Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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In a previous study, we had shown that anastomoses established in the 24th hour of reperfusion healed less than the ones established in earlier periods. In this study, we aimed to assess the impacts of polyethyleneglycol-superoxide dismutase (PEG-SOD), a free oxygen radical scavenger and of pentoxyfilline, a methyl-xanthine derivative on anastomotic healing at 24th hour of reperfusion. 18 Wistar-albino rats were divided into 3 groups (n = 6). In all groups superior mesenteric artery was occluded for 40 minutes and the intestine was reperfused for 24 hours. Rats were relaparotomized in the 24th hour and small intestinal anastomoses were established. In Sham group, saline (0.5ml); in Group PTX, pentoxyfilline (25mg/kg); and in Group PGS, PEG-SOD (1,500U/kg) was administered intravenously 20 minutes before anastomoses. In the 5th day, anastomotic healing was evaluated by bursting pressures and hydroxyproline contents. Results were analized by Mann-Whitney U test, p < 0.05 was considered significant. Both of average bursting pressures and average hydroxyproline contents were highest in Group PGS (240 mmHg +/- 23.9; 7.71 +/- 0.68 micromol/g-tissue), followed by sham group (168.3 +/- 18.3 mmHg; 5.94 +/- 0.62 micromol/g-tissue) and Group PTX (83.8 +/- 9.2 mmHg, 5.94 +/- 0.62 micromol/g-tissue). Differences of these two parameters between all groups were statistically significant (p < 0.05). Best anastomotic healing in the 24th hour of reperfusion was achieved by PEG-SOD administration, whereas pentoxyfilline did not favor the healing.
Res Commun Mol Pathol Pharmacol
PMID:Effects of polyethyleneglycol-superoxide dismutase (PEG-SOD) and pentoxifylline on small intestinal anastomoses established in the 24th hour of reperfusion: an experimental study in rats. 1209 Mar 60

The crystal structure of acetylcholinesterase from Torpedo californica complexed with the uncharged inhibitor, PEG-SH-350 (containing mainly heptameric polyethylene glycol with a terminal thiol group) is determined at 2.3 A resolution. This is an untypical acetylcholinesterase inhibitor, since it lacks the cationic moiety typical of the substrate (acetylcholine). In the crystal structure, the elongated ligand extends along the whole of the deep and narrow active-site gorge, with the terminal thiol group bound near the bottom, close to the catalytic site. Unexpectedly, the cation-binding site (formed by the faces of aromatic side-chains) is occupied by CH(2) groups of the inhibitor, which are engaged in C-H...pi interactions that structurally mimic the cation-pi interactions made by the choline moiety of acetylcholine. In addition, the PEG-SH molecule makes numerous other weak but specific interactions of the C-H...O and C-H...pi types.
J Mol Biol 2002 Jul 19
PMID:A neutral molecule in a cation-binding site: specific binding of a PEG-SH to acetylcholinesterase from Torpedo californica. 1209 50

Conventional methods that are used to overcome multidrug resistance (MDR) often involve the coadministration of chemosensitizers and anticancer drugs. However, coadministration of many chemosensitizers with anticancer drugs, such as doxorubicin (Dox) has resulted in the exacerbation of anticancer drug toxicity. Here, we hypothesized that optimization of the anticancer drug delivery using a liposomal carrier, a suitable targeting moiety, and a physical factor such as hyperthermia offer a significant advantage in the treatment of MDR cancer cells. Since, receptors for the vitamin folic acid are frequently overexpressed on epithelial cancer cells, we used folate as our targeting moiety against two types of cell lines, the human cervical carcinoma derived KB-31 (KB31) and the resistance type KB-85 (KB85). Folate-targeted thermosensitive liposomes were prepared by incorporating 1 mol% of a folate-polyethyleneglycol-distearoylphosphatidylethanolamine (folate-PEG-DSPE) construct into a lipid bilayer composed of dipalmitoylphosphatidylcholine (DPPC), hydrogenated soy phosphatidylcholine (HSPC), cholesterol (Chol) and phosphatidylethanolamine derivatized at the amino position with polyethyleneglycol (PEG-PE) at a molar ratio of 100:50:30:6. Incorporation of folate-PEG-PE in the bilayer, did not affect the thermal sensitivity of the resultant liposome vesicles. Uptake of folate-PEG-liposomal Dox by KB31 cells was 15-fold higher than that of non-targeted liposomal Dox. However, in the case of MDR type KB85, the uptake of the folate PEG liposomal Dox was 2-fold higher than the non-targeted liposomal Dox. Cytotoxicity measurements showed that folated liposomes combined with hyperthermia were found to be over 3-fold more effective (IC(50)=0.16 microM) than the free drug (IC(50)=0.543 microM) for growth inhibition of KB31. For the MDR cell type KB85, the cytotoxicity of the targeted liposomes combined with hyperthermia were found to be 4.8 times (IC(50)=0.38 microM) more effective than the free drug (IC(50)=1.81 microM). Thus, liposome associated Dox may bypass the vesicular drug transport in MDR cells, resulting in the enhancement of the drug biological activity.
J Biochem Mol Biol Biophys 2002 Oct
PMID:Modulation of doxorubicin resistance in multidrug-resistance cells by targeted liposomes combined with hyperthermia. 1238 65

