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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

The chemical structure of DMPF-1.
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fig1: The chemical structure of DMPF-1.

Mentions: DMPF-1 (3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one; Figure 1) is a synthetic chalcone analogue. Chalcones, which belong to flavonoid family, are made up of two aromatic rings joined by a three-carbon α,β-unsaturated carbonyl system [13]. Studies have shown that synthetic and naturally occurring chalcones possess a diverse array of pharmacological activities including antimicrobial, antioxidant, anticancer, and anti-inflammatory properties [13, 14]. Furthermore, several chalcone derivatives have also been shown to inhibit airway inflammation and BHR in allergic asthma [15]. We have previously demonstrated that DMPF-1 inhibited nitric oxide production by LPS-stimulated RAW 264.7 murine macrophages [16]. However, the effect of DMPF-1 on airway inflammation has never been studied. Therefore, the objectives of this study were to determine the effect of DMPF-1 upon the synthesis of asthma-related proinflammatory chemokines in TNF-α-induced pulmonary epithelial cells and OVA-challenged BALB/c mice. We also attempted to determine the effect of DMPF-1 upon the proinflammatory NF-κB and MAPK signaling pathways in TNF-α-induced A549 cells. A final objective in the future involves assessment of the effect of orally administered DMPF-1 upon Th2 cytokine synthesis, eosinophilia, goblet cell hyperplasia, peripheral blood total IgE, and BHR in OVA-challenged BALB/c mice.


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)

The chemical structure of DMPF-1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: The chemical structure of DMPF-1.
Mentions: DMPF-1 (3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one; Figure 1) is a synthetic chalcone analogue. Chalcones, which belong to flavonoid family, are made up of two aromatic rings joined by a three-carbon α,β-unsaturated carbonyl system [13]. Studies have shown that synthetic and naturally occurring chalcones possess a diverse array of pharmacological activities including antimicrobial, antioxidant, anticancer, and anti-inflammatory properties [13, 14]. Furthermore, several chalcone derivatives have also been shown to inhibit airway inflammation and BHR in allergic asthma [15]. We have previously demonstrated that DMPF-1 inhibited nitric oxide production by LPS-stimulated RAW 264.7 murine macrophages [16]. However, the effect of DMPF-1 on airway inflammation has never been studied. Therefore, the objectives of this study were to determine the effect of DMPF-1 upon the synthesis of asthma-related proinflammatory chemokines in TNF-α-induced pulmonary epithelial cells and OVA-challenged BALB/c mice. We also attempted to determine the effect of DMPF-1 upon the proinflammatory NF-κB and MAPK signaling pathways in TNF-α-induced A549 cells. A final objective in the future involves assessment of the effect of orally administered DMPF-1 upon Th2 cytokine synthesis, eosinophilia, goblet cell hyperplasia, peripheral blood total IgE, and BHR in OVA-challenged BALB/c mice.

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