A theoretical and experimental study of positive and neutral LiF clusters produced by fast ion impact on a polycrystalline LiF target.

The positive and neutral clusters produced by the impact of approximately 60 MeV (252)Cf fission fragments on a LiF polycrystalline target are analyzed. The positive ion spectrum is dominated by the (LiF)(n)Li(+) series, n = 0-7, exhibiting a total yield 2 orders of magnitude higher than that of the (LiF)(n)(+) series. The yield for the dominant (LiF)(n)Li(+) series decreases roughly as exp(-kn), where k approximately 0.9 for n = 0-3 and k approximately 0.6 for the heavier clusters (n = 4-9), while the yield of the (LiF)(n)(+) series also decreases exponentially as n increases with k approximately 0.6. Theoretical calculations were performed for the (LiF)(n)Li(0), (LiF)(n)Li(+), and (LiF)(n)(0) series for n up to 9. For the smaller clusters the structures first obtained with a genetic algorithm generator were further optimized at the DFT/B3LYP/6-311+G(3df), DFT/B3LYP/LACV3P*, and MP2/LACV3P* levels of theory. An energy criterion is used for a proper taxonomic description of the optimized cluster isomers. Cluster properties such as fragmentation energy and stability are discussed for the proposed configurations. The results show that for all three series the most stable isomers present a linear structure for small cluster size (n = 1-3), while cubic cells or polyhedral structures are preferred for larger cluster sizes (n = 4-9). Fragmentation energy results suggest that a desorbed excited (LiF)(n)Li(+) ion preferentially dissociates via a cascade of (LiF)(n)(0) units, in agreement with the slope modification in the exponential decay of the (LiF)(n)Li(+) ion abundances for n > or = 3.

Permeation of beta-defensin-3 encapsulated with polyethylene glycol in lung surfactant models at air-water interface.

Coarse grained molecular dynamics of the permeation of the peptide human beta-defensin-3 (HBD3) in two different lung surfactant models (BLES and CUROSURF) at surface tension of 20 mN m-1 was performed in order to simulate the effect of charge distribution on the permeation process. We found that HBD3 permeates in lung surfactant models at surface tension of 20 mN m-1. However, it sticks to the phospholipid polar heads, possibly having its bactericidal properties inactivated by electrostatic interaction. The HBD3 encapsulated with polyethylene glycol (PEG) molecules does permeate, but it does not interact with the polar heads. The Gibbs free energies of this process in both models were estimated to be -39 and -64 Kcal mol-1 for HBD3 and PEG-encapsulated HBD3, respectively. The peptide HBD3 was pulled from the polar heads to the water phase overcoming an energy barrier of around 17 and 22 Kcal mol-1, respectively. The peptide was encapsulated with PEG molecules in order to reduce this barrier, thereby decreasing to roughly 12 and 0 Kcal mol-1 in BLES and CUROSURF models, respectively. After permeation of the HBD3 encapsulated with PEG, it freely moves in the water phase with little or none interaction with the phospholipid head groups. Lung surfactant with low charge distribution seems to have less or none electrostatic interaction with HBD3, possibly preserving its antimicrobial activity.

Penetration of antimicrobial peptides in a lung surfactant model.

Molecular dynamics simulations were successfully performed to understand the absorption mechanism of antimicrobial peptides LL-37, CATH-2, and SMAP-29 in a lung surfactant model. The antimicrobial peptides quickly penetrate in the lung surfactant model in dozens or hundreds nanoseconds, but they electrostatically interact with the lipid polar heads during the simulation time of 2 µs. This electrostatic interaction should be the explanation for the inactivation of the antimicrobial peptides when co-administrated with lung surfactant. As they strongly interact with the lipid polar heads of the lung surfactant, there is no positive charge available on the antimicrobial peptide to attack the negatively charged bacteria membrane. In order to avoid the interaction of peptides with the lipid polar heads, sodium cholate was used to form nanoparticles which act as an absorption enhancer of all antimicrobial peptides used in this investigation. The nanoparticles of 150 molecules of sodium cholate with one peptide were inserted on the top of the lung surfactant model. The nanoparticles penetrated into the lung surfactant model, spreading the sodium cholate molecules around the lipid polar heads. The sodium cholate molecules seem to protect the peptides from the interaction with the lipid polar heads, leaving them free to be delivered to the water phase. The penetration of peptides alone or even the peptide nanoparticles with sodium cholate do not collapse the lung surfactant model, indicating to be a promisor drug delivery system to the lung. The implications of this finding are that antimicrobial peptides may only be co-administered with an absorption enhancer such as sodium cholate into lung surfactant in order to avoid inactivation of their antimicrobial activity.

