Abstract
The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) which was initially known for its role in the repair of oxidative stress-induced DNA damage, has also been reported to play a mediating role in the inflammatory response. Studies with PARP-1 knockout models have shown that PARP-1 is a co-activator of Nuclear Factor-kappa B (NF-kappaB), although this appears not to require its enzyme activity. In addition, drug-induced inhibition of the enzyme activity of PARP-1 was observed to reduce the production of pro-inflammatory mediators. In this study, the flavonoid compound flavone was demonstrated to significantly inhibit the enzyme activity of PARP-1. Further evaluation of flavone in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-treated human pulmonary epithelial and vascular endothelial cells revealed that both the decrease in NAD(+) levels, as well as the formation of PAR-polymers was dose-dependently attenuated by flavone. In addition, flavone was found to reduce the lipopolysaccharide (LPS)-induced interleukin (IL)-8 production in pulmonary epithelial cells, which was confirmed by transcription analysis. Furthermore, the transcription Inhibitor kappa B alpha (of IkappaBalpha) was significantly increased by flavone. The results of the present study indicate that the flavonoid flavone could be a potential candidate for application in treatment of chronic inflammatory diseases. PARP-1 inhibition could have beneficial effects in such diseases as Chronic Obstructive Pulmonary Disease (COPD) and diabetes, by preservation of cellular NAD(+) levels and attenuating inflammatory conditions.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alcohol Oxidoreductases / antagonists & inhibitors
-
Alcohol Oxidoreductases / metabolism
-
Antioxidants / chemistry
-
Antioxidants / metabolism
-
Benzamides / pharmacology
-
Cell Line, Tumor
-
Cell Nucleus / drug effects
-
Cell Nucleus / metabolism
-
Cyclic N-Oxides / metabolism
-
Dose-Response Relationship, Drug
-
Enzyme Inhibitors / pharmacology
-
Ferrous Compounds / metabolism
-
Ferrous Compounds / pharmacology
-
Flavones
-
Flavonoids / chemistry
-
Flavonoids / pharmacology*
-
Gene Expression Regulation / drug effects*
-
Humans
-
Hydrogen Peroxide / metabolism
-
Hydrogen Peroxide / pharmacology
-
Interleukin-8 / genetics
-
Interleukin-8 / metabolism
-
Lipopolysaccharides / pharmacology*
-
Methylnitronitrosoguanidine / pharmacology
-
Molecular Structure
-
NAD / metabolism
-
NF-kappa B / genetics
-
NF-kappa B / metabolism
-
Nucleotidases / pharmacology
-
Phenanthrenes / pharmacology
-
Poly (ADP-Ribose) Polymerase-1
-
Poly(ADP-ribose) Polymerase Inhibitors*
-
Poly(ADP-ribose) Polymerases / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction
-
Spin Trapping / methods
-
Transcription, Genetic / drug effects
Substances
-
Antioxidants
-
Benzamides
-
Cyclic N-Oxides
-
Enzyme Inhibitors
-
Ferrous Compounds
-
Flavones
-
Flavonoids
-
Interleukin-8
-
Lipopolysaccharides
-
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
-
NF-kappa B
-
Phenanthrenes
-
Poly(ADP-ribose) Polymerase Inhibitors
-
NAD
-
Methylnitronitrosoguanidine
-
ferrous sulfate
-
2,2-dimethyl-5-hydroxy-1-pyrrolidinyloxy
-
3-aminobenzamide
-
Hydrogen Peroxide
-
Alcohol Oxidoreductases
-
phenylacetaldehyde reductase
-
PARP1 protein, human
-
Poly (ADP-Ribose) Polymerase-1
-
Poly(ADP-ribose) Polymerases
-
2'-nucleotidase
-
Nucleotidases
-
flavone