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91.
Designing Dual Transglutaminase 2/Histone Deacetylase Inhibitors Effective at Halting Neuronal Death
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Dr. Manuela Basso Dr. Huan Huan Chen Dr. Debasmita Tripathy Dr. Mariarosaria Conte Dr. Kim Y. P. Apperley Dr. Angela De Simone Prof. Dr. Jeffrey W. Keillor Prof. Dr. Rajiv Ratan Dr. Angela Nebbioso Dr. Federica Sarno Prof. Dr. Lucia Altucci Dr. Andrea Milelli 《ChemMedChem》2018,13(3):227-230
In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein we report that combined inhibition of transglutaminase 2 (TG2) and histone deacetylases (HDACs) synergistically protects against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2–HDAC binding agents. Compound 3 [(E)‐N‐hydroxy‐5‐(3‐(4‐(3‐oxo‐3‐(pyridin‐3‐yl)prop‐1‐en‐1‐yl)phenyl)thioureido)pentanamide] emerged as the most interesting of the series, being able to inhibit TG2 and HDACs both in vitro (TG2 IC50=13.3±1.5 μm , HDAC1 IC50=3.38±0.14 μm , HDAC6 IC50=4.10±0.13 μm ) and in cell‐based assays. Furthermore, compound 3 does not exert any toxic effects in cortical neurons up to 50 μm and protects neurons against toxic insults induced by glutamate (5 mm ) with an EC50 value of 3.7±0.5 μm . 相似文献
92.
Federica Paganelli Terence Ambra Alessandro Fantechi Dino Giuli 《Telecommunication Systems》2017,64(1):75-85
This paper proposes an instantaneous recovery route design scheme using multiple coding-aware link protection scenarios to achieve higher link cost reduction in the network. In this scheme, two protection scenarios, namely, (i) traffic splitting (TS), and (ii) two sources and a common destination (2SD) are used to integrate multiple sources and a common destination. The proposed scheme consists of two phases. In the first phase, the proposed scheme determines routes for 2SD and TS scenarios of all possible source-destination pairs to minimize the total link cost. In this phase, the network coding is applied to the common path within each scenario, individually. In the second phase, network coding is applied to the common path between two scenarios (or a scenario pair) in order to enhance the resource saving. This phase develops conditions that select the most appropriate combination of scenario pairs, such as TS–TS, 2SD–2SD, and 2SD–TS for network coding, including their proofs. Using these conditions, a heuristic algorithm is introduced in order to select the most appropriate combination of scenario pairs for further enhancing of resource saving. Simulation results show that the proposed scheme outperforms the conventional 1 + 1 protection scheme, the TS scenario, and the 2SD scenario in terms of link cost reduction in the network. 相似文献
93.
A critical analysis of the procedures available in the literature for the serviceability assessment of footbridges in unrestricted pedestrian traffic conditions is presented. Based on a full probabilistic model of the loading, Monte Carlo simulations are carried out and a critical discussion concerning the role of the statistical distribution of the random walking parameters on the footbridge dynamic response is provided. Furthermore, numerical results are compared with the ones obtained by simplified procedures. Finally, a graphical procedure is proposed which permits a simple evaluation of footbridge maximum acceleration as a function of the modal mass, damping ratio and expected average pedestrian flow. 相似文献
94.
Evangelisti C Raffa P Balzano F Barretta GU Vitulli G Salvadori P 《Journal of nanoscience and nanotechnology》2008,8(4):2096-2101
Pt nanoclusters have been generated by reaction of Pt vapour and mesitylene vapour and the role of the mesitylene/platinum ratio and the Pt particle size has been evaluated, quenching the resulting mesitylene solvated Pt atoms with 1,3-divinyltetramethyldisiloxane (DVS) as additional ligand. The Pt particle sizes have been estimated on the basis of DOSY (Diffusion-Ordered SpectroscopY) analysis and information on their structure features have been obtained by combined use of 2D NMR techniques. 相似文献
95.
