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"Functional selectivity", although new to many chemists and biologists only a few years ago, has now become a dominant theme in drug discovery. This concept posits that different ligands engender unique receptor conformations such that only a subset of signaling pathways linked to a given receptor are recruited. However, successful exploitation of the phenomenon to achieve pathway-based selectivity requires the ability to routinely detect it when assessing ligand behavior. We have utilized different strains of the yeast S. cerevisiae, each expressing a specific human Galpha/yeast Gpa1 protein chimera coupled to a MAP kinase-linked reporter gene readout, to investigate the signaling of the M(3) muscarinic receptor, a G protein-coupled receptor (GPCR) for which various antagonists are used clinically. Using this novel platform, we found that the "antagonists", atropine, N-methylscopolamine, and pirenzepine, were inverse agonists for Gpa1/Galpha(q) but low efficacy agonists for Gpa1/Galpha(12.) Subsequent studies with atropine performed in mammalian 3T3 cells validated these findings by demonstrating inverse agonism for G(q/11)-mediated calcium mobilization but positive agonism for G(12)-mediated membrane ruffling. This is the first study to utilize a yeast platform to discover pathway-biased functional selectivity in a GPCR. In addition to the likely applicability of this approach for identifying biased signaling by novel chemical entities, our findings also suggest that currently marketed medications may exhibit hitherto unappreciated functional selectivity.
ACS Chem Biol 2010 Apr 16
PMID:Detection of novel functional selectivity at M3 muscarinic acetylcholine receptors using a Saccharomyces cerevisiae platform. 2015 33

Protein organization on biomembranes and their dynamics are essential for cellular function. It is not clear, however, how protein binding may influence the assembly of underlying lipids or how the membrane structure leads to functional protein organization. Toward this goal, we investigated the effects of annexin a5 binding to biomimetic membranes using fluorescence imaging and correlation spectroscopy. Annexin a5 (anx a5), a peripheral intracellular protein that plays a membrane remodeling role in addition to other functions, binds specifically and tightly to anionic (e.g., phosphatidylserine)-containing membranes in the presence of calcium ion. Our fluorescence microscopy reveals that annexin likely forms assemblies, along with a more dispersed population, upon binding to anionic biomembranes in the presence of calcium ion, which is reflected in its two-component Brownian motion. To investigate the effects of annexin binding on the underlying lipids, we used specific acyl chain labeled phospholipid analogues, NBD-phosphatidylcholine (NBD-PC) and NBD-phosphatidylserine (NBD-PS). We find that both NBD-labeled lipids cluster under anx a5 assemblies, as compared with when they are found under the dispersed annexin population, and NBD-PS exhibits two-component lateral diffusion under the annexin assemblies. In contrast, NBD-PC diffusion is slower by an order of magnitude under the annexin assemblies in contrast to its diffusion when not localized under anx a5 assemblies. Our results indicate that, upon binding to membranes, the peripheral protein annexin organizes the underlying lipids into domains, which may have functional implications in vivo.
ACS Chem Biol 2010 Apr 16
PMID:Peripheral protein organization and its influence on lipid diffusion in biomimetic membranes. 2017 60

The early diagnosis of cancer is the critical element in successful treatment and long-term favorable patient prognoses. The high rate of mortality is mainly attributed to the tendency for late diagnoses as symptoms may not occur until the disease has metastasized, as well as the lack of effective systemic therapies. Late diagnosis is often associated with the lack of timely sensitive imaging modalities. The promise of nanotechnology is presently limited by the inability to simultaneously seek, treat, and image cancerous lesions. This study describes the design and synthesis of fluorescent calcium phosphosilicate nanocomposite particles (CPNPs) that can be systemically targeted to breast and pancreatic cancer lesions. The CPNPs are a approximately 20 nm diameter composite composed of an amorphous calcium phosphate matrix doped with silicate in which a near-infrared imaging agent, indocyanine green (ICG), is embedded. In the present studies, we describe and validate CPNP bioconjugation of human holotransferrin, anti-CD71 antibody, and short gastrin peptides via an avidin-biotin or a novel PEG-maleimide coupling strategy. The conjugation of biotinylated human holotransferrin (diferric transferrin) and biotinylated anti-CD71 antibody (anti-transferrin receptor antibody) to avidin-conjugated CPNPs (Avidin-CPNPs) permits targeting of transferrin receptors, which are highly expressed on breast cancer cells. Similarly, the conjugation of biotinylated pentagastrin to Avidin-CPNPs and decagastrin (gastrin-10) to PEG-CPNPs via PEG-maleimide coupling permits targeting of gastrin receptors, which are overexpressed in pancreatic cancer lesions. These bioconjugated CPNPs have the potential to perform as a theranostic modality, simultaneously enhancing drug delivery, targeting, and imaging of breast and pancreatic cancer tumors.
ACS Nano 2010 Mar 23
PMID:Bioconjugation of calcium phosphosilicate composite nanoparticles for selective targeting of human breast and pancreatic cancers in vivo. 2018 May 85

