Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article reports on a novel two-step strategy for the coating of cardiovascular stents by strongly adhering biocompatible and biodegradable aliphatic polyesters. First, a precoating of poly(ethylacrylate) (PEA) was electrografted onto the metallic substrate by cathodic reduction of the parent monomer in dimethylformamide (DMF). The electrodeposition of PEA, in a good solvent of it, was confirmed by both Infra-red and Raman spectroscopies. The pendant ester groups of PEA were then chemically reduced into aluminum alkoxides, able to initiate the ring-opening polymerization (ROP) of either D,L-lactide (LA) or epsilon-caprolactone (CL). Growth of biodegradable PLA or PCL coatings from the adhering precoating was confirmed by both Infra-red and Raman spectroscopies, and directly observed by scanning electron microscopy (SEM). This type of coating can act as an anchoring layer for the subsequent casting of drug-loaded polyester films allowing the controlled release of antiproliferative agents for the treatment of in-stent restenosis.
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PMID:Surface modification of metallic cardiovascular stents by strongly adhering aliphatic polyester coatings. 1631 21

In this study, selective cancer cell targeting of biodegradable poly(lactic acid) (PLA) nanoparticles (NPs) has been investigated in vitro. SKOV-3 (HER2 positive) ovarian cancer and Daudi (CD20 positive) lymphoma cell targeting was mediated by anti-HER2 (trastuzumab, Herceptin) and anti-CD20 (rituximab, Mabthera) monoclonal antibodies (mAbs), respectively. The mAb against nonexpressed antigen serving on each cell as isotype matched irrelevant control. Two different targeting approaches have been studied, a direct method using antibody-labeled NPs (mAb-NPs) and a pretargeting method using the avidin-biotin technology. For the direct protocol, fluorescent PLA-NPs were prepared including 10% 1-pyrenebutanol (PB)-labeled PLA in the NP-preparation (PB-NP). Thiol groups were covalently bound to the PB-NP, and the resulting thiolated PB-NP were coupled with the two mAbs using a bifunctional cross-linker. The effective targeting of cells by mAb-PB-NP was shown by flow cytometry analysis. Clearly anti-HER2-PB-NP specifically bound to the SKOV-3 cells and not to the Daudi cells, while anti-CD20-PB-NPs bound to Daudi cells but not to SKOV-3 cells. Specific mAb-PB-NP binding to tumor cells produced a mean 10-fold or higher signal increase compared to irrelevant IgG-PB-NPs. For the pretargeting protocol, plain PLA-NPs were also thiolated and NeutrAvidin-Rhodamine Red-X (NAR) coupled to the functionalized PLA-NPs with sulfo-MBS. The two-step method was evaluated in vitro by incubating SKOV-3 cells first with biotinylated mAbs followed by NAR-NPs. The relative fluorescence associated to the specific binding of NPs produced a 6-fold increase in flow cytometry signal compared to nonspecific binding. In conclusion, these experiments have shown that NPs covalently coupled with antibodies or NAR can specifically and efficiently bind to cancer cells in both a pretargeting and a direct approach, suggesting that functionalized NPs may be a useful drug carrier for tumor targeting.
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PMID:Biodegradable nanoparticles for direct or two-step tumor immunotargeting. 1641 62

Aiming to develop a scaffold architecture mimicking morphological and mechanically that of a blood vessel, a sequential multi-layering electrospinning (ME) was performed on a rotating mandrel-type collector. A bi-layered tubular scaffold composed of a stiff and oriented PLA outside fibrous layer and a pliable and randomly oriented PCL fibrous inner layer (PLA/PCL) was fabricated. Control over the level of fibre orientation of the different layers was achieved through the rotation speed of the collector. The structural and mechanical properties of the scaffolds were examined using scanning electron microscopy (SEM) and tensile testing. To assess their capability to support cell attachment, proliferation and migration, 3T3 mouse fibroblasts and later human venous myofibroblasts (HVS) were cultured, expanded and seeded on the scaffolds. In both cases, the cell-polymer constructs were cultured under static conditions for up to 4 weeks. Environmental-scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), histological examination and biochemical assays for cell proliferation (DNA) and extracellular matrix production (collagen and glycosaminoglycans) were performed. The findings suggest the feasibility of ME to design scaffolds with a hierarchical organization through a layer-by-layer process and control over fibre orientation. The resulting scaffolds achieved the desirable levels of pliability (elastic up to 10% strain) and proved to be capable to promote cell growth and proliferation. The electrospun PLA/PCL bi-layered tube presents appropriate characteristics to be considered a candidate scaffold for blood vessel tissue engineering.
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PMID:Design of scaffolds for blood vessel tissue engineering using a multi-layering electrospinning technique. 1670 37

