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Search Results: 1 - 10 of 689209 matches for " Miguel A. R. B. Castanho "
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Pop-Science: Facts or Fiction? Friend or Foe?
Castanho,Miguel A.R.B.;
Interciencia , 2003,
Abstract: scientific production and public understanding of science are linked but public images of science are not always realistic. scientific work is mostly pictured in the media as in-lab activity and evolving in big steps, overlooking the "extra-lab" work and all the daily small-step contributions to scientific progress. misconceptions in public awareness of science may seriously hinder scientific progress (e.g. in chemistry). journalists play a role in building a more realistic image of science. unbiased communication between journalists and scientists is thus crucial. unfortunately, such communication is not always simple. this essay is a scientist?s view on the interplay between journalists and scientists.
Lipossomas: a bala mágica acertou?
Santos, Nuno C.;Castanho, Miguel A. R. B.;
Química Nova , 2002, DOI: 10.1590/S0100-40422002000700019
Abstract: efficient drug delivery systems are as important as drug themselves. a powerful drug unable to reach the target cell is useless in practice. ehrlich's magic bullet was the first carrier system to be proposed. the evolution in this domain has been quite slow as the natural mechanisms of mammals against foreign products are hard to overcome. however, lipid-based systems (liposomes and related vesicles) have attained reasonable success. the basic preparations and structural features of liposomes and related vesicles as well as their applications are addressed from the chemist's and biochemist's point of view.
Lipossomas: a bala mágica acertou?
Santos Nuno C.,Castanho Miguel A. R. B.
Química Nova , 2002,
Abstract: Efficient drug delivery systems are as important as drug themselves. A powerful drug unable to reach the target cell is useless in practice. Ehrlich's Magic Bullet was the first carrier system to be proposed. The evolution in this domain has been quite slow as the natural mechanisms of mammals against foreign products are hard to overcome. However, lipid-based systems (liposomes and related vesicles) have attained reasonable success. The basic preparations and structural features of liposomes and related vesicles as well as their applications are addressed from the chemist's and biochemist's point of view.
The Application of Biophysical Techniques to Study Antimicrobial Peptides
Inês M. Torcato,Miguel A. R. B. Castanho,Sónia T. Henriques
Spectroscopy: An International Journal , 2012, DOI: 10.1155/2012/460702
Abstract: The increasing bacteria resistance to conventional antibiotics has led to the need for alternative therapies. Being part of the human innate defence system and with a broad spectrum of activity against bacteria, viruses, protozoa, and cancer cells, antimicrobial peptides (AMPs) are a very promising alternative. The mechanism of action of AMPs seems to broadly correlate with their ability to target the bacterial cell membrane. To understand and improve their effect, it is of major importance to unravel their mechanism of action and, in particular, to understand the peptide-membrane binding. Several biophysical techniques such as fluorescence spectroscopy, circular dichroism, zeta potential determination, and atomic force microscopy can be used to achieve this goal. Characteristics of AMPs-membranes interactions and the use of these biophysical techniques will be discussed.
HIV-1 Fusion Inhibitor Peptides Enfuvirtide and T-1249 Interact with Erythrocyte and Lymphocyte Membranes
Pedro M. Matos,Miguel A. R. B. Castanho,Nuno C. Santos
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009830
Abstract: Enfuvirtide and T-1249 are two HIV-1 fusion inhibitor peptides that bind to gp41 and prevent its fusogenic conformation, inhibiting viral entry into host cells. Previous studies established the relative preferences of these peptides for membrane model systems of defined lipid compositions. We aimed to understand the interaction of these peptides with the membranes of erythrocytes and peripheral blood mononuclear cells. The peptide behavior toward cell membranes was followed by di-8-ANEPPS fluorescence, a lipophilic probe sensitive to the changes in membrane dipole potential. We observed a fusion inhibitor concentration-dependent decrease on the membrane dipole potential. Quantitative analysis showed that T-1249 has an approximately eight-fold higher affinity towards cells, when compared with enfuvirtide. We also compared the binding towards di-8-ANEPPS labeled lipid vesicles that model cell membranes and obtained concordant results. We demonstrated the distinct enfuvirtide and T-1249 membranotropism for circulating blood cells, which can be translated to a feasible in vivo scenario. The enhanced interaction of T-1249 with cell membranes correlates with its higher efficacy, as it can increase and accelerate the drug binding to gp41 in its pre-fusion state.
