PEGylation of coenzyme Q10 and in vitro release studies.

Methoxy polyethylene glycol conjugated with coenzyme Q10 (mPEG)-CoQ10 and analog adducts with amino acids as spacers were synthesized as a new drug delivery systems for CoQ10. Alanine and branched chain amino acids (valine, leucine and isoleucine) were conjugated to mPEG by an amide linkage and to CoQ10 by an ester bond. Recently, branched chain amino acids (BCAAs), which are released along with CoQ10, have received increasing attention as 'anti-fatigue' elements. FT-IR and 1H NMR spectroscopic analysis were useful to characterize the synthesized conjugates. Studies in vitro, in buffer solutions at different pH and in the presence of esterase were conducted. The hydrolysis studies showed a specific cleavage dependent on the pH of the medium and by the presence of proteolytic enzymes. The results showed the improvement of the pharmacokinetic properties of CoQ10. The antioxidant activity of the synthesized conjugates was also evaluated by DPPH assay.

Evidence for a Strong Topological Insulator Phase in ZrTe_{5}.

The complex electronic properties of ZrTe_{5} have recently stimulated in-depth investigations that assigned this material to either a topological insulator or a 3D Dirac semimetal phase. Here we report a comprehensive experimental and theoretical study of both electronic and structural properties of ZrTe_{5}, revealing that the bulk material is a strong topological insulator (STI). By means of angle-resolved photoelectron spectroscopy, we identify at the top of the valence band both a surface and a bulk state. The dispersion of these bands is well captured by ab initio calculations for the STI case, for the specific interlayer distance measured in our x-ray diffraction study. Furthermore, these findings are supported by scanning tunneling spectroscopy revealing the metallic character of the sample surface, thus confirming the strong topological nature of ZrTe_{5}.

Ultrafast Optical Control of the Electronic Properties of ZrTe5.

We report on the temperature dependence of the ZrTe(5) electronic properties, studied at equilibrium and out of equilibrium, by means of time and angle resolved photoelectron spectroscopy. Our results unveil the dependence of the electronic band structure across the Fermi energy on the sample temperature. This finding is regarded as the dominant mechanism responsible for the anomalous resistivity observed at T*∼160 K along with the change of the charge carrier character from holelike to electronlike. Having addressed these long-lasting questions, we prove the possibility to control, at the ultrashort time scale, both the binding energy and the quasiparticle lifetime of the valence band. These experimental evidences pave the way for optically controlling the thermoelectric and magnetoelectric transport properties of ZrTe(5).

Momentum-resolved spin dynamics of bulk and surface excited States in the topological insulator Bi(2)Se(3).

The prospect of optically inducing and controlling a spin-polarized current in spintronic devices has generated wide interest in the out-of-equilibrium electronic and spin structure of topological insulators. In this Letter we show that only measuring the spin intensity signal over several orders of magnitude by spin-, time-, and angle-resolved photoemission spectroscopy can provide a comprehensive description of the optically excited electronic states in Bi_{2}Se_{3}. Our experiments reveal the existence of a surface resonance state in the second bulk band gap that is benchmarked by fully relativistic ab initio spin-resolved photoemission calculations. We propose that the newly reported state plays a major role in the ultrafast dynamics of the system, acting as a bottleneck for the interaction between the topologically protected surface state and the bulk conduction band. In fact, the spin-polarization dynamics in momentum space show that these states display macroscopically different temperatures and, more importantly, different cooling rates over several picoseconds.

Experimental study of the incoherent spectral weight in the photoemission spectra of the misfit cobaltate [Bi_{2}Ba{2}O{4}][CoO{2}]{2}.

Previous angle-resolved photoemission spectroscopy experiments in NaxCoO2 reported both a strongly renormalized bandwidth near the Fermi level and moderately renormalized Fermi velocities, leaving it unclear whether the correlations are weak or strong and how they could be quantified. We explain why this situation occurs and solve the problem by extracting clearly the coherent and incoherent parts of the band crossing the Fermi level. We show that one can use their relative weight to estimate self-consistently a quasiparticle weight Z=0.15+/-0.05. We suggest this method could be a reliable way to study the evolution of correlations in cobaltates and for comparison with other strongly correlated systems.

Direct investigation of orbital ordering in a colossal magnetoresistance manganite by means of X-ray linear dichroism at the Mn L edge.

