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891.
Alessandra De Robertis Federica Mennillo Marco Rossi Silvia Valensin Patrizia Tunici Elisa Mori Nicola Caradonna Maurizio Varrone Massimiliano Salerno 《PloS one》2014,9(5)
Sarcomas are mesenchymal tumors showing high molecular heterogeneity, reflected at the histological level by the existence of more than fifty different subtypes. Genetic and epigenetic evidences link aberrant activation of the Wnt signaling to growth and progression of human sarcomas. This phenomenon, mainly accomplished by autocrine loop activity, is sustained by gene amplification, over-expression of Wnt ligands and co-receptors or epigenetic silencing of endogenous Wnt antagonists. We previously showed that pharmacological inhibition of Wnt signaling mediated by Axin stabilization produced in vitro and in vivo antitumor activity in glioblastoma tumors. Here, we report that targeting different sarcoma cell lines with the Wnt inhibitor/Axin stabilizer SEN461 produces a less transformed phenotype, as supported by modulation of anchorage-independent growth in vitro. At the molecular level, SEN461 treatment enhanced the stability of the scaffold protein Axin1, a key negative regulator of the Wnt signaling with tumor suppressor function, resulting in downstream effects coherent with inhibition of canonical Wnt signaling. Genetic phenocopy of small molecule Axin stabilization, through Axin1 over-expression, coherently resulted in strong impairment of soft-agar growth. Importantly, sarcoma growth inhibition through pharmacological Axin stabilization was also observed in a xenograft model in vivo in female CD-1 nude mice. Our findings suggest the usefulness of Wnt inhibitors with Axin stabilization activity as a potentialyl clinical relevant strategy for certain types of sarcomas. 相似文献
892.
Ilaria Naldi Monia Taranta Lisa Gherardini Gualtiero Pelosi Federica Viglione Settimio Grimaldi Luca Pani Caterina Cinti 《PloS one》2014,9(5)
Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2′-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours. 相似文献
893.
Federica Prati Adele Goldman-Pinkovich Federica Lizzi Federica Belluti Roni Koren Dan Zilberstein Maria Laura Bolognesi 《PloS one》2014,9(9)
The aim of the present study was to investigate the feasibility of targeting Leishmania transporters via appropriately designed chemical probes. Leishmania donovani, the parasite that causes visceral leishmaniasis, is auxotrophic for arginine and lysine and has specific transporters (LdAAP3 and LdAAP7) to import these nutrients. Probes 1–15 were originated by conjugating cytotoxic quinone fragments (II and III) with amino acids (i.e. arginine and lysine) by means of an amide linkage. The toxicity of the synthesized conjugates against Leishmania extracellular (promastigotes) and intracellular (amastigotes) forms was investigated, as well their inhibition of the relevant amino acid transporters. We observed that some conjugates indeed displayed toxicity against the parasites; in particular, 7 was identified as the most potent derivative (at concentrations of 1 µg/mL and 2.5 µg/mL residual cell viability was reduced to 15% and 48% in promastigotes and amastigotes, respectively). Notably, 6, while retaining the cytotoxic activity of quinone II, displayed no toxicity against mammalian THP1 cells. Transport assays indicated that the novel conjugates inhibited transport activity of lysine, arginine and proline transporters. Furthermore, our analyses suggested that the toxic conjugates might be translocated by the transporters into the cells. The non-toxic probes that inhibited transport competed with the natural substrates for binding to the transporters without being translocated. Thus, it is likely that 6, by exploiting amino acid transporters, can selectively deliver its toxic effects to Leishmania cells. This work provides the first evidence that amino acid transporters of the human pathogen Leishmania might be modulated by small molecules, and warrants their further investigation from drug discovery and chemical biology perspectives. 相似文献
894.
Alessandro Ghezzo Stefano Salvioli Maria Caterina Solimando Alice Palmieri Chiara Chiostergi Maria Scurti Laura Lomartire Federica Bedetti Guido Cocchi Daniela Follo Emanuela Pipitone Paolo Rovatti Jessica Zamberletti Tiziano Gomiero Gastone Castellani Claudio Franceschi 《PloS one》2014,9(11)
Down Syndrome (DS) is characterised by premature aging and an accelerated decline of cognitive functions in the vast majority of cases. As the life expectancy of DS persons is rapidly increasing, this decline is becoming a dramatic health problem. The aim of this study was to thoroughly evaluate a group of 67 non-demented persons with DS of different ages (11 to 66 years), from a neuropsychological, neuropsychiatric and psychomotor point of view in order to evaluate in a cross-sectional study the age-related adaptive and neuropsychological features, and to possibly identify early signs predictive of cognitive decline. The main finding of this study is that both neuropsychological functions and adaptive skills are lower in adult DS persons over 40 years old, compared to younger ones. In particular, language and short memory skills, frontal lobe functions, visuo-spatial abilities and adaptive behaviour appear to be the more affected domains. A growing deficit in verbal comprehension, along with social isolation, loss of interest and greater fatigue in daily tasks, are the main features found in older, non demented DS persons evaluated in our study. It is proposed that these signs can be alarm bells for incipient dementia, and that neuro-cognitive rehabilitation and psycho-pharmacological interventions must start as soon as the fourth decade (or even earlier) in DS persons, i.e. at an age where interventions can have the greatest efficacy. 相似文献
895.
