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61.
62.
Francesca Orlandi Marcella Coronnello Cristina Bellucci Silvia Dei Luca Guandalini Dina Manetti Cecilia Martelli Maria Novella Romanelli Serena Scapecchi Milena Salerno Hayette Menif Ivan Bello Enrico Mini Elisabetta Teodori 《Bioorganic & medicinal chemistry》2013,21(2):456-465
As a continuation of previous research on a new series of potent and efficacious P-gp-dependent multidrug resistant (MDR) reversers with a N,N-bis(cyclohexanol)amine scaffold, we have designed and synthesized several analogs by modulation of the two aromatic moieties linked through ester functions to the N,N-bis(cyclohexanol)amine, aiming to optimize activity and to extend structure–activity relationships (SAR) within the series. This scaffold, when esterified with two different aromatic carboxylic acids, gives origin to four geometric isomers (cis/trans, trans/trans, cis/cis and trans/cis).The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Most of them resulted in being potent modulators of the extrusion pump P-gp, showing potency values ([I]0.5) in the submicromolar and nanomolar range. Of these, compounds 2b, 2c, 3d, 5a–d and 6d, showed excellent efficacy with a αmax close to 1. Selected compounds (2d, 3a, 3b, 5a–d) were further studied to evaluate their doxorubicin cytotoxicity potentiation (RF) on doxorubicin-resistant erythroleukemia K562 cells and were found able to enhance significantly doxorubicin cytotoxicity on K562/DOX cells.The results of both pirarubicin uptake and the cytotoxicity assay, indicate that the new compounds of the series are potent P-gp-mediated MDR reversers. They present a structure with a mix of flexible and rigid moieties, a property that seems critical to allow the molecules to choose the most productive of the several binding modes possible in the transporter recognition site.In particular, compounds 5c and 5d, similar to the already reported analogous isomers 1c and 1d,29 are potent and efficacious modulators of P-gp-dependent MDR and may be promising leads for the development of MDR-reversal drugs. 相似文献
63.
Connie Lu Stewart Turley Samuel T. Marionni Young-Jun Park Kelly K. Lee Marcella Patrick Ripal Shah Maria Sandkvist Matthew F. Bush Wim G.J. Hol 《Structure (London, England : 1993)》2013,21(9):1707-1717
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64.
Tamer B. Shabaneh Sondra L. Downey Ayrton L. Goddard Michael Screen Marcella M. Lucas Alan Eastman Alexei F. Kisselev 《PloS one》2013,8(2)
The proteasome inhibitor bortezomib (Velcade) is prescribed for the treatment of multiple myeloma. Clinically achievable concentrations of bortezomib cause less than 85% inhibition of the chymotrypsin-like activity of the proteasome, but little attention has been paid as to whether in vitro studies are representative of this level of inhibition. Patients receive bortezomib as an intravenous or subcutaneous bolus injection, resulting in maximum proteasome inhibition within one hour followed by a gradual recovery of activity. In contrast, most in vitro studies use continuous treatment so that activity never recovers. Replacing continuous treatment with 1 h-pulse treatment increases differences in sensitivity in a panel of 7 multiple myeloma cell lines from 5.3-fold to 18-fold, and reveals that the more sensitive cell lines undergo apoptosis at faster rates. Clinically achievable inhibition of active sites was sufficient to induce cytotoxicity only in one cell line. At concentrations of bortezomib that produced similar inhibition of peptidase activities a different extent of inhibition of protein degradation was observed, providing an explanation for the differential sensitivity. The amount of protein degraded per number of active proteasomes correlated with sensitivity to bortezomib. Thus, (i) in vitro studies of proteasome inhibitors should be conducted at pharmacologically achievable concentrations and duration of treatment; (ii) a similar level of inhibition of active sites results in a different extent of inhibition of protein breakdown in different cell lines, and hence a difference in sensitivity. 相似文献
65.
Edivaldo Herculano C. de Oliveira Marcella Mergulh?o Tagliarini Michelly S. dos Santos Patricia C. M. O'Brien Malcolm A. Ferguson-Smith 《PloS one》2013,8(7)
Buteoninae (Falconiformes, Accipitridae) consist of the widely distributed genus Buteo, and several closely related species in a group called “sub-buteonine hawks”, such as Buteogallus, Parabuteo, Asturina, Leucopternis and Busarellus, with unsolved phylogenetic relationships. Diploid number ranges between 2n = 66 and 2n = 68. Only one species, L. albicollis had its karyotype analyzed by molecular cytogenetics. The aim of this study was to present chromosomal analysis of three species of Buteoninae: Rupornis magnirostris, Asturina nitida and Buteogallus meridionallis using fluorescence in situ hybridization (FISH) experiments with telomeric and rDNA probes, as well as whole chromosome probes derived from Gallus gallus and Leucopternis albicollis. The three species analyzed herein showed similar karyotypes, with 2n = 68. Telomeric probes showed some interstitial telomeric sequences, which could be resulted by fusion processes occurred in the chromosomal evolution of the group, including the one found in the tassociation GGA1p/GGA6. In fact, this association was observed in all the three species analyzed in this paper, and also in L. albicollis, suggesting that it represents a cytogenetic signature which reinforces the monophyly of Neotropical buteoninae species. 相似文献
66.
