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

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.

Chalcones: Synthetic Chemistry Follows Where Nature Leads

“…Chalcones that induce transcription factors: chalcone (1), lophirone B (12) and C (13) induce the Nrf2 pathway, while synthetic chalcones DK-139 (24), L6H9 (25) and DMPF-1 (26) induce the NF-κB pathway.Several studies have examined the effect of chalcones on NF-κB signaling as a plausible way to modulate inflammation and cancer, and found that several natural chalcones, e.g., butein(16), calomelanone (17), flavokawain C (18), homobutein(19), 4-hydroxychalcone (20), 4 -hydroxychalcone (21), isoliquiritigenin (22), 4-methoxychalcone (2), and phloretin (23) (Figure4) have the ability to suppress NF-κB signaling[22]. Similarly, NF-κB activation could be stimulated by several synthetic chalcones, such as 2-hydroxy-3 ,5,5trimethoxychalcone (DK-139) (24)[23], (E)-2,6-difluoro-4 -methoxychalcone (L6H9) (25)[24], and 3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one (DMPF-1) (26)[25] (Figure3).Biomolecules 2021, 11, x FOR PEER REVIEW 7 of 38…”

Evaluation of antinociceptive profile of chalcone derivative (3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl) prop-2-en-1-one (DMPF-1) in vivo

“…[ 1 ] Furthermore, it is also capable to inhibit the nuclear translocation and suppression of nuclear factor kappa B (NF-kB), which explains its anti-inflammatory action. [ 6 ] This finding was supported by other in vitro studies using interferon-c/lipopolysaccharide (IFN-c/LPS)-activated RAW 264.7 macrophages cells showing that chalcones bearing furanyl group revealed remarkable anti-inflammatory activity via inhibition of NO and prostaglandin E2 (PGE2) production. [ 7 ]…”

Comparison of Immune Response To Human Rhinovirus C And Respiratory Syncytial Virus In Highly Differentiated Human Airway Epithelial Cells

“…In patients with asthma, an increased expression of MCP-1 has been reported with the activation of a dysregulated Th2 response [34]. Inhibition of MCP-1 expression signi cantly reduced airway reactivity in an experimental model of asthma [35]. A study by Giuffrida has shown that MCP-1 was signi cantly increased in asthmatic patients when compared with non-asthmatic patients, and only RSV induced signi cant increase in MCP-1 expression, when compared with parain uenza virus and adenovirus [34].…”