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101.
Bernardo R Tura Helena F Martino Luis H Gowdak Ricardo Ribeiro dos Santos Hans F Dohmann José E Krieger Gilson Feitosa Fábio Vilas-Boas Sérgio A Oliveira Suzana A Silva Augusto Z Bozza Radovan Borojevic Antonio C Campos de Carvalho 《Trials》2007,8(1):1-4
Background
Cardiovascular diseases are the major cause of death in the world. Current treatments have not been able to reverse this scenario, creating the need for the development of new therapies. Cell therapies have emerged as an alternative for cardiac diseases of distinct causes in experimental animal studies and more recently in clinical trials.Method/Design
We have designed clinical trials to test for the efficacy of autologous bone marrow derived mononuclear cell therapies in four different cardiopathies: acute and chronic ischemic heart disease, and Chagasic and dilated cardiomyopathy. All trials are multicenter, randomized, double-blind and placebo controlled. In each trial 300 patients will be enrolled and receive optimized therapy for their specific condition. Additionally, half of the patients will receive the autologous bone marrow cells while the other half will receive placebo (saline with 5% autologous serum). For each trial there are specific inclusion and exclusion criteria and the method for cell delivery is intramyocardial for the chronic ischemic heart disease and intracoronary for all others. Primary endpoint for all studies will be the difference in ejection fraction (determined by Simpson's rule) six and twelve months after intervention in relation to the basal ejection fraction. The main hypothesis of this study is that the patients who receive the autologous bone-marrow stem cell implant will have after a 6 month follow-up a mean increase of 5% in absolute left ventricular ejection fraction in comparison with the control group.Discussion
Many phase I clinical trials using cell therapy for cardiac diseases have already been performed. The few randomized studies have yielded conflicting results, rendering necessary larger well controlled trials to test for efficacy of cell therapies in cardiopathies. The trials registration numbers at the NIH registry are the following: Chagasic cardiomyopathy (NCT00349271), dilated cardiomyopathy (NCT00333827), acute myocardial infarction (NCT00350766) and Chronic Ischemic Heart Disease (NCT00362388). 相似文献102.
BACKGROUND AND AIMS: Oncidium hookeri is a neotropical species of epiphytic Orchidaceae found in the Brazilian Atlantic rainforest at the top of the Mantiqueira Range of mountains. The genetic variation of O. hookeri was studied to assess the distribution of genetic variability within and among six populations localized in Atlantic rainforest remnants. Gene flow among populations and the occurrence of recent bottlenecks were investigated in order to infer the degree of isolation of these populations. METHODS: Thirteen polymorphic loci were used for allozyme electrophoresis. The data were analysed by means of standard statistical approaches, to estimate gene diversity and the genetic structure of the populations. KEY RESULTS: The mean gene diversity and allelic richness were H(e) = 0.099 and A = 1.75, respectively. F-statistics revealed high heterozygote deficiencies in all populations (F(IS) = 0.43-0.82). Several rare alleles were found in all the populations, and three populations presented private alleles. Low genetic differentiation among O. hookeri populations was detected (F(ST) = 0.029); natural selection may be involved in PGM locus differentiation among populations. The genetic differentiation between paired populations was low, bearing no correlation with geographic distance (Mantel test: r = -0.34, P = 0.72). Only two populations showed signs of recent bottlenecks. CONCLUSIONS: The heterozygote deficiency found seems to be caused by pollinator behaviour; the low frequencies of several alleles of different loci can be maintained due to clonal propagation. Despite the stochastic nature of the wind-dispersal of seeds to long distances, this process may promote an effective gene flow among populations, thus avoiding genetic differentiation. 相似文献
103.
Gerardino D’Errico Giuseppe Vitiello Anna Maria D’Ursi Derek Marsh 《European biophysics journal : EBJ》2009,38(7):873-882
A tryptophan-rich octapeptide, C8 (Ac-Trp-Glu-Asp-Trp-Val-Gly-Trp-Ile-NH2), modelled on the membrane-proximal external region of the feline immunodeficiency virus (FIV) gp36 glycoprotein ectodomain,
exhibits potent antiviral activity against FIV. A mechanism has been proposed by which the peptide, being positioned on the
surface of the cell membrane, inhibits its fusion with the virus. In the present work, peptide–lipid interactions of C8 with
dimyristoyl phosphatidylcholine liposomes are investigated using electron spin resonance spectroscopy of spin-labelled lipids.