Targeting is one of the primary considerations in designing a specific and efficient gene delivery system. Here, an angiogenic endothelial cell-targeted polymeric gene delivery carrier was developed by conjugating an alpha(v)beta3/alpha(v)beta5 integrin-binding RGD peptide, ACDCRGDCFC, into the cationic polymer polyethyleneimine (PEI) via a hydrophilic poly(ethylene glycol) (PEG) spacer. The incorporation of PEG into PEI improved the poor physicochemical properties of PEI-DNA complexes. At a neutral charge ratio, DNA complexes with PEI were polydisperse and substantially aggregated, whereas DNA complexes with PEI-g-1PEG-RGD were homogeneous with 100-200 nm effective diameter. Their surface charge was also significantly reduced due to the charge shielding effect of PEG. However, the extensive grafting of PEI with PEG was shown to inhibit the DNA condensation process, significantly decreasing transfection efficiency. In in vitro transfection experiments with angiogenic endothelial cells, PEI-g-1PEG-RGD showed an approximately fivefold increase in transfection efficiency over PEI, due to an integrin-mediated internalization pathway. PEI-g-1PEG-RGD also exhibited high specificity to angiogenic endothelial cells compared with normal endothelial cells, which was confirmed by in vitro transfection experiments with non-targeting PEI-g-1PEG-RAE in angiostatic endothelial cells.
Mol Ther 2002 Nov
PMID:An angiogenic, endothelial-cell-targeted polymeric gene carrier. 1240 65

The serotonin1A (5-HT1A) receptors are members of a superfamily of seven transmembrane domain receptors that couple to G-proteins. They appear to be involved in various behavioural and cognitive functions. This paper reports an efficient strategy to solubilize 5-HT1A receptors from bovine hippocampal membranes using the zwitterionic detergent CHAPS which is mild and non-denaturing. Since high concentration of CHAPS has earlier been shown to induce dissociation and depletion of G-protein sub-units, a low (pre-micellar) concentration of CHAPS was used for solubilizing 5-HT1A receptors in the presence of NaCl followed by PEG precipitation. This results in solubilization of 5-HT1A receptors with a high degree of efficiency and gives rise to high affinity, functionally active G-protein-sensitive solubilized receptors. Optimal solubilization of the receptor from the native source with high ligand binding affinity and intact signal transduction components may constitute the first step in the molecular characterization of the 5-HT1A receptor in particular, and G-protein-coupled receptors in general.
Mol Membr Biol
PMID:Solubilization of high affinity G-protein-coupled serotonin1A receptors from bovine hippocampus using pre-micellar CHAPS at low concentration. 1246 20