Sol-Gel chemistry has been used to prepare undoped and Mg-substituted biphasic calcium phosphate (BCP) ceramics composed of hydroxyapatite (HAp) and whitlockite (beta-TCP) phases. Different series of samples have been synthesized with different Mg-doping levels (from 0 to 5 atomic % of Ca atoms substituted) and different temperatures of calcination (from 500 to 1100 degrees C). All of the powdered samples were systematically treated by Rietveld refinement to extract the quantitative phase analysis and the structural and microstructural parameters, to locate the Mg crystallographic sites, and to refine the composition of the Mg-substituted phases. The temperature dependence of the weight amount ratio between HAp and beta-TCP is not monotonic because of the formation of minor phases such as Ca(2)P(2)O(7), CaO, MgO, and CaCO(3) and certainly an amorphous phase. On the other hand, the Mg stabilizing feature on the beta-TCP phase has been evidenced and explained. The mechanism of stabilization by small Mg(2+) is different from that by large Sr(2+). Nevertheless, in both cases, the beta-TCP stabilization is realized by an improvement of the environment of the Ca4 site unusually face-coordinated to a PO(4) tetrahedron. The substitution of a Mg atom in the Ca5 site allows considerable improvement of the bond valence sum of the unusual Ca4 polyhedron. The temperatures of calcination combined with the amount of Mg atoms introduced allow monitoring of the phase composition of the BCP ceramics as well as their microstructural properties. The bioactivity properties of the BCP samples are improved by the presence of Mg atoms in the structure of the beta-TCP phase. The mechanism of improvement is mainly attributed to an accelerated kinetic of precipitation of a calcium phosphate layer at the surface comprising HAp and/or beta-TCP phases.
ACS Appl Mater Interfaces 2009 Feb
PMID:Structural characterization and biological fluid interaction of Sol-Gel-derived Mg-substituted biphasic calcium phosphate ceramics. 2035 43

Three-dimensional chitosan self-assembled nanostructures are reported whose morphology can be adjusted by tuning of the processing parameters, including the rate of solvent removal, the surface roughness of the substrate, and the polarity of the solvent used. Upon this, chitosan nanostructures of more interesting morphology and even higher complexity can be prepared, which can serve as nanotemplates for subsequent biomineralization of calcium carbonate, leading to controllable three-dimensional biominerals having the same complex morphology as that exhibited by the self-assembled chitosan nanotemplates.
ACS Appl Mater Interfaces 2009 Jan
PMID:Self-assembled chitosan nanotemplates for biomineralization of controlled calcite nanoarchitectures. 2035 47

Dissolution of biologically important sparingly soluble salts, such as calcium carbonate and calcium oxalate, is possible by use of carboxyl- and carboxyl/phosphonate-bearing, anionic additives, citrate, malate, carboxyphosphonate, and butane tetracarboxylate. Calcium-containing dissolution products have been identified, characterized, and independently synthesized. These are polymeric materials composed of calcium and the additive as the ligand. Their full characterization was carried out by single-crystal X-ray crystallography and other techniques.
ACS Appl Mater Interfaces 2009 Jan
PMID:Novel calcium carboxyphosphonate/polycarboxylate inorganic-organic hybrid materials from demineralization of calcitic biomineral surfaces. 2035 49

