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Taste is important in the selection of food and is orchestrated by a group of distinct receptors, the taste G protein-coupled receptors (GPCRs). Taste 1 receptors (Tas1rs in mice and TAS1Rs in humans; also known as T1Rs) detect sweet and umami tastes, and taste 2 receptors (Tas2rs in mice and TAS2Rs in humans; also known as T2Rs) detect bitterness. These receptors are also expressed in extraoral sites, including the gastrointestinal mucosa. Tas2rs/TAS2Rs have gained interest as potential targets to prevent or treat metabolic disorders. These bitter taste receptors are expressed in functionally distinct types of gastrointestinal mucosal cells, including enteroendocrine cells, which, upon stimulation, increase intracellular Ca 2+ and release signalling molecules that regulate gut chemosensory processes critical for digestion and absorption of nutrients, for neutralization and expulsion of harmful substances, and for metabolic regulation. Expression of Tas2rs/TAS2Rs in gut mucosa is upregulated by high-fat diets, and intraluminal bitter 'tastants' affect gastrointestinal functions and ingestive behaviour through local and gut-brain axis signalling. Tas2rs/TAS2Rs are also found in Paneth and goblet cells, which release antimicrobial peptides and glycoproteins, and in tuft cells, which trigger type 2 immune response against parasites, thus providing a direct line of defence against pathogens. This Review will focus on gut Tas2r/TAS2R distribution, signalling and regulation in enteroendocrine cells, supporting their role as chemosensors of luminal content that serve distinct functions as regulators of body homeostasis and immune response., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Springer Nature Limited.)

Objective: With the rapid increase in the pace of life, people are facing increasing pressures of all kinds, and depression has gradually become a serious psychological disorder in human society, strongly affecting normal social and physiological activities. Depression can disrupt an individual's taste perception and potentially result in taste disorders by affecting and altering taste receptors. This disruption can consequently impact their food preferences and overall eating experiences., Design: In this study, we used the chronic unpredictable mild stress (CUMS) method to establish a depression model in male C57BL/6 J mice and explored the changes in taste receptor expression in the lingual circumvallate papillae (CP) to elucidate the effects of depression on taste. After 6 weeks of CUMS, behavioral performance evaluations, such as forced swim, open field, and elevated plus maze tests, were conducted in depression model mice. A further two-bottle choice test was subsequently performed to determine the effect of depression on bitter taste, and the expression of bitter taste receptors in the lingual CP was detected via immunofluorescence staining., Results: In this study, we found for the first time that mice with CUMS-induced depression had decreased bitter taste sensitivity through a two-bottle choice test and demonstrated that the expression of T2r5, a receptor related to bitter taste perception, and the expression of secondary taste signaling proteins in the lingual CP were significantly decreased in mice exposed to CUMS, as determined via qRTPCR and immunofluorescence staining., Conclusions: Our study highlights how CUMS influences the perception of bitterness in the peripheral taste system, potentially elucidating stress-induced changes in eating habits., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wang Zhaoxiang reports financial support was provided by Chinese PLA General Hospital. Cao Junkai reports a relationship with Chinese PLA General Hospital that includes: employment. Medical School of Chinese PLA is an affiliated unit of Chinese PLA General Hospital If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Gastroesophageal reflux disease (GERD) is a chronic condition of the digestive tract with limited therapeutic options. Bitter taste receptors (TAS2Rs) and transient receptor potential vanilloid-1 (TRPV1) are implicated in modulating inflammatory responses. Berberine (BBR) and evodiamine (EVO) are known to activate TAS2Rs and TRPV1, respectively. However, whether BBR and EVO can ameliorate GERD by targeting TAS2Rs and TRPV1 remains uncertain., Purpose: This study aims to determine whether BBR and EVO mitigate esophageal injury by targeting TAS2R38 and TRPV1 and to elucidate their underlying molecular mechanisms., Methods: A GERD rat model was developed using esophagogastric anastomosis, while