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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 bronchial hyperresponsiveness to methacholine. Female BALB/c mice were sensitized and challenged with OVA 1 hour after treatment with various doses of DMPF-1. After 24 hours of the last OVA challenge, the mice were exposed to (a) increasing doses of methacholine (6.25, 12.5, 25, and 50 mg/mL) in an enclosed chamber for 3 min and the readings were taken for 5 min after each nebulization. (b) The Penh of all groups at the highest dose of methacholine. The values are expressed as mean ± SEM (n = 10). ∗∗∗P < 0.005, significantly different from the OVA-challenged group.
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fig7: Effect of DMPF-1 on bronchial hyperresponsiveness to methacholine. Female BALB/c mice were sensitized and challenged with OVA 1 hour after treatment with various doses of DMPF-1. After 24 hours of the last OVA challenge, the mice were exposed to (a) increasing doses of methacholine (6.25, 12.5, 25, and 50 mg/mL) in an enclosed chamber for 3 min and the readings were taken for 5 min after each nebulization. (b) The Penh of all groups at the highest dose of methacholine. The values are expressed as mean ± SEM (n = 10). ∗∗∗P < 0.005, significantly different from the OVA-challenged group.

Mentions: BHR of mice was plotted as percentage increase of enhanced pause (Penh). Methacholine doses were increased from 6.25 mg/mL to 50 mg/mL while PBS was set as a baseline. Figure 7 shows that exposure to methacholine increased Penh in OVA-sensitized and OVA-challenged mice as opposed to naïve mice (OVA-sensitized and PBS-challenged). DMPF-1 treatment of OVA-challenged mice caused significant reduction of Penh at the highest methacholine dose (50 mg/mL). However, there was no clear dose-response effect among the treatment groups.


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 bronchial hyperresponsiveness to methacholine. Female BALB/c mice were sensitized and challenged with OVA 1 hour after treatment with various doses of DMPF-1. After 24 hours of the last OVA challenge, the mice were exposed to (a) increasing doses of methacholine (6.25, 12.5, 25, and 50 mg/mL) in an enclosed chamber for 3 min and the readings were taken for 5 min after each nebulization. (b) The Penh of all groups at the highest dose of methacholine. 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

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

fig7: Effect of DMPF-1 on bronchial hyperresponsiveness to methacholine. Female BALB/c mice were sensitized and challenged with OVA 1 hour after treatment with various doses of DMPF-1. After 24 hours of the last OVA challenge, the mice were exposed to (a) increasing doses of methacholine (6.25, 12.5, 25, and 50 mg/mL) in an enclosed chamber for 3 min and the readings were taken for 5 min after each nebulization. (b) The Penh of all groups at the highest dose of methacholine. The values are expressed as mean ± SEM (n = 10). ∗∗∗P < 0.005, significantly different from the OVA-challenged group.
Mentions: BHR of mice was plotted as percentage increase of enhanced pause (Penh). Methacholine doses were increased from 6.25 mg/mL to 50 mg/mL while PBS was set as a baseline. Figure 7 shows that exposure to methacholine increased Penh in OVA-sensitized and OVA-challenged mice as opposed to naïve mice (OVA-sensitized and PBS-challenged). DMPF-1 treatment of OVA-challenged mice caused significant reduction of Penh at the highest methacholine dose (50 mg/mL). However, there was no clear dose-response effect among the treatment groups.

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