Francesco Demetrio Lofaro Barbara Cisterna Maria Assunta Lacavalla Federico Boschi Manuela Malatesta Daniela Quaglino Carlo Zancanaro Federica Boraldi 《International journal of molecular sciences》2021,22(19)
Aging is characterized by a progressive decline of skeletal muscle (SM) mass and strength which may lead to sarcopenia in older persons. To date, a limited number of studies have been performed in the old SM looking at the whole, complex network of the extracellular matrix (i.e., matrisome) and its aging-associated changes. In this study, skeletal muscle proteins were isolated from whole gastrocnemius muscles of adult (12 mo.) and old (24 mo.) mice using three sequential extractions, each one analyzed by liquid chromatography with tandem mass spectrometry. Muscle sections were investigated using fluorescence- and transmission electron microscopy. This study provided the first characterization of the matrisome in the old SM demonstrating several statistically significantly increased matrisome proteins in the old vs. adult SM. Several proteomic findings were confirmed and expanded by morphological data. The current findings shed new light on the mutually cooperative interplay between cells and the extracellular environment in the aging SM. These data open the door for a better understanding of the mechanisms modulating myocellular behavior in aging (e.g., by altering mechano-sensing stimuli as well as signaling pathways) and their contribution to age-dependent muscle dysfunction. 相似文献
96.
Francesca Biagioni Federica Mastroiacovo Paola Lenzi Stefano Puglisi-Allegra Carla L. Busceti Larisa Ryskalin Rosangela Ferese Domenico Bucci Alessandro Frati Ferdinando Nicoletti Francesco Fornai 《International journal of molecular sciences》2021,22(19)
The peri-infarct region, which surrounds the irreversible ischemic stroke area is named ischemic penumbra. This term emphasizes the borderline conditions for neurons placed within such a critical region. Area penumbra separates the ischemic core, where frank cell loss occurs, from the surrounding healthy brain tissue. Within such a brain region, nervous matter, and mostly neurons are impaired concerning metabolic conditions. The classic biochemical marker, which reliably marks area penumbra is the over-expression of the heat shock protein 70 (HSP70). However, other proteins related to cell clearing pathways are modified within area penumbra. Among these, autophagy proteins like LC3 increase in a way, which recapitulates Hsp70. In contrast, components, such as P20S, markedly decrease. Despite apparent discrepancies, the present study indicates remarkable overlapping between LC3 and P20S redistribution within area penumbra. In fact, the amount of both proteins is markedly reduced within vacuoles. Specifically, a massive loss of LC3 + P20S immuno-positive vacuoles (autophagoproteasomes) is reported here. This represents the most relevant sub-cellular alteration here described in cell clearing pathways within area penumbra. The functional significance of these findings remains to be determined and it will take a novel experimental stream to decipher the fine-tuning of such a phenomenon. 相似文献
97.
Vertical greenery modular systems (VGMSs) are an increasingly widespread building envelope solution aimed at improving the aesthetical quality of both new and existing façades, contemporarily achieving high energy efficiency performance. Within a research project, a new prototype of VGMS was developed, designed and tested. An experimental monitoring campaign was carried out on a test cell located in Turin (northern Italy), aimed at assessing both biometric parameters and energy-related issues. Two different types of growing media and two plant species, Lonicera nitida L. and Bergenia cordifolia L., have been tested on a south-facing lightweight wall. Results have been compared to the same wall without VGMS and plaster finished, in order to characterise the thermal insulation effectiveness in the winter period and the heat gain reduction in the summer period. Measured equivalent thermal transmittance values of the green modular system showed a 40 % reduction, when compared to the plastered wall, thus noticeably impacting on the energy crossing the façade during the heating season. Benefits of the VGMS are measured also during the summer season, when the presence of vegetation lowers the outdoor surface temperatures of the wall up to 23 °C compared to the plastered finishing, with a positive effect on outdoor comfort and urban heat island mitigation. Nevertheless, as far as the entering energies are concerned, not significant reduction was observed for VGMS, compared to the reference plastered wall, since the green coverage acts as a thermal buffer and solar radiation is stored and slowly released to the indoor environment. 相似文献
98.
