Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors

Pizio, Antonella Di; Behrens, Maik; Krautwurst, Dietmar

doi:10.3390/ijms20061402

Cited by 57 publications

(57 citation statements)

References 200 publications

(240 reference statements)

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“…Our data on the inhibitory effect of the majority of the tested bitter avonoids on the proliferation of BECs are consistent with that of the canonical bitter tastant denatonium, as previously reported by Wen et al [5]. Additionally, these bitter avonoids exhibited inhibitory effect on the proliferation of BECs at a dose of a few hundred micromoles, which falls within the dosage level for the bitter tastant to be used to relax ASMCs [25]. Thus, many bitter avonoids may be pharmacologically harmful to the integrity of BECs if used at the concentration effective for ASMC relaxation.…”

Section: Discussionsupporting

confidence: 91%

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

Luo

et al. 2020

Preprint

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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.

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Section: Discussionsupporting

confidence: 91%

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

Luo

et al. 2020

Preprint

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“…Menthol is known to have very low irritating properties to the skin or mucosa; therefore, it is used in very high concentrations. However, continuous exposure to elevated levels of menthol was shown to cause severe systemic symptoms in mice due to its interactions with the TRPM8 receptors, which act as calcium ion channels not only on the olfactory bulb but also in other organs of the body 57 .…”

Section: Toxicity Levelsmentioning

confidence: 99%

“…Recent studies have also shown that aroma compounds play a role in cell signalling outside the olfactory region 57,102 . The olfactory receptors are a class of chemosensory G-protein-coupled receptors (csGPCRs), which are guanine nucleotide-binding proteins acting as molecular switches inside cells, by translating stimuli into chemical signals inside the cell 57 . They are the largest groups of GPCRs, that we use on a daily basis to distinguish food flavour and other environmental stimuli.…”

Section: Interactions Of Flavour Compounds With Biological Structuresmentioning

confidence: 99%

“…It remains unknown whether these low-molecular-weight flavour compounds interact with the receptors, not for olfaction, but for affecting or regulating the internal environments in their presence. Based on these findings, it was therefore hypothesised that csGPCRs have a high potential for pharmacological relevance as drug targets, since nonetheless the majority (35%) of approved drugs act by modulating 7 transmembrane (7TM) receptors, which are GPCRs 57 . At the moment, the number of GPCRs targeted by drugs represents 16% of the~800 GPCRs identified in the human genome 103,104 .…”

Section: Interactions Of Flavour Compounds With Biological Structuresmentioning

confidence: 99%

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Policy, toxicology and physicochemical considerations on the inhalation of high concentrations of food flavour

et al. 2020

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Food flavour ingredients are required by law to obtain prior approval from regulatory bodies, such as the U.S. Food and Drug Administration (FDA) or the European Food Safety Authority (EFSA) in terms of toxicological data and intended use levels. However, there are no regulations for labelling the type and concentration of flavour additives on the product, primarily due to their low concentration in food and generally recognised as safe (GRAS) status determined by the flavour and extract manufacturers’ association (FEMA). Their status for use in e-cigarettes and other vaping products challenges these fundamental assumptions, because their concentration can be over ten-thousand times higher than in food, and the method of administration is through inhalation, which is currently not evaluated by the FEMA expert panel. This work provides a review of some common flavour ingredients used in food and vaping products, their product concentrations, inhalation toxicity and aroma interactions reported with different biological substrates. We have identified several studies, which suggest that the high concentrations of flavour through inhalation may pose a serious health threat, especially in terms of their cytotoxicity. As a result of the wide range of possible protein-aroma interactions reported in our diet and metabolism, including links to several non-communicable diseases, we suggest that it is instrumental to update current flavour- labelling regulations, and support new strategies of understanding the effects of flavour uptake on the digestive and respiratory systems, in order to prevent the onset of future non-communicable diseases.

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“…Moreover, bitter taste receptors are also expressed in extra-oral tissues such as in the hearth, in the brain, and in the gastrointestinal tract [ 17 ]. Therefore, investigations of the interaction of TAS2Rs with amino acids and peptides can help shed light on the function of the ‘ecnomotopically’ [ 18 ] expressed TAS2Rs, whose endogenous ligands are not known yet, but peptides are definitely good candidates.…”

Section: Introductionmentioning

confidence: 99%

In Silico Molecular Study of Tryptophan Bitterness

Pizio

Nicoli

2020

Molecules

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Tryptophan is an essential amino acid, required for the production of serotonin. It is the most bitter amino acid and its bitterness was found to be mediated by the bitter taste receptor TAS2R4. Di-tryptophan has a different selectivity profile and was found to activate three bitter taste receptors, whereas tri-tryptophan activated five TAS2Rs. In this work, the selectivity/promiscuity profiles of the mono-to-tri-tryptophans were explored using molecular modeling simulations to provide new insights into the molecular recognition of the bitter tryptophan. Tryptophan epitopes were found in all five peptide-sensitive TAS2Rs and the best tryptophan epitope was identified and characterized at the core of the orthosteric binding site of TAS2R4.

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Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors

Cited by 57 publications

References 200 publications

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

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

Policy, toxicology and physicochemical considerations on the inhalation of high concentrations of food flavour

In Silico Molecular Study of Tryptophan Bitterness

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