Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several independent studies indicate that synthetic inhibitors of cyclic-3',5'-nucleotide phosphodiesterase (PDE) isozymes, especially inhibitors of PDE-IV, are potent agents which suppress generation of reactive oxygen metabolites (ROM) by NADPH oxidase in leukocytes. Recent studies also show that NADPH oxidase is present in all cell types populating glomeruli. In view of this, we investigated PDE isozymes and their relation to ROM in isolated rat glomeruli. Glomeruli have the capacity to hydrolyze cAMP by isozymes PDE-II, PDE-III and PDE-IV, whereas cGMP is hydrolyzed by PDE-I and PDE-V. Inhibitor of PDE-IV rolipram inhibited significantly (cca 40 to 50%) ROM generation in response to stimulation by phorbol myristate acetate (PMA). Inhibitor of PDE-III cilostamide had only minor suppressive effects and inhibitors of other PDE isozymes did not influence ROM generation. Rolipram (3 microM) suppressed ROM generation without detectable increase in cAMP content. Incubation of glomeruli with forskolin, which increased cAMP content in glomeruli tenfold, inhibited ROM generation to a similar degree as rolipram. The suppression of ROM generation by rolipram was prevented by Rp-cAMPS, a specific inhibitor of protein kinase A (PKA) activity. Further, incubation of glomeruli with rolipram elicited marked in situ activation of PKA (+ 100%), as documented by increase in the (-cAMP/+cAMP) PKA activity ratio. We suggest that selective inhibitor of PDE-IV rolipram acted via the cAMP-signaling pathway and suppressed ROM generation possibly via phosphorylating ras-type GTP-binding protein component of NADPH oxidase and thereby blocking assembly of functional NADPH oxidase complex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Formation of reactive oxygen metabolites in glomeruli is suppressed by inhibition of cAMP phosphodiesterase isozyme type IV. 793 46

The human promyelocytic HL60 cells acquired a neutrophilic phenotype after a 7- to 10-day DMSO treatment. Fc gammaRII was up-regulated. Fc gammaRI was also up-regulated by an additional IFN-gamma treatment. These cells are able to produce O2*- by NADPH oxidase activation in the presence of immune complexes or phorbol-12-myristate-13-acetate (PMA). A change of their PDE4 subtype profile was also observed: PDE4B was the predominant isoenzyme, PDE4D was down-regulated and PDE4A was no longer detectable. Additionally, the more NADPH oxidase was activated by PMA, the less PDE4A was expressed, suggesting that NADPH oxidase activity could be used as a surrogate marker of PDE4A down-regulation. Rolipram and Ariflo (cilomilast), two selective PDE4 inhibitors, dose-dependently inhibited receptor-coupled activation of superoxide. These results suggest that PDE4B is the main subtype involved in regulating superoxide induced by Fc gammaRs activation. Furthermore, these cells, expressing almost exclusively PDE4B subtype, could be useful to identify selective PDE4B inhibitors.
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PMID:DMSO-treated HL60 cells: a model of neutrophil-like cells mainly expressing PDE4B subtype. 1246 39