Krizia Sagini Sandra Buratta Federica Delo Roberto Maria Pellegrino Stefano Giovagnoli Lorena Urbanelli Carla Emiliani 《International journal of molecular sciences》2021,22(23)
Amiodarone is a cationic amphiphilic drug used as an antiarrhythmic agent. It induces phospholipidosis, i.e., the accumulation of phospholipids within organelles of the endosomal–lysosomal system. Extracellular vesicles (EVs) are membrane-enclosed structures released by any type of cell and retrieved in every fluid of the body. EVs have been initially identified as a system to dispose cell waste, but they are also considered to be an additional manner to transmit intercellular signals. To understand the role of EVs in drug-induced phospholipidosis, we investigated EVs release in amiodarone-treated HEK-293 cells engineered to produce fluorescently labelled EVs. We observed that amiodarone induces the release of a higher number of EVs, mostly of a large/medium size. EVs released upon amiodarone treatment do not display significant morphological changes or altered size distribution, but they show a dose-dependent increase in autophagy associated markers, indicating a higher release of EVs with an autophagosome-like phenotype. Large/medium EVs also show a higher content of phospholipids. Drugs inducing lysosomal impairment such as chloroquine and bafilomycin A1 similarly prompt a higher release of EVs enriched in autophagy markers. This result suggests a mechanism associated with amiodarone-induced lysosomal impairment more than a connection with the accumulation of specific undigested substrates. Moreover, the implementation of the lysosomal function by overexpressing TFEB, a master gene regulator of lysosomal biogenesis, prevents the amiodarone-induced release of EVs, suggesting that this could be a feasible target to attenuate drug-induced abnormalities. 相似文献
99.
Roberto Fabiani Raffaela Fuccelli Federica Pieravanti Angelo De Bartolomeo Guido Morozzi 《Molecular nutrition & food research》2009,53(7):887-896
Hydroxytyrosol [3,4‐dihydroxyphenylethanol (3,4‐DHPEA)], a phenolic compound found exclusively in olive oil, exerts growth‐suppressive and pro‐apoptotic effects on different cancer cells. Although some molecular mechanisms involved in the pro‐apoptotic activity of 3,4‐DHPEA have been proposed, the initial stress signals responsible of this phenomenon are not known. Our aim was to assess the involvement of reactive oxygen species as mediators of apoptosis induced by 3,4‐DHPEA on HL60 cells. Apoptosis was determined by analyzing the nuclear fragmentation by both fluorescence microscopy and flow cytometry. The externalization of phosphatidylserine was evidenced using an Annexin V‐FITC kit. The concentration of H2O2 in the culture medium was measured by the ferrous ion oxidation‐xylenol orange method. The pro‐apoptotic effect of 3,4‐DHPEA (100 μM) was prevented by N‐acetyl‐cysteine, ascorbate, and α‐tocopherol. Catalase suppressed the 3,4‐DHPEA‐induced apoptosis, while the Fe(II)‐chelating reagent o‐phenantroline showed no effect, suggesting the involvement of H2O2 but not of OH?. Indeed, 3,4‐DHPEA caused accumulation of H2O2 in the culture medium. Tyrosol (p‐hydroxyphenylethanol) and caffeic acid, compounds structurally similar to 3,4‐DHPEA but not able to generate H2O2, did not induce an appreciable apoptotic effect. This is the first study demonstrating that apoptosis induction by 3,4‐DHPEA is mediated by the extracellular production of H2O2. 相似文献
100.
Federica Maltese Cornelis Erkelens Frank van der Kooy Young Hae Choi Robert Verpoorte 《Food chemistry》2009
Recently advanced analytical technology has provided evidence of the existence of stereoisomers of many natural products. Particularly, flavanones which might have two different configurations at C-2 exist in many food additives, e.g., citrus fruits. In this study, the possible stereoisomers of flavanone glycosides were identified by NMR spectroscopy. Based on NMR spectra of common flavanone glycosides such as naringin, hesperidin, and neohesperidin, the two existing diastereomeric forms of the molecules could clearly be distinguished. The 1H NMR resonances of two diastereomers of each flavanone glycosides investigated in this study were fully assigned with the assistance of diverse 2D NMR spectroscopy methods. 相似文献