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For pharmaceuticals to deliver their full benefits with maximum efficacy, patients need to follow recommended dosing schedules, in terms of amount and frequency. Unfortunately, the aversive taste of many drugs, especially bitterness, can reduce patient compliance in oral liquid formulations. Given common genetic differences in bitter taste receptor genes (TAS2Rs), some individuals may be at increased risk for poor compliance due to heightened bitterness that becomes a barrier to proper use. Here we report on the sensory profile of two antibiotics, chloramphenicol and ofloxacin, investigating whether bitterness intensity associates with nominally functional TAS2R variants. Participants (n = 143) rated suprathreshold intensity on a general Labeled Magnitude Scale (gLMS) for chloramphenicol and ofloxacin; propylthiouracil (PROP) was included as a control, given robust prior associations with TAS2R38 variants. The dominant sensation from chloramphenicol and ofloxacin was bitterness, falling just below "moderate" on a gLMS. TAS2R38 diplotype associated with variable bitterness of chloramphenicol and PROP, but not ofloxacin. The bitterness of ofloxacin associated with a TAS2R9 SNP (V187A). This pilot study provides novel evidence on differences in the bitterness from two antibiotics, which are associated with TAS2R variants. Improved understanding of individualized barriers to patient compliance, especially for oral formulations, can guide future efforts to optimize delivery systems for improved compliance. [ABSTRACT FROM AUTHOR]

For pharmaceuticals to deliver their full benefits with maximum efficacy, patients need to follow recommended dosing schedules, in terms of amount and frequency. Unfortunately, the aversive taste of many drugs, especially bitterness, can reduce patient compliance in oral liquid formulations. Given common genetic differences in bitter taste receptor genes (TAS2Rs), some individuals may be at increased risk for poor compliance due to heightened bitterness that becomes a barrier to proper use. Here we report on the sensory profile of two antibiotics, chloramphenicol and ofloxacin, investigating whether bitterness intensity associates with nominally functional TAS2R variants. Participants (n = 143) rated suprathreshold intensity on a general Labeled Magnitude Scale (gLMS) for chloramphenicol and ofloxacin; propylthiouracil (PROP) was included as a control, given robust prior associations with TAS2R38 variants. The dominant sensation from chloramphenicol and ofloxacin was bitterness, falling just below “moderate” on a gLMS. TAS2R38 diplotype associated with variable bitterness of chloramphenicol and PROP, but not ofloxacin. The bitterness of ofloxacin associated with a TAS2R9 SNP (V187A). This pilot study provides novel evidence on differences in the bitterness from two antibiotics, which are associated with TAS2R variants. Improved understanding of individualized barriers to patient compliance, especially for oral formulations, can guide future efforts to optimize delivery systems for improved compliance.

One of the hallmarks of acute respiratory distress syndrome (ARDS) is an excessive increase in pulmonary vascular permeability. In settings of ARDS, the loss of barrier integrity is mediated by cell–cell contact disassembly and actin remodelling. Studies into molecular mechanisms responsible for improving microvascular barrier function are therefore vital in the development of therapeutic targets for reducing vascular permeability seen in ARDS. Bitter taste receptors (T2Rs) belong to the superfamily of G-protein-coupled receptors found in several extraoral systems, including lung epithelial and smooth muscle cells. In the present study, we show for the first time that several T2Rs are expressed in human pulmonary arterial endothelial cells (HPAECs). Our results focus on those which are highly expressed as: T2R10, T2R14 and T2R38. Agonists for T2R10 (denatonium) and T2R38 (phenylthiourea), but not T2R14 (noscapine), significantly attenuated lipopolysaccharide (LPS)-induced permeability and VE-cadherin internalisation in HPAECs. In T2R10- or T2R38-siRNA knockdown cells, these endothelial-protective effects were abolished, indicating a direct effect of agonists in regulating barrier integrity. Our further findings indicate that T2R10 and T2R38 exert their barrier-protective function through cAMP but via Rac1-dependent and independent pathways, respectively. However, using an in vivo model of ARDS, the T2R38 agonist, phenylthiourea, was not able to protect against pulmonary edema formation. Taken together, these studies identify bitter taste sensing in the pulmonary endothelium to regulate barrier integrity in vitro through cAMP-Rac1 signalling. [ABSTRACT FROM AUTHOR]

One of the hallmarks of acute respiratory distress syndrome (ARDS) is an excessive increase in pulmonary vascular permeability. In settings of ARDS, the loss of barrier integrity is mediated by cell–cell contact disassembly and actin remodelling. Studies into molecular mechanisms responsible for improving microvascular barrier function are therefore vital in the development of therapeutic targets for reducing vascular permeability seen in ARDS. Bitter taste receptors (T2Rs) belong to the superfamily of G-protein-coupled receptors found in several extraoral systems, including lung epithelial and smooth muscle cells. In the present study, we show for the first time that several T2Rs are expressed in human pulmonary arterial endothelial cells (HPAECs). Our results focus on those which are highly expressed as: T2R10, T2R14 and T2R38. Agonists for T2R10 (denatonium) and T2R38 (phenylthiourea), but not T2R14 (noscapine), significantly attenuated lipopolysaccharide (LPS)-induced permeability and VE-cadherin internalisation in HPAECs. In T2R10- or T2R38-siRNA knockdown cells, these endothelial-protective effects were abolished, indicating a direct effect of agonists in regulating barrier integrity. Our further findings indicate that T2R10 and T2R38 exert their barrier-protective function through cAMP but via Rac1-dependent and independent pathways, respectively. However, using an in vivo model of ARDS, the T2R38 agonist, phenylthiourea, was not able to protect against pulmonary edema formation. Taken together, these studies identify bitter taste sensing in the pulmonary endothelium to regulate barrier integrity in vitro through cAMP-Rac1 signalling.