Thermodynamic and infrared analyses of the interaction of chlorpromazine with phospholipid monolayers.

An investigation has been made of the interaction between chlorpromazine (CPZ) and monolayers of 1,2-dipalmitoyl-sn-3-glycerophosphatidylcholine (DPPC) and 1,2-dipalmitoyl-sn-3-glycero[phospho-rac-(1-glycerol)] (DPPG), both at the air/water interface and in transferred Langmuir-Blodgett films. The Gibbs free energy, DeltaG, and the compressibility modulus (C(S)(-1)), obtained from the surface pressure isotherms, indicated changes in the in-plane interactions of CPZ/DPPG mixed monolayers, with positive values of DeltaG. The arrangement of CPZ in the zwitterionic DPPC monolayers causes a weaker interaction in CPZ/DPPC mixed monolayers, with the DeltaG fluctuating around zero. IR measurements in transferred monolayers showed that CPZ did not affect the conformational order of the acyl chains, its effects being limited to the bands corresponding to the headgroups. Furthermore, since no shift was observed for the acyl chain bands, the phase transition induced by CPZ is not a liquid expanded (LE) to liquid condensed (LC) transition, as the latter is associated with chain ordering. Taken together, the IR and compressibility results demonstrate that the effect from CPZ cannot be correlated with temperature changes in the subphase for pure monolayers, in contrast to models proposed by other authors.

Reversibility of cardiac fibrosis in mice chronically infected with Trypanosoma cruzi, under specific chemotherapy.

UNLABELLED: This investigation was performed to verify the effect of specific chemotherapy (Benznidazole or MK-436) on the inflammatory and fibrotic cardiac alterations in mice chronically infected with the strains 21 SF (Type II) and Colombian (Type III) of Trypanosoma cruzi. To obtain chronically infected mice, two groups of 100 Swiss mice each, were infected with either the 21 SF or the Colombian strain (2 x 10(4) and 5 x 10(4) blood forms respectively). The rate of mortality in the acute phase was of 80% for both groups. Twenty surviving mice chronically infected with the 21 SF strain and 20 with the Colombian strain were then divided in treated and untreated groups. Excluding those that died during the course of treatment, 14 mice chronically infected with the 21 SF strain and 15 with the Colombian strain were finally evaluated in the present study. Chemotherapy was performed with Benznidazole (N-benzil-2-nitro-1-imidazolacetamide) in the dose of 100 mg/k.b.w/day, for 60 days, or with the MK-436 (3(1-methyl-5 nitroimidazol-2-yl) in two daily doses of 250 mg/k.b.w, for 20 days. Parasitological cure tests were performed (xenodiagnosis, haemoculture, subinoculation of the blood into newborn mice), and serological indirect immunofluorescence test. The treated and untreated mice as well as intact controls were killed at different periods after treatment and the heart were submitted to histopathological study with hematoxilineosin and picrosirius staining; ultrastructural study; collagen immunotyping, fibronectin and laminin identification by immunofluorescence tests. RESULTS: the untreated controls either infected with 21 SF or Colombian strain, showed inflammatory and fibrotic alterations that were mild to moderate with the 21 SF strain and intense with the Colombian strain. Redpicrosirius staining showed bundles of collagen in the interstitial space and around cardiac fibers. Increased deposits of matritial components and collagen fibers, macrophages and fibroblasts appeared at the ultrastructural examination. Deposits of fibronectin, laminin, pro-III and IV collagens were seen, most intense in those infected with the Colombian strain. Treated mice, parasitologically cured, presented clear-cut regression of the inflammatory lesions and of the interstitial matrix thickening. Mice infected with the Colombian strain and treated with MK-436, was parasitologically cured in 5/6 cases and showed mild inflammatory infiltration and fibrosis. The mice treated with Benznidazole (Colombian strain) did not cure and showed moderate fibrosis and inflammation. Treatment of the mice infected with the 21 SF with Benznidazole determined parasitological cure of all animals, that showed mild inflammation and fibrosis of the myocardium.(ABSTRACT TRUNCATED AT 400 WORDS)