896.
Gagliotti C Sarti M Sabia C Gargiulo R Rossolini GM Carillo C Cassani C Cipolloni AP Pedna F Rossi MR Incerti SS Testa G Venturelli C Moro ML 《The new microbiologica》2011,34(1):97-99
This study aimed to evaluate the accuracy of routine systems (Vitek2 cards AST-N022 and AST-N026; Kirby Bauer; Etest) for susceptibility testing of Pseudomonas aeruginosa to piperacillin and piperacillin-tazobactam. Vitek2 (card AST-N022) showed the worst performance; the other three methods (Vitek2 card AST-N026, Kirby-Bauer and E-test) performed comparably but never fulfilled the minimal standard proposed by FDA. 相似文献
897.
Castagnola M Inzitari R Fanali C Iavarone F Vitali A Desiderio C Vento G Tirone C Romagnoli C Cabras T Manconi B Sanna MT Boi R Pisano E Olianas A Pellegrini M Nemolato S Heizmann CW Faa G Messana I 《Molecular & cellular proteomics : MCP》2011,10(1):M110.003467
Saliva is a body fluid of a unique composition devoted to protect the mouth cavity and the digestive tract. Our high performance liquid chromatography (HPLC)-electrospray ionization-MS analysis of the acidic soluble fraction of saliva from preterm human newborn surprisingly revealed more than 40 protein masses often undetected in adult saliva. We were able to identify the following proteins: stefin A and stefin B, S100A7 (two isoforms), S100A8, S100A9 (four isoforms), S100A11, S100A12, small proline-rich protein 3 (two isoforms), lysozyme C, thymosins β(4) and β(10), antileukoproteinase, histone H1c, and α and γ globins. The average mass value reported in international data banks was often incongruent with our experimental results mostly because of post-translational modifications of the proteins, e.g. acetylation of the N-terminal residue. A quantitative label-free MS analysis showed protein levels altered in relation to the postconceptional age and suggested coordinate and hierarchical functions for these proteins during development. In summary, this study shows for the first time that analysis of these proteins in saliva of preterm newborns might represent a noninvasive way to obtain precious information of the molecular mechanisms of development of human fetal oral structures. 相似文献
898.
899.
Conforti F Modesto S Menichini F Statti GA Uzunov D Solimene U Duez P Menichini F 《化学与生物多样性》2011,8(3):518-531
Twenty samples of two caper species were collected from various natural habitats of Calabria (South Italy). A sample program was designed in order to cover all taxa and morphotypes present in the studied area, trying to correlate ecological conditions, phytochemical content, and biological activities. These species were characterized through the detection, isolation, and capillary GC-GC/MS quantitative evaluation of chemical markers (phytosterols and vitamin E). The antioxidant activity of MeOH caper extracts was assayed using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and β-carotene bleaching tests. The chemical investigation showed a different composition according to the species and the populations. The best free radical (DPPH) scavenging activity was exerted by Capparis orientalis sample C4 (collected near Copanello village, granodiorite sea cliff) and Capparis sicula ssp. sicula sample C5 (collected near Tarsia village, clay soil). Sample C2 (Galatrella Valley, clay soil) showed the highest inhibition of linoleic acid oxidation with more efficacy than propyl gallate, the reference drug. 相似文献
900.
Federica Marcolini Paolo Piras Tassos Kotsakis Julien Claude Jacques Michaux Jacint Ventura Jorge Cubo 《Comptes Rendus Palevol》2011,10(5-6):479-487
Many genera of arvicolid rodents (voles) contain species that spend a considerable amount of time underground. Incisors provide a considerable effort in the digging process and a difference in the enamel microstructure of incisors is expected between species that spend most of their life above ground and those who have greater specializations for a subterranean habitat. The ratio between the thicknesses of the two layers composing the enamel of the incisors has proved to be an effective proxy to infer fossorial activity of extinct forms of Arvicola but this ratio exhibited no phylogenetic signal (although lifestyle was in a greater extent related to phylogeny). We were able to infer ancestral lifestyles (of extinct populations and of nodes of the phylogeny) from enamel morphologies. Inclusion of fossils did not solve the uncertainties associated with the lifestyle for the last common ancestor of extant Arvicola species and it did not change the inferred lifestyle of several other, less inclusive, clades. 相似文献