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71.
Radiolabeled somatostatin analogues have been successfully used for targeted radiotherapy and for imaging of somatostatin receptor (sst1-5)-positive tumors. Nevertheless, these analogues are subject to improving their tumor-to-nontarget ratio to enhance their diagnostic or therapeutic properties, preventing nephrotoxicity. In order to understand the influence of lipophilicity and charge on the pharmacokinetic profile of [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)]-somatostatin-based radioligands such as [DOTA,1-Nal3]-octreotide (DOTA-NOC), different spacers (X) based on 8-amino-3,6-dioxaoctanoic acid (PEG2), 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG4), N-acetyl glucosamine (GlcNAc), triglycine, beta-alanine, aspartic acid, and lysine were introduced between the chelator DOTA and the peptide NOC. All DOTA-X-NOC conjugates were synthesized by Fmoc solid-phase synthesis. The partition coefficient (log D) at pH = 7.4 indicated that higher hydrophilicity than [111In-DOTA]-NOC was achieved with the introduction of the mentioned spacers, except with triglycine and beta-alanine. The high affinity of [InIII-DOTA]-NOC for human sst2 (hsst2) was preserved with the structural modifications, while an overall drop for hsst3 affinity was observed, except in the case of [InIII-DOTA]-beta-Ala-NOC. The new conjugates preserved the good affinity for hsst5, except for [InIII-DOTA]-Asn(GlcNAc)-NOC, which showed decreased affinity. A significant 1.2-fold improvement in the specific internalization rate in AR4-2J rat pancreatic tumor cells (sst2 receptor expression) at 4 h was achieved with the introduction of Asp as a spacer in the parent compound. In sst3-expressing HEK cells, the specific internalization rate at 4 h for [111In-DOTA]-NOC (13.1% +/- 0.3%) was maintained with [111In-DOTA]-beta-Ala-NOC (14.0% +/- 1.8%), but the remaining derivatives showed <2% specific internalization. Biodistribution studies were performed with Lewis rats bearing the AR4-2J rat pancreatic tumor. In comparison to [111In-DOTA]-NOC (2.96% +/- 0.48% IA/g), the specific uptake in the tumor at 4 h p.i. was significantly improved for the 111In-labeled sugar analogue (4.17% +/- 0.46% IA/g), which among all the new derivatives presented the best tumor-to-kidney ratio (1.9). 相似文献
72.
73.
Filipa Loureiro Luís Miguel Rosalino David W. Macdonald Margarida Santos-Reis 《Ecological Research》2007,22(5):837-844
Movement is the process by which individual organisms are displaced over time to eat, reproduce and defend resources. Fractal
analysis is a technique used to study animal movement that measures spatial complexity of path tortuosity; here, we apply
it to characterize the movement patterns of the Eurasian badger (Meles meles) in a Mediterranean landscape. We calculated path tortuosity overall and seasonally, and for individuals of different sexes
and social groups. The influence of variables related to badgers’ resources (food, shelter, water), human infra-structures
and weather conditions were analysed with respect to the tortuosity of each badger’s path. A total of 55 search paths from
six badgers were considered for this study. Although badgers generally displayed convoluted movement, there were two exceptions:
(a) males overall and (b) all badgers in summer; for both, movements had a lower fractal value, i.e. were less tortuous. The
convoluted movement pattern generally observed is probably adapted to the clumped distribution of food in the study area.
Nevertheless, our results suggest that the use of dens and latrines were the principal determinants of tortuosity of badgers’
paths while foraging. 相似文献
74.
Cíntia Júnia Monteiro Suianne Letícia Antunes Mota Lívia de Figueiredo Diniz Maria Terezinha Bahia Karen CM Moraes 《Memórias do Instituto Oswaldo Cruz》2015,110(8):996-1002
Chagas disease, which is caused by the intracellular protozoanTrypanosoma
cruzi, is a serious health problem in Latin America. The heart is one of
the major organs affected by this parasitic infection. The pathogenesis of tissue
remodelling, particularly regarding cardiomyocyte behaviour after parasite infection,
and the molecular mechanisms that occur immediately following parasite entry into
host cells are not yet completely understood. Previous studies have reported that the
establishment of parasitism is connected to the activation of the
phosphatidylinositol-3 kinase (PI3K), which controls important steps in cellular
metabolism by regulating the production of the second messenger
phosphatidylinositol-3,4,5-trisphosphate. Particularly, the tumour suppressor PTEN is
a negative regulator of PI3K signalling. However, mechanistic details of the
modulatory activity of PTEN on Chagas disease have not been elucidated. To address
this question, H9c2 cells were infected with T. cruzi Berenice 62
strain and the expression of a specific set of microRNAs (miRNAs) were investigated.
Our cellular model demonstrated that miRNA-190b is correlated to the decrease of
cellular viability rates by negatively modulating PTEN protein expression in
T. cruzi-infected cells. 相似文献
75.
