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81.
Potent,Metabolically Stable 2‐Alkyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands 下载免费PDF全文
Dr. Silvia Pace Dr. Giandomenico Brogin Dr. Maria Antonietta Stasi Dr. Teresa Riccioni Franco Borsini Dr. Francesca Capocasa Dr. Francesco Manera Carlo Tallarico Dr. Pietro Grossi Dr. Federica Vacondio Dr. Michele Bassi Dr. Francesca Bartoccini Dr. Simone Lucarini Dr. Giovanni Piersanti Prof. Giorgio Tarzia Walter Cabri Dr. Patrizia Minetti 《ChemMedChem》2015,10(7):1149-1152
Inhibition of adenosine A2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9H‐purine, ST1535, as a potent A2AR antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω‐1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω‐1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A2AR was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A2AR (Ki=0.4 nM and 2 nM , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours). 相似文献
82.
Characterisation of CYP102A25 from Bacillus marmarensis and CYP102A26 from Pontibacillus halophilus: P450 Homologues of BM3 with Preference towards Hydroxylation of Medium‐Chain Fatty Acids 下载免费PDF全文
Dr. Joanne L. Porter Jack Manning Selina Sabatini Michele Tavanti Prof. Nicholas J. Turner Prof. Sabine L. Flitsch 《Chembiochem : a European journal of chemical biology》2018,19(5):513-520
Cytochrome P450 monooxygenases are highly desired biocatalysts owing to their ability to catalyse a wide variety of chemically challenging C?H activation reactions. The CYP102A subfamily of enzymes are natural catalytically self‐sufficient proteins consisting of a haem and FMN‐FAD reductase domain fused in a single‐component system. They catalyse the oxygenation of saturated and unsaturated fatty acids to produce primarily ω?1, ω?2 and ω?3 hydroxy acids. These monooxygenases have potential applications in biotechnology; however, their substrate range is still limited and there is a continued need to add diversity to this class of biocatalysts. Herein, we present the characterisation of two new members of this class of enzymes, CYP102A25 (BMar) from Bacillus marmarensis and CYP102A26 (PHal) from Pontibacillus halophilus, both of which express readily in a recombinant bacterial host. BMar exhibits the highest activity toward myristic acid and shows moderate activity towards unsaturated fatty acids. PHal exhibits broader activity towards mid‐chain‐saturated (C14–C18) and unsaturated fatty acids. Furthermore, PHal shows good regioselectivity for the hydroxylation of myristic acid, targeting the ω?2 position for C?H activation. 相似文献
83.
Michele Iuliani Sonia Simonetti Giulia Ribelli Andrea Napolitano Umile Giuseppe Longo Bruno Vincenzi Paolo Orsaria Vincenzo Denaro Giuseppe Tonini Daniele Santini Pantano Francesco 《International journal of molecular sciences》2022,23(5)
The CDK4/6 inhibitors (CDKi) palbociclib, ribociclib, and abemaciclib are currently approved in combination with anti-estrogen therapy for the treatment of advanced and/or metastatic hormone receptor-positive/HER2-neu-negative breast cancer patients. Given the high incidence of bone metastases in this population, we investigated and compared the potential effects of palbociclib, ribociclib, and abemaciclib on the breast cancer bone microenvironment. Primary osteoclasts (OCs) and osteoblasts (OBs) were obtained from human monocyte and mesenchymal stem cells, respectively. OC function was evaluated by tartrate-resistant acid phosphatase assay and real-time PCR; OB activity was assessed by an alizarin red assay. OB/breast cancer co-culture models were generated via the seeding of MCF-7 cells on a layer of OBs, and tumor cell proliferation was analyzed using flow cytometry. Here, we showed that ribociclib, palbociclib, and abemaciclib exerted similar inhibitory effects on the OC differentiation and expression of bone resorption markers without affecting OC viability. On the other hand, the three CDKi did not affect the ability of OB to produce bone matrix, even if the higher doses of palbociclib and abemaciclib reduced the OB viability. In OB/MCF-7 co-culture models, palbociclib demonstrated a lower anti-tumor effect than ribociclib and abemaciclib. Overall, our results revealed the direct effects of CDKi on the tumor bone microenvironment, highlighting differences potentially relevant for clinical practice. 相似文献
84.
Elvira Sondo Federico Cresta Cristina Pastorino Valeria Tomati Valeria Capurro Emanuela Pesce Mariateresa Lena Michele Iacomino Ave Maria Baffico Domenico Coviello Tiziano Bandiera Federico Zara Luis J. V. Galietta Renata Bocciardi Carlo Castellani Nicoletta Pedemonte 《International journal of molecular sciences》2022,23(6)
Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators. 相似文献
85.
