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71.
Giovanna Poce Robert H. Bates Salvatore Alfonso Martina Cocozza Giulio Cesare Porretta Lluís Ballell Joaquin Rullas Fátima Ortega Alessandro De Logu Emanuela Agus Valentina La Rosa Maria Rosalia Pasca Edda De Rossi Baojie Wae Scott G. Franzblau Fabrizio Manetti Maurizio Botta Mariangela Biava 《PloS one》2013,8(2)
1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in
vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene. The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. The resulting ED99 of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery. 相似文献
72.
Matteo Surdo Emanuela Balestra Patrizia Saccomandi Fabiola Di Santo Marco Montano Domenico Di Carlo Loredana Sarmati Stefano Aquaro Massimo Andreoni Valentina Svicher Carlo Federico Perno Francesca Ceccherini-Silberstein 《PloS one》2013,8(7)
Background
Dual/mixed-tropic HIV-1 strains are predominant in a significant proportion of patients, though little information is available regarding their replication-capacity and susceptibility against CCR5-antagonists in-vitro. The aim of the study was to analyze the replication-capacity and susceptibility to maraviroc of HIV-1 clinical isolates with different tropism characteristics in primary monocyte-derived-macrophages (MDM), peripheral-blood-mononuclear-cells (PBMC), and CD4+T-lymphocytes.Methods
Twenty-three HIV-1 isolates were phenotipically and genotipically characterized as R5, X4 or dual (discriminated as R5+/X4, R5/X4, R5/X4+). Phenotypic-tropism was evaluated by multiple-cycles-assay on U87MG-CD4+-CCR5+−/CXCR4+-expressing cells. Genotypic-tropism prediction was obtained using Geno2Pheno-algorithm (false-positive-rate [FPR] = 10%). Replication-capacity and susceptibility to maraviroc were investigated in human-primary MDM, PBMC and CD4+T-cells. AMD3100 was used as CXCR4-inhibitor. Infectivity of R5/Dual/X4-viruses in presence/absence of maraviroc was assessed also by total HIV-DNA, quantified by real-time polymerase-chain-reaction.Results
Among 23 HIV-1 clinical isolates, phenotypic-tropism-assay distinguished 4, 17 and 2 viruses with R5-tropic, dual/mixed-, and X4-tropic characteristics, respectively. Overall, viruses defined as R5+/X4-tropic were found with the highest prevalence (10/23, 43.5%). The majority of isolates efficiently replicated in both PBMC and CD4+T-cells, regardless of their tropism, while MDM mainly sustained replication of R5- or R5+/X4-tropic isolates; strong correlation between viral-replication and genotypic-FPR-values was observed in MDM (rho = 0.710;p-value = 1.4e-4). In all primary cells, maraviroc inhibited viral-replication of isolates not only with pure R5- but also with dual/mixed tropism (mainly R5+/X4 and, to a lesser extent R5/X4 and R5/X4+). Finally, no main differences by comparing the total HIV-DNA with the p24-production in presence/absence of maraviroc were found.Conclusions
Maraviroc is effective in-vitro against viruses with dual-characteristics in both MDM and lymphocytes, despite the potential X4-mediated escape. This suggests that the concept of HIV-entry through one of the two coreceptors “separately” may require revision, and that the use of CCR5-antagonists in patients with dual/mixed-tropic viruses may be a therapeutic-option that deserves further investigations in different clinical settings. 相似文献73.
Silvia Rossi Valeria Studer Alessandro Moscatelli Caterina Motta Giancarlo Coghe Giuseppe Fenu Stacy Caillier Fabio Buttari Francesco Mori Francesca Barbieri Maura Castelli Valentina De Chiara Fabrizia Monteleone Raffaele Mancino Giorgio Bernardi Sergio E. Baranzini Maria G. Marrosu Jorge R. Oksenberg Diego Centonze 《PloS one》2013,8(6)
Synaptic transmission and plasticity mediated by NMDA receptors (NMDARs) could modulate the severity of multiple sclerosis (MS). Here the role of NMDARs in MS was first explored in 691 subjects carrying specific allelic variants of the NR1 subunit gene or of the NR2B subunit gene of this glutamate receptor. The analysis was replicated for significant SNPs in an independent sample of 1548 MS subjects. The C allele of rs4880213 was found to be associated with reduced NMDAR-mediated cortical excitability, and with increased probability of having more disability than the CT/TT MS subjects. MS severity was higher in the CC group among relapsing-remitting MS (RR-MS) patients, while primary progressive MS (PP-MS) subjects homozygous for the T allele had more pronounced clinical worsening. Mean time to first relapse, but not to an active MRI scan, was lower in the CC group of RR-MS patients, and the number of subjects with two or more clinical relapses in the first two years of the disease was higher in CC compared to CT/TT group. Furthermore, the percentage of relapses associated with residual disability was lower in subjects carrying the T allele. Lesion load at the MRI was conversely unaffected by the C or T allele of this SNP in RR-MS patients. Axonal and neuronal degeneration at the optical coherence tomography was more severe in the TT group of PP-MS patients, while reduced retinal nerve fiber thickness had less consequences on visual acuity in RR-MS patients bearing the T allele. Finally, the T allele was associated with preserved cognitive abilities at the Rao’s brief repeatable neuropsychological battery in RR-MS. Signaling through glutamate NMDARs enhances both compensatory synaptic plasticity and excitotoxic neurodegeneration, impacting in opposite ways on RR-MS and PP-MS pathophysiological mechanisms. 相似文献
74.
