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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

Representative hematoxylin and eosin- (H&E-) stained lung sections. Airways and blood vessels of (a) naïve mice, (b) OVA-challenged mice, (c) dexamethasone-treated mice, (d) 100 mg/kg DMPF-1-treated mice, (e) 20 mg/kg DMPF-1-treated mice, (f) 2 mg/kg DMPF-1-treated mice, and (g) 0.2 mg/kg DMPF-1-treated mice. These photos were taken under 40x objective (400x magnification) using light microscope (Bar = 50 μm). This experiment used 10 mice per group (n = 10). (h) For quantitative analysis of infiltration of inflammatory cells, the numbers of total inflammatory cells per airway and blood vessel were obtained by adding the average number of cells from perivascular count/number of airways and peribronchial count/number of blood vessels. The values are expressed as mean ± SEM (n = 10). ∗∗∗P < 0.005, significantly different from the OVA-challenged group.
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fig9: Representative hematoxylin and eosin- (H&E-) stained lung sections. Airways and blood vessels of (a) naïve mice, (b) OVA-challenged mice, (c) dexamethasone-treated mice, (d) 100 mg/kg DMPF-1-treated mice, (e) 20 mg/kg DMPF-1-treated mice, (f) 2 mg/kg DMPF-1-treated mice, and (g) 0.2 mg/kg DMPF-1-treated mice. These photos were taken under 40x objective (400x magnification) using light microscope (Bar = 50 μm). This experiment used 10 mice per group (n = 10). (h) For quantitative analysis of infiltration of inflammatory cells, the numbers of total inflammatory cells per airway and blood vessel were obtained by adding the average number of cells from perivascular count/number of airways and peribronchial count/number of blood vessels. The values are expressed as mean ± SEM (n = 10). ∗∗∗P < 0.005, significantly different from the OVA-challenged group.

Mentions: Inflammatory cell infiltration of the area surrounding the airways and blood vessels in the lung as well as goblet cell hyperplasia was evaluated histologically. Figures 9 and 10 show representative micrographs of both H&E- and PAS-stained sections. In comparison to naïve mice, OVA-sensitized and OVA-challenged mice showed robust pathological changes in allergic pulmonary inflammation which were characterized by extensive infiltration of eosinophils and mononuclear cells around airways and vessels with goblet cell hyperplasia. Mice treated with DMPF-1 demonstrated significant attenuation of pathological changes. To be more specific, H&E-stained sections in Figure 9 show that, in comparison to naïve mice (Figure 9(a)), there were a large number of inflammatory cells concentrated near the airways and in the perivascular and peribronchial areas of OVA-challenged mice (Figure 9(b)). However, the number was markedly decreased following treatment with increasing doses of DMPF-1 (Figures 9(d)–9(g)). Lung histology slides were also stained with PAS to show goblet cells. Figure 10 shows that OVA-challenged mice (Figure 10(b)) had most PAS-staining goblet cells compared to the naïve mice (Figure 10(a)). Similarly, mice treated with increasing doses of DMPF-1 significantly reduced goblet cell hyperplasia (Figures 10(d)–10(g)).


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)

Representative hematoxylin and eosin- (H&E-) stained lung sections. Airways and blood vessels of (a) naïve mice, (b) OVA-challenged mice, (c) dexamethasone-treated mice, (d) 100 mg/kg DMPF-1-treated mice, (e) 20 mg/kg DMPF-1-treated mice, (f) 2 mg/kg DMPF-1-treated mice, and (g) 0.2 mg/kg DMPF-1-treated mice. These photos were taken under 40x objective (400x magnification) using light microscope (Bar = 50 μm). This experiment used 10 mice per group (n = 10). (h) For quantitative analysis of infiltration of inflammatory cells, the numbers of total inflammatory cells per airway and blood vessel were obtained by adding the average number of cells from perivascular count/number of airways and peribronchial count/number of blood vessels. The values are expressed as mean ± SEM (n = 10). ∗∗∗P < 0.005, significantly different from the OVA-challenged group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig9: Representative hematoxylin and eosin- (H&E-) stained lung sections. Airways and blood vessels of (a) naïve mice, (b) OVA-challenged mice, (c) dexamethasone-treated mice, (d) 100 mg/kg DMPF-1-treated mice, (e) 20 mg/kg DMPF-1-treated mice, (f) 2 mg/kg DMPF-1-treated mice, and (g) 0.2 mg/kg DMPF-1-treated mice. These photos were taken under 40x objective (400x magnification) using light microscope (Bar = 50 μm). This experiment used 10 mice per group (n = 10). (h) For quantitative analysis of infiltration of inflammatory cells, the numbers of total inflammatory cells per airway and blood vessel were obtained by adding the average number of cells from perivascular count/number of airways and peribronchial count/number of blood vessels. The values are expressed as mean ± SEM (n = 10). ∗∗∗P < 0.005, significantly different from the OVA-challenged group.
Mentions: Inflammatory cell infiltration of the area surrounding the airways and blood vessels in the lung as well as goblet cell hyperplasia was evaluated histologically. Figures 9 and 10 show representative micrographs of both H&E- and PAS-stained sections. In comparison to naïve mice, OVA-sensitized and OVA-challenged mice showed robust pathological changes in allergic pulmonary inflammation which were characterized by extensive infiltration of eosinophils and mononuclear cells around airways and vessels with goblet cell hyperplasia. Mice treated with DMPF-1 demonstrated significant attenuation of pathological changes. To be more specific, H&E-stained sections in Figure 9 show that, in comparison to naïve mice (Figure 9(a)), there were a large number of inflammatory cells concentrated near the airways and in the perivascular and peribronchial areas of OVA-challenged mice (Figure 9(b)). However, the number was markedly decreased following treatment with increasing doses of DMPF-1 (Figures 9(d)–9(g)). Lung histology slides were also stained with PAS to show goblet cells. Figure 10 shows that OVA-challenged mice (Figure 10(b)) had most PAS-staining goblet cells compared to the naïve mice (Figure 10(a)). Similarly, mice treated with increasing doses of DMPF-1 significantly reduced goblet cell hyperplasia (Figures 10(d)–10(g)).

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