Gene/Protein Disease Symptom Drug Enzyme Compound
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A novel interference with measurements of serum free thyroxine (FT4) caused by rheumatoid factor (RhF) is described. We found misleading, sometimes gross, increases of FT4 results in 5 clinically euthyroid elderly female patients with high RhF concentrations. All 5 patients had high FT4 on Abbott AxSYM or IMx analyzers. "NETRIA" immunoassays gave misleading results in 4 of the 5 patients; Amerlex-MAB in 2 of 4 patients; AutoDELFIA in 2 of the 5; and Corning ACS-180 and Bayer Diagnostics Immuno 1 in 1 of the 5. BM-ES700 system results for FT4 in these women remained within the reference range. Results for serum T4, thyroid-stimulating hormone, free triiodothyronine, thyroid-hormone-binding globulin, and FT4 measured by equilibrium dialysis were normal in all 5 patients. Drugs, albumin-binding variants, and anti-thyroid-hormone antibodies were excluded as interferences. Addition to normal serum of the RhF isolated from each of the 5 patients increased the apparent FT4 (Abbott AxSYM). Screening of 83 unselected patients demonstrated a highly significant positive correlation between FT4 (Abbott AxSYM) and RhF concentrations. Discrepant, apparently increased FT4 with a normal result for thyroid-stimulating hormone should lead to measurement of the patient's RhF concentration.
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PMID:Misleading results from immunoassays of serum free thyroxine in the presence of rheumatoid factor. 919 46

Suppression of postprandial hyperglycemia reduces lipogenic enzyme activities in the adipose tissues of normal rats. The present study investigated the expression of genes related to lipogenesis and insulin sensitivity in mesenteric adipose and epididymal adipose tissues to evaluate the effects of wheat albumin (WA) and a crude preparation of WA (CWA) with alpha-amylase inhibitory activity on lipid metabolism. Rats fed 2.5% WA, which had 12.7-fold inhibitory activity compared with CWA, exhibited reduced mRNA levels for G6PDH, ACO, ACS, PEPCK, and LPL in the mesenteric adipose, but not in the epididymal adipose tissue. Linear regression analyses showed that the gene expression levels of FAS, G6PDH, ACS, and LPL were reduced in dose-dependent manners in the mesenteric adipose tissue of rats fed the CWA diet. These results suggest that supplementation with CWA as well as WA reduces the expression of genes related to lipogenesis and insulin sensitivity in mesenteric adipose tissue.
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PMID:Effects of wheat albumin consumption on expression of genes related to lipogenesis and insulin sensitivity in adipose tissues of rats. 1917 May 1

We report the preparation and preliminary in vitro studies of nanocarriers termed "buckysomes," which are self-assembled, spherical nanostructures composed of the amphiphilic fullerene AF-1. By inducing AF-1 self-assembly at an elevated temperature of 70 degrees C, dense spherical buckysomes with diameters of 100-200 nm were formed, as observed by electron microscopy and dynamic light scattering. The amphiphilic nature of AF-1 results in the formation of many hydrophobic regions within the buckysomes, making them ideal for embedding hydrophobic molecules to be tested in a drug delivery scheme. After confirming the cellular internalization of buckysomes embedded with the hydrophobic fluorescent dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, we embedded paclitaxel, a highly hydrophobic anticancer drug. The in vitro therapeutic efficacy of the paclitaxel-embedded buckysomes toward suppression of MCF-7 breast cancer cell growth was compared to that of Abraxane, a commercially available, nanoparticle-albumin-bound formulation of paclitaxel. Notably, the paclitaxel-embedded buckysomes demonstrated a similar efficacy to that observed with Abraxane in cell viability studies; these results were confirmed microscopically. Moreover, negative control studies of MCF-7 viability using empty buckysomes demonstrated that the buckysomes were not cytotoxic. The results of our studies suggest that buckysomes prepared from self-assembly of AF-1 at 70 degrees C are promising nanomaterials for the delivery of hydrophobic molecules.
ACS Nano 2008 Sep 23
PMID:Buckysomes: fullerene-based nanocarriers for hydrophobic molecule delivery. 1920 36

