Limits...
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.

Show MeSH

Related in: MedlinePlus

Protective effect of DCO-6 against LPS-induced septic shock in mice.BALB/c mice were administered LPS (10 mg/kg) and DCO-6 (10 or 20 mg/kg) or vehicle (olive oil) intraperitoneally. (A) Survival rate. (B) Serum cytokine levels of IL-1β and IL-6 were measured by ELISA 3 h after LPS injection. Data are shown as means ± S.D. of three independent experiments. n  = 10. *P<0.05 vs model control. (C) Peritoneal macrophages were isolated from the mice 3 h after LPS injection. Whole cell lysates were prepared, and the protein levels of total and phosphorylated p38 was detected by Western blotting analysis. Traces shown are representative of three independent experiments. Bands from (C) were analyzed by densitometry. Quantitative data are shown. *P<0.05 vs model control. (D) Peritoneal macrophages were isolated from the mice 3 h after LPS injection and incubated with DCFH-DA. DCF fluorescence distribution was detected by flow cytrometry. Data were analyzed by Cell Quest software. *P<0.05 vs model control.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3376149&req=5

pone-0037168-g006: Protective effect of DCO-6 against LPS-induced septic shock in mice.BALB/c mice were administered LPS (10 mg/kg) and DCO-6 (10 or 20 mg/kg) or vehicle (olive oil) intraperitoneally. (A) Survival rate. (B) Serum cytokine levels of IL-1β and IL-6 were measured by ELISA 3 h after LPS injection. Data are shown as means ± S.D. of three independent experiments. n  = 10. *P<0.05 vs model control. (C) Peritoneal macrophages were isolated from the mice 3 h after LPS injection. Whole cell lysates were prepared, and the protein levels of total and phosphorylated p38 was detected by Western blotting analysis. Traces shown are representative of three independent experiments. Bands from (C) were analyzed by densitometry. Quantitative data are shown. *P<0.05 vs model control. (D) Peritoneal macrophages were isolated from the mice 3 h after LPS injection and incubated with DCFH-DA. DCF fluorescence distribution was detected by flow cytrometry. Data were analyzed by Cell Quest software. *P<0.05 vs model control.

Mentions: To assess the protective effects of DCO-6 against LPS-induced lethal shock in vivo, BALB/c mice were intraperitoneally administered LPS (10 mg/kg) and DCO-6 (10 and 20 mg/kg). Cumulative proportions of mice surviving after lethal dose of LPS were shown in Fig. 6A. Single administration of DCO-6 improved survival in a dose-dependent manner. At 48 h after LPS injection, survival rate of DCO-6 treated mice (20 mg/kg) was 50% while none of untreated mice were alive. Moreover, LPS-induced IL-6 and IL-1β were significantly reduced in serum of DCO-6-treated groups (Fig. 6B). In addition, inhibition of p38 activation and ROS production was also observed in peritoneal macrophages from septic mice treated with DCO-6 (Fig. 6C and 6D).


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)

Protective effect of DCO-6 against LPS-induced septic shock in mice.BALB/c mice were administered LPS (10 mg/kg) and DCO-6 (10 or 20 mg/kg) or vehicle (olive oil) intraperitoneally. (A) Survival rate. (B) Serum cytokine levels of IL-1β and IL-6 were measured by ELISA 3 h after LPS injection. Data are shown as means ± S.D. of three independent experiments. n  = 10. *P<0.05 vs model control. (C) Peritoneal macrophages were isolated from the mice 3 h after LPS injection. Whole cell lysates were prepared, and the protein levels of total and phosphorylated p38 was detected by Western blotting analysis. Traces shown are representative of three independent experiments. Bands from (C) were analyzed by densitometry. Quantitative data are shown. *P<0.05 vs model control. (D) Peritoneal macrophages were isolated from the mice 3 h after LPS injection and incubated with DCFH-DA. DCF fluorescence distribution was detected by flow cytrometry. Data were analyzed by Cell Quest software. *P<0.05 vs model control.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0037168-g006: Protective effect of DCO-6 against LPS-induced septic shock in mice.BALB/c mice were administered LPS (10 mg/kg) and DCO-6 (10 or 20 mg/kg) or vehicle (olive oil) intraperitoneally. (A) Survival rate. (B) Serum cytokine levels of IL-1β and IL-6 were measured by ELISA 3 h after LPS injection. Data are shown as means ± S.D. of three independent experiments. n  = 10. *P<0.05 vs model control. (C) Peritoneal macrophages were isolated from the mice 3 h after LPS injection. Whole cell lysates were prepared, and the protein levels of total and phosphorylated p38 was detected by Western blotting analysis. Traces shown are representative of three independent experiments. Bands from (C) were analyzed by densitometry. Quantitative data are shown. *P<0.05 vs model control. (D) Peritoneal macrophages were isolated from the mice 3 h after LPS injection and incubated with DCFH-DA. DCF fluorescence distribution was detected by flow cytrometry. Data were analyzed by Cell Quest software. *P<0.05 vs model control.
Mentions: To assess the protective effects of DCO-6 against LPS-induced lethal shock in vivo, BALB/c mice were intraperitoneally administered LPS (10 mg/kg) and DCO-6 (10 and 20 mg/kg). Cumulative proportions of mice surviving after lethal dose of LPS were shown in Fig. 6A. Single administration of DCO-6 improved survival in a dose-dependent manner. At 48 h after LPS injection, survival rate of DCO-6 treated mice (20 mg/kg) was 50% while none of untreated mice were alive. Moreover, LPS-induced IL-6 and IL-1β were significantly reduced in serum of DCO-6-treated groups (Fig. 6B). In addition, inhibition of p38 activation and ROS production was also observed in peritoneal macrophages from septic mice treated with DCO-6 (Fig. 6C and 6D).

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