rBPI21 Promotes Lipopolysaccharide Aggregation and Exerts Its Antimicrobial Effects by (Hemi)fusion of PG-Containing Membranes
Marco M. Domingues,Miguel A. R. B. Castanho,Nuno C. Santos
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008385
Abstract: Antimicrobial peptides (AMPs) are important potential alternatives to conventional therapies against bacterial infections. rBPI21 is a 21 kDa peptide based on the N-terminal region of the neutrophil bactericidal/permeability-increasing protein (BPI). This AMP possesses highly selective bactericidal effects on Gram-negative bacteria and have affinity for lipopolysaccharide (LPS) which is believed to be at the origin of its neutralizing effect of the LPS segregated into the bloodstream. We aim at understanding the molecular bases of rBPI21 bactericidal and LPS neutralization actions, using biomembrane model systems. Using dynamic light scattering spectroscopy we demonstrate that rBPI21 promotes aggregation of negatively charged large unilamellar vesicles (LUV), even in the absence of LPS, and LPS aggregates, while for zwitterionic phosphatidylcholine (POPC) LUV the size remains unchanged. The peptide also promotes the fusion (or hemifusion) of membranes containing phosphatidylglycerol (POPG). The aggregation and fusion of negatively charged LUV are peptide concentration-dependent until massive aggregation is reached, followed by sample flocculation/precipitation. Concomitantly, there is a progressive change in the zeta-potential of the LUV systems and LPS aggregates. LUV systems composed of phosphatidylglycerol (POPG) and lipid mixtures with POPG have higher zeta-potential variations than in the absence of POPG. The interaction of rBPI21 with lipid vesicles is followed by leakage, with higher effect in POPG-containing membranes. LPS aggregation can be related with a decreased toxicity, possibly by facilitating its clearance by macrophage phagocytosis and/or blocking of LPS specific receptor recognition. Our data indicate that rBPI21 mechanism of action at the molecular level involves the interaction with the LPS of the outer membrane of Gram-negative bacteria, followed by internalization and leakage induction through the (hemi)fusion of the bacterial outer and inner membranes, both enriched in phosphatidylglycerol.
Conjugation of Cholesterol to HIV-1 Fusion Inhibitor C34 Increases Peptide-Membrane Interactions Potentiating Its Action
Axel Hollmann, Pedro M. Matos, Marcelo T. Augusto, Miguel A. R. B. Castanho, Nuno C. Santos
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060302
Abstract: Recently, the covalent binding of a cholesterol moiety to a classical HIV-1 fusion inhibitor peptide, C34, was shown to potentiate its antiviral activity. Our purpose was to evaluate the interaction of cholesterol-conjugated and native C34 with membrane model systems and human blood cells to understand the effects of this derivatization. Lipid vesicles and monolayers with defined compositions were used as model membranes. C34-cholesterol partitions more to fluid phase membranes that mimic biological membranes. Importantly, there is a preference of the conjugate for liquid ordered membranes, rich in cholesterol and/or sphingomyelin, as observed both from partition and surface pressure studies. In human erythrocytes and peripheral blood mononuclear cells (PBMC), C34-cholesterol significantly decreases the membrane dipole potential. In PBMC, the conjugate was 14- and 115-fold more membranotropic than T-1249 and enfuvirtide, respectively. C34 or cholesterol alone did not show significant membrane activity. The enhanced interaction of C34-cholesterol with biological membranes correlates with its higher antiviral potency. Higher partitions for lipid-raft like compositions direct the drug to the receptor-rich domains where membrane fusion is likely to occur. This intermediary membrane binding step may facilitate the drug delivery to gp41 in its pre-fusion state.