Encapsulation of technetium-99m sestamibi ((99m)Tc-MIBI) in polyethyleneglycol-liposomes ((99m)Tc-MIBI-PEG-liposomes) could extend the duration of its circulation in blood and alter its biodistribution, enabling its concentration in tumours to be increased. An original method to encapsulate (99m)Tc-MIBI in PEG-liposomes is described. The (99m)Tc-MIBI-PEG-liposomes were compared with free (99m)Tc-MIBI with respect to (a) tumour availability (b) ability to distinguish between chemotherapy-sensitive and -resistant cells and (c) uptake ratio in tumour imaging. PEG-liposomal systems composed of distearoylphosphatidylcholine/cholesterol/PEG(2000)-distearoyl phosphatidylethanolamine and lissamine-rhodamine B-labelled liposomes were used. The encapsulation of (99m)Tc-MIBI in liposomes was achieved using the K(+) diffusion potential method. We compared the uptake of free versus encapsulated (99m)Tc-MIBI by sensitive and resistant erythroleukaemia (K562) and breast tumour (MCF-7ras) cells. To assess the internalisation of these liposomes into cells, rhodamine B-labelled PEG-liposomes were used and visualised by fluorescence microscopy. Biodistribution and imaging characteristics of encapsulated and free radiotracer were determined in rats and tumour-bearing nude mice. The efficiency of (99m)Tc-MIBI encapsulation in PEG-liposomes was 50+/-5%. Use of (99m)Tc-MIBI-PEG-liposomes did not impair the ability of this tracer to distinguish between chemotherapy-sensitive and -resistant tumour cells; the percentage of radioactivity accumulated in the sensitive K562 cells was 1.24+/-0.04%, as compared with 0.41+/-0.04% in the resistant K562 cells. One hour post injection in rats, PEG-liposomes showed a ten times higher activity in blood than free (99m)Tc-MIBI, whereas activity of free (99m)Tc-MIBI in kidneys and bladder was markedly higher than that of encapsulated (99m)Tc-MIBI, indicating faster clearance of the free radiotracer. In the (MCF7-ras)-bearing nude mice, PEG-liposome uptake in tumour was two times that of free (99m)Tc-MIBI. Summarising, the (99m)Tc-MIBI-PEG-liposomes demonstrated a longer blood circulation time, enabled distinction between chemotherapy-sensitive and -resistant cells and improved tumour to background contrast in in vivo imaging. (99m)Tc-MIBI-PEG-liposomes therefore show promising potential for tumour imaging.
Eur J Nucl Med Mol Imaging 2003 Apr
PMID:In vitro and in vivo study of 99mTc-MIBI encapsulated in PEG-liposomes: a promising radiotracer for tumour imaging. 1253 43

Two polyethylene oxide-based delivery systems comprised of reacting PEG polymers were designed for the delivery of DNA expression vectors. The polymers are formulated with the DNA and injected into the muscle, wherein a crosslinked matrix forms in-situ. The matrix resembles a viscous solution (formulation A) or a gel (formulation B). The reacting PEG polymers do not interact with, but entrap the DNA. The formation of the matrix does not affect the supercoiling of the incorporated DNA. The polymers are biocompatible and biodegradable due to the presence of hydrolytically labile bonds in one of the components. Measurement of degradation in vivo suggests that a significant amount of the polymer disappears from the injected muscle by 28 days post injection. Administration to mice of SEAP plasmid DNA formulated with the PEG polymers results in SEAP expression. Expression levels are similar to those of unformulated DNA, but the duration of gene expression is significantly longer in immunocompetent animals receiving the formulated DNA. Significantly lower anti-SEAP IgG titers are elicited by network-formulated DNA relative to unformulated DNA, even though expression levels are comparable. The data suggests that the matrix extends duration of expression by reducing the anti-SEAP immune response so that these delivery systems may be useful for prolonged gene expression following a single intramuscular injection.
Mol Ther 2003 Mar
PMID:Gene delivery with in-situ crosslinking polymer networks generates long-term systemic protein expression. 1266 36

Bifunctional PEG (polyethylene glycol) molecules provide a novel approach to retargeting viral vectors without the need to genetically modify the vector. In a previous report we showed that modification of the viral capsid by the addition of a peptide with binding preference for differentiated ciliated airway epithelia allowed gene delivery to those cells by a novel entry pathway. Here we demonstrate further the versatility of this method by coupling a protein, FGF2, to the surface of an adenovirus (Ad). This modification results in the elimination of the endogenous tropism of the virus and confers upon the virus a novel route of entry. Adenoviral vectors modified by the addition of FGF2 show enhanced efficiency of transduction of the ovarian cancer cell line SKOV3.ip1. This enhancement in transduction is dependent on the binding of the coupled FGF2 to its high-affinity receptor and is independent of coxsackie and adenovirus viral receptors. In an intraperitoneal model of ovarian cancer, Ad/PEG/FGF2 generates increased transgene expression in tumor tissue compared to unmodified Ad. Furthermore, polymer modification of adenovirus vectors results in reduced localization of adenovirus to nontarget tissues and a marked decrease in Th1 and Th2 T cell responses. In conclusion, the approach described here may lead to the development of a gene therapy vector capable of targeting a therapeutic gene to diseased cells, while minimizing toxicity and expression in other tissues.
Mol Ther 2003 Jul
PMID:Targeting adenoviral vectors using heterofunctional polyethylene glycol FGF2 conjugates. 1284 33

Among the three different non-covalent forces acting in aqueous media, i.e. Lifshitz-van der Waals (LW), Lewis acid-base (AB) and electrical double layer (EL) forces, the AB forces or electron-acceptor/electron-donor interactions are quantitatively by far the predominant ones. A subset of the AB forces acting in water causes the hydrophobic effect, which is the attraction caused by the hydrogen-bonding (AB) free energy of cohesion between the water molecules which surround all apolar as well as polar molecules and particles when they are immersed in water. As the polar energy of cohesion among water molecules is an innate property of water, the hydrophobic attraction (due to the hydrophobic effect) is unavoidably always present in aqueous media and has a value of DeltaG(hydrophobic) = -102 mJ/m(2), at 20 degrees C, being equal to the AB free energy of cohesion between the water molecules at that temperature. The strong underlying hydrophobic attraction due to this effect can, however, be surmounted by very hydrophilic molecules and particles that attract water molecules more strongly than the free energy of attraction of these molecules or particles for one another, plus the hydrogen-bonding free energy of cohesion between the water molecules, thus resulting in a net non-electrical double layer repulsion. Each of the three non-covalent forces, LW, AB or EL, any of which can be independently attractive or repulsive, decays, dependent on the circumstances, as a function of distance according to different rules. These rules, following an extended DLVO (XDLVO) approach, are given, as well as the measurement methods for the LW, AB and EL surface thermodynamic properties, determined at "contact". The implications of the resulting hydrophobic attractive and hydrophilic repulsive free energies, as a function of distance, are discussed with respect to specific and aspecific interactions in biological systems. The discussion furnishes a description of the manner by which shorter-range specific attractions can surmount the usually much stronger long-range aspecific repulsion, and ends with examples of in vitro and in vivo effects of hydrophilization of biopolymers, particles or surfaces by linkage with polyethylene oxide (PEO; also called polyethylene glycol, PEG).
J Mol Recognit
PMID:Long-range and short-range mechanisms of hydrophobic attraction and hydrophilic repulsion in specific and aspecific interactions. 1289 68

Phenylketonuria (PKU) is a disease in which phenylalanine and phenylalanine-derived metabolites build up to neurotoxic levels due to mutations in the phenylalanine hydroxylase gene (PAH). Enzyme replacement therapy is a viable option to supply active PAH. However, the inherent protease sensitivity and potential immunogenicity of PAH have precluded adoption of this approach. In this report, we have used polyethylene glycol derivatization (PEGylation) to produce protected forms of PAH for potential therapeutic use. Three recombinantly produced PAH enzymes were reacted with activated PEG species, with the aim of developing a stable and active PKU enzyme replacement. Tetrameric full-length human PAH, dimeric double-truncated (DeltaN102-DeltaC428) human PAH, and monomeric Chromobacterium violaceum PAH were PEGylated with succinimidyl succinate polyethylene glycol of molecular weight 5000 or 20,000 Da. Characterization of the PEGylated species was accomplished with MALDI-TOF mass spectrometry, SDS-PAGE, and specific activity measurements using ESI mass spectrometry. All PEG-derivatized PAH species retained catalytic activity, and, at low numbers of PEG molecules attached, these PEGylated PAH proteins were found to be more active and more stable than their non-derivatized PAH counterparts.
Mol Ther 2004 Jan
PMID:Toward PKU enzyme replacement therapy: PEGylation with activity retention for three forms of recombinant phenylalanine hydroxylase. 1474 85


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