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1.
Microbiol Immunol ; 62(2): 132-136, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29194753

ABSTRACT

Respiratory syncytial virus (RSV) is a common cause of respiratory infections in infants. Effective vaccines are currently being sought, but no vaccine is thus far available. In our previous study, recombinant AIK-C measles vaccine expressing the RSV fusion protein (MVAIK/RSV/F) was developed and protective immunity against RSV demonstrated in cotton rats. In the present study, the immunogenicity and protective effects were investigated in three cynomolgus monkeys immunized with MVAIK/RSV/F. Neutralizing test antibodies against RSV were detected and no infectious virus was recovered from the lungs of monkeys immunized with MVAIK/RSV/F after challenge. MVAIK/RSV/F has the potential to inhibit RSV infection.


Subject(s)
Immunogenicity, Vaccine/immunology , Lung/virology , Measles Vaccine/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Vaccines/immunology , Respiratory Syncytial Viruses/metabolism , Vaccines, Synthetic/immunology , Viral Fusion Proteins/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Disease Models, Animal , Immunity, Humoral , Immunization , Lung/immunology , Lung/pathology , Macaca fascicularis , Male , Neutralization Tests , Recombinant Proteins/immunology , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/genetics , Sigmodontinae , Viral Proteins/genetics , Viral Proteins/immunology
2.
J Appl Toxicol ; 27(1): 78-85, 2007.
Article in English | MEDLINE | ID: mdl-17146843

ABSTRACT

It is presumed that phosphodiesterase (PDE) inhibitors have two mechanisms for inhibition of hERG currents in the acute applications to cells: direct channel block, and downregulation of human ether-a-go-go related gene (hERG) activities by PKA-dependent pathway mediated phosphorylation through their inhibitory effects against PDE enzymes. However, it is unknown whether PDE inhibition contributes to the inhibitory effects of PDE inhibitors on hERG currents. This study examined the effects of various PDE inhibitors on hERG currents using both the whole-cell and perforated patch-clamp techniques in hERG transfected CHO-K1 cells. The study also investigated the contribution of the PKA-dependent pathway to the inhibitory effects of PDE inhibitors on hERG currents. Of the PDE inhibitors tested, vinpocetine, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), vesnarinone, rolipram and dipyridamole decreased hERG currents in a concentration-dependent manner. Vinpocetine and vesnarinone markedly decreased the hERG current with an IC (50)of 0.13 and 20.6 microm, respectively, at comparatively low concentrations. Furthermore, vinpocetine caused a cumulative block of hERG currents. Milrinone, amrinone and zaprinast had no effect on the hERG current up to 100 microm. Of the PDE3 inhibitors (vesnarinone, amrinone and milrinone), only vesnarinone showed an hERG inhibitory effect. The inhibitory effects of vinpocetine and vesnarinone were not significantly affected by the co-application of protein kinase inhibitors. Furthermore, the protein kinase activators had no effect on hERG currents. It is concluded that vinpocetine and vesnarinone block the hERG channel directly, and that the inhibitory effect on intracellular PDE in the PKA-dependent pathway may not be involved in the inhibition of hERG currents in hERG transfected CHO-K1 cells.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Signal Transduction/drug effects , Adenine/analogs & derivatives , Adenine/pharmacology , Amrinone/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Dipyridamole/pharmacology , Dose-Response Relationship, Drug , Down-Regulation/drug effects , ERG1 Potassium Channel , Enzyme Activators/pharmacology , Ether-A-Go-Go Potassium Channels/genetics , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Isoenzymes , Membrane Potentials/drug effects , Milrinone/pharmacology , Patch-Clamp Techniques , Protein Kinase Inhibitors/pharmacology , Purinones/pharmacology , Pyrazines , Quinolines/pharmacology , Rolipram/pharmacology , Time Factors , Transfection , Vinca Alkaloids/pharmacology
3.
Pharm Res ; 21(4): 625-34, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15139519

ABSTRACT

PURPOSE: The purpose of this study is to reveal the contribution of membrane components to the inhibitory effect of 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD) on P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) function in vinblastine-resistant Caco-2 (Caco-2R) cell monolayers. METHODS: The transport of rhodamine-123 and 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) was studied in Caco-2R cell monolayers. P-gp and MRP2 residing in the monolayers and releasing in cell supernatants were detected by Western blotting. The mRNA levels of MDR1 and MRP2 were detected by reverse transcription-polymerase chain reaction (RT-PCR) method. Cholesterol, phospholipids, and proteins were mainly determined by each assay kit. RESULTS: Of various beta-cyclodextrin derivatives (beta-CyDs), DM-beta-CyD most significantly impaired the efflux function of P-gp and MRP2 without changing cell viability and membrane integrity. The treatment with CyDs did not change the mRNA levels of MDR1 and MRP2. DM-beta-CyD lowered cholesterol content and P-gp level in caveolar membranes. In addition, DM-beta-CyD released not only cholesterol and phospholipids but also proteins including P-gp and MRP2 from apical membranes of the monolayers. CONCLUSIONS: DM-beta-CyD may impair P-gp and MRP2 function in Caco-2R cell monolayers, probably, at least in part, through the release of these transporters from the apical membranes of monolayers, and the exertion of the inhibitory effect of DM-beta-CyD may require the extraction of not only cholesterol but also phospholipids from the monolayers.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Drug Resistance, Neoplasm/drug effects , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Vinblastine/pharmacology , beta-Cyclodextrins/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Caco-2 Cells , Cholesterol/metabolism , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/physiology , Humans , Multidrug Resistance-Associated Protein 2 , Phospholipids/metabolism
4.
FEBS Lett ; 536(1-3): 225-31, 2003 Feb 11.
Article in English | MEDLINE | ID: mdl-12586368

ABSTRACT

We compared the inhibitory effect of various cyclodextrins (CyDs) on P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) function and examined the contribution of cholesterol to the inhibitory effect of 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD) on the efflux activity of the function in Caco-2 cell monolayers. Of various CyDs, DM-beta-CyD significantly impaired the efflux activity of P-gp and MRP2. DM-beta-CyD released P-gp and MRP2 from the monolayers in the apical side's transport buffer and decreased the extent of cholesterol as well as P-gp and MRP2 in caveolae of Caco-2 cell monolayers, but not caveolin and flotillin-1. On the other hand, DM-beta-CyD did not change MDR1 and MRP2 mRNA levels. Therefore, these results suggest that the inhibitory effect of DM-beta-CyD on P-gp and MRP2 function, at least in part, could be attributed to the release of these transporters from the apical membranes into the medium as secondary effects through cholesterol-depletion in caveolae after treatment of Caco-2 cell monolayers with DM-beta-CyD.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Cholesterol/metabolism , Cyclodextrins/pharmacology , Membrane Transport Proteins , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , beta-Cyclodextrins , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Biological Transport/drug effects , Caco-2 Cells , Caveolae/chemistry , Cholesterol/analysis , Cyclodextrins/toxicity , Dose-Response Relationship, Drug , Humans , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/metabolism
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