The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation

Abstract Increased airway smooth muscle (ASM) mass is a prominent hallmark of airway remodeling in asthma. Inhaled corticosteroids and long-acting beta2-agonists remain the mainstay of asthma therapy, however are not curative and ineffective in attenuating airway remodeling. The geranyl acetophenone...

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Autores principales:	Hui Min Yap, Yu Zhao Lee, Hanis Hazeera Harith, Chau Ling Tham, Manraj Singh Cheema, Khozirah Shaari, Daud Ahmad Israf
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Human Bronchial Smooth Muscle Cells Airway Remodeling Growth Factor-enriched Media PDK1 Kinase Activity Chronic Murine Model Medicine R Science Q
Acceso en línea:	https://doaj.org/article/928b5b5919c84c4aa574d2dabe069998
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spelling	oai:doaj.org-article:928b5b5919c84c4aa574d2dabe0699982021-12-02T15:08:23ZThe geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation10.1038/s41598-018-34847-02045-2322https://doaj.org/article/928b5b5919c84c4aa574d2dabe0699982018-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-34847-0https://doaj.org/toc/2045-2322Abstract Increased airway smooth muscle (ASM) mass is a prominent hallmark of airway remodeling in asthma. Inhaled corticosteroids and long-acting beta2-agonists remain the mainstay of asthma therapy, however are not curative and ineffective in attenuating airway remodeling. The geranyl acetophenone 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA), an in-house synthetic non-steroidal compound, attenuates airway hyperresponsiveness and remodeling in murine models of asthma. The effect of tHGA upon human ASM proliferation, migration and survival in response to growth factors was assessed and its molecular target was determined. Following serum starvation and induction with growth factors, proliferation and migration of human bronchial smooth muscle cells (hBSMCs) treated with tHGA were significantly inhibited without any significant effects upon cell survival. tHGA caused arrest of hBSMC proliferation at the G1 phase of the cell cycle with downregulation of cell cycle proteins, cyclin D1 and diminished degradation of cyclin-dependent kinase inhibitor (CKI), p27Kip1. The inhibitory effect of tHGA was demonstrated to be related to its direct inhibition of AKT phosphorylation, as well as inhibition of JNK and STAT3 signal transduction. Our findings highlight the anti-remodeling potential of this drug lead in chronic airway disease.Hui Min YapYu Zhao LeeHanis Hazeera HarithChau Ling ThamManraj Singh CheemaKhozirah ShaariDaud Ahmad IsrafNature PortfolioarticleHuman Bronchial Smooth Muscle CellsAirway RemodelingGrowth Factor-enriched MediaPDK1 Kinase ActivityChronic Murine ModelMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Human Bronchial Smooth Muscle Cells Airway Remodeling Growth Factor-enriched Media PDK1 Kinase Activity Chronic Murine Model Medicine R Science Q
spellingShingle	Human Bronchial Smooth Muscle Cells Airway Remodeling Growth Factor-enriched Media PDK1 Kinase Activity Chronic Murine Model Medicine R Science Q Hui Min Yap Yu Zhao Lee Hanis Hazeera Harith Chau Ling Tham Manraj Singh Cheema Khozirah Shaari Daud Ahmad Israf The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation
description	Abstract Increased airway smooth muscle (ASM) mass is a prominent hallmark of airway remodeling in asthma. Inhaled corticosteroids and long-acting beta2-agonists remain the mainstay of asthma therapy, however are not curative and ineffective in attenuating airway remodeling. The geranyl acetophenone 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA), an in-house synthetic non-steroidal compound, attenuates airway hyperresponsiveness and remodeling in murine models of asthma. The effect of tHGA upon human ASM proliferation, migration and survival in response to growth factors was assessed and its molecular target was determined. Following serum starvation and induction with growth factors, proliferation and migration of human bronchial smooth muscle cells (hBSMCs) treated with tHGA were significantly inhibited without any significant effects upon cell survival. tHGA caused arrest of hBSMC proliferation at the G1 phase of the cell cycle with downregulation of cell cycle proteins, cyclin D1 and diminished degradation of cyclin-dependent kinase inhibitor (CKI), p27Kip1. The inhibitory effect of tHGA was demonstrated to be related to its direct inhibition of AKT phosphorylation, as well as inhibition of JNK and STAT3 signal transduction. Our findings highlight the anti-remodeling potential of this drug lead in chronic airway disease.
format	article
author	Hui Min Yap Yu Zhao Lee Hanis Hazeera Harith Chau Ling Tham Manraj Singh Cheema Khozirah Shaari Daud Ahmad Israf
author_facet	Hui Min Yap Yu Zhao Lee Hanis Hazeera Harith Chau Ling Tham Manraj Singh Cheema Khozirah Shaari Daud Ahmad Israf
author_sort	Hui Min Yap
title	The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation
title_short	The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation
title_full	The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation
title_fullStr	The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation
title_full_unstemmed	The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation
title_sort	geranyl acetophenone thga attenuates human bronchial smooth muscle proliferation via inhibition of akt phosphorylation
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/928b5b5919c84c4aa574d2dabe069998
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The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation

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