Three other peptides, obtained from modifications of C8, have also been investigated, in an attempt to clarify the essential
molecular features of the interactions involving the tryptophan residues. The results show that C8 adsorbs strongly on the
bilayer surface. Membrane binding requires not only the presence of the Trp residues in the sequence, but also their common
orientation on one side of the peptide that is engendered by the WX2 WX2 W motif. Membrane interaction correlates closely with peptide antiviral activity, indicating that the membrane is essential
in stabilizing the peptide conformation that will be able to inhibit viral infection. 相似文献
104.
Pasqualina D’Ursi Federica Chiappori Ivan Merelli Ermanna Rovida 《Biochemical and biophysical research communications》2009,383(4):445-449
The H5N1 virus neuraminidase structure was solved in two different conformations depending on the inhibitor concentration. In the absence of oseltamivir or at a low concentration, the neuraminidase structure assumes an open form that closes at a high oseltamivir concentration due to the shift of the so-called 150-loop near the active site. Although the close conformation is similar to all the other structurally known neuraminidase types, it doesn’t appear to be the most likely physiological condition for N1.To investigate the specific ligand binding properties of the open form, we screened by docking simulation, a large dataset of ligands and compared the results with closed form. The virtual screening procedure was implemented in a docking pipeline that also performs a step-by-step, target specific, filtering approach for data reduction. The selected ligands display binding ability involving multiple sites of interaction including the active site and an adjacent cavity made available by the 150-loop shift. Two ligands are especially interesting and are proposed as substituents to design oseltamivir derivatives specifically suited for the open conformation. 相似文献
105.
Tatjana Mihajilov-Krstev Dragan Radnović Dušanka Kitić Bojan Zlatković Mihailo Ristić Suzana Branković 《Central European Journal of Biology》2009,4(3):411-416
Essential oil of Satureja hortensis L. was analyzed by GC and GC/MS and tested by a broth micro-well dilution method for activity against multiresistant clinical
isolates of pathogenic bacteria from 10 different genera: Klebsiella, Escherichia, Proteus, Staphylococcus, Streptococcus, Pseudomonas, Enterococcus, Enterobacter, Citrobacter and Acinetobacter. The main compounds in the oil were carvacrol (67%), γ-terpinene (15.3%) and p-cymene (6.73%). The oil showed activity against
all tested strains. MIC/MBC values were in the range of 0.78-25 μl/ml, with the exception of the strain P. aeruginosa. Microbicidal
concentration for this particular strain (50 μl/ml) was the highest tested concentration. The oil showed inhibitory and bactericidal
effect at the same concentration (MIC=MBC) for all but three strains. 相似文献
106.
Cheng JT Hale JD Kindrachuk J Jenssen H Jessen H Elliott M Hancock RE Straus SK 《Biophysical journal》2010,99(9):2926-2935
Previous studies on aurein 2.2 and 2.3 in DMPC/DMPG and POPC/POPG membranes have shown that bilayer thickness and phosphatidylglycerol content have a significant impact on the interaction of these peptides with membrane bilayers. Further examination with the DiSC35 assay has indicated that aurein 2.2 induces greater membrane leakage than aurein 2.3 in Staphylococcus aureus C622. The only difference between these peptides is a Leu to Ile mutation at residue 13. To better understand the importance of this residue, the structure and activity of the L13A, L13F, and L13V mutants were investigated. In addition, we investigated a number of peptides with truncations at the C-terminus to determine whether the C-terminus, which contains residue 13, is crucial for antimicrobial activity. Solution circular dichroism results demonstrated that the L13F mutation and the truncation of the C-terminus by six residues resulted in decreased helical content, whereas the L13A or L13V mutation and the truncation of the C-terminus by three residues showed little to no effect on the structure. Oriented circular dichroism results demonstrated that only an extensive C-terminal truncation reduced the ability of the peptide to insert into lipid bilayers. 31P NMR spectroscopy showed that all peptides disorder the headgroups. The implications of these results in terms of antimicrobial activity and the ability of these peptides to induce leakage in S. aureus are discussed. The results suggest that the presence of the 13th residue in aurein 2.2 is important for structure and activity, but the exact nature of residue 13 is less important as long as it is a hydrophobic residue. 相似文献
107.