GERD in human esophageal epithelial cells (HEECs) was induced via bile acid (BA) exposure. Esophageal pathology was analyzed through hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM). mRNA and protein levels were measured via qRT-PCR, immunofluorescence, immunohistochemistry and Western blot analysis. Small interfering RNA was used to silence TAS2R38 and TRPV1 in HEECs. The activation of TAS2R38 and TRPV1 by BBR and EVO was assessed through Ca 2+ mobilization assays. Finally, in vivo validation was conducted using U73122 to inhibit TAS2Rs and resiniferatoxin (RTX) to ablate TRPV1., Results: BBR and EVO treatments significantly improved esophageal pathology in GERD rats and reduced BA-induced inflammation in HEECs. Additionally, BBR and EVO suppressed proinflammatory factors expression, upregulated barrier proteins such as E-cadherin and claudin-1, and inhibited the phosphorylation of p65, JNK, and ERK in the MAPK/NF-κB signaling pathways in both in vivo and in vitro models. Furthermore, BBR and EVO, whether individually or in combination, reduced dilated intercellular spaces (DIS), increased desmosome numbers, and modulated macrophage polarization in GERD rats. Knockdown of TAS2R38 and TRPV1 in HEECs notably diminished the stimulatory effects of BBR and EVO. Moreover, the regulation of barrier function and MAPK/NF-κB pathway proteins by BBR and EVO in BA-induced HEECs was abrogated upon TAS2R38 and TRPV1 knockdown. Similarly, U73122 and RTX reversed the effects of BBR and EVO on macrophage polarization and MAPK/NF-κB signaling pathways in vivo., Conclusion: We firstly demonstrate that BBR and EVO alleviate GERD, with enhanced synergistic efficacy observed when used in combination. Mechanistically, BBR and EVO activate the TAS2R38 and TRPV1, respectively, leading to downregulation of phosphorylation in MAPK/NF-κB signaling pathways and modulation of macrophage polarization. These findings offer a novel foundation for the clinical application of BBR and EVO in GERD treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Taste receptors, first described for their gustatory functions within the oral cavity and oropharynx, are now known to be expressed in many organ systems. Even intraoral taste receptors regulate non-sensory pathways, and recent literature has connected bitter taste receptors to various states of health and disease. These extragustatory pathways involve previously unexplored, clinically relevant roles for taste signaling in areas including susceptibility to infection, antibiotic efficacy, and cancer outcomes. Among other physicians, otolaryngologists who manage head and neck diseases should be aware of this growing body of evidence and its relevance to their fields. In this review, we describe the role of extragustatory taste receptors in head and neck health and disease, highlighting recent advances, clinical implications, and directions for future investigation. Additionally, this review will discuss known TAS2R polymorphisms and the associated implications for clinical prognosis., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Bitter is one of the five basic taste qualities, along with salty, sour, sweet and umami, used by mammals to access the quality of their food and orient their eating behaviour. Bitter taste detection prevents the ingestion of food potentially contaminated by bitter-tasting toxins. Bitter taste perception is mediated by a family of G protein-coupled receptors (GPCRs) called TAS2Rs. Humans possess 25 TAS2Rs (human type II taste receptors), enabling the detection of thousands of chemically diverse bitter compounds. The identification of agonists/antagonists and molecular mechanisms that govern receptor-ligand interaction has been primarily achieved through functional expression of TAS2Rs in heterologous cells. However, TAS2R receptors, like many other GPCRs, suffer from marginal cell surface expression. In this study, we compared the functionality of 9 engineered chimeric receptors, focusing our experiments on TAS2R14, a broadly tuned receptor that recognizes over 151 identified compounds. Among the different tested signal peptides, rat somatostatin receptor subtype 3 results in higher potency of aristolochic acid-induced calcium signalling than other tested export tags, such as bovine rhodopsin, murine Igκ-chain or human mGluR5. The addition of a MAX sequence enhances both TAS2R14 potency and efficacy. We also confirm that the FLAG epitope, when located at the C-terminal, interferes less with the TAS2R14 functionality, enabling reliable evaluation of this receptor at the cell surface using immunohistochemistry. Finally