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Inhibition of Epithelial CC-Family Chemokine Synthesis by the Synthetic Chalcone DMPF-1 via Disruption of NF-κB Nuclear Translocation and Suppression of Experimental Asthma in Mice.

Rajajendram R, Tham CL, Akhtar MN, Sulaiman MR, Israf DA - Mediators Inflamm. (2015)

Bottom Line: Western blot analysis further demonstrated that the inhibitory activity resulted from disruption of p65NF-κB nuclear translocation without any effects on the mitogen-activated protein kinase (MAPK) pathway.Treatment of ovalbumin-sensitized and ovalbumin-challenged BALB/c mice with DMPF-1 (0.2-100 mg/kg) demonstrated significant reduction in the secretion and gene expression of CC chemokines (RANTES, eotaxin-1, and MCP-1) and Th2 cytokines (IL-4, IL-5, and IL-13).In conclusion, these findings demonstrate the potential of DMPF-1, a nonsteroidal compound, as an antiasthmatic agent for further pharmacological evaluation.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Science, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.

ABSTRACT
Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The interaction between airway epithelium and inflammatory mediators plays a key role in the pathogenesis of asthma. In vitro studies evaluated the inhibitory effects of 3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one (DMPF-1), a synthetic chalcone analogue, upon inflammation in the A549 lung epithelial cell line. DMPF-1 selectively inhibited TNF-α-stimulated CC chemokine secretion (RANTES, eotaxin-1, and MCP-1) without any effect upon CXC chemokine (GRO-α and IL-8) secretion. Western blot analysis further demonstrated that the inhibitory activity resulted from disruption of p65NF-κB nuclear translocation without any effects on the mitogen-activated protein kinase (MAPK) pathway. Treatment of ovalbumin-sensitized and ovalbumin-challenged BALB/c mice with DMPF-1 (0.2-100 mg/kg) demonstrated significant reduction in the secretion and gene expression of CC chemokines (RANTES, eotaxin-1, and MCP-1) and Th2 cytokines (IL-4, IL-5, and IL-13). Furthermore, DMPF-1 treatment inhibited eosinophilia, goblet cell hyperplasia, peripheral blood total IgE, and airway hyperresponsiveness in ovalbumin-sensitized and ovalbumin-challenged mice. In conclusion, these findings demonstrate the potential of DMPF-1, a nonsteroidal compound, as an antiasthmatic agent for further pharmacological evaluation.

No MeSH data available.


Related in: MedlinePlus

Effect of DMPF-1 on TNF-α-stimulated phosphorylation of MAP kinases in A549 cells. Cells were treated with DMPF-1 (7.5 μM) or positive controls in the presence or absence of TNF-α for 30 min. Whole cell protein extract was subjected to Western blot analysis. Expression levels of phosphorylated protein of (a) p38, (b) JNK, and (c) ERK were quantified and normalized to nonphosphorylated proteins. The values are expressed as mean ± SEM of three independent experiments. ∗∗P < 0.01 and ∗∗∗P < 0.005, significantly different from the TNF-α-stimulated control group; SB: SB203580; SP: SP600125; PD: PD98059.
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fig6: Effect of DMPF-1 on TNF-α-stimulated phosphorylation of MAP kinases in A549 cells. Cells were treated with DMPF-1 (7.5 μM) or positive controls in the presence or absence of TNF-α for 30 min. Whole cell protein extract was subjected to Western blot analysis. Expression levels of phosphorylated protein of (a) p38, (b) JNK, and (c) ERK were quantified and normalized to nonphosphorylated proteins. The values are expressed as mean ± SEM of three independent experiments. ∗∗P < 0.01 and ∗∗∗P < 0.005, significantly different from the TNF-α-stimulated control group; SB: SB203580; SP: SP600125; PD: PD98059.

Mentions: When stimulated with TNF-α, p65NF-κB translocates from the cytoplasm into the nucleus (Figure 5). However, treatment with DMPF-1 significantly inhibited the translocation of p65 from cytoplasm into the nucleus. Figure 6 shows that DMPF-1 had no effect upon the phosphorylation of p38, ERK1/2, and JNK.


