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A novel chromone derivative with anti-inflammatory property via inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway.

Liu H, Xu R, Feng L, Guo W, Cao N, Qian C, Teng P, Wang L, Wu X, Sun Y, Li J, Shen Y, Xu Q - PLoS ONE (2012)

Bottom Line: In the present study, we show that a novel chromone derivative, DCO-6, significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide, IL-1β and IL-6, decreased the levels of iNOS, IL-1β and IL-6 mRNA expression in both RAW264.7 cells and mouse primary peritoneal macrophages, and inhibited LPS-induced activation of p38 MAPK but not of JNK, ERK.LPS-induced production of intracellular reactive oxygen species (ROS) was remarkably impaired by DCO-6, which disrupted the formation of the TRAF6-ASK1 complex.Our results indicate that DCO-6 showed anti-inflammatory properties through inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.

ABSTRACT
The p38 MAPK signaling pathway plays a pivotal role in inflammation. Targeting p38 MAPK may be a potential strategy for the treatment of inflammatory diseases. In the present study, we show that a novel chromone derivative, DCO-6, significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide, IL-1β and IL-6, decreased the levels of iNOS, IL-1β and IL-6 mRNA expression in both RAW264.7 cells and mouse primary peritoneal macrophages, and inhibited LPS-induced activation of p38 MAPK but not of JNK, ERK. Moreover, DCO-6 specifically inhibited TLR4-dependent p38 activation without directly inhibiting its kinase activity. LPS-induced production of intracellular reactive oxygen species (ROS) was remarkably impaired by DCO-6, which disrupted the formation of the TRAF6-ASK1 complex. Administering DCO-6 significantly protected mice from LPS-induced septic shock in parallel with the inhibition of p38 activation and ROS production. Our results indicate that DCO-6 showed anti-inflammatory properties through inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway. Blockade of the upstream events required for p38 MAPK action by DCO-6 may provide a new therapeutic option in the treatment of inflammatory diseases.

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Related in: MedlinePlus

The effect of DCO-6 on cell viability of murine macrophages.(A) The chemical structure of DCO-6. (B) RAW264.7 cells or peritoneal macrophages from BALB/c mice were treated with various concentrations of DCO-6. After 24 h of incubation, LDH in the culture supernatant was tested. The absorbance value at 420 nm was measured by a microplate reader. The percentage of LDH released from the cells was determined using the formula: % release  =  LDH activity in supernatant/(LDH activity in supernatant + LDH activity in cell lysate). Data are shown as means ± S.D. of three independent experiments. *P<0.05 vs medium control.
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pone-0037168-g001: The effect of DCO-6 on cell viability of murine macrophages.(A) The chemical structure of DCO-6. (B) RAW264.7 cells or peritoneal macrophages from BALB/c mice were treated with various concentrations of DCO-6. After 24 h of incubation, LDH in the culture supernatant was tested. The absorbance value at 420 nm was measured by a microplate reader. The percentage of LDH released from the cells was determined using the formula: % release  =  LDH activity in supernatant/(LDH activity in supernatant + LDH activity in cell lysate). Data are shown as means ± S.D. of three independent experiments. *P<0.05 vs medium control.

Mentions: The synthesis of (E)-5,7-dihydroxy-3-(3-oxo-3-phenylprop-1-en-1-yl)-4H-chromen-4- one (DCO-6) is outlined in supplementary material S1, and the 1H NMR spectrum of DCO-6 was shown in Fig. S1. DCO-6 at concentrations ranging from 1 to 30 µM failed to affect cell viability of both mouse RAW264.7 macrophages and primary mouse peritoneal macrophages (Fig. 1B and Fig. S2). Thus, up to 30 µM of DCO-6 was used in the following in vitro experiments.


A novel chromone derivative with anti-inflammatory property via inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway.

Liu H, Xu R, Feng L, Guo W, Cao N, Qian C, Teng P, Wang L, Wu X, Sun Y, Li J, Shen Y, Xu Q - PLoS ONE (2012)

The effect of DCO-6 on cell viability of murine macrophages.(A) The chemical structure of DCO-6. (B) RAW264.7 cells or peritoneal macrophages from BALB/c mice were treated with various concentrations of DCO-6. After 24 h of incubation, LDH in the culture supernatant was tested. The absorbance value at 420 nm was measured by a microplate reader. The percentage of LDH released from the cells was determined using the formula: % release  =  LDH activity in supernatant/(LDH activity in supernatant + LDH activity in cell lysate). Data are shown as means ± S.D. of three independent experiments. *P<0.05 vs medium control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376149&req=5

pone-0037168-g001: The effect of DCO-6 on cell viability of murine macrophages.(A) The chemical structure of DCO-6. (B) RAW264.7 cells or peritoneal macrophages from BALB/c mice were treated with various concentrations of DCO-6. After 24 h of incubation, LDH in the culture supernatant was tested. The absorbance value at 420 nm was measured by a microplate reader. The percentage of LDH released from the cells was determined using the formula: % release  =  LDH activity in supernatant/(LDH activity in supernatant + LDH activity in cell lysate). Data are shown as means ± S.D. of three independent experiments. *P<0.05 vs medium control.
Mentions: The synthesis of (E)-5,7-dihydroxy-3-(3-oxo-3-phenylprop-1-en-1-yl)-4H-chromen-4- one (DCO-6) is outlined in supplementary material S1, and the 1H NMR spectrum of DCO-6 was shown in Fig. S1. DCO-6 at concentrations ranging from 1 to 30 µM failed to affect cell viability of both mouse RAW264.7 macrophages and primary mouse peritoneal macrophages (Fig. 1B and Fig. S2). Thus, up to 30 µM of DCO-6 was used in the following in vitro experiments.

Bottom Line: In the present study, we show that a novel chromone derivative, DCO-6, significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide, IL-1β and IL-6, decreased the levels of iNOS, IL-1β and IL-6 mRNA expression in both RAW264.7 cells and mouse primary peritoneal macrophages, and inhibited LPS-induced activation of p38 MAPK but not of JNK, ERK.LPS-induced production of intracellular reactive oxygen species (ROS) was remarkably impaired by DCO-6, which disrupted the formation of the TRAF6-ASK1 complex.Our results indicate that DCO-6 showed anti-inflammatory properties through inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.

ABSTRACT
The p38 MAPK signaling pathway plays a pivotal role in inflammation. Targeting p38 MAPK may be a potential strategy for the treatment of inflammatory diseases. In the present study, we show that a novel chromone derivative, DCO-6, significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide, IL-1β and IL-6, decreased the levels of iNOS, IL-1β and IL-6 mRNA expression in both RAW264.7 cells and mouse primary peritoneal macrophages, and inhibited LPS-induced activation of p38 MAPK but not of JNK, ERK. Moreover, DCO-6 specifically inhibited TLR4-dependent p38 activation without directly inhibiting its kinase activity. LPS-induced production of intracellular reactive oxygen species (ROS) was remarkably impaired by DCO-6, which disrupted the formation of the TRAF6-ASK1 complex. Administering DCO-6 significantly protected mice from LPS-induced septic shock in parallel with the inhibition of p38 activation and ROS production. Our results indicate that DCO-6 showed anti-inflammatory properties through inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway. Blockade of the upstream events required for p38 MAPK action by DCO-6 may provide a new therapeutic option in the treatment of inflammatory diseases.

Show MeSH
Related in: MedlinePlus