Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Int J Impot Res ; 15(1): 53-62, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12605241

ABSTRACT

Corpus cavernosum smooth muscle (CCSM) from rabbits made diabetic for 6 months as a result of alloxan injection exhibited increased sensitivity (3vs 9 nM EC(50)) and generated 20-50% greater force to endothelin-1 (ET-1) compared to CCSM from normal rabbits. In contrast, the force produced by the CCSM in response to KCl and phenylephrine was not significantly altered in diabetic CCSM. The increased ET-1 sensitivity is associated with a two to three-fold upregulation of ET receptor A at both mRNA and protein levels in diabetic CCSM. ET-1-induced CCSM contraction is largely dependent upon Rho-kinase (ROK), since it is almost completely blocked by Y-27632 (a highly selective ROK inhibitor). Furthermore, expression of ROKbeta isoform is selectively upregulated in CCSM from diabetic rabbits. Thus, an increased CCSM tone, modulated by sensitization of the endothelin-mediated contractile pathway via ROK, may be a key component of the molecular mechanism of diabetes-induced erectile dysfunction.


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Endothelin-1/pharmacology , Erectile Dysfunction/metabolism , Muscle, Smooth/enzymology , Protein Serine-Threonine Kinases/metabolism , Animals , Diabetes Mellitus, Experimental/physiopathology , Disease Models, Animal , Erectile Dysfunction/physiopathology , Fluorescent Antibody Technique , Gene Expression Regulation, Enzymologic , Intracellular Signaling Peptides and Proteins , Male , Muscle Contraction/drug effects , Muscle Contraction/physiology , Penis/enzymology , Protein Serine-Threonine Kinases/genetics , Rabbits , Receptor, Endothelin A , Receptor, Endothelin B , Receptors, Endothelin/genetics , rho-Associated Kinases , rhoA GTP-Binding Protein/metabolism
2.
Cancer Res ; 60(11): 2919-25, 2000 Jun 01.
Article in English | MEDLINE | ID: mdl-10850438

ABSTRACT

Eicosapentaenoic acid (EPA), an n-3 polyunsaturated fatty acid that is abundant in the fish-based diets of populations that exhibit a remarkably low incidence of cancer, exerts anticancer activity in vitro and in animal models of experimental cancer. Here we define the molecular basis for the anticancer effects of EPA. EPA inhibits cell division by inhibiting translation initiation. This is a consequence of the ability of EPA to release Ca2+ from intracellular stores while inhibiting their refilling via capacitative Ca2+ influx that results in partial emptying of intracellular Ca2+ stores and thereby activation of protein kinase R. Protein kinase R phosphorylates and inhibits eukaryotic initiation factor 2alpha, resulting in inhibition of protein synthesis at the level of translation initiation, preferentially reducing the synthesis and expression of growth-regulatory proteins, including G1 cyclins, and causes cell cycle arrest in G1. In a KLN-205 squamous cell carcinoma mouse model, daily oral administration of EPA resulted in a significant reduction of tumor size and expression of cyclin D1 in the tumor tissues. Furthermore, EPA-treated tumors showed a significant increase in the proportion of diploid cells, indicative of cell cycle arrest in G0-G1, and a significant reduction of malignant hypertetraploid cells. These results characterize EPA as a member of an emerging new class of anticancer compounds that inhibit translation initiaton.


Subject(s)
Antineoplastic Agents/pharmacology , Eicosapentaenoic Acid/pharmacology , Protein Biosynthesis/drug effects , 3T3 Cells , Administration, Oral , Animals , Calcium/metabolism , Carcinoma, Squamous Cell/drug therapy , Cell Cycle/drug effects , Cyclin D1/metabolism , Cyclin E/metabolism , Dose-Response Relationship, Drug , Eicosapentaenoic Acid/genetics , Female , G1 Phase/drug effects , Mice , Mice, Inbred DBA , Neoplasms, Experimental , Phosphorylation , Ploidies , Resting Phase, Cell Cycle/drug effects , Time Factors , Transfection , Ubiquitins/metabolism , ras Proteins/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...