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

Lee, Yu Zhao; Yap, Hui Min; Shaari, Khozirah; Tham, Chau Ling; Sulaiman, Mohd Roslan; Israf, Daud Ahmad

doi:10.3389/fphar.2017.00837

Cited by 18 publications

(19 citation statements)

References 45 publications

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“…The anti-inflammatory activity of tHGA has been demonstrated by various in vitro and in vivo studies [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. This is the first report on the anti-inflammatory effects of tHGA in alveolar epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Several in vitro and in vivo studies have established its anti-inflammatory activity in a range of cellular and disease models [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. In particular, tHGA displays therapeutic potential for the treatment of asthma, a chronic inflammatory airway disease, owing to its anti-inflammatory activity and ability to attenuate airway remodeling [ 12 , 14 , 17 ]. Recently, tHGA demonstrated protective effects against vascular endothelial barrier dysfunction, suggesting its therapeutic potential in treating vascular inflammatory disorders [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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The Protective Effects of a Synthetic Geranyl Acetophenone in a Cellular Model of TNF-α-Induced Pulmonary Epithelial Barrier Dysfunction

et al. 2018

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Alveolar epithelial barrier dysfunction contributes to lung edema and can lead to acute lung injury (ALI). The features include increased epithelial permeability, upregulation of inflammatory mediators and downregulation of junctional complex molecules; these changes are often induced by inflammation. tHGA is an acetophenone analogue with therapeutic potential in asthma. Its therapeutic potential in ALI is presently unknown. Herein, the effects of tHGA on epithelial barrier dysfunction were determined in TNF-α-induced human alveolar epithelial cells. The anti-inflammatory properties of tHGA were assessed by monocyte adhesion assay and analysis of MCP-1 and ICAM-1 expression. The epithelial barrier function was assessed by paracellular permeability and transepithelial electrical resistance (TEER) assays, and analysis of junctional complex molecules expression. To elucidate the mechanism of action, the effects of tHGA on the NF-κB and MAPK pathways were determined. Gene and protein expression were analyzed by RT-PCR and Western blotting or ELISA, respectively. tHGA suppressed leukocyte adhesion to TNF-α-induced epithelium and reduced MCP-1 and ICAM-1 gene expression and secretion. tHGA also increased TEER readings, reduced epithelial permeability and enhanced expression of junctional complex molecules (zona occludens-1, occludin and E-cadherin) in TNF-α-induced cells. Correspondingly, the NF-κB, ERK and p38 MAPK pathways were also inhibited by tHGA. These findings suggest that tHGA is able to preserve alveolar epithelial barrier function in response to acute inflammation, via its anti-inflammatory activity and stabilization of epithelial barrier integrity, mediated by NF-κB, ERK and p38 MAPK signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Protective Effects of a Synthetic Geranyl Acetophenone in a Cellular Model of TNF-α-Induced Pulmonary Epithelial Barrier Dysfunction

et al. 2018

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“…Previous studies showed that HMGB1 induces epithelial-mesenchymal transition (EMT) in airway epithelial tissue [19,20]. EMT, the transition of epithelial and endothelial cells to a motile phenotype, namely, transformation to mesenchymal stem cells, which not only associated with embryonic development, inflammation, tissue regeneration, and tumor formation, but also play an important role in the pathogenesis of ECRSwNP [21][22][23]. At the molecular level, epithelial cells lose their epithelial character and gain mesenchymal properties.…”

Section: Ivyspringmentioning

confidence: 99%

Agonist of PPAR-γ Reduced Epithelial-Mesenchymal Transition in Eosinophilic Chronic Rhinosinusitis with Nasal Polyps via Inhibition of High Mobility Group Box1

Yang¹,

Chen²,

Zhong³

et al. 2019

Int. J. Med. Sci.

