Biosupramolecular complexes of amphiphilic photosensitizers with human serum albumin and cucurbit[7]uril as carriers for photodynamic therapy.

In the present work, we evaluated the supramolecular interactions between three photosensitizers, namely toluidine blue O (TBO, positively charged) and two fatty acid conjugates of 6 and 14 carbon atoms chain lengths (TBOC6 and TBOC14), with human serum albumin (HSA) and the macrocycle cucurbit[7]uril (CB[7]), alone or in combination within a biosupramolecular system as potential carriers of photosensitizers for Photodynamic therapy (PDT). Binding studies were carried out using photophysical and calorimetric techniques and accompanied with molecular docking simulations. Amphiphilic photosensitizers, particularly TBOC14, showed stronger binding to HSA and (CB[7]).

Riboflavin Surface Modification of Poly(vinyl chloride) for Light-Triggered Control of Bacterial Biofilm and Virus Inactivation.

Poly(vinyl chloride) (PVC) is the most used biomedical polymer worldwide. PVC is a stable and chemically inert polymer. However, microorganisms can colonize PVC producing biomedical device-associated infections.

Fatty Acid Conjugates of Toluidine Blue O as Amphiphilic Photosensitizers: Synthesis, Solubility, Photophysics and Photochemical Properties.

Toluidine blue O (TBO) is a water-soluble photosensitizer that has been used in photodynamic antimicrobial and anticancer treatments, but suffers from limited solubility in hydrophobic media. In an effort to incrementally increase TBO's hydrophobicity, we describe the synthesis of hexanoic (TBOC6) and myristic (TBOC14) fatty acid derivatives of TBO formed in low to moderate percent yields by condensation with the free amine site. Covalently linking 6 and 14 carbon chains led to modifications of not only TBO's solubility, but also its photophysical and photochemical properties.

Mechanism of Visible-Light Photooxidative Demethylation of Toluidine Blue O.

Experiments and theoretical calculations by density functional theory (DFT) have been carried out to examine a self-sensitized type I photooxidation of toluidine blue O (TBO). This study attempts to build a connection between visible-light photolysis and demethylation processes of methylamine compounds, such as TBO. We show that controlled photoinduced mono- and double-demethylation of TBO can be achieved.

Photodynamic performance of zinc phthalocyanine in HeLa cells: A comparison between DPCC liposomes and BSA as delivery systems.

Comparable intracellular concentrations (≈30pmol/10(6) cells) of bovine serum albumin-ZnPc (BSA) adduct outperformed dipalmitoyl-phosphatidyl-choline (DPPC) liposomes containing ZnPc at photodynamic-killing of human cervical cancer cells (HeLa) after only 15min of irradiation using red light (λ>620nm, 30W/cm(2)). This result could not be simply explained in terms of dye aggregation within the carrier, since in the liposomes the dye was considerably less aggregated than in bovine serum albumin, formulation that was capable to induce cell apoptosis upon red light exposure. Thus, using specific organelle staining, our cumulative data points towards intrinsic differences in intra-cellular localization depending on the cargo vehicle used, being ZnPc:BSA preferentially located in the near vicinity of the nucleus and in the Golgi structures, while the liposomal formulation ZnPc:DPPC was preferentially located in cellular membrane and cytoplasm.

Short-term dynamics of indoor and outdoor endotoxin exposure: Case of Santiago, Chile, 2012.

Indoor and outdoor endotoxin in PM2.5 was measured for the very first time in Santiago, Chile, in spring 2012. Average endotoxin concentrations were 0.

Comparison of the Superagonist Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models.

IL15, a potent stimulant of CD8(+) T cells and natural killer (NK) cells, is a promising cancer immunotherapeutic. ALT-803 is a complex of an IL15 superagonist mutant and a dimeric IL15 receptor αSu/Fc fusion protein that was found to exhibit enhanced biologic activity in vivo, with a substantially longer serum half-life than recombinant IL15. A single intravenous dose of ALT-803, but not IL15, eliminated well-established tumors and prolonged survival of mice bearing multiple myeloma.

Morphological Effects Induced In Vitro by Propranolol on Human Erythrocytes.

Despite the extended use and well-documented information, there are insufficient reports concerning the effects of propranolol on the structure and functions of cell membranes, particularly those of human erythrocytes. Aimed to better understand the molecular mechanisms of its interactions with cell membranes, human erythrocyte and molecular models of the red cell membrane were utilized. The latter consisted of bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), representative of phospholipid classes located in the outer and inner monolayers of the human erythrocyte membrane, respectively.

Silica nanoreactors from silylated riboflavin for efficient singlet oxygen delivery.

Silylation of riboflavin allowed its incorporation into spherical SiO nanoparticles that were able to generate singlet oxygen and oxidize human serum albumin while conferring riboflavin remarkable photostability.

Structure and general properties of flavins.