Xingxing Cai Jing Fan Zhuxi Jiang Barbara Basso Francesco Sala Alberto Spada Fabrizio Grassi Bao-Rong Lu 《PloS one》2013,8(11)
The characterization of genetic divergence and relationships of a set of germplasm is essential for its efficient applications in crop breeding and understanding of the origin/evolution of crop varieties from a given geographical region. As the largest rice producing country in Europe, Italy holds rice germplasm with abundant genetic diversity. Although Italian rice varieties and the traditional ones in particular have played important roles in rice production and breeding, knowledge concerning the origin and evolution of Italian traditional varieties is still limited. To solve the puzzle of Italian rice origin, we characterized genetic divergence and relationships of 348 rice varieties from Italy and Asia based on the polymorphisms of microsatellite fingerprints. We also included common wild rice O. rufipogon as a reference in the characterization. Results indicated relatively rich genetic diversity (H
e = 0.63-0.65) in Italian rice varieties. Further analyses revealed a close genetic relationship of the Italian traditional varieties with those from northern China, which provides strong genetic evidence for tracing the possible origin of early established rice varieties in Italy. These findings have significant implications for the rice breeding programs, in which appropriate germplasm can be selected from a given region and utilized for transferring unique genetic traits based on its genetic diversity and evolutionary relationships. 相似文献
75.
76.
77.
Sara Bruschini Simona di Martino Maria Elena Pisanu Luigi Fattore Claudia De Vitis Valentina Laquintana Simonetta Buglioni Eugenio Tabbì Andrea Cerri Paolo Visca Gabriele Alessandrini Francesco Facciolo Christian Napoli Marcella Trombetta Antonio Santoro Anna Crescenzi Gennaro Ciliberto Rita Mancini 《Journal of cellular physiology》2020,235(3):1877-1887
78.
79.
Andrea Berruti Roberto Borriello Maria Teresa Della Beffa Valentina Scariot Valeria Bianciotto 《Symbiosis (Philadelphia, Pa.)》2013,61(2):63-76
Camellia japonica L. (Theaceae, Theales) is an acidophilic evergreen flowering shrub and is traded worldwide. Symbiotic associations between the roots of this plant species and arbuscular mycorrhizal fungi (AMF), commonly recognized as natural biofertilizers and biocontrol agents, have been poorly studied so far. The aim of our study was to verify whether the application of nonspecific commercial AMF-based inocula could succeed and improve the growth of C. japonica. An experiment was conducted concerning the application of commercial inocula constituted by a specific AMF isolate (Funneliformis mosseae) or a consortium of different fungi and bacteria as alternatives to fertilization in pot cultivated C. japonica ‘Dr. Burnside’. Several growth parameters, plant nutrition and mycorrhization levels were monitored at the end of plant cultivation. Generally, increases in some macroelements (Ca, Mg, K) and microelements (Cu, Mn, Fe, Zn) were detected in the root system of inoculated camellias, while only Cu and Mn accumulation was increased in the leaves. Plants inoculated with the consortium inoculum exhibited increased chlorophyll content and foliage diameter while plants inoculated with F. mosseae exhibited increased number of flowers. Based on the polymorphism of an 18S rDNA region, we assessed the inoculated AMF that colonized C. japonica roots. The experiments showed that the applied AMF poorly colonized the root system of C. japonica. We suggest that commercial AMF formulations should be more targeted and host-specific in order to successfully colonize the host root and, potentially, fully express their benefits. 相似文献
80.
Miriam Rossi Francesco Caruso Erica J. Crespi Jens Z. Pedersen Gail Nakano Michelle Duong Celia Mckee Sharon Lee Manasi Jiwrajka Charles Caldwell Francis Baffour Dylan Alex Karlin Genevieve Lidoff Stefano Leone Valentina Balducci Jaroslav Miler Sandra Incerpi 《Biochimie》2013
In order to better understand the antioxidant behavior of a series of polyphenolic 2′-hydroxychalcones, we describe the results of several chemical and biological studies, in vitro and in vivo. Single crystal X-ray methods elucidated their molecular structures and important intermolecular interactions such as H-bonding and molecular stacking in the crystal structures that contribute to our knowledge in explaining antioxidant activity. The results of experiments using the 1,1-diphenyl-2-dipicrylhydrazyl (DPPH) UV–vis spectroscopic method indicate that a hydroxyl group in position 5′ induces the highest antioxidant activity. Consequently, 2,2′,5′-trihydroxychalcone was selected for further study in vitro towards ROS scavenging in L-6 myoblasts and THP-1 human monocytes, where it shows an excellent antioxidant activity in a concentration range lower than that reported by most studies of related molecules. In addition, this chalcone shows a very selective activity: it inhibits the proliferation of leukemic cells, but it does not affect the normal L-6 myoblasts and human fibroblasts. In studying 2,2′,5′-trihydroxychalcone's effect on weight gain and serum glucose and insulin levels in Zucker fatty (fa−/fa−) rats we found that supplementing the diet with a 10 mg/kg dose of this chalcone (3 times weekly) blunted the increase in glucose that co-occurs with weight gain over the 6-week treatment period. It is concluded that 2,2′,5′-trihydroxychalcone has the potential to serve as a protective agent for some debilitating diseases. 相似文献