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 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.

IL-1β augments TGF-β inducing epithelial-mesenchymal transition of epithelial cells and associates with poor pulmonary function improvement in neutrophilic asthmatics

“…And the effect of LTRA on attenuate airway remodeling by inhibiting TGF-β/Smad signaling has been also demonstrated [ 36 ]. However, recent studies have also focused on the ineffective of glucocorticoid in treating airway remodeling [ 37 , 38 ]. Our results showed that neither glucocorticoid or montelukast sodium can reverse the changes of EMT markers induced by TGF-β1/IL-1β.…”

“…Previous studies have demonstrated the critical role of MAPK signaling pathways (such as ERK1/2, JNK, and p38 signaling pathways) and other signaling pathways (such as PI3K/AKT, NF-κb, and Smads signaling pathways) in EMT induced by TGF-β1 or other cytokines and airway remodeling [ 39 – 46 ].Some of drugs, chemicals, and probiotics can alleviate airway remodeling through attenuation these signaling pathways [ 38 , 47 – 50 ]. To further investigate the mechanism of IL-1β augmenting TGF-β1 induced EMT, candidate signaling pathways related proteins were detected.…”

Investigation of the Active Ingredients and Mechanism of Polygonum cuspidatum in Asthma Based on Network Pharmacology and Experimental Verification

“…It had been reported AKT activation played an important role in the pathogenesis of asthma, such as by promoting ASM cell proliferation. 21 We then verified whether Polygonum cuspidatum showed an inhibitory effect on ASM proliferation. We used CCK-8 assays to analyse the effect of Polygonum cuspidatum extraction on the proliferation of ASM cells induced by platelet-derived growth factor (PDGF)-BB (a well-known ASM mitogen that promotes ASM proliferation).…”

Targeting Airway Smooth Muscle Hypertrophy in Asthma: An Approach Whose Time Has Come

“…Cell apoptosis was not significantly affected. 91 Mitochondrial activity sustaining cell proliferation and ASM hypertrophy can be reduced using artificial sphingosine analogs that act as a substrate for sphingosine kinase-2 (SPHK-2). The analog (R)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol reduces ASM cell numbers by decreasing oxidative energy metabolism and reducing airway hyperresponsiveness.…”