Two types of antibody-labeled nanoparticles (mAb-NPs) were prepared with the aim to achieve specific tumor targeting. Anti-HER2 and anti-CD20 monoclonal antibodies (mAb) were used as model ligands. Small poly(dl-lactic acid) nanoparticles (PLA NPs) with a mean size of about 170 nm were prepared by the salting out method. Thereafter, the coating of PLA NPs with mAbs was performed in two steps. First, thiol groups (-SH) were introduced on the surface of PLA-NPs by a two-step carbodiimide reaction. The number of -SH groups on the surface of NPs increased from 150 to 400 mmol-SH/mol PLA when cystamine concentrations of 25-1518 mol cystamine/mol PLA were used during the thiolation reaction. In the second step, covalent coupling of antibodies to thiolated NPs (NPs-SH) was obtained via a bifunctional cross-linker, m-maleimidobenzoyl-N-hydroxy-sulfosuccinimide ester (sulfo-MBS). For both mAbs anti-HER2 and anti-CD20, respectively, the number of -SH functions on the NPs had no influence on the amount of mAb coupled to the NPs. Approximately, 295 anti-HER2 and 557 anti-CD20 molecules, respectively, were covalently coupled per nanoparticle. The NPs size after the coupling reactions was about 250 nm. The specific interaction between tumor cells and mAb-NPs was determined by confocal microscopy using two cell lines: SKOV-3 human ovarian cancer cells (overexpressing HER2) and Daudi lymphoma cells (overexpressing CD20). The results showed the selective targeting of mAb-NPs to tumor cells overexpressing the specific antigen. While anti-CD20 labeled NPs (anti-CD20 NPs) bound to and remained at the cellular surface, anti-HER2 labeled NPs (anti-HER2 NPs) were efficiently internalized. The mAb-NPs represent a promising approach to improve the efficacy of NPs in active targeting for cancer therapy while the choice of the antibody-target system defines the fate of the mAb-NPs after their binding to the cells.
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PMID:Differential tumor cell targeting of anti-HER2 (Herceptin) and anti-CD20 (Mabthera) coupled nanoparticles. 1719 47

The main objective of the present study was to evaluate the reduction in halofantrine (Hf) toxicity, an antimalarial drug frequently associated with QT interval prolongation in electrocardiogram, by its entrapment in poly-epsilon-caprolactone nanocapsules (NC). The acute lethal dose (LD(100)) of Hf.HCl experimentally observed was 200 mg/kg whereas the calculated LD(50) was 154 mg/kg. In contrast, the LD(100) for Hf-NC was 300 mg/kg with a longer mean time to death than Hf.HCl. The calculated LD(50) was 249 mg/kg for Hf-NC. The Hf entrapped in PCL NC presented a greater efficacy than PLA-PEG NC and than Hf solution in P. berghei-infected mice at 1 mg/kg. The cardiovascular parameters, ECG and arterial blood pressure, were evaluated in anaesthetized Wistar rats after the IV administration of a single, especially high dose (100 and 150 mg/kg) of halofantrine base loaded-nanocapsules (Hf-NC) or halofantrine chlorhydrate (Hf.HCl) solution. It was observed that Hf solution caused prolongation of the QT and PR intervals of the ECG; however, this effect was significantly (P<0.001) reduced when Hf was administered entrapped in nanocapsules. The treatment with Hf.HCl induced a pronounced bradycardia and severe hypotension leading to death. The effect of Hf-NC upon heart rate was reduced from 58 to 75% for 100 and 150 mg/kg, respectively, when compared with Hf.HCl solution. These findings show that the encapsulation of halofantrine reduces the QT interval prolongation of ECG in rats and suggest that a modification of drug distribution was possible by using nanocapsules. Hf encapsulation was the main factor responsible for the significant reduction in cardiac toxicity observed.
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PMID:Cardiotoxicity reduction induced by halofantrine entrapped in nanocapsule devices. 1730 79

Tubules are the building blocks of epithelial organs and form in response to cues derived from morphogens such as hepatocyte growth factor (HGF). Relatively little is known about signaling pathways that orchestrate the cellular behaviors that constitute tubule development. Here, using three-dimensional cell cultures of Madin-Darby canine kidney cells, we show that the ARF6 GTPase is a critical determinant of tubule initiation in response to HGF. ARF6 is transiently activated during tubulogenesis and perturbing the ARF6 GTP/GDP cycle by inducible expression of ARF6 mutants defective in GTP binding or hydrolysis, inhibits the development of mature tubules. Further, we show that activation of ARF6 is necessary and sufficient to initiate tubule extension. The effect of ARF6 on tubule initiation is two-fold. First, ARF6 regulates the subcellular distribution of the GTPase, Rac1, to tubule extensions. Second, ARF6-induced ERK activation regulates Rac1 activation during tubule initiation through the expression of the receptor for urokinase type plasminogen activator. Thus, we have identified a cellular apparatus downstream of ARF6 activation, which regulates membrane and cytoskeleton remodeling necessary for the early stages of tubule development.
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PMID:ARF6-dependent activation of ERK and Rac1 modulates epithelial tubule development. 1736 98