A series of nanoporous membranes prepared from polyethylene-block-polystyrene were applied for size-selective diffusion of glucose and albumin molecules. Millimeter-sized test cells for characterization of such molecular diffusions were designed assuming an implantable glucose sensor. The prepared nanoporous membrane exhibits excellent flexibility and toughness compared to conventional nanoporous membranes of brittle alumina. Pore size of the membranes could be controlled from 5 to 30 nm by varying preparation conditions. All of these nanoporous membranes prepared in this study let glucose pass through, indicating a continuous pore connection through the entire thickness of the membrane in a few tens of micrometers. In contrast, membranes prepared under optimum conditions could perfectly block albumin permeation. This means that these vital molecules having different sizes can be selectively diffused through the nanoporous membranes. Such a successful combination of size selectivity of molecular diffusion in nanoscale and superior mechanical properties in macroscale is also beneficial for other devices requesting down-sized manufacture.
ACS Nano 2009 Apr 28
PMID:Size-selective diffusion in nanoporous but flexible membranes for glucose sensors. 1932 85

Caveolae are plasma membrane invaginations prominent in all endothelial cells lining blood vessels. Caveolae characteristically bud to form free cytoplasmic vesicles capable of transporting carrier proteins such as albumin through the cell. However, caveolae size distribution and dynamics in living endothelial cells and ability of caveolae to internalize nanoparticles are not well understood. We demonstrate here the design of a dual-color nanoparticle pair to measure noninvasively caveolae size and dynamics. First, we coated nanoparticles with BSA (bovine serum albumin) to address whether albumin promoted their delivery. Albumin has been shown to bind to protein on endothelial cell surface localized in caveolae and activate albumin endocytosis. Imaging of BSA-coated nanoparticles varying from 20 to 100 nm in diameter in endothelial cells demonstrated that caveolae-mediated nanoparticle uptake was dependent on albumin coating of particles. We also showed that caveolae could accommodate up to 100 nm diameter nanoparticles, a size larger than the diameter of typical caveolae, suggesting compliant property of caveolae. Together, our results show the feasibility of tracking multicolored nanoparticles in living endothelial cells and potential usefulness for designing therapeutic nanoparticle cargo to cross the limiting vessel wall endothelial barrier.
ACS Nano 2009 Dec 22
PMID:Size and dynamics of caveolae studied using nanoparticles in living endothelial cells. 1991 48

In order to better understand the physical basis of the biological activity of nanoparticles (NPs) in nanomedicine applications and under conditions of environmental exposure, we performed an array of photophysical measurements to quantify the interaction of model gold NPs having a wide range of NP diameters with common blood proteins. In particular, absorbance, fluorescence quenching, circular dichroism, dynamic light scattering, and electron microscopy measurements were performed on surface-functionalized water-soluble gold NPs having a diameter range from 5 to 100 nm in the presence of common human blood proteins: albumin, fibrinogen, gamma-globulin, histone, and insulin. We find that the gold NPs strongly associate with these essential blood proteins where the binding constant, K, as well as the degree of cooperativity of particle--protein binding (Hill constant, n), depends on particle size and the native protein structure. We also find tentative evidence that the model proteins undergo conformational change upon association with the NPs and that the thickness of the adsorbed protein layer (bare NP diameter <50 nm) progressively increases with NP size, effects that have potential general importance for understanding NP aggregation in biological media and the interaction of NP with biological materials broadly.
ACS Nano 2010 Jan 26
PMID:Interaction of gold nanoparticles with common human blood proteins. 2002 Jul 53

Improved chemical inhibitors are required to dissect the role of specific antigen processing enzymes and to complement genetic models. In this study we explore the in vitro and in vivo properties of a novel class of targeted inhibitor of aspartic proteinases, in which pepstatin is coupled to mannosylated albumin (MPC6), creating an inhibitor with improved solubility and the potential for selective cell tropism. Using these compounds, we have demonstrated that MPC6 is taken up via mannose receptor facilitated endocytosis, leading to a slow but continuous accumulation of inhibitor within large endocytic vesicles within dendritic cells and a parallel inhibition of intracellular aspartic proteinase activity. Inhibition of intracellular proteinase activity is associated with reduction in antigen processing activity, but this is epitope-specific, preferentially inhibiting processing of T cell epitopes buried within compact proteinase-resistant protein domains. Unexpectedly, we have also demonstrated, using quenched fluorescent substrates, that little or no cleavage of the disulfide linker takes place within dendritic cells. This does not appear to affect the activity of MPC6 as an inhibitor of cathepsins D and E in vitro and in vivo. Finally, we have shown that MPC6 selectively targets dendritic cells and macrophages in spleen in vivo. Preliminary results suggest that access to nonlymphoid tissues is very limited in the steady state but is strongly enhanced at local sites of inflammation. The strategy adopted for MPC6 synthesis may therefore represent a more general way to deliver chemical inhibitors to cells of the innate immune system, especially at sites of inflammation.
ACS Chem Biol 2010 May 21
PMID:Targeted delivery of antigen processing inhibitors to antigen presenting cells via mannose receptors. 2034 16