Parathyroidectomy Improves Survival In Patients with Severe Hyperparathyroidism: A Comparative Study
Patricia Taschner Goldenstein Rosilene Motta Elias Lilian Pires de Freitas do Carmo Fernanda Oliveira Coelho Luciene Pereira Magalh?es Gisele Lins Antunes Melani Ribeiro Custódio Fábio Luiz de Menezes Montenegro Silvia Maria Titan Vanda Jorgetti Rosa Maria Affonso Moysés 《PloS one》2013,8(8)
Background and objectives
Secondary hyperparathyroidism (SHPT) in CKD is associated with an increased risk for mortality, but definitive data showing that parathormone control decreases mortality is still lacking. This study aimed to compare the mortality of patients with severe SHPT submitted to parathyroidectomy(PTX) with those who did not have access to surgery.Methods
This is a retrospective study in a cohort of 251 CKD patients with severe SHPT who were referred to a CKD-MBD Center for PTX from 2005 until 2012.Results
Most of our patients had indication of PTX, but only 49% of them had access to this surgical procedure. After a mean follow-up of 23 months, 72 patients had died. Non-survivors were older; more often had diabetes, lower serum 25 vitamin D and mostly had not been submitted to surgery. The relative risk of death was lower in the PTX patients (0.428; 95% CI, 0.28 to 0.67; p<0.0001). After adjustments, mortality risk was dependent on age (1.04; 95% CI, 1.01 to 1.07; p = 0.002), 25 vitamin D (0.43; 95% CI, 0.24 to 0.81; p = 0.006) and no access to PTX (4.13; 95% CI, 2.16 to 7.88; p<0.0001). Results remained the same in a second model using the PTX date as the study start date for the PTX group.Conclusions
Our data confirms the benefit of PTX on mortality in patients with severe SHPT. The high mortality encountered in our population is significant and urges the need to better treat these patients. 相似文献67.
Asia J. Murphy Zach J. Farris Sarah Karpanty Felix Ratelolahy Marcella J. Kelly 《International journal of primatology》2016,37(3):371-389
Primate populations, including Madagascar’s lemurs, are threatened worldwide and conservationists need accurate population estimates to develop targeted conservation plans. We sought to fill knowledge gaps for three lemur taxa —white-fronted brown lemur (Eulemur albifrons); eastern woolly lemur (Avahi laniger); and Allocebus/Microcebus, a category combining observations of hairy-eared dwarf lemurs (Allocebus trichotis) and mouse lemurs (Microcebus spp.)— in northeastern Madagascar by estimating their density, examining how their encounter rates and densities vary across three different forest types, and monitoring trends in encounter rates and densities at resurveyed sites, using data from surveys at six forest sites over a 4-year period (2010–2013). Landscape density for white-fronted brown lemur, eastern woolly lemur, and Allocebus/Microcebus was 21.5 (SE 3.67), 57.7 (SE 9.17), and 39.1 (SE 9.55) individuals/km2, respectively. There was no difference in density estimates at intact and intermediately degraded forest sites; however, we encountered white-fronted brown lemurs more often in intact forest (1.64 ± SE 0.40 individuals/km) than in intermediately degraded and degraded forest (0.15 ± SE 0.06 and 0.16 ± SE 0.06 individuals/km). In addition, we encountered white-fronted brown lemurs at lower rates in 2013 (0.15 ± SE 0.06 individuals/km) compared to 2010 (0.82 ± SE 0.12 individuals/km) at a resurveyed site. Our findings emphasize that primate researchers must account for variation in how lemur encounter rates and densities differ between intact and degraded forests, and although we observed a decline in white-fronted brown lemur encounter rate at our resurveyed site, we caution that changes in lemur encounter rates may simply reflect lower detection rates rather than lower density. Future research should focus on using conventional distance sampling techniques, which are infrequently used in primate studies, to provide more robust density estimates as a way to accurately assess trends and the effects of anthropogenic pressures on lemur populations. 相似文献
68.
Length–weight relationships (LWR) for 36 deep‐sea fish species belonging to 22 families are provided. Samples were collected during 2009 by trawling with the sampling design stratified by depths ranging from 200 to 550 m in the Colombian Caribbean Sea. To the best knowledge of the authors, this study represents the first study on length–weight relationships for 17 species worldwide, as well as 13 new maximum lengths. 相似文献
69.
70.
Elaine da Conceição Petronilho Magdalena do Nascimento Rennó Newton Gonçalves Castro Fernanda Motta R. da Silva Angelo da Cunha Pinto 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):1069-1078
Analogs of pralidoxime, which is a commercial antidote for intoxication from neurotoxic organophosphorus compounds, were designed, synthesized, characterized, and tested as potential inhibitors or reactivators of acetylcholinesterase (AChE) using the Ellman’s test, nuclear magnetic resonance, and molecular modeling. These analogs include 1-methylpyridine-2-carboxaldehyde hydrazone, 1-methylpyridine-2-carboxaldehyde guanylhydrazone, and six other guanylhydrazones obtained from different benzaldehydes. The results indicate that all compounds are weak AChE reactivators but relatively good AChE inhibitors. The most effective AChE inhibitor discovered was the guanylhydrazone derived from 2,4-dinitrobenzaldehyde and was compared with tacrine, displaying similar activity to this reference material. These results indicate that guanylhydrazones as well as future similar derivatives may function as drugs for the treatment of Alzheimer's disease. 相似文献