Here we report the fabrication of magnetically responsive calcium carbonate microcrystals produced by coprecipitation of calcium carbonate in the presence of citrate-stabilized iron oxide nanoparticles. We demonstrate that the calcite microcrystals obtained possess superparamagnetic properties due to incorporated magnetite nanoparticles and can be manipulated by an external magnetic field. The microcrystals doped with magnetic nanoparticles were utilized as templates for the fabrication of hollow polyelectrolyte microcapsules, which retain the magnetic properties of the sacrificial cores and might be spatially manipulated using a permanent magnet, thus providing the magnetic-field-facilitated delivery and separation of materials templated on magnetically responsive calcite microcrystals.
ACS Appl Mater Interfaces 2009 Sep
PMID:Magnetically responsive calcium carbonate microcrystals. 2035 3

Polydiacetylene (PDA)-doped calcium alginate fibers were created by the solution blending of polymerized 10,12-pentacosadiynoic acid liposomes with sodium alginate in water prior to extrusion. The liposomes maintained their blue color during wet spinning and drying of the fibers but changed to red with exposure to specific external stimuli (heat, solvent, and chemical). In the latter case, the color change only occurred when the fibers were sufficiently permeable for the reacting species to reach the interior. A parameter termed the "Raman response" (RR) has been developed to quantify the amount of PDA liposomes in each of two critical conformations within the fibers. The RR attributes a quantitative measure of PDA response to individual stimuli. This method provides advantages over the commonly used "colorimetric response" in systems where sample limitations and chromophore activity make UV-vis spectroscopic measurements difficult or inaccurate. PDA liposomes are shown to effectively add a versatile sensing component to alginate fibers.
ACS Appl Mater Interfaces 2009 Jun
PMID:Preparation, characterization, and sensing behavior of polydiacetylene liposomes embedded in alginate fibers. 2035 25

The hydration of the surface of a highly bioactive silicate glass was modeled using ab initio (Car-Parrinello) molecular dynamics (CPMD) simulations, focusing on the structural and chemical modifications taking place at the glass-water interface immediately after contact and on the way in which they can affect the bioactivity of these materials. The adsorption of a water dimer and trimer on the dry surface was studied first, followed by the extended interface between the glass and liquid water. The CPMD trajectories provide atomistic insight into the initial stages relevant to the biological activity of these materials: following contact of the glass with an aqueous (physiological) medium, the initial enrichment of the surface region in Na+ cations establishes dominant Na+-water interactions at the surface, which allow water molecules to penetrate into the open glass network and start its partial dissolution. The model of a Na/H-exchanged interface shows that Ca2+-water interactions are mainly established after the dominant fraction of Na is leached into the solution. Another critical role of modifier cations was highlighted: they provide the Lewis acidity necessary to neutralize OH(-) produced by water dissociation and protonation of nonbridging oxygen (NBO) surface sites. The CPMD simulations also highlighted an alternative, proton-hopping mechanism by which the same process can take place in the liquid water film. The main features of the bioactive glass surface immediately after contact with an aqueous medium, as emerged from the simulations, are (a) silanol groups formed by either water dissociation at undercoordinated Si sites or direct protonation of NBOs, (b) OH(-) groups generally stabilized by modifier cations and coupled with the protonated NBOs, and (c) small rings, relatively stable and unopened even after exposure to liquid water. The possible role and effect of these sites in the bioactive process are discussed.
ACS Appl Mater Interfaces 2009 Jun
PMID:Modeling the water-bioglass interface by ab initio molecular dynamics simulations. 2035 29

A new process, laser-induced precursor formation and subsequent aging in a supersaturated calcium phosphate aqueous solution (CP solution), was applied for coating a hydroxyapatite (HAP) film on a polymeric material, ethylene-vinyl alcohol copolymer (EVOH). Laser irradiation onto EVOH immersed in the CP solution induced the formation of CP precursors, and an HAP film composed of a submicrometer-scale cavernous structure was formed by subsequent aging in a CP solution without laser irradiation. The resulting HAP film coated on EVOH demonstrated excellent structural and chemical uniformity and cell adhesion with the CHO-K1 and BHK-21 cells. This process provides a practical technique for coating HAP onto polymeric materials.
ACS Appl Mater Interfaces 2009 Jul
PMID:A new approach for hydroxyapatite coating on polymeric materials using laser-induced precursor formation and subsequent aging. 2035 55


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