We have investigated for the first time the orbital ordering in a three-dimensional colossal magnetoresistance manganite, namely La(7/8)Sr(1/8)MnO3, by applying soft X-ray linear dichroism (XLD) to the Mn L edge. We found that the cooperative Jahn-Teller distorted orthorhombic phase, which is present at a temperature of 240 K, is probably accompanied by a predominantly cross type (x2 - z2)/(y2 - z2) orbital ordering. This result is discussed in the light of different exchange interaction models.

Dynamical properties of the one-dimensional band insulator (NbSe4)3I

Optical and photoemission experiments reveal unexpected spectral signatures of one-dimensional band insulators. In the model compound (NbSe (4))3I the optical conductivity decays as a power law sigma(1)(omega) approximately omega(-4.25) above a sharp gap edge. Photoemission observes both the valence and a shadow band, produced by a commensurate superstructure. We identify an optical and photoemission band gap consistent with other measurements but much smaller than the energy scale defined by the dispersion of the band peak in the photoemission spectra.

Stimulation of GALT and activation of mesenteric lymph node lymphocytes by a modified lysozyme in CBA mice with MCa mammary carcinoma.

Lysozyme (hen egg-white lysozyme) and its derivative mPEG-lyso (lysozyme coupled with polyoxyethyleneglycol) were tested in CBA mice bearing MCa mammary carcinoma for their effects on intestinal mucosal immunity (GALT) and mesenteric lymph node lymphocytes (MLNL), after oral administration. Following a cycle of administration of 100 mg/kg/day lysozyme or 350 mg/kg/day mPEG-lyso for 9 consecutive days, GALT was analyzed by using optical histology, and mesenteric lymph node lymphocytes were studied by cytofluorimetric analysis of CD3, CD4 and CD8 antigens, and of DNA and RNA content following in vitro culture with concanavalin A. Both lysozymes significantly increase the number of lymphatic nodules on gut epithelium as determined by histological analysis of sections of small bowel. mPEG-lyso, unlike native lysozyme, gives protection from the decline of the blastogenic activity of MLNL observed at early stages of tumor growth, as shown by the increased nucleic acid content of these cells. On the same cells, both lysozyme and mPEG-lyso also seem to prevent the decline of CD4+ cells observed during tumor growth in control animals. These data confirm the effects of lysozyme on GALT and show that the new lysozyme derivative mPEG-lyso has effects on host immunity greater than those of the native molecule.

Antimetastatic action and lymphocyte activation by the modified lysozyme mPEG-Lyso in mice with MCa mammary carcinoma.

The effects of Lysozyme (hen egg-white lysozyme) and of its modified derivative mPEG-Lyso, (Lysozyme coupled with monomethoxypolyethylenglycol) were tested on CBA mice bearing MCa mammary carcinoma. mPEG-Lyso, given by the oral route at a dose comparable to 100 mg/kg/day of native Lysozyme, is at least as active as Lysozyme for the activation of lymphocytes obtained from different districts along the axis GALT-spleen. These effects were evidenced by measuring the in vitro response of lymphocytes of animals treated in vivo with ConA and LPS using the SRB test, and measuring the content of nucleic acids by cytofluorimetric analysis. Lymphocytes obtained from the mesenteric lymph nodes of animals treated with mPEG-Lyso, show a response to ConA and to LPS at early stages of treatment, when tumor growth reduces the response to controls. mPEG-Lyso, was also effective on lung metastasis formation. Considering that mPEG-Lyso,, compared to the native Lysozyme, completely lost its enzymatic action on Micrococcus lysodehycticus cell walls, this data suggest that the effects of lysozyme on immunity and on tumour growth are unrelated to the production of immunoactive peptidoglycans in the gut.

Improved activity in acidic media of immobilized lysozyme.

Polyethylene glycols (PEGs) of various chain length were used to crosslink lysozyme onto an insoluble support such as oxirane. A very high degree of modification and no inactivation of lysozyme were obtained with PEG 20000, but enzymatic activity increased up to 20 times at pH 3.0, at which point the activity of the native enzyme was lower when using Leuconostok oenus as a macromolecular substrate.

Syntheses, chemical and enzymatic stability of new poly(ethylene glycol)-acyclovir prodrugs.

Two known antiherpetic agents, acyclovir and valaciclovir, were coupled with activated poly(ethylene glycol). In vitro drug release studies demonstrated the conjugates to be stable in buffer solutions at pH 7.4 and 5.5, while only PEG-valacyclovir2 was stable in a buffer solution at pH 1.2. The ability of the macromolecular conjugate to release the free drug was also evaluated in plasma, in which the most stable prodrug also proved to be PEG-valacyclovir2. The derivatives are degraded in the presence of proteolytic enzyme. The rate of hydrolysis was monitored by HPLC-analysis.

