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141.
González Díaz H Olazabal E Castañedo N Sánchez IH Morales A Serrano HS González J de Armas RR 《Journal of molecular modeling》2002,8(8):237-245
A novel method for in silico selection of fluckicidal drugs is introduced. Two QSARs that permit us to discriminate between fasciolicide and non-fasciolicide drugs (the first) and to outline some conclusions about the possible mechanism of action of a chemical (the second) are performed. The first model correctly classified 93.85% of compounds in the training series and 89.5% of the compounds in the predicting one. This model correctly classified 87.7, 93.8, 92.2 and 93.9% of compounds in leave- n-out cross validation procedures when n takes values from 2 to until 6. The model seems to be stable in around 92% of good classification in leave- n-out cross validation analysis when n>6. The second model correctly classified 70% of non-fasciolicide compounds, 85.71% of beta-tubulin inhibitors and 100% of proton ionophores in the training set. This model recognizes as proton ionophores 100% of any nitrosalicylanilides in the predicting series. Both models have a low p-level <0.05. Finally, the experimental assay of six organic chemicals by an in vivo test permit us to carry out an assessment of the model with a fairly good 100% agreement between experiment and theoretical prediction. 相似文献
142.
Sarria B Naline E Zhang Y Cortijo J Molimard M Moreau J Therond P Advenier C Morcillo EJ 《American journal of physiology. Lung cellular and molecular physiology》2002,283(5):L1125-L1132
The muscarinic functional antagonism of isoproterenol relaxation and the contribution of muscarinic M2 receptors were examined in human isolated bronchus. In intact tissues, acetylcholine (ACh) precontraction decreased isoproterenol potency and maximal relaxation (-log EC50 shift = -1.49 +/- 0.16 and E(max) inhibition for 100 microM ACh = 30%) more than the same levels of histamine contraction. The M2 receptor-selective antagonist methoctramine (1 microM) reduced this antagonism in ACh- but not histamine-contracted tissues. Similar results were obtained for forskolin-induced relaxation. After selective inactivation of M3 receptors with 4-diphenylacetoxy-N-(2-chloroethyl)piperadine hydrochloric acid (30 nM), demonstrated by abolition of contractile and inositol phosphate responses to ACh, muscarinic recontractile responses were obtained in U-46619-precontracted tissues fully relaxed with isoproterenol. Methoctramine antagonized recontraction, with pK(B) (6.9) higher than in intact tissues (5.4), suggesting participation of M2 receptors. In M3-inactivated tissues, methoctramine augmented the isoproterenol relaxant potency in U-46619-contracted bronchus and reversed the ACh-induced inhibition of isoproterenol cAMP accumulation. These results indicate that M2 receptors cause indirect contraction of human bronchus by reversing sympathetically mediated relaxation and contribute to cholinergic functional antagonism. 相似文献
143.
Prieto A Díaz D Barcenilla H García-Suárez J Reyes E Monserrat J San Antonio E Melero D de la Hera A Orfao A Alvarez-Mon M 《Cytometry》2002,48(4):185-193
BACKGROUND: Late apoptotic cells divide into apoptotic bodies and are missed by current detection methods. This results in an artificially low apoptotic index (AI). METHODS: This study proposes a flow cytometry-based ratiometric method that uses an internal reference standard of microbeads combined with fluorescein-annexin V binding and 7-aminoactinomycin D to enumerate viable, necrotic, and early and late apoptotic cells within specific subsets of a heterogeneous culture. RESULTS: In the absence of cell growth, the number of apoptotic cells that undergo fragmentation into apoptotic bodies in culture can also be determined accurately by this method. This information can then be used to obtain the apoptotic rate (AR), a new indicator of apoptosis that calculates the proportion of cells that have undergone apoptosis with respect to the total number of seeded cells. The main limitation of the method is that the AR is only suitable for the study of apoptosis in noncycling cells. CONCLUSIONS: This study reveals the superiority of the proposed method over the widely used Nicoletti method and current annexin-V binding methods. The AI did not reflect the true incidence of lymphocyte apoptosis, neither in response to lectins or phorbol esters, nor to serum deprivation. AR was more sensitive than AI, detecting apoptosis at lower concentrations of cell death inducers in all the subsets studied. 相似文献
144.
In vitro self-assembled HCV core virus-like particles induce a strong antibody immune response in sheep. 总被引:3,自引:0,他引:3
Nelson Acosta-Rivero Julio C Alvarez-Obregón Alexis Musacchio Viviana Falcón Santiago Due?as-Carrera Jeny Marante Ivón Menéndez Juan Morales 《Biochemical and biophysical research communications》2002,290(1):300-304
The in vitro self-assembly properties of the entire hepatitis C virus core protein (HCcAg) obtained from Pichia pastoris cells and the induction of specific antibody immune response were studied. HCcAg was purified as a low-molecular-weight species by electroelution under denaturing conditions for confirmation of its self-assembly properties. After renaturalization, electron microscopy showed that HCcAg assembled into spherical particles of 30 nm. HCcAg also showed homogeneity and was specifically recognized by serum from a chronic HCV carrier patient. The data indicated that in vitro assembly of HCcAg, into virus-like particles resembling HCV nucleocapsid particles at a mature stage, is an intrinsic quality of this protein. Finally, HCcAg generated a strong antibody immune response in sheep, suggesting its usefulness for stimulating the host immune response against HCV. 相似文献
145.