Yolanda Karla Cupertino da Silva Cristina Villarinho Augusto Maria Letícia de Castro Barbosa Gabriela Muniz de Albuquerque Melo Aline Cavalcanti de Queiroz Thays de Lima Matos Freire Dias Walfrido Bispo Júnior Eliezer J. Barreiro Lídia Moreira Lima Magna Suzana Alexandre-Moreira 《Bioorganic & medicinal chemistry》2010,18(14):5007-5015
In this paper, we report the synthesis and pharmacological evaluation of pyrazine N-acylhydrazone (NAH) derivatives (2a–s) designed as novel analgesic and anti-inflammatory drug candidates. This series was planned by molecular simplification of prototype 1 (LASSBio-1018), previously described as a non-selective cyclooxygenase inhibitor. Derivatives 2a–s were evaluated in several animal models of pain and inflammation, standing-out compound 2o (2-N′-[(E)-(3,4,5-trimethoxyphenyl) methylidene]-2-pyrazinecarbohydrazide; LASSBio-1181), that was also active in a murine model of chronic inflammation (i.e., adjuvant-induced arthritis test in rats) and can be considered a new analgesic and anti-inflammatory lead for drug development. 相似文献
108.
Zendelovska D Simeska S Sibinovska O Kostova E Milosevska K Jakovski K Jovanovska E Kikerkov I Trojacanec J Zafirov D 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2006,839(1-2):85-88
Nifedipine, a dihydropyridine calcium channel antagonist, is widely used in the treatment of hypertension and other cardiovascular disorders. A selective, sensitive and accurate high-performance liquid chromatographic method has been developed, validated and applied for determination of nifedipine in human plasma samples. A series of studies were conducted in order to investigate the effects of mobile phase composition, buffer concentration, mobile phase pH and concentration of organic modifiers, and to develop a convenient and easy-to-use method for quantitative analysis of nifedipine. The method involves solid-phase extraction on C18 cartridges. The chromatographic separation was accomplished on a Lichrocart Lichrospher 60 RP selectB column with a mobile phase composed of 0.020 mol/L KH2PO4 (pH 4.8) and acetonitrile (42:58, v/v). UV detection was set at 240 nm. The calibration curve was linear in the concentration range of 5.0-200.0 ng/mL for nifedipine in plasma and the limit of quantification was 5.0 ng/mL. 相似文献
109.
A key determinant for the survival of intracellular pathogens is their ability to subvert the cellular processes of the host to establish a compartment that allows replication. Although most microorganisms internalized by host cells are efficiently cleared following fusion with lysosomes, many pathogens have evolved mechanisms to escape this degradation. In this Review, we provide insight into the molecular processes that are targeted by pathogens that interact with the endoplasmic reticulum and thereby subvert the immune response, ensure their survival intracellularly and cause disease. We also discuss how the endoplasmic reticulum 'strikes back' and controls microbial growth. 相似文献
110.
Highly reactive aldehyde 4-hydroxynonenal (HNE) is the final product of lipid peroxidation, known as a second messenger of free radicals and a signaling molecule. It forms protein conjugates involved in pathology of various diseases. To determine cellular HNE-protein conjugates we developed indirect ELISA based on well-known, monoclonal antibody against HNE-histidine (HNE-His) adducts. The method was calibrated using HNE-albumin conjugates as standards (R2 = 0.999) and validated on human osteosarcoma cell cultures (HOS). The ELISA showed good sensitivity (8.1 pmol HNE-His/mg of protein), precision ( ± 8% intra-assay and ± 12% inter-assay) and spiking recovery ( ± 9%). The assay revealed 60-fold increase of cellular HNE-His adducts upon copper-induced lipid peroxidation of HOS. The ELISA matched HNE-immunocytochemistry of HNE-treated HOS cells and quantified the increase of cellular HNE-His conjugates in parallel to the decrease of free HNE in culture medium. The ELISA was developed as ELISA Stress for severe lipid peroxidation and ELISA Fine for studies on HNE physiology. 相似文献