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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 the mRNA level of chemokines and Th2 cytokines on OVA-sensitized mice. Expression levels of mRNA were determined by RT-PCR analysis. After the mice were sacrificed, the lung tissue was collected and the mRNA levels of (a) eotaxin-1, (b) RANTES, (c) IL-4, (d) IL-5, and (e) IL-13 were measured. The values are expressed as mean ± SEM (n = 10). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.005, significantly different from the OVA-challenged group.
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fig12: Effect of DMPF-1 on the mRNA level of chemokines and Th2 cytokines on OVA-sensitized mice. Expression levels of mRNA were determined by RT-PCR analysis. After the mice were sacrificed, the lung tissue was collected and the mRNA levels of (a) eotaxin-1, (b) RANTES, (c) IL-4, (d) IL-5, and (e) IL-13 were measured. The values are expressed as mean ± SEM (n = 10). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.005, significantly different from the OVA-challenged group.

Mentions: In comparison to naïve mice, the levels of eotaxin, RANTES, IL-4, IL-5, and IL-13 significantly increased in BALF of OVA-challenged mice (Figures 11(a)–11(e)). However, following treatment with all doses of DMPF-1, the levels of eotaxin, RANTES, IL-4, IL-5, and IL-13 reduced markedly. Figure 11(f) shows that DMPF-1 had a similar inhibitory effect on IgE level found in the serum of OVA-challenged mice. To further determine whether DMPF-1 modulated eotaxin, RANTES, IL-4, IL-5, and IL-13 in OVA-challenged mice at the transcriptional level, their mRNA levels were determined by RT-PCR. As shown in Figure 12, OVA-challenged group had the highest mRNA expression in comparison to the naïve mice. However, these highly expressed mRNAs were significantly inhibited by all doses of DMPF-1.


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 the mRNA level of chemokines and Th2 cytokines on OVA-sensitized mice. Expression levels of mRNA were determined by RT-PCR analysis. After the mice were sacrificed, the lung tissue was collected and the mRNA levels of (a) eotaxin-1, (b) RANTES, (c) IL-4, (d) IL-5, and (e) IL-13 were measured. The values are expressed as mean ± SEM (n = 10). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.005, significantly different from the OVA-challenged group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig12: Effect of DMPF-1 on the mRNA level of chemokines and Th2 cytokines on OVA-sensitized mice. Expression levels of mRNA were determined by RT-PCR analysis. After the mice were sacrificed, the lung tissue was collected and the mRNA levels of (a) eotaxin-1, (b) RANTES, (c) IL-4, (d) IL-5, and (e) IL-13 were measured. The values are expressed as mean ± SEM (n = 10). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.005, significantly different from the OVA-challenged group.
Mentions: In comparison to naïve mice, the levels of eotaxin, RANTES, IL-4, IL-5, and IL-13 significantly increased in BALF of OVA-challenged mice (Figures 11(a)–11(e)). However, following treatment with all doses of DMPF-1, the levels of eotaxin, RANTES, IL-4, IL-5, and IL-13 reduced markedly. Figure 11(f) shows that DMPF-1 had a similar inhibitory effect on IgE level found in the serum of OVA-challenged mice. To further determine whether DMPF-1 modulated eotaxin, RANTES, IL-4, IL-5, and IL-13 in OVA-challenged mice at the transcriptional level, their mRNA levels were determined by RT-PCR. As shown in Figure 12, OVA-challenged group had the highest mRNA expression in comparison to the naïve mice. However, these highly expressed mRNAs were significantly inhibited by all doses of DMPF-1.

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