Flavins are a family of yellow-colored compounds with the basic structure of 7,8-dimethyl-10-alkylisoalloxazine. Riboflavin, commonly known as vitamin B2, is an essential component of living organisms and is the precursor of all biologically important flavins. In this chapter, the redox properties of flavins are described, with special emphasis in their ability to participate in both one-electron and two-electron transfer processes; hence, flavins are indispensable mediators between two-electron and one-electron processes in biological systems.

Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor αSu/Fc fusion complex in syngeneic murine models of multiple myeloma.

ALT-803, a complex of an interleukin (IL)-15 superagonist mutant and a dimeric IL-15 receptor αSu/Fc fusion protein, was found to exhibit significantly stronger in vivo biologic activity on NK and T cells than IL-15. In this study, we show that a single dose of ALT-803, but not IL-15 alone, eliminated well-established 5T33P and MOPC-315P myeloma cells in the bone marrow of tumor-bearing mice. ALT-803 treatment also significantly prolonged survival of myeloma-bearing mice and provided resistance to rechallenge with the same tumor cells through a CD8(+) T-cell-dependent mechanism.

Computational basis for risk stratification of peripheral neuropathy from thermal imaging.

The goal of this paper is to present a computer-based system for analyzing thermal images in the detection of preclinical stages of peripheral neuropathy (PN) or diabetic foot. Today, vibration perception threshold (VPT) and sensory tests with a monofilament are used as simple, noninvasive methods for identifying patients who have lost sensation in their feet. These tests are qualitative and are ineffective in stratifying risk for PN in a diabetic patient.

Human cells and cell membrane molecular models are affected in vitro by the nonsteroidal anti-inflammatory drug ibuprofen.

This report presents evidence that ibuprofen interacts with red cell membranes as follows: a) in scanning electron microscopy (SEM) studies on human erythrocytes induced shape changes at a concentration as low as 10μM; b) in isolated unsealed human erythrocyte membranes (IUM) induced mild increase in the water content or in their molecular dynamics at the hydrophobic-hydrophilic interphase, while a corresponding ordering decrease at the deep phospholipids acyl chain level; c) at physiological temperature (37°C), 300μM ibuprofen induced a significant increase in the generalized polarization (GP) of dimyristoylphosphatidylcholine (DMPC) large unilamellar vesicles (LUV), an indication that ibuprofen molecules locate in the head polar group region of DMPC; d) X-ray diffraction studies showed that ibuprofen concentrations≥300μM induced increasing structural perturbation to DMPC bilayers; e) differential scanning calorimetry (DSC) data showed that ibuprofen was able to alter the cooperativity of DMPC phase transition in a concentration-dependent manner, to destabilize the gel phase and that ibuprofen did not significantly perturb the organization of the lipid hydrocarbon chains. Additionally, the effect on the viability of both human promyelocytic leukemia HL-60 and human cervical carcinoma HeLa cells was studied.

Different cell death mechanisms are induced by a hydrophobic flavin in human tumor cells after visible light irradiation.

Riboflavin (RF) is an endogenous cell component and an efficient photosensitizer that can act by both types I and II photochemical mechanisms. Human tumor cells lines cultured in vitro, were used as model to study the effect of a photosensitizer synthesized from riboflavin, the 2',3',4',5'-riboflavin-tetrabutyrate (RTB), to increase the flavin concentration in the human promyelocytic leukemia cell line HL-60 and the human epithelial cervical cancer cell line HeLa. We demonstrate that this compound, alone or with Trp, has a toxic dose-response effect evidenced by abnormal cell morphology and a decrease in the cell proliferation rate.

Photophysical behaviour and photodynamic activity of zinc phthalocyanines associated to liposomes.

Phthalocyanines are macrocyclic compounds that can be employed as photosensitizers in the treatment of various infections and diseases, as well as in photodynamic therapy. Nevertheless, a disadvantage for the clinical application of these compounds is their strong tendency to form oligomers (especially dimers), a phenomenon that reduces their efficiency as photosensitizers. In the present contribution, we have studied the photophysical and photochemical properties of ZnPc and ZnF(16)Pc in an organic solvent (THF) and liposomal formulations (DMPC, DPPC and DSPC).

Inhibition of acute vascular thrombosis in chimpanzees by an anti-human tissue factor antibody targeting the factor X binding site.

Tissue factor (TF) antagonists targeting the factor VII (FVII) binding domain have been shown to interrupt acute vascular thrombus formation without impairing haemostasis in non-human primates. In this study, we evaluate whether a human/mouse chimeric monoclonal antibody (ALT-836, formerly known as Sunol-cH36) blocking the factor X/factor IX (FX/FIX) binding site of tissue factor could achieve similar clinical benefits in an arterial thrombosis model induced by surgical endarterectomy in chimpanzees. In this model, sequential surgical endarterectomies on right and left superficial femoral arteries were performed 30 days apart in five chimpanzees.

Photophysics and photochemistry of dyes bound to human serum albumin are determined by the dye localization.

