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71.
Toward the Development of Dual‐Targeted Glyceraldehyde‐3‐phosphate Dehydrogenase/Trypanothione Reductase Inhibitors against Trypanosoma brucei and Trypanosoma cruzi
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Prof. Dr. Federica Belluti Elisa Uliassi Giacomo Veronesi Dr. Christian Bergamini Dr. Marcel Kaiser Prof. Dr. Reto Brun Angelo Viola Prof. Dr. Romana Fato Prof. Dr. Paul A. M. Michels Prof. Dr. R. Luise Krauth‐Siegel Prof. Dr. Andrea Cavalli Prof. Dr. Maria Laura Bolognesi 《ChemMedChem》2014,9(2):371-382
A significant improvement in the treatment of trypanosomiases has been achieved with the recent development of nifurtimox–eflornithine combination therapy (NECT). As an alternative to drug combinations and as a means to overcome most of the antitrypanosomatid drug discovery challenges, a multitarget drug design strategy has been envisaged. To begin testing this hypothesis, we designed and developed a series of quinone–coumarin hybrids against glyceraldehyde‐3‐phosphate dehydrogenase/trypanothione reductase (GAPDH/TR). These enzymes belong to metabolic pathways that are vital to Trypanosoma brucei and Trypanosoma cruzi, and have thus been considered promising drug targets. The synthesized molecules were characterized for their dual‐target antitrypanosomal profile, both in enzyme assays and in in vitro parasite cultures. The merged derivative 2‐{[3‐(3‐dimethylaminopropoxy)‐2‐oxo‐2H‐chromen‐7‐yl]oxy}anthracene‐1,4‐dione ( 10 ) showed an IC50 value of 5.4 μM against TbGAPDH and a concomitant Ki value of 2.32 μM against TcTR. Notably, 2‐{4‐[6‐(2‐dimethylaminoethoxy)‐2‐oxo‐2H‐chromen‐3‐yl]phenoxy}anthracene‐1,4‐dione (compound 6 ) displayed a remarkable EC50 value for T. brucei parasites (0.026 μM ) combined with a very low cytotoxicity toward mammalian L6 cells (7.95 μM ). This promising low toxicity of compound 6 might be at least partially due to the fact that it does not interfere with human glutathione reductase. 相似文献
72.
73.
Elizaveta Kon Giuseppe Filardo Francesco Perdisa Alessandro Di Martino Maurizio Busacca Federica Balboni Andrea Sessa Maurilio Marcacci 《Journal of materials science. Materials in medicine》2014,25(10):2437-2444
The increasing interest in the role of subchondral bone with regard to articular surface disease led to the development of new bioengineered strategies. Aim of this study is to evaluate the clinical and MRI outcome after the implantation of a nanostructured biomimetic three-phasic collagen–hydroxyapatite construct for the treatment of chondral and osteochondral defects of the knee in a large cohort of patients. Seventy-nine patients (63 M, 16 W), affected by grade III–IV femoral condyle or trochlea chondral lesions or osteochondritis dissecans (OCD) were consecutively treated. Mean age was 31.0 ± 11.3 years, mean lesion size was 3.2 ± 2.0 cm2. Fifty patients underwent previous surgeries, concurrent procedures were necessary in 39 cases. The clinical outcome was evaluated using the IKDC and Tegner scores at 12 and 24 months of follow-up. At follow-up times an MRI was performed and evaluated with the MOCART score. All the scores improved significantly from the baseline. IKDC subjective score showed a further increase between 12 and 24 months of follow-up, and 82.2 % of the patients improved their symptoms at the final evaluation. Patients affected by OCDs had better results than those with degenerative lesions. Some abnormal MRI findings were present, even though no correlation was found with the clinical outcome. This one-step biomimetic approach developed to favor osteochondral tissue regeneration is effective in treating knees affected by damages of the articular surface, leading to a significant clinical improvement. However, abnormal MRI findings were present, even if not correlated with the clinical outcome. 相似文献
74.
