Naringin as a natural bitter tastant promotes proliferation of cultured human bronchial epithelial cells via activation of TAS2R signaling

Abstract

Bitter tastants can activate bitter taste receptors (TAS2Rs) and thus initiate the relaxation of airway smooth muscle cells, which have great potential in the development of novel asthma therapy. However, recent study shows that canonical bitter substance denatonium induces apoptosis of bronchial epithelial cells (BECs), indicating the toxic effect of bitter tastants on airways. Considering the diversity of bitter tastants in nature and TAS2Rs expressed in airway cells, it is thus necessary to carefully evaluate the bitter tastant for its effect on the proliferation of BECs, if aimed to treat airway disease. Here we first screened a group of bitter flavonoids, including apignenin, hespretin, kaempferol, naringenin, naringin and quercetin which are commonly used in food and traditional medicine, and then quantitatively evaluated the effects of this group of bitter flavonoids on the proliferation of BECs (i.e. 16HBE14o- cells) cultured in vitro. The results show that five of the six tested bitter tastants inhibited, but only naringin promoted the proliferation of 16HBE14o- BECs in vitro at the dose of a few hundred micromoles. Furthermore, the naringin-promoted cell proliferation was associated with enhanced cell cycle progression, mRNA expression of cyclin E, and evoked calcium signaling/ERK signaling. Inhibition of the TAS2R signaling pathways with specific blockers attenuated the naringin-enhanced cell proliferation, cyclin E expression and calcium signaling/ERK activation. Taken together, these findings indicate that although many bitter flavonoids may inhibit the proliferation of BECs, naringin emerges as one of the kind that promotes the proliferation of BECs via cell cycle progression and TAS2R-activated intracellular signaling. Only such bitter tastant proven to be unharmful to the epithelial structure and function could be further developed as safe and effective TAS2Rs-based bronchodilator in asthma therapy.