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Epithelial-mesenchymal transition (EMT) has been reported to occur in eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP). Among the cytokines that cause EMT, high mobility group box 1 (HMGB1) has been shown to give rise to EMT in airway epithelial cells. However, the mechanism of HMGB1-induced EMT in ECRSwNP is unknown. We explored the mechanism and possible inhibitor. Immunohistochemistry (IHC), immunofluorescence (IF), and western blot assay were used to detect the expression and location of HMGB1, peroxisome proliferator-activated receptor-γ (PPAR-γ), and EMT markers in eighteen ECRSwNP and twelve normal nasal mucosa tissues. Epithelial cells isolated from ECRSwNP were cultured with various doses of recombinant human HMGB1 (rhHMGB1) to study the expression of PPAR-γ, and EMT markers. Additionally, the ligand of PPAR-γ was incubated with epithelial cells to interfere with the effects of lipopolysaccharide (LPS) or rhHMGB1 to explore the effect on expression of HMGB1 and EMT markers. These results suggest that HMGB1 was highly expressed in ECRSwNP compared with its expression in control tissues, and EMT was also found highly in ECRSwNP compared with control tissues. Moreover, the cytoplasmic accumulation of HMGB1 in ECRSwNP was obvious compared with normal tissues. We also found dose-dependent induction by rhHMGB1 of up-regulation of N-cadherin and vimentin and down-regulation of ZO-1 and E-cadherin in epithelial cells isolated from ECRSwNP. The agonist of PPAR-γ not only reduced release of HMGB1 induced by LPS, but also reversed the EMT. The protective role of PPAR-γ also appeared in cells that had been incubated with rhHMGB1. In the current study, we discovered that the agonist of PPAR-γ has a potential role in inhibited HMGB1-induced EMT in ECRSwNP. The agonist of PPAR-γ may contribute to inhabit epithelial cells to become mesenchymal-like cells which play an important role in the pathogenesis of ECRSwNP.

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“…To date, various pharmacological activities of tHGA have been discovered. These include anti-inflammatory ( Shaari et al, 2011 ), endothelial and epithelial barrier protective ( Chong et al, 2016 ; Sim et al, 2018 ; Chan et al, 2021 ), anti-asthmatic ( Ismail et al, 2012 ; Lee et al, 2017a ; Lee et al, 2017b ; Yap et al, 2018 ; Ismail et al, 2019 ), anti-allergic ( Tan et al, 2017a ; Tan et al, 2017b ), and anti-cancer ( Cho et al, 2012a ; Cho et al, 2012b ) activities. Therefore, this mini review aims to summarize the reported pharmacological activities of tHGA and the underlying signaling pathways, as well as to pinpoint the potentials of this compound for drug development processes in the future.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Properties of 2,4,6-Trihydroxy-3-Geranyl Acetophenone and the Underlying Signaling Pathways: Progress and Prospects

et al. 2021

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2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) is a bioactive phloroglucinol compound found in Melicope pteleifolia (Champ. ex Benth.) T.G.Hartley, a medicinal plant vernacularly known as “tenggek burung”. A variety of phytochemicals have been isolated from different parts of the plant including leaves, stems, and roots by using several extraction methods. Specifically, tHGA, a drug-like compound containing phloroglucinol structural core with acyl and geranyl group, has been identified in the methanolic extract of the young leaves. Due to its high nutritional and medicinal values, tHGA has been extensively studied by using various experimental models. These studies have successfully discovered various interesting pharmacological activities of tHGA such as anti-inflammatory, endothelial and epithelial barrier protective, anti-asthmatic, anti-allergic, and anti-cancer. More in-depth investigations later found that these activities were attributable to the modulatory actions exerted by tHGA on specific molecular targets. Despite these findings, the association between the mechanisms and signaling pathways underlying each pharmacological activity remains largely unknown. Also, little is known about the medicinal potentials of tHGA as a drug lead in the current pharmaceutical industry. Therefore, this mini review aims to summarize and relate the pharmacological activities of tHGA in terms of their respective mechanisms of action and signaling pathways in order to present a perspective into the overall modulatory actions exerted by tHGA. Besides that, this mini review will also pinpoint the unexplored potentials of this compound and provide some valuable insights into the potential applications of tHGA which may serve as a guide for the development of modern medication in the future.

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

Cited by 18 publications

References 45 publications

The Protective Effects of a Synthetic Geranyl Acetophenone in a Cellular Model of TNF-α-Induced Pulmonary Epithelial Barrier Dysfunction

The Protective Effects of a Synthetic Geranyl Acetophenone in a Cellular Model of TNF-α-Induced Pulmonary Epithelial Barrier Dysfunction

Agonist of PPAR-γ Reduced Epithelial-Mesenchymal Transition in Eosinophilic Chronic Rhinosinusitis with Nasal Polyps via Inhibition of High Mobility Group Box1

Pharmacological Properties of 2,4,6-Trihydroxy-3-Geranyl Acetophenone and the Underlying Signaling Pathways: Progress and Prospects

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