Inhibition of Epithelial CC-Family Chemokine Synthesis by the Synthetic Chalcone DMPF-1 via Disruption of NF-κB Nuclear Translocation and Suppression of Experimental Asthma in Mice.

Rajajendram R, Tham CL, Akhtar MN, Sulaiman MR, Israf DA - Mediators Inflamm. (2015)

Effect of DMPF-1 on TNF-α-stimulated phosphorylation of MAP kinases in A549 cells. Cells were treated with DMPF-1 (7.5 μM) or positive controls in the presence or absence of TNF-α for 30 min. Whole cell protein extract was subjected to Western blot analysis. Expression levels of phosphorylated protein of (a) p38, (b) JNK, and (c) ERK were quantified and normalized to nonphosphorylated proteins. The values are expressed as mean ± SEM of three independent experiments. ∗∗P < 0.01 and ∗∗∗P < 0.005, significantly different from the TNF-α-stimulated control group; SB: SB203580; SP: SP600125; PD: PD98059.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4537758&req=5

fig6: Effect of DMPF-1 on TNF-α-stimulated phosphorylation of MAP kinases in A549 cells. Cells were treated with DMPF-1 (7.5 μM) or positive controls in the presence or absence of TNF-α for 30 min. Whole cell protein extract was subjected to Western blot analysis. Expression levels of phosphorylated protein of (a) p38, (b) JNK, and (c) ERK were quantified and normalized to nonphosphorylated proteins. The values are expressed as mean ± SEM of three independent experiments. ∗∗P < 0.01 and ∗∗∗P < 0.005, significantly different from the TNF-α-stimulated control group; SB: SB203580; SP: SP600125; PD: PD98059.
Mentions: When stimulated with TNF-α, p65NF-κB translocates from the cytoplasm into the nucleus (Figure 5). However, treatment with DMPF-1 significantly inhibited the translocation of p65 from cytoplasm into the nucleus. Figure 6 shows that DMPF-1 had no effect upon the phosphorylation of p38, ERK1/2, and JNK.

Bottom Line: Western blot analysis further demonstrated that the inhibitory activity resulted from disruption of p65NF-κB nuclear translocation without any effects on the mitogen-activated protein kinase (MAPK) pathway.Treatment of ovalbumin-sensitized and ovalbumin-challenged BALB/c mice with DMPF-1 (0.2-100 mg/kg) demonstrated significant reduction in the secretion and gene expression of CC chemokines (RANTES, eotaxin-1, and MCP-1) and Th2 cytokines (IL-4, IL-5, and IL-13).In conclusion, these findings demonstrate the potential of DMPF-1, a nonsteroidal compound, as an antiasthmatic agent for further pharmacological evaluation.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Science, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.

ABSTRACT
Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The interaction between airway epithelium and inflammatory mediators plays a key role in the pathogenesis of asthma. In vitro studies evaluated the inhibitory effects of 3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one (DMPF-1), a synthetic chalcone analogue, upon inflammation in the A549 lung epithelial cell line. DMPF-1 selectively inhibited TNF-α-stimulated CC chemokine secretion (RANTES, eotaxin-1, and MCP-1) without any effect upon CXC chemokine (GRO-α and IL-8) secretion. Western blot analysis further demonstrated that the inhibitory activity resulted from disruption of p65NF-κB nuclear translocation without any effects on the mitogen-activated protein kinase (MAPK) pathway. Treatment of ovalbumin-sensitized and ovalbumin-challenged BALB/c mice with DMPF-1 (0.2-100 mg/kg) demonstrated significant reduction in the secretion and gene expression of CC chemokines (RANTES, eotaxin-1, and MCP-1) and Th2 cytokines (IL-4, IL-5, and IL-13). Furthermore, DMPF-1 treatment inhibited eosinophilia, goblet cell hyperplasia, peripheral blood total IgE, and airway hyperresponsiveness in ovalbumin-sensitized and ovalbumin-challenged mice. In conclusion, these findings demonstrate the potential of DMPF-1, a nonsteroidal compound, as an antiasthmatic agent for further pharmacological evaluation.

No MeSH data available.


Related in: MedlinePlus