Louisy Sanches dos Santos Camila Azevedo Antunes Cintia Silva dos Santos José Augusto Adler Pereira Priscila Soares Sabbadini Maria das Gra?as de Luna Vasco Azevedo Raphael Hirata Júnior Andreas Burkovski Lídia Maria Buarque de Oliveira Asad Ana Luíza Mattos-Guaraldi 《Memórias do Instituto Oswaldo Cruz》2015,110(5):662-668
Corynebacterium diphtheriae, the aetiologic agent of diphtheria,
also represents a global medical challenge because of the existence of invasive
strains as causative agents of systemic infections. Although tellurite
(TeO32-) is toxic to most microorganisms, TeO32--resistant
bacteria, including C. diphtheriae, exist in
nature. The presence of TeO32--resistance (TeR)
determinants in pathogenic bacteria might provide selective advantages in the natural
environment. In the present study, we investigated the role of the putative
TeR determinant (CDCE8392_813gene) in the virulence
attributes of diphtheria bacilli. The disruption of CDCE8392_0813 gene expression in
the LDCIC-L1 mutant increased susceptibility to TeO32- and reactive oxygen
species (hydrogen peroxide), but not to other antimicrobial agents. The LDCIC-L1
mutant also showed a decrease in both the lethality of Caenorhabditis elegans
and the survival inside of human epithelial cells compared to wild-type
strain. Conversely, the haemagglutinating activity and adherence to and formation of
biofilms on different abiotic surfaces were not regulated through the CDCE8392_0813
gene. In conclusion, the CDCE8392_813 gene contributes to the TeR and
pathogenic potential of C. diphtheriae. 相似文献
76.
77.
GMP synthase is essential for viability and infectivity of Trypanosoma brucei despite a redundant purine salvage pathway
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Filipa Rijo‐Ferreira Jun Chen Igor Cestari Kenneth Stuart Benjamin P. Tu Margaret A. Phillips 《Molecular microbiology》2015,97(5):1006-1020
The causative agent of human African trypanosomiasis, Trypanosoma brucei, lacks de novo purine biosynthesis and depends on purine salvage from the host. The purine salvage pathway is redundant and contains two routes to guanosine‐5′‐monophosphate (GMP) formation: conversion from xanthosine‐5′‐monophosphate (XMP) by GMP synthase (GMPS) or direct salvage of guanine by hypoxanthine‐guanine phosphoribosyltransferase (HGPRT). We show recombinant T. brucei GMPS efficiently catalyzes GMP formation. Genetic knockout of GMPS in bloodstream parasites led to depletion of guanine nucleotide pools and was lethal. Growth of gmps null cells was only rescued by supraphysiological guanine concentrations (100 μM) or by expression of an extrachromosomal copy of GMPS. Hypoxanthine was a competitive inhibitor of guanine rescue, consistent with a common uptake/metabolic conversion mechanism. In mice, gmps null parasites were unable to establish an infection demonstrating that GMPS is essential for virulence and that plasma guanine is insufficient to support parasite purine requirements. These data validate GMPS as a potential therapeutic target for treatment of human African trypanosomiasis. The ability to strategically inhibit key metabolic enzymes in the purine pathway unexpectedly bypasses its functional redundancy by exploiting both the nature of pathway flux and the limited nutrient environment of the parasite's extracellular niche. 相似文献
78.
79.
80.
Guillermín Agüero-Chapin Gisselle Pérez-Machado Reinaldo Molina-Ruiz Yunierkis Pérez-Castillo Aliuska Morales-Helguera Vítor Vasconcelos Agostinho Antunes 《Amino acids》2011,40(2):431-442
Bacteriocins are proteinaceous toxins produced and exported by both gram-negative and gram-positive bacteria as a defense
mechanism. The bacteriocin protein family is highly diverse, which complicates the identification of bacteriocin-like sequences
using alignment approaches. The use of topological indices (TIs) irrespective of sequence similarity can be a promising alternative
to predict proteinaceous bacteriocins. Thus, we present Topological Indices to BioPolymers (TI2BioP) as an alignment-free
approach inspired in both the Topological Substructural Molecular Design (TOPS-MODE) and Markov Chain Invariants for Network
Selection and Design (MARCH-INSIDE) methodology. TI2BioP allows the calculation of the spectral moments as simple TIs to seek
quantitative sequence-function relationships (QSFR) models. Since hydrophobicity and basicity are major criteria for the bactericide
activity of bacteriocins, the spectral moments (HPμ
k
) were derived for the first time from protein artificial secondary structures based on amino acid clustering into a Cartesian
system of hydrophobicity and polarity. Several orders of HPμ
k
characterized numerically 196 bacteriocin-like sequences and a control group made up of 200 representative CATH domains.
Subsequently, they were used to develop an alignment-free QSFR model allowing a 76.92% discrimination of bacteriocin proteins
from other domains, a relevant result considering the high sequence diversity among the members of both groups. The model
showed a prediction overall performance of 72.16%, detecting specifically 66.7% of proteinaceous bacteriocins whereas the
InterProScan retrieved just 60.2%. As a practical validation, the model also predicted successfully the cryptic bactericide
function of the Cry 1Ab C-terminal domain from Bacillus thuringiensis’s endotoxin, which has not been detected by classical alignment methods. 相似文献