Salvatore Micali Gianmarco Isgro Giampaolo Bianchi Natalizia Miceli Gioacchino Calapai Michele Navarra 《Critical reviews in food science and nutrition》2014,54(8):1063-1075
Epidemiologic studies indicate that millions of people suffer from recurrent cystitis, a pathology requiring antibiotic prophylaxis and entailing high social costs. Cranberry is a traditional folk remedy for cystitis and, which, in the form of a variety of products and formulations has over several decades undergone extensive evaluation for the management of urinary tract infections (UTI). The aim of this retrospective study is to summarize and review the most relevant and recent preclinical and clinical studies on cranberries for the treatment of UTIs. The scientific literature selected for this review was identified by searches of Medline via PubMed. A variety of recent experimental evidence has shed light on the mechanism underlying the anti-adhesive properties of proanthrocyanidins, their structure–activity relationships, and pharmacokinetics. Analysis of clinical studies and evaluation of the cranberry efficacy/safety ratio in the prevention of UTIs strongly support the use of cranberry in the prophylaxis of recurrent UTIs in young and middle-aged women. However, evidence of its clinical use among other patients remains controversial. 相似文献
86.
Luigi Catuogno Roberto Gassirà Michele Masullo Ivan Visconti 《Information Security Technical Report》2013,17(3):93-104
A smart card is a tamper-resistant miniature computer that performs some basic computations on input a secret information. So far, smart cards have been widely used for securing many digital transactions (e.g., pay television, ATM machines).We focus on the implementation of operating system security services leveraging on smart cards. This very challenging feature allows one to personalize some functionalities of the operating system by simply changing a smart card. Current solutions for integrating smart card features in operating system services require at least a partial execution of some of the operating system functionalities at “user level”. Unfortunately, system functionalities built on top of components lying at both kernel and user levels may negatively affect the overall system security, due to the introduction of multiple points of failure.In this work, we present the design and implementation of SmartK: a framework that integrates features of smart cards uniquely in the Linux kernel. In order to validate our approach, we propose a host of enhancements to the Linux operating system built on top of SmartK: 1) in-kernel clients' authentication with Kerberos; 2) execution of trusted code; 3) key management in secure network filesystems.In particular, we present an experimental Linux OS distribution (SalSA), which addresses the security issues related to downloading packages and to updating an operating system through the Internet. 相似文献
87.
Kennard Betsy D.; Clarke Greg N.; Weersing V. Robin; Asarnow Joan Rosenbaum; Shamseddeen Wael; Porta Giovanna; Berk Michele; Hughes Jennifer L.; Spirito Anthony; Emslie Graham J.; Keller Martin B.; Wagner Karen D.; Brent David A. 《Canadian Metallurgical Quarterly》2009,77(6):1033
In this report, we conducted a secondary analysis of the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study to explore the impact of specific cognitive–behavioral therapy (CBT) treatment components on outcome. In TORDIA, 334 youths (ages 12 to 18 years) with major depressive disorder who had failed to respond to an adequate course of selective serotonin reuptake inhibitor (SSRI) medication were randomized to a medication switch (either to an alternative SSRI or venlafaxine) with or without 12 weeks of adjunctive CBT. Participants who had more than 9 CBT sessions were 2.5 times more likely to have adequate treatment response than those who had 9 or fewer sessions. CBT participants who received problem-solving and social skills treatment components, controlling for number of sessions and other confounding variables, were 2.3 and 2.6 times, respectively, more likely to have a positive response. These preliminary findings underscore the importance of receiving an adequate number of sessions to attain an adequate clinical response. Finally, social skills and problem solving may be active elements in CBT for adolescent depression and should be considered in treatment by those working with seriously depressed youths. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
88.
Michele A. Lewis Joseph G. Masin Patrick A. O'Hare 《International Journal of Hydrogen Energy》2009,34(9):4115-4124
The Nuclear Hydrogen Initiative (NHI) of the U.S. Department of Energy′s Office of Nuclear Energy Science and Technology is supporting an effort to reevaluate thermochemical cycles reported in the literature as having both promising efficiencies and proof-of-concept results. Recognizing that the calculation of efficiencies was not always consistently done or well defined in the literature, we first developed a consistent methodology for reevaluating the candidate thermochemical cycles. This methodology was defined for three levels of maturity in process knowledge. Argonne National Laboratory and a group of universities recalculated the efficiency for each level and identified the most critical R&D necessary to further assess the cycles' potential. This methodology is illustrated with the Cu–Cl in Part I of this series of three papers. Current results of the analyses for all of the cycles are summarized in Part II. Part III contains a more detailed Level 3 analysis for the Cu–Cl cycle. 相似文献
89.
90.
Multi-objective optimisation problems have seen a large impulse in the last decades. Many new techniques for solving distinct variants of multi-objective problems have been proposed. Production scheduling, as with other operations management fields, is no different. The flowshop problem is among the most widely studied scheduling settings. Recently, the Iterated Greedy methodology for solving the single-objective version of the flowshop problem has produced state-of-the-art results. This paper proposes a new algorithm based on Iterated Greedy technique for solving the multi-objective permutation flowshop problem. This algorithm is characterised by an effective initialisation of the population, management of the Pareto front, and a specially tailored local search, among other things. The proposed multi-objective Iterated Greedy method is shown to outperform other recent approaches in comprehensive computational and statistical tests that comprise a large number of instances with objectives involving makespan, tardiness and flowtime. Lastly, we use a novel graphical tool to compare the performances of stochastic Pareto fronts based on Empirical Attainment Functions. 相似文献