Giorgina Barbara Piccoli Gabriella Guzzo Federica Neve Vigotti Irene Capizzi Roberta Clari Stefania Scognamiglio Valentina Consiglio Emiliano Aroasio Silvana Gonella Andrea Veltri Paolo Avagnina 《Hemodialysis international. International Symposium on Home Hemodialysis》2014,18(3):590-595
Renal function recovery (RFR), defined as the discontinuation of dialysis after 3 months of replacement therapy, is reported in about 1% of chronic dialysis patients. The role of personalized, intensive dialysis schedules and of resuming low‐protein diets has not been studied to date. This report describes three patients with RFR who were recently treated at a new dialysis unit set up to offer intensive hemodialysis. All three patients were females, aged 73, 75, and 78 years. Kidney disease included vascular‐cholesterol emboli, diabetic nephropathy and vascular and dysmetabolic disease. At time of RFR, the patients had been dialysis‐dependent from 3 months to 1 year. Dialysis was started with different schedules and was progressively discontinued with a “decremental” policy, progressively decreasing number and duration of the sessions. A moderately restricted low‐protein diet (proteins 0.6 g/kg/day) was started immediately after dialysis discontinuation. The most recent update showed that two patients are well off dialysis for 5 and 6 months; the diabetic patient died (sudden death) 3 months after dialysis discontinuation. Within the limits of small numbers, our case series may suggest a role for personalized dialysis treatments and for including low‐protein diets in the therapy, in enhancing long‐term RFR in elderly dialysis patients. 相似文献
75.
"Personalized medicine" is a new concept in health care, one aspect of which defines the specificity and dosage of drugs according to effectiveness and safety for each patient. Dosage strongly depends from the rate of metabolism which is primarily regulated by the activity of cytochrome P450. In addition to the need for a genetic characterization of the patients, there is also the necessity to determine the drug-clearance properties of the polymorphic P450 enzyme. To address this issue, human P450 2D6 and 2C9 were engineered and covalently linked to an electrode surface allowing fast, accurate, and reliable measurements of the kinetic parameters of these phase-1 drug metabolizing polymorphic enzymes. In particular, the catalytic activity of P450 2C9 on the electrode surface was found to be improved when expressed from a gene-fusion with flavodoxin from Desulfovibrio vulgaris (2C9/FLD). The results are validated using marker drugs for these enzymes, bufuralol for 2D6, and warfarin for 2C9/FLD. The platform is able to measure the same small differences in K(M), and it allows a fast and reproducible mean to generated the product identified by HPLC from which the k(cat) is calculated. 相似文献
76.
Pasini F Verardo V Cerretani L Caboni MF D'Antuono LF 《Journal of the science of food and agriculture》2011,91(15):2858-2864
BACKGROUND: Salad crops of the Brassicaceae family, such as Diplotaxis tenuifolia and Eruca vesicaria, commonly referred to as ‘rocket salads’, have attracted considerable interest as culinary vegetables because of their strong flavour and their content of putative health‐promoting compounds. Among such compounds, glucosinolates and phenolics are well‐known phytochemicals with an important role also in determining the characteristic flavour of these species. In this study, to identify potentially high‐value rocket salads, 37 cultivated types were examined for sensory characters and their relations with glucosinolate and phenolic contents, which ranged from 0.76 to 3.03 g kg?1 dry weight (DW) and from 4.68 to 31.39 g kg?1 DW, respectively. RESULTS: The perception of bitter taste was significantly affected by specific glucosinolates, namely progoitrin/epiprogoitrin and dimeric glucosativin. Aroma intensity was negatively related to glucoalyssin content, whereas pungency was significantly related to total glucosinolate content. Kaempferol‐3‐(2‐sinapoyl‐glucoside)‐4′‐glucoside was positively and significantly related to all flavour trait perceptions. Aroma intensity, pungency, crunchiness and juiciness were positively related to typical rocket salad flavour perception through a prominent direct effect. CONCLUSION: Aroma intensity, pungency, crunchiness and juiciness were strong determinants of overall rocket salad flavour perception. Visual traits also characterised sensory components. Bitterness, usually considered a negative flavour trait, was moderately perceived in the examined material, without negatively affecting typical flavour perception. In the range of the examined material, glucosinolate content did not contrast with typical flavour, demonstrating that good taste and putative health‐promoting properties may coexist. Copyright © 2011 Society of Chemical Industry 相似文献
77.
