Inhibitory effect of DCDC on lipopolysaccharide-induced nitric oxide synthesis in RAW 264.7 cells.
In the present study we have examined the effect of DCDC (2',5'-dihydroxy-4-chloro-dihydrochalcone) on lipopolysaccharide (LPS)-induced responses in murine macrophage cell line RAW 264.7. Exposure of LPS-stimulated cells to DCDC inhibited the nitrite accumulation in culture medium. DCDC also concentration-dependently inhibited LPS-stimulated increase of iNOS expression; however, it had little effect on iNOS enzyme activity, suggesting that the inhibitory action to DCDC is mainly due to the inhibition on iNOS expression rather than iNOS enzyme activity. DCDC significantly inhibited LPS-evoked degradation of IkappaB-alpha and the nuclear translocation of NF-kappaB; it also exhibited the activity of scavenging the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH). DCDC also inhibited cyclooxygenase-2 activity in RAW 264.7 cells with an IC50 of 3.0 microM; furthermore, it also significantly decreased LPS-induced mortality rate in mice. Taken together, we demonstrate that DCDC exhibits inhibitory effects on nitric oxide production through the inhibition of IkappaB-alpha degradation and NF-kappaB activation, and therefore the suppression of iNOS expression. DCDC also shows the antioxidant activity and COX-2 inhibitory action. Moreover, it improves survival in a murine model of endotoxaemia suggesting that DCDC may be potential in the therapy of septic shock.
Huang
Y C
YC
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
Guh
J H
JH
Cheng
Z J
ZJ
Chang
Y L
YL
Hwang
T L
TL
Lin
C N
CN
Teng
C M
CM
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D002599:Chalcone / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D047188:Chalcones; D051546:Cyclooxygenase 2; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008136:Longevity / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000517:prevention & control
C111054:2',5'-dihydroxy-4-chlorochalcone; D000975:Antioxidants; D047188:Chalcones; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D002599:Chalcone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases