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11.
Cecilia Marini Barbara Salani Michela Massollo Adriana Amaro Alessia Isabella Esposito Anna Maria Orengo Selene Capitanio Laura Emionite Mattia Riondato Gianluca Bottoni Cinzia Massara Simona Boccardo Marina Fabbi Cristina Campi Silvia Ravera Giovanna Angelini Silvia Morbelli Michele Cilli Renzo Cordera Mauro Truini Davide Maggi Ulrich Pfeffer Gianmario Sambuceti 《Cell cycle (Georgetown, Tex.)》2013,12(22):3490-3499
Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of 18F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters. The profound energetic imbalance activates phosphorylation and is subsequently followed by cell death. More importantly, the “in vivo” relevance of this effect is confirmed by studies of orthotopic xenografts of MDA-MB-231 cells in athymic (nu/nu) mice. Administration of high drug doses after tumor development caused an evident tumor necrosis in a time as short as 48 h. On the other hand, 1 mo metformin treatment markedly reduced cancer glucose consumption and growth. Taken together, our results strongly suggest that HK inhibition contributes to metformin therapeutic and preventive potential in breast cancer. 相似文献
12.
Alpine grouses are particularly vulnerable to climate change due to their adaptation to extreme conditions and to their relict distributions in the Alps where global warming has been particularly marked in the last half century. Grouses are also currently threatened by habitat modification and human disturbance, and an assessment of the impact of multiple stressors is needed to predict the fate of Alpine populations of these birds in the next decades. We estimated the effect of climate change and human disturbance on a rock ptarmigan population living in the western Italian Alps by combining an empirical population modelling approach and stochastic simulations of the population dynamics under the a1B climate scenario and two different disturbance scenarios, represented by the development of a ski resort, through 2050.The early appearance of snow-free ground in the previous spring had a favorable effect on the rock ptarmigan population, probably through a higher reproductive success. On the contrary, delayed snowfall in autumn had a negative effect possibly due to a mismatch in time to molt to white winter plumage which increases predation risk. The regional climate model PROTHEUS does not foresee any significant change in snowmelt date in the study area, while the start date of continuous snow cover is expected to be significantly delayed. The net effect in the stochastic projections is a more or less pronounced (depending on the model used) decline in the studied population. The addition of extra-mortality due to collision with ski-lift wires led the population to fatal consequences in most projections. Should these results be confirmed by larger studies the conservation of Alpine populations would deserve more attention. To counterbalance the effects of climate change, the reduction of all causes of death should be pursued, through a strict preservation of the habitats in the present area of occurrence. 相似文献
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Adriano Redler Giorgio Di Rocco Domenico Giannotti Francesca Frezzotti Maria Giulia Bernieri Simona Ceccarelli Sirio D’Amici Enrica Vescarelli Anna Paola Mitterhofer Antonio Angeloni Cinzia Marchese 《PloS one》2013,8(8)
Fibroblast growth factor receptor-2 (FGFR-2) plays an important role in tumorigenesis. In thyroid cancer it has been observed a FGFR-2 down-modulation, but the role of this receptor has not been yet clarified. Therefore, we decided to examine the expression of both FGFR-2 isoform, FGFR-2-IIIb and FGFR-2-IIIc, in different histological thyroid variants such as hyperplasia, follicular adenoma and papillary carcinoma. Immunohistochemistry and quantitative Real-Time PCR analyses were performed on samples of hyperplasia, follicular adenoma and papillary carcinoma, compared with normal thyroid tissue. Thyroid hyperplasia did not show statistically significant reduction in FGFR-2 protein and mRNA levels. Interestingly, in both follicular adenoma and papillary carcinoma samples we observed a strongly reduced expression of both FGFR-2 isoforms. We speculate that FGFR-2 down-modulation might be an early event in thyroid carcinogenesis. Furthermore, we suggest the potential use of FGFR-2 as an early marker for thyroid cancer diagnosis. 相似文献
15.
Daniela Calzia Simona Candiani Greta Garbarino Federico Caicci Silvia Ravera Maurizio Bruschi Lucia Manni Alessandro Morelli Carlo Enrico Traverso Giovanni Candiano Carlo Tacchetti Isabella Panfoli 《Cellular and molecular neurobiology》2013,33(5):637-649
Vertebrate retinal rod outer segments (OS) consist of a stack of disks surrounded by the plasma membrane, where phototransduction takes place. Energetic metabolism in rod OS remains obscure. Literature described a so-called Mg2+-dependent ATPase activity, while our previous results demonstrated the presence of oxidative phosphorylation (OXPHOS) in OS, sustained by an ATP synthetic activity. Here we propose that the OS ATPase and ATP synthase are the expression of the same protein, i.e., of F1Fo-ATP synthase. Imaging on bovine retinal sections showed that some OXPHOS proteins are expressed in the OS. Biochemical data on bovine purified rod OS, characterized for purity, show an ATP synthase activity, inhibited by classical F1Fo-ATP synthase inhibitors. Moreover, OS possess a pH-dependent ATP hydrolysis, inhibited by pH values below 7, suggestive of the functioning of the inhibitor of F1 (IF1) protein. WB confirmed the presence of IF1 in OS, substantiating the expression of F1Fo ATP synthase in OS. Data suggest that the OS F1Fo ATP synthase is able to hydrolyze or synthesize ATP, depending on in vitro or in vivo conditions and that the role of IF1 would be pivotal in the prevention of the reversal of ATP synthase in OS, for example during hypoxia, granting photoreceptor survival. 相似文献
16.