Quinazolinone derivatives: synthesis and binding evaluation on cholecystokinin receptors.

A series of 2-methyl-3-amino-4(H)-quinazolinone and of 2-phenyl-3-amino-4(H)-quinazolinone derivatives were synthesized and examined for their CCK receptor affinities. These compounds displayed micromolar affinities for CCK-B rather than CCK-A receptor and the obtained results confirm that the 4(3H)-quinazolinone nucleous represent a useful template for the development of selective CCK-B receptor ligands.

Enzymatic synthesis of ampicillin: a chemometric optimization.

Statistical methods of optimization were applied to the enzymatic semisynthesis of ampicillin catalyzed by penicillin acylase. Since the traditional approach fails in determining both the presence of interactions between the variables and their magnitude, the reaction was reconsidered by means of chemometric techniques. In this work we determined the interaction between temperature and pH for the first time.

Quinolone derivatives: synthesis and binding evaluation on cholecystokinin receptors.

A series of 1,2-dihydro-4-phenylquinolin-2-one-3-carboxylic acid and of 3-amino-4-phenylcarbostyril derivatives were synthesized and examined for their CCK receptor affinities. These compounds displayed micromolar affinities for CCK-A rather than CCK-B receptor and the results have been discussed on the basis of a molecular modelling study.

Synthesis and pharmacological investigation of new chiral muscarinic antagonists.

The two pairs of enantiomers of isoxazolidin-3-ones 3 and 4 were synthesized by means of Lipase PS-catalyzed hydrolyses of suitable racemic butyrates. The same butyrates were also employed as key intermediates in the preparation of racemic 3 and 4. The antimuscarinic potency of the new compounds was assayed in two in vitro functional tests. The eutomers (-)-3 and (-)-4 share the same stereochemistry (5R) of the most potent enantiomer of "azamuscarone" 2, a structurally related muscarinic agonist. Such a spatial arrangement around the chiral center of 2-4, coupled with the low values of eudismic ratio, represents an anomaly among the chiral muscarinic ligands. This anomaly was accounted for by the absence of a chiral center at C-2, a position whose configuration is crucial in determining the high enantioselectivity of muscarinic agonists and antagonists.

[Ion pair HPLC determination of p-aminobenzoic acid as an impurity in procaine and procainamide hydrochlorides]. / Determinazione dell'acido p-amino-benzoico quale impurezza nei cloridrati di procaina e procainamide mediante HPLC a coppia ionica.

A simple, specific and sensitive high-performance liquid chromatographic method for the determination of p-amino benzoic acid (PABA) as impurity in procaine and procainamide hydrochlorides has been developed. The compounds were chromatographed on reversed phase C-18 using water-methanol-acetonitrile solvent system containing sodium lauryl sulphate ion-pair reagent.

Lipid metabolites with free-radical scavenging activity from Euphorbia helioscopia L.

The methanolic extract of the plant Euphorbia helioscopia L. exhibited an interesting free-radical scavenging activity. From the aerial parts of Euphorbia helioscopia L. (Euphorbiaceae), a complex mixture of seven cerebrosides together with glucoclionasterol, a digalactosyldiacylglycerol and a diacylmonogalactosylglycerol were identified. The structures of the cerebrosides were characterized as 1-O-ß-D-glucosides of phytosphingosines, which comprised (2S, 3S, 4E, 8E)-2-amino-4(E),8(E)-octadecadiene-1,3-diol, (2S, 3S, 4E, 8Z)-2-amino-4(E),8(Z)-octadecadiene-1,3-diol, (2S, 3S, 4R, 8Z)-2-amino-8(Z)-octadecene-1,3,4-triol as long chain bases with seven 2-hydroxy fatty acids of varying chain lengths (C16, C24:1, C26:1, C24, C26, C28:1) linked to the amino group. The glycosylglycerides were characterized as (2S)-2,3-O-di-(9,12,15-octadecatrienoyl)-glyceryl-6-O-(α-D-galactopyranosyl)-ß-D-galactopyranoside and (2S)-2,3-O-di-(9,12,15-octadecatrienoyl)-glyceryl-1-O-ß-D-galactopyranoside. The structures were established on the basis of spectroscopic data and chemical reactions.

The chlorophyll catabolite pheophorbide a as a photosensitizer for the photodynamic therapy.

Pheophorbide a is a clorophyll catabolite that recently has drawn the attention of several investigators for its potential in photodynamic therapy. In this review we summarize its photophysical properties, phototoxicity, cellular localization, biodistribution and PDT activity as a free or conjugated molecule.