This paper describes a novel surface engineering approach that combines oxygen plasma treatment and electrochemical activation to create micropatterned cocultures on indium tin oxide (ITO) substrates. In this approach, photoresist was patterned onto an ITO substrate modified with poly(ethylene) glycol (PEG) silane. The photoresist served as a stencil during exposure of the surface to oxygen plasma. Upon incubation with collagen (I) solution and removal of the photoresist, the ITO substrate contained collagen regions surrounded by nonfouling PEG silane. Chemical analysis carried out with time-of-flight secondary ion mass spectrometry (ToF-SIMS) at different stages in micropatterned construction verified removal of PEG-silane during oxygen plasma and presence of collagen and PEG molecules on the same surface. Imaging ellipsometry and atomic force microscopy (AFM) were employed to further investigate micropatterned ITO surfaces. Biological application of this micropatterning strategy was demonstrated through selective attachment of mammalian cells on the ITO substrate. Importantly, after seeding the first cell type, the ITO surfaces could be activated by applying negative voltage (-1.4 V vs Ag/AgCl). This resulted in removal of nonfouling PEG layer and allowed to attach another cell type onto the same surface and to create micropatterned cocultures. Micropatterned cocultures of primary hepatocytes and fibroblasts created by this strategy remained functional after 9 days as verified by analysis of hepatic albumin. The novel surface engineering strategy described here may be used to pattern multiple cell types on an optically transparent and conductive substrate and is envisioned to have applications in tissue engineering and biosensing.
ACS Appl Mater Interfaces 2009 Nov
PMID:Micropatterning of proteins and mammalian cells on indium tin oxide. 2035 32

Some studies have demonstrated that amino groups, acting as nucleophiles, are potent activators of the complement system, but others not. To clarify these contradictory results, we examined complement activation on two series of NH(2)/CH(3) and NH(2)/COOH mixed self-assembled monolayers (SAMs). NH(2)/CH(3) mixed SAMs were not potent activators of the complement system regardless of the ratio of NH(2)/CH(3) in mixed SAMs. Numerous serum proteins, such as albumin, were adsorbed onto those SAMs and formed a protein layer which inhibited access of C3b to amino groups. In contrast, much C3b and/or C3bBb were deposited on NH(2)/COOH mixed SAMs with approximately 50-60% NH(2) density on the surface and SC5b-9 was found in serum exposed to this SAM, indicating activation of the complement system. These results suggest that C3b can easily access nucleophilic NH(2) groups because of the decrease in electrostatic interaction between negatively charged proteins and the NH(2) SAM surface.
ACS Appl Mater Interfaces 2010 Apr
PMID:Effects of hydrophobicity and electrostatic charge on complement activation by amino groups. 2038 Mar 87

To date, limited examples of polyelectrolyte multilayers (PEMs) can be found that truly exploit the power of layer-by-layer nanoassembly to combine multiple functions into a complex multilayer. We demonstrate that PEMs can be designed as optimized coatings for implantable biosensors, exhibiting both diffusion control and protein resistance. PEM coatings comprising strong-weak and weak-weak pairs were evaluated, resulting in decreases in glucose diffusivity up to 5 orders of magnitude compared to water. Addition of poly(ethylene glycol) (PEG)-grafted terminal layers on the base diffusion-controlling multilayers substantially improved resistance to albumin adsorption relative to unmodified PEMs. For transport-controlling films comprising strong-weak polyelectrolyte pairs, the consistent diffusivity was observed even after exposure to protein-containing solutions, indicating minimal effects of biofouling. In contrast, the transport behavior of weak-weak polyelectrolyte pairs was susceptible to alteration by protein exposure, resulting in large variation in diffusivity, even when protein-resistant outer layers were employed.
ACS Appl Mater Interfaces 2010 Apr
PMID:Dual-function nanofilm coatings with diffusion control and protein resistance. 2038 92


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