective cytotoxic effects on human tumour cell lines in vitro. Few clinical trials suggest beneficial effects in the treatment of human cancer. Aim of the present study was to elucidate the importance of apoptosis induction for the antineoplastic activity of Ukrain, to define the molecular mechanism of its cytotoxic effects and to identify its active constituents by mass spectrometry. METHODS: Apoptosis induction was analysed in a Jurkat T-lymphoma cell model by fluorescence microscopy (chromatin condensation and nuclear fragmentation), flow cytometry (cellular shrinkage, depolarisation of the mitochondrial membrane potential, caspase-activation) and Western blot analysis (caspase-activation). Composition of Ukrain was analysed by mass spectrometry and LC-MS coupling. RESULTS: Ukrain turned out to be a potent inducer of apoptosis. Mechanistic analyses revealed that Ukrain induced depolarisation of the mitochondrial membrane potential and activation of caspases. Lack of caspase-8, expression of cFLIP-L and resistance to death receptor ligand-induced apoptosis failed to inhibit Ukrain-induced apoptosis while lack of FADD caused a delay but not abrogation of Ukrain-induced apoptosis pointing to a death receptor independent signalling pathway. In contrast, the broad spectrum caspase-inhibitor zVAD-fmk blocked Ukrain-induced cell death. Moreover, over-expression of Bcl-2 or Bcl-x(L )and expression of dominant negative caspase-9 partially reduced Ukrain-induced apoptosis pointing to Bcl-2 controlled mitochondrial signalling events. However, mass spectrometric analysis of Ukrain failed to detect the suggested trimeric chelidonine thiophosphortriamide or putative dimeric or monomeric chelidonine thiophosphortriamide intermediates from chemical synthesis. Instead, the Chelidonium majus L. alkaloids chelidonine, sanguinarine, chelerythrine, protopine and allocryptopine were identified as major components of Ukrain. Apart from sanguinarine and chelerythrine, chelidonine turned out to be a potent inducer of apoptosis triggering cell death at concentrations of 0.001 mM, while protopine and allocryptopine were less effective. Similar to Ukrain, apoptosis signalling of chelidonine involved Bcl-2 controlled mitochondrial alterations and caspase-activation. CONCLUSION: The potent proapoptotic effects of Ukrain are not due to the suggested "Ukrain-molecule" but to the cytotoxic efficacy of Chelidonium majus L. alkaloids including chelidonine

Collider aspects of flavour physics at high Q

This review presents flavour related issues in the production and decays of heavy states at LHC, both from the experimental side and from the theoretical side. We review top quark physics and discuss flavour aspects of several extensions of the Standard Model, such as supersymmetry, little Higgs model or models with extra dimensions. This includes discovery aspects as well as measurement of several properties of these heavy states. We also present public available computational tools related to this topic.Comment: Report of Working Group 1 of the CERN Workshop ``Flavour in the era of the LHC'', Geneva, Switzerland, November 2005 -- March 200

On the Anisotropy of the Ductile to Brittle Transition Behavior in a Wrought and in Two Oxide Dispersion Strengthened FeCrAl Steels

The directionality of the ductile-brittle transition behavior of two oxide-dispersion-strengthened (ODS) FeCrAl steels with similar chemical compositions, tensile properties, and sub-micrometric grain sizes but different processing routes, and a Zr-particle strengthened FeCrAl steel manufactured by high vacuum melting is discussed. Despite the similarities of the ODS FeCrAl steels, strong differences in the lower and upper shelf energy and the ductile to brittle transition temperature were observed for longitudinal through thickness notched specimens. Although the lower and upper shelf energies of longitudinal surface-notched specimens of ODS FeCrAl steels are similar, a strong difference in the ductile-to-brittle transition temperature is observed. For through-thickness notched and surface-notched specimens taken transversely, the analyzed ODS FeCrAl steels show a similar ductile-to-brittle behavior. In general, the FeCrAl alloy strengthened with Zr-particles presents a more isotropic behavior and a higher ductile-to-brittle transition temperature than the ODS FeCrAl steels. In addition, the upper shelf energy of the FeCrAl steel strengthened with Zr-particles is significantly higher than that of the ODS FeCrAl steels.The authors acknowledge financial support to Spanish Ministerio de Economia y Competitividad (MINECO) in the form of a Coordinate Project (MAT2016-80875-C3-1-R). The authors are grateful for the dilatometer tests by Phase Transformation laboratory. This work contributes to the Joint Programme on Nuclear Materials (JPNM) of the European Energy Research Alliance (EERA).Peer Reviewe