The photophysics and photochemistry of rose bengal (RB) and methylene blue (MB) bound to human serum albumin (HSA) have been investigated under a variety of experimental conditions. Distribution of the dyes between the external solvent and the protein has been estimated by physical separation and fluorescence measurements. The main localization of protein-bound dye molecules was estimated by the intrinsic fluorescence quenching, displacement of fluorescent probes bound to specific protein sites, and by docking modelling.

Blocking of CD27-CD70 pathway by anti-CD70 antibody ameliorates joint disease in murine collagen-induced arthritis.

Rheumatoid arthritis (RA) is characterized by inflammation and cellular proliferation in the synovial lining of joints that result in cartilage and bone destruction. Although the etiology of RA is unclear, activated lymphocytes and proinflammatory molecules, in particular TNF superfamily members, have been implicated in the disease pathology. A TNF superfamily member, CD70, is found on activated lymphocytes and shown to be important in memory and effector responses of lymphocytes.

Photophysics and photochemistry of rose bengal bound to human serum albumin.

Rose bengal (RB) readily binds to human serum albumin (HSA). At low RB concentrations, 90% of the dye is associated to the protein (5 microM), This association takes place in specific binding sites I and/or II. At higher RB concentrations, unspecific binding takes place with up to 10 RB molecules bound per protein molecule.

Photophysics and photochemistry of zinc phthalocyanine/bovine serum albumin adducts.

Zinc phthalocyanine (ZnPc) is a well known Type II (singlet oxygen mediated) hydrophobic photosensitizer with potential use in PDT. We have found that the presence of bovine serum albumin diminishes the aggregation degree of ZnPc in aqueous solution, indicating that albumins could be potentially useful carriers for this type of photosensitizer in PDT. In order to explore the photochemical and photophysical behavior of ZnPc associated to the protein, we have evaluated triplet excited state lifetime and yield, dye bleaching, oxygen consumption, formation of carbonyls and peroxides, and the spontaneous chemiluminescence emitted after photolysis.

Biological evaluation of novel 6-Arylbenzimidazo[1,2-c]quinazoline derivatives as inhibitors of LPS-induced TNF-alpha secretion.

This study describes the effect of novel 6-Arylbenzimidazo[1,2-c]quinazoline derivatives as tumor necrosis factor alpha (TNF-alpha) production inhibitors. The newly synthesized compounds were tested for their in vitro ability to inhibit the lipolysaccharide (LPS) induced TNF-alpha secretion in the human promyelocytic cell line HL-60. The compound 6-Phenyl-benzimidazo[1,2-c]quinazoline, coded as Gl, resulted as the most potent inhibitor and with no significant cytotoxic activity.

Distribution of urocanic acid isomers between aqueous solutions and n-octanol, liposomes or bovine serum albumin.

The distribution of urocanic acid (UCA) isomers between aqueous solutions and n-octanol, egg yolk phosphatidylcholine (eggPC) liposomes or bovine serum albumin (BSA) has been evaluated. Regarding its partitioning between water and n-octanol, the behaviour of both isomers is very similar, and the amount incorporated to the organic solvent is mostly determined by the fraction of the compound that, in the aqueous phase, is present as uncharged species. This implies that the highest hydrophobicity occurs near the isoelectric point.

Enhancement of riboflavin-mediated photo-oxidation of glucose 6-phosphate dehydrogenase by urocanic acid.

We have investigated the riboflavin (RF)-sensitized inactivation of glucose 6-phosphate dehydrogenase (G6PD) in the presence and absence of trans-urocanic acid (UCA). The inactivation of the enzyme results from its direct oxidation by the excited triplet RF in a Type-I-photosensitized reaction whose efficiency increases at low oxygen concentration. The addition of histidine to the system produced no change in the inactivation rate, discarding the participation of singlet oxygen in the reaction.

Study of the interaction between triplet riboflavin and the alpha-, betaH- and betaL-crystallins of the eye lens.

Time-resolved photolysis studies of riboflavin (RF) were carried out in the presence and absence of alpha-, betaH- and betaL-crystallins of bovine eye lens. The transient absorption spectra, recorded 5 micros after the laser pulse, reveal the presence of the absorption band (625-675 nm) of the RF neutral triplet state (tau = 42 micros) accompanied by the appearance of a long-lived absorption (tau = 320 micros) in the 500-600 nm region due to the formation of the semireduced RF radical. The RF excited state is quenched by the crystallin proteins through a mechanism that involves electron transfer from the proteins to the flavin, as shown by the decrease of the triplet RF band with the concomitant increase of the band of its semireduced form.

Lysozyme modification by the fenton reaction and gamma radiation.

A comparative study was performed on lysozyme modification after exposure to Fenton reagent (Fe(II)/H2 O2) or hydroxyl radicals produced by y radiation. The conditions were adjusted to obtain, with both systems, a 50% loss of activity of the modified ensemble. Gamma radiation modified almost all types of amino acid residues in the enzyme, with little specificity.