Mutations in neuronal voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A may play an important role in the etiology of neurological diseases and psychiatric disorders, besides various types of epilepsy. Here we describe a 3-year-old boy with autistic features, language delay, microcephaly and no history of seizures. Array-CGH analysis revealed an interstitial deletion of ~ 291.9 kB at band 2q24.3 disrupting the entire SCN2A gene and part of SCN3A. We discuss the effects of haploinsufficiency of SCN2A and SCN3A on the genetic basis of neurodevelopmental and neurobehavioral disorders and we propose that this haploinsufficiency may be associated not only with epilepsy, but also with autistic features. 相似文献
17.
Julio Caballero Szymon Zilocchi William Tiznado Daniela Rossi Simona Collina 《Molecular simulation》2013,39(3):227-235
Sigma-1 (σ1) affinities of methyl 2-(aminomethyl)-1-phenylcyclopropane-1-carboxylate (MAPCC) derivatives were modelled by the genetic algorithm with linear assignment of hypermolecular alignment of datasets (GALAHAD) and the comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) methods. GALAHAD was used for deriving the 3D pharmacophore pattern that encompasses the most potent σ1 ligands within this series. Five MAPCC derivatives with a high σ1 affinity were used for deriving this model. The obtained model included a nitrogen atom, the hydrophobes and the hydrogen bond acceptor features; it was able to identify other potent σ1 ligands. On the other hand, CoMFA and CoMSIA methods were used for deriving quantitative structure–activity relationship (QSAR) models. All QSAR models were trained with 17 compounds, after which they were evaluated for predictive ability with additional five compounds. The best QSAR model was obtained by using CoMSIA, including steric, electrostatic and hydrophobic fields, and had a good predictive quality according to both internal and external validation criteria. In general, the models described herein provide meaningful information relevant for the rational design of new σ1 ligands. 相似文献
18.
Simona Maria Monti Giuseppina De Simone Nina A. Dathan Martha Ludwig Daniela Vullo Andrea Scozzafava Clemente Capasso Claudiu T. Supuran 《Bioorganic & medicinal chemistry letters》2013,23(6):1626-1630
Several β-carbonic anhydrases (CAs, EC 4.2.1.1) are present in all land plants examined thus far. Here we report the first detailed biochemical characterization of one such isoform, FbiCA 1, from the C4 plant Flaveria bidentis, which was cloned, purified and characterized as recombinant protein. FbiCA 1 has an interesting CO2 hydrase catalytic activity (kcat of 1.2 × 105 and kcat/Km of 7.5 × 106 M?1 × s?1) and was moderately inhibited by most simple/complex inorganic anions. Potent FbiCA 1 inhibitors were also detected, such as trithiocarbonate, diethyldithiocarbamate, sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid (KIs in the range of 4–60 μM). Such inhibitors may be used as tools to better understand the role of various β-CA isoforms in photosynthesis. 相似文献
19.
Lisa Dalla Via Aída N. García-Argáez Arianna Adami Silvia Grancara Pamela Martinis Antonio Toninello Daniela Belli Dell’Amico Luca Labella Simona Samaritani 《Bioorganic & medicinal chemistry》2013,21(22):6965-6972
A convenient synthetic route and the characterization of complexes trans-[PtCl2(L)(PPh3)] (L = Et2NH (2), (PhCH2)2NH (3), (HOCH2CH2)2NH) (4) are reported. The antiproliferative activity was evaluated on three human tumor cell lines. The investigation on the mechanism of action highlighted for the most active complex 4 the capacity to affect mitochondrial functions. In particular, both the induction of the mitochondrial permeability transition phenomenon and an aspecific membrane damage occurred, depending on concentration. 相似文献
20.
Claudio Battilocchio Giovanna Poce Salvatore Alfonso Giulio Cesare Porretta Sara Consalvi Lidia Sautebin Simona Pace Antonietta Rossi Carla Ghelardini Lorenzo Di Cesare Mannelli Silvia Schenone Antonio Giordani Luigia Di Francesco Paola Patrignani Mariangela Biava 《Bioorganic & medicinal chemistry》2013,21(13):3695-3701
We report the synthesis and bio-pharmacological evaluation of a class of pyrrole derivatives featuring a small appendage fragment (carbaldehyde, oxime, nitrile) on the central core. Compound 1c proved to be extremely effective in vivo, showing an interesting anti-nociceptic profile that is comparable to reference compounds already marketed, hence representing a great stimulus for a further improvement of this class of molecules. 相似文献