The role of cytokines in osteoarthritis pathophysiology 总被引:54,自引:0,他引:54
146.
147.
de Bedout C Ayabaca J Vega R Méndez M Santiago AR Pabón ML Tabares A Arango M Restrepo A Newell V 《Biomédica : revista del Instituto Nacional de Salud》2003,23(1):31-37
Infections caused by yeasts belonging to the genus Candida have increased dramatically in the last decades, especially in hospital settings. Concomittantly, antimycotic resistance has emerged, as well as the appearance of non-Candida albicans isolates. To standardize in vitro antifungal susceptibility tests, the agar diffusion test was developed using disks impregnated with the antimycotic compound. Electronic recording of the inhibition zone (BIOMIC), furnishes objective values for the minimal inhibitory concentration (MIC). The fluconazole susceptibility patterns were determined for Candida species isolated from 2.139 patients seen in outpatient clinics or in health-care centers in Colombia, Ecuador and Venezuela. Candida albicans was the species most frequently isolated (62%), followed at a distance by Candida parapsilosis (11%), Candida tropicalis (8.5%), Candida glabata (3.5%) and Candida krusei (2.2%). MIC determinations showed that 88.1% of these isolates were susceptible to fluconazole, 5.1% were susceptible-dose-dependant and 6.8% resistant. An important proportion (92.1%) of the C. albicans isolates proved susceptible while resistance predominated in the remaining species. These results indicate that the BIOMIC method is rapid and simple, constituting a suitable tool for the epidemiologic surveillance of resistance in Candida species. 相似文献
148.
Based on the ability of bile acids to vectorialize the cytostatic activity of other agents, we have designed and synthesized a new series of platinum and gold complexes. These compounds were studied and characterized by elemental analysis, FT-IR, FAB(+)/MS, 1H, 13C and 195Pt NMR, UV-Vis spectroscopy and conductivity measurements in solution, among other techniques. Kinetic studies carried out in aqueous solution and in the presence of different NaCl concentrations: 4 mM (similar to cytoplasmic concentration), 150 mM (similar to plasmatic concentration). The effects on the electrophoretic mobility of the pUC18 plasmid, the DNA denaturation temperature, and ethidium bromide (EtBr) binding to DNA were studied. The complexes are able to inter-react with DNA to inhibit DNA synthesis and hence, to reduce cell proliferation. The complexes were evaluated for in vitro cytostatic activity against human colon adenocarcinoma, mouse hepatoma, human hepatoma, mouse leukemia, etc. The antitumor effect of some of the compounds prepared was similar to that of cisplatin. However, other compounds had lower cytostatic activity. This different behavior can be accounted for by the structure/activity relationship (SAR), although other factors, such as uptake and the different kinetic behavior in solution, may be responsible for these differences. 相似文献
149.
The mechanical stability of ubiquitin is linkage dependent 总被引:12,自引:0,他引:12
Carrion-Vazquez M Li H Lu H Marszalek PE Oberhauser AF Fernandez JM 《Nature structural biology》2003,10(9):738-743
Ubiquitin chains are formed through the action of a set of enzymes that covalently link ubiquitin either through peptide bonds or through isopeptide bonds between their C terminus and any of four lysine residues. These naturally occurring polyproteins allow one to study the mechanical stability of a protein, when force is applied through different linkages. Here we used single-molecule force spectroscopy techniques to examine the mechanical stability of N-C-linked and Lys48-C-linked ubiquitin chains. We combined these experiments with steered molecular dynamics (SMD) simulations and found that the mechanical stability and unfolding pathway of ubiquitin strongly depend on the linkage through which the mechanical force is applied to the protein. Hence, a protein that is otherwise very stable may be easily unfolded by a relatively weak mechanical force applied through the right linkage. This may be a widespread mechanism in biological systems. 相似文献
150.
Chagas disease, caused by Trypanosoma cruzi, is a major public health problem in Latin America, where it constitutes one of the largest parasitic disease burdens. Specific treatment of this condition has been controversial, but there is a growing consensus that elimination of T. cruzi could be a prerequisite to arrest the evolution of the disease. Currently available chemotherapy, based on a nitrofuran (nifurtimox) and a nitroimidazole (benznidazole), is unsatisfactory because of their limited efficacy in the prevalent chronic stage of the disease and their toxic side effects. New approaches to specific chemotherapy are being advanced. Biochemical routes such as the de novo sterol biosynthesis pathway, cruzipain-mediated proteolysis and pyrophosphate metabolism have been chemically validated, and the selective in vitro and in vivo anti-T. cruzi activities of inhibitors of these pathways have been demonstrated. Several of these compounds have now completed pre-clinical studies and are poised for clinical trials in the near future. Other promising approaches include interference with trypanothione synthesis and redox metabolism, in addition to inhibition of purine salvage, dihydrofolate reductase, phospholipid biosynthesis, and protein prenylation and acylation. 相似文献