The contribution of cell-extrinsic factors in Acute Myeloid Leukemia (AML) generation and persistence has gained interest. Bitter taste receptors (TAS2Rs) are G protein-coupled receptors known for their primary role as a central warning signal to induce aversion toward noxious or harmful substances. Nevertheless, the increasing amount of evidence about their extra-oral localization has suggested a wider function in sensing microenvironment, also in cancer settings. In this study, we found that AML cells express functional TAS2Rs. We also highlighted a significant association between the modulation of some TAS2Rs and the poor-prognosis AML groups, i.e., TP53- and TET2-mutated, supporting a potential role of TAS2Rs in AML cell biology. Gene expression profile analysis showed that TAS2R activation with the prototypical agonist, denatonium benzoate, significantly modulated a number of genes involved in relevant AML cellular processes. Functional assay substantiated molecular data and indicated that denatonium reduced AML cell proliferation by inducing cell cycle arrest in G0/G1 phase or induced apoptosis via caspase cascade activation. Moreover, denatonium exposure impaired AML cell motility and migratory capacity, and inhibited cellular respiration by decreasing glucose uptake and oxidative phosphorylation. In conclusion, our results in AML cells expand the observation of cancer TAS2R expression to the setting of hematological neoplasms and shed light on a role of TAS2Rs in the extrinsic regulation of leukemia cell functions.

The gastrointestinal tract stores ingested nutrients in the stomach which are then delivered to the small intestine at a controlled rate to optimize their digestion and absorption. The interaction of nutrients with the small and large intestine generates feedback that slows gastric emptying, induces satiation, and reduces postprandial glycemic excursions. The mechanisms underlying these nutrient-gut interactions are complex; it has only recently been appreciated that the gut has the capacity to detect intraluminal contents in much the same way as the tongue, via activation of specific G-protein-coupled receptors, and that ensuing signaling mechanisms modulate the release of an array of gut hormones that influence gastrointestinal motility, appetite and glycemia. Interestingly, evidence from preclinical models supports a functional link between intestinal bitter taste receptor (BTRs) and gastrointestinal hormone secretion, and the outcomes of recent studies indicate that stimulation of intestinal BTRs may be used to modulate gastrointestinal function, to diminish energy intake and limit postprandial blood glucose excursions in humans. This review summarizes current evidence about the expression and function of intestinal BTRs in relation to enteroendocrine hormone release and discusses the clinical implications of this pathway for the management of obesity and type 2 diabetes.

Bitter (T2R) and sweet taste (T1R) receptors have emerged as regulators of upper airway immune responses. Genetic variation of these taste receptors additionally confers susceptibility to infection and has been implicated in severity of disease in chronic rhinosinusitis (CRS). Ongoing taste receptor research has identified a variety of biologically active compounds that activate T1R and T2R receptors, increasing our understanding of not only additional receptor isoforms and their function but also how receptor function may contribute to the pathophysiology of CRS. This review will discuss the function of taste receptors in mediating airway immunity with a focus on recently described modulators of receptor function and directions for future research into the potential role of genotypic and phenotypic receptor variation as a predictor of airway disease and response to therapy.

Vertebrates can perceive at least five different taste qualities, each of which is thought to have a specific role in the evolution of different species. The avoidance of potentially poisonous foods, which are generally bitter or sour tasting, and the search for more nutritious ones, those with high-fat and high-sugar content, are two of the most well-known examples. The study of taste genes encoding receptors that recognize ligands triggering taste sensations has helped to reconstruct several evolutionary adaptations to dietary changes. In addition, an increasing number of studies have focused on pseudogenes, genomic DNA sequences that have traditionally been considered defunct relatives of functional genes mostly because of the presence of deleterious mutations interrupting their open reading frames. The study of taste receptor pseudogenes has helped to shed light on how the evolutionary history of taste in vertebrates has been the result of a succession of gene gain and loss processes. This dynamic role in evolution has been explained by the “less-is-more” hypothesis, suggesting gene loss as a mechanism of evolutionary change in response to a dietary shift. This mini-review aims at depicting the major lineage-specific loss of function of taste receptor genes in vertebrates, stressing their evolutionary importance and recapitulating signatures of natural selection and their correlations with food habits.

Keywords: acute myeloid leukemia; bitter taste receptors; denatonium benzoate; bone marrow microenvironment; bitter compounds EN acute myeloid leukemia bitter taste receptors denatonium benzoate bone marrow microenvironment bitter compounds N.PAG N.PAG 2 04/26/21 20210408 NES 210408 In the original article, there was an error in the GEO database accession number. Acute myeloid leukemia, bitter taste receptors, denatonium benzoate, bone marrow microenvironment, bitter compounds. [Extracted from the article]