Characterization of a lab-scale platinum filament pyrolyzer for studying the fast devolatilization of solid fuels 总被引:1,自引:0,他引:1
Platinum filament pyrolyzers achieve very high temperature and heating rate and can provide useful parameters for practical applications in combustion, pyrolysis and gasification processes. The critical use of an experimental instrument is necessary to provide reliable data. In this work, a commercial pyrolyzer (CDS Pyroprobe 2000) is characterized to obtain a correspondence between the nominal and the effective operating conditions. This is the basis for the modeling estimation of the effective thermal history of the sample during each experimental run. The experimental results obtained performing the devolatilization of coals, biomass and waste fuels using the pyrolyzer are compared with those obtained in a conventional thermogravimetric balance, to evaluate the effects of extremely different operating conditions. The amount of volatile released programming the most severe thermal conditions using the pyrolyzer (thus in conditions more similar to large-scale plants) differs significantly from that of thermogravimetric runs. Global kinetics are obtained fitting the experimental results and using the thermal history of the sample from the model results. They depend strongly on the conditions used for the devolatilization. Global kinetics obtained in the thermogravimetric balance runs (low heating rate) overestimate the rate of devolatilization in the pyrolyzer (high heating rate). 相似文献
78.
Otovestibular performance was investigated in divers undergoing air and helium-oxygen hyperbaric saturation cycles. The subjects were all very experienced deep-sea divers. Before cycles, they presented various signs of altered otovestibular performance. These were not altered when controlled subsequently. No conclusions can be drawn from this small series, though its heterogeneity lends some significance to the results and it has been presented on account of the lack of other studies of this question. 相似文献
79.
Sabrine Bilel Micaela Tirri Raffaella Arf Chiara Sturaro Anna Fantinati Virginia Cristofori Tatiana Bernardi Federica Boccuto Marco Cavallo Alessandro Cavalli Fabio De-Giorgio Girolamo Cal Matteo Marti 《International journal of molecular sciences》2021,22(14)
1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm. 相似文献
80.
Lorenzo Ball Emanuela Barisione Luca Mastracci Michela Campora Delfina Costa Chiara Robba Denise Battaglini Marco Micali Federico Costantino Giuseppe Cittadini Nicol Patroniti Paolo Pelosi Roberto Fiocca Federica Grillo 《International journal of molecular sciences》2021,22(14)
Lung fibrosis has specific computed tomography (CT) findings and represents a common finding in advanced COVID-19 pneumonia whose reversibility has been poorly investigated. The aim of this study was to quantify the extension of collagen deposition and aeration in postmortem cryobiopsies of critically ill COVID-19 patients and to describe the correlations with qualitative and quantitative analyses of lung CT. Postmortem transbronchial cryobiopsy samples were obtained, formalin fixed, paraffin embedded and stained with Sirius red to quantify collagen deposition, defining fibrotic samples as those with collagen deposition above 10%. Lung CT images were analyzed qualitatively with a radiographic score and quantitatively with computer-based analysis at the lobe level. Thirty samples from 10 patients with COVID-19 pneumonia deceased during invasive mechanical ventilation were included in this study. The median [interquartile range] percent collagen extension was 6.8% (4.6–16.2%). In fibrotic compared to nonfibrotic samples, the qualitative score was higher (260 (250–290) vs. 190 (120–270), p = 0.036) while the gas fraction was lower (0.46 (0.32–0.47) vs. 0.59 (0.37–0.68), p = 0.047). A radiographic score above 230 had 100% sensitivity (95% confidence interval, CI: 66.4% to 100%) and 66.7% specificity (95% CI: 41.0% to 92.3%) to detect fibrotic samples, while a gas fraction below 0.57 had 100% sensitivity (95% CI: 66.4% to 100%) and 57.1% specificity (95% CI: 26.3% to 88.0%). In COVID-19 pneumonia, qualitative and quantitative analyses of lung CT images have high sensitivity but moderate to low specificity to detect histopathological fibrosis. Pseudofibrotic CT findings do not always correspond to increased collagen deposition. 相似文献