A geranyl acetophenone targeting cysteinyl leukotriene synthesis prevents allergic airway inflammation in ovalbumin-sensitized mice

Ismail, Norazren; Jambari, Nuzul Noorahya; Zareen, Seema; Akhtar, M.N.; Shaari, Khozirah; Zamri-Saad, M.; Tham, Chau Ling; Sulaiman, Mohd Roslan; Lajis, Nordin Hj; Israf, Daud Ahmad

doi:10.1016/j.taap.2012.01.003

Cited by 19 publications

(31 citation statements)

References 36 publications

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“…The geranyl acetophenone, 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA), originally discovered in Melicope ptelefolia , contains a bioactive principle of the phloroglucinol core (Shaari et al, 2006 ). We previously demonstrated that synthetic tHGA inhibited airway inflammation in ovalbumin (OVA)-induced murine experimental asthma (Ismail et al, 2012 ). Recently, we also demonstrated that tHGA is orally active and able to exert a dose-dependent inhibitory effect on airway remodeling in a similar model (Lee et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Blockade of Eosinophil-Induced Bronchial Epithelial-Mesenchymal Transition with a Geranyl Acetophenone in a Coculture Model

et al. 2017

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Epithelial-mesenchymal transition (EMT) is currently recognized as the main cellular event that contributes to airway remodeling. Eosinophils can induce EMT in airway epithelial cells via increased transforming growth factor (TGF)-β production. We assessed the effect of synthetic 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA) upon eosinophil-induced EMT in a cellular model. The human eosinophil cell line EoL-1 was used to induce EMT in BEAS-2B human bronchial epithelial cells. The induction of EMT was dose-dependently suppressed following tHGA treatment in which the epithelial morphology and E-cadherin expression were not altered. Protein and mRNA expression of vimentin, collagen I and fibronectin in eosinophil-induced epithelial cells were also significantly suppressed by tHGA treatment. Following pathway analysis, we showed that tHGA suppressed eosinophil-induced activator protein-1-mediated TGF-β production by targeting c-Jun N-terminal kinase and phosphoinositide 3-kinase signaling pathways. These findings corroborated previous findings on the ability of tHGA to inhibit experimental murine airway remodeling.

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Section: Introductionmentioning

confidence: 99%

Blockade of Eosinophil-Induced Bronchial Epithelial-Mesenchymal Transition with a Geranyl Acetophenone in a Coculture Model

et al. 2017

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“…Prenylated analogues were synthesized by reacting the acylphloroglucinols ( 2a – g ) with prenyl bromide through direct C -alkylation, using potassium carbonate as a base in dry methanol. A geranylated analogue ( 3d ) was also synthesized, by reacting acylphloroglucinol ( 2d ) with geranyl bromide [ 11 ]. In order to investigate the importance of the hydroxyl group to the bioactivity, the hydroxyl group was methylated using methyl iodide as a methylating agent, as described by Smith (2005), to yield compounds 5a , 5e and 6a , 6e [ 15 ].…”

Section: Resultsmentioning

confidence: 99%

“…The organic layers were combined, dried, and concentrated. Column chromatography over silica gel eluted with petroleum ether/ethyl acetate (10:1) gave geranylated/prenylated compounds [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

“…Our earlier bioassay-guided identification studies identified this compound in the medicinal plant Melicope ptelefolia [ 10 ]. This compound can also be synthesized via direct C -alkylation, using 2,4,6-trihydroxyacetophenone and geranyl bromide as the starting material [ 11 ]. Further exploration into the chemistry and pharmacology of tHGA revealed that it is a dual inhibitor of LOX and Cyclooxygenase (COX) [ 10 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Further exploration into the chemistry and pharmacology of tHGA revealed that it is a dual inhibitor of LOX and Cyclooxygenase (COX) [ 10 , 12 ]. When tested in an acute murine model, tHGA was as effective as Zileuton, a commercial LOX inhibitor, in preventing allergic airway inflammation [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Hits-to-Lead Optimization of the Natural Compound 2,4,6-Trihydroxy-3-geranyl-acetophenone (tHGA) as a Potent LOX Inhibitor: Synthesis, Structure-Activity Relationship (SAR) Study, and Computational Assignment

Rullah

Abas

et al. 2018

Molecules

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A new series of 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) analogues were synthesized and evaluated for their lipoxygenase (LOX) inhibitory activity. Prenylated analogues 4a–g (half maximal inhibitory concentration (IC50) values ranging from 35 μM to 95 μM) did not exhibit better inhibitory activity than tHGA (3a) (IC50 value: 23.6 μM) due to the reduction in hydrophobic interaction when the alkyl chain length was reduced. One geranylated analogue, 3d, with an IC50 value of 15.3 μM, exhibited better LOX inhibitory activity when compared to tHGA (3a), which was in agreement with our previous findings. Kinetics study showed that the most active analogue (3e) and tHGA (3a) acted as competitive inhibitors. The combination of in silico approaches of molecular docking and molecular dynamic simulation revealed that the lipophilic nature of these analogues further enhanced the LOX inhibitory activity. Based on absorption, distribution, metabolism, excretion, and toxicity (ADMET) and toxicity prediction by komputer assisted technology (TOPKAT) analyses, all geranylated analogues (3a–g) showed no hepatotoxicity effect and were biodegradable, which indicated that they could be potentially safe drugs for treating inflammation.

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Britanin attenuates ovalbumin-induced airway inflammation in a murine asthma model

et al. 2016

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We previously demonstrated the alleviation of ovalbumin (OVA)-induced airway inflammation by Inulae flos. In the present study, the effects of britanin, a sesquiterpene compound isolated from Inulae flos, were evaluated in an in vivo animal model for anti-asthma activity through observation of airway hyperresponsiveness (AHR), eosinophil recruitment, Th2 cytokine and IgE levels, and lung histopathology. Britanin administration effectively reduced AHR induced by aerosolized methacholine, airway eosinophilia, Th2 cytokines in bronchoalveolar lavage fluids and the supernatant of cultured splenocytes compared with OVA-induced mice. Histological studies showed that increased inflammatory cell infiltration and mucus secretion were reduced by britanin administration. Thus, britanin may have therapeutic potential for treating allergic asthma.

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A geranyl acetophenone targeting cysteinyl leukotriene synthesis prevents allergic airway inflammation in ovalbumin-sensitized mice

Cited by 19 publications

References 36 publications

Blockade of Eosinophil-Induced Bronchial Epithelial-Mesenchymal Transition with a Geranyl Acetophenone in a Coculture Model

Blockade of Eosinophil-Induced Bronchial Epithelial-Mesenchymal Transition with a Geranyl Acetophenone in a Coculture Model

Hits-to-Lead Optimization of the Natural Compound 2,4,6-Trihydroxy-3-geranyl-acetophenone (tHGA) as a Potent LOX Inhibitor: Synthesis, Structure-Activity Relationship (SAR) Study, and Computational Assignment

Britanin attenuates ovalbumin-induced airway inflammation in a murine asthma model

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