Translocating the blood-brain barrier using electrostatics
Marta M. B. Ribeiro,Marco M. Domingues,Jo?o M. Freire,Nuno C. Santos,Miguel A. R. B. Castanho
Frontiers in Cellular Neuroscience , 2012, DOI: 10.3389/fncel.2012.00044
Abstract: Mammalian cell membranes regulate homeostasis, protein activity, and cell signaling. The charge at the membrane surface has been correlated with these key events. Although mammalian cells are known to be slightly anionic, quantitative information on the membrane charge and the importance of electrostatic interactions in pharmacokinetics and pharmacodynamics remain elusive. Recently, we reported for the first time that brain endothelial cells (EC) are more negatively charged than human umbilical cord cells, using zeta-potential measurements by dynamic light scattering. Here, we hypothesize that anionicity is a key feature of the blood-brain barrier (BBB) and contributes to select which compounds cross into the brain. For the sake of comparison, we also studied the membrane surface charge of blood components—red blood cells (RBC), platelets, and peripheral blood mononuclear cells (PBMC). To further quantitatively correlate the negative zeta-potential values with membrane charge density, model membranes with different percentages of anionic lipids were also evaluated. From all the cells tested, brain cell membranes are the most anionic and those having their lipids mostly exposed, which explains why lipophilic cationic compounds are more prone to cross the blood-brain barrier.
Prediction of Antibacterial Activity from Physicochemical Properties of Antimicrobial Peptides
Manuel N. Melo, Rafael Ferre, Lídia Feliu, Eduard Bardají, Marta Planas, Miguel A. R. B. Castanho
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028549
Abstract: Consensus is gathering that antimicrobial peptides that exert their antibacterial action at the membrane level must reach a local concentration threshold to become active. Studies of peptide interaction with model membranes do identify such disruptive thresholds but demonstrations of the possible correlation of these with the in vivo onset of activity have only recently been proposed. In addition, such thresholds observed in model membranes occur at local peptide concentrations close to full membrane coverage. In this work we fully develop an interaction model of antimicrobial peptides with biological membranes; by exploring the consequences of the underlying partition formalism we arrive at a relationship that provides antibacterial activity prediction from two biophysical parameters: the affinity of the peptide to the membrane and the critical bound peptide to lipid ratio. A straightforward and robust method to implement this relationship, with potential application to high-throughput screening approaches, is presented and tested. In addition, disruptive thresholds in model membranes and the onset of antibacterial peptide activity are shown to occur over the same range of locally bound peptide concentrations (10 to 100 mM), which conciliates the two types of observations.
Neuropeptide Kyotorphin (Tyrosyl-Arginine) has Decreased Levels in the Cerebro-Spinal Fluid of Alzheimer’s Disease Patients: Potential Diagnostic and Pharmacological Implications
Sara Matos Santos,Laura Garcia-Nimo,Sónia Sá Santos,Isaura Tavares,José A. Cocho,Miguel A. R. B. Castanho
Frontiers in Aging Neuroscience , 2013, DOI: 10.3389/fnagi.2013.00068
Abstract: In Alzheimer’s disease (AD), besides the characteristic deterioration of memory, studies also point to a higher pain tolerance in spite of sensibility preservation. A change in the normal tau protein phosphorylation is also characteristic of AD, which contributes to the pathogenesis of the disease and is useful in early diagnosis. Kyotorphin (KTP) is an endogenous analgesic dipeptide (Tyr-Arg) for which there is evidence of eventual neuroprotective and neuromodulatory properties. The objective of this work was to study the possible correlation between KTP and phosphorylated tau protein (p-tau) levels in cerebro-spinal fluid (CSF) samples of AD patients. CSF samples were collected from 25 AD patients and 13 age-matched controls (N), where p-tau and KTP levels were measured. We found a statistically significant difference between p-tau/KTP values in AD and N groups with an inverse correlation between p-tau and KTP values in AD samples. These results suggest that in the future KTP may be a candidate biomarker for neurodegeneration and may be a lead compound to be used pharmacologically for neuroprotection.
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