Adenovirus carrying BMP-2 gene, after being mixed with fibrinous gel, was siphoned off on biodegradable scaffolds (PLA/PCL). The composite was used to repair 1.5 cm long radius defect in rabbits. Four methods were in use in the experiments: Ad-BMP-2 plus fibrinous gel and PLA/PCL (Group A), reconstructed hBMP-2 plus fibrinous gel and PLA/PCL (Group B), Ad-Lacz plus fibrinous gel and PLA/PCL (Group C), and fibrinous gel and PLA/PCL (Group D). Results showed that the defects treated in Group A were repaired with much more new bone regenerated, bridged earlier and stronger than those in Group B 12 weeks after operation. The defects treated in the other two groups could not attain osseous tissue healing. BMP-2 gene carried by biodegradable scaffold and fibrinous gel is easy to conduct and has very strong osteoinduction ability. It is really a good method to repair segmental bone defects.
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PMID:[BMP-2 gene carried by biodegradable scaffold and fibrinous gel for repairing segmental radial defect in rabbit]. 1759 Dec 57

This study investigated the effects of high-intensity training, with or without induced metabolic alkalosis, on lactate transporter (MCT1 and MCT4) and sodium bicarbonate cotransporter (NBC) content in rat skeletal muscles. Male Wistar rats performed high-intensity training on a treadmill 5 times/wk for 5 wk, receiving either sodium bicarbonate (ALK-T) or a placebo (PLA-T) prior to each training session, and were compared with a group of control rats (CON). MCT1, MCT4, and NBC content was measured by Western blotting in soleus and extensor digitorum longus (EDL) skeletal muscles. Citrate synthase (CS) and phosphofructokinase (PFK) activities and muscle buffer capacity (betam) were also evaluated. Following training, CS and PFK activities were significantly higher in the soleus only (P < 0.05), whereas betam was significantly higher in both soleus and EDL (P < 0.05). MCT1 (PLA-T: 30%; ALK-T: 23%) and NBC contents (PLA-T: 85%; ALK-T: 60%) increased significantly only in the soleus following training (P < 0.01). MCT4 content in the soleus was significantly greater in ALK-T (115%) but not PLA-T compared with CON. There was no significant change in protein content in the EDL. Finally, NBC content was related only to MCT1 content in soleus (r = 0.50, P < 0.01). In conclusion, these results suggest that MCT1, MCT4, and NBC undergo fiber-specific adaptive changes in response to high-intensity training and that induced alkalosis has a positive effect on training-induced changes in MCT4 content. The correlation between MCT1 and NBC expression suggests that lactate transport may be facilitated by NBC in oxidative skeletal muscle, which may in turn favor better muscle pH regulation.
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PMID:Effects of high-intensity training on MCT1, MCT4, and NBC expressions in rat skeletal muscles: influence of chronic metabolic alkalosis. 1760 57

Fast dynamics within the microwave frequency range (approximately gigahertz) in polymer systems as a function of temperature (in the range from 20 to 190 degrees C) were studied using high frequency dielectric spectroscopy. The frequency of radiation was varied from 0.5 to 18 GHz. The isochronal dielectric loss data were taken to eliminate the complexity arising from the frequency-independent, temperature-dependent background loss in the condensed phase. These studies were conducted for poly(caprolactone) (PCL), poly(ethylene oxide) (PEO), poly(ethylene oxide) with methoxy end group (PEO-CH3), PLA-b-PEO-b-PLA triblock copolymers, and several polymers with high glass transition temperatures. These polymers possess glass temperatures ranging from -62 degrees C (PCL) to 110 degrees C (PMMA). One broad relaxation process was found only for polymers (PCL, PEO, and PLA-b-PEO-b-PLA) with low glass transition temperatures. The effect due to end groups was investigated by comparing the results of PEO with hydroxy versus methoxy end groups. The measured relaxation process was determined not to be associated with end groups. The results from temperature-dependent dielectric spectroscopy indicate that the relaxation process follows an Arrhenius T dependence suggesting that it is due to local motions. The activation energy of the relaxation process was measured and investigated based on the coupling model. The results suggest that the observed relaxation process behaves as a Johari-Goldstein beta relaxation.
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PMID:Analysis of rapid chain dynamics in isochronal dielectric measurements of polymers. 1768 58

To compare the effects between gene therapy and gradual release carrier for bone morphogenetic protein-2 (BMP-2) in repairing bone defects, bone defects for 15 mm were created.on the bilateral radius in rabbits and treated with four kinds of implantations, ie, composite of transgeneic MSCs and PLA/PCL (Group A), composite of MSCs and gradual release carrier for BMP-2 (Group B), composite of MSCs and PLA/PCL (Group C), and PLA/PCL alone (Group D). After 4, 8, and 12 weeks of the operations, X-ray, histological examination, biomechanics analysis, and bone density measurement were conducted. Results showed that both osteoblasts and mesenchymal cells displayed strongly positive expression of BMP-2 in Group A after 4 weeks of the operation, the speed and quality of bone formation in Group A were much better than those in Group B. After 12 weeks of the operations, bone defects were completely repaired in Group A. BMP-2 gene therapy is really a good method to repair segmental bone defects.
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PMID:[Comparison between gene therapy and gradual release carrier for bone morphogenetic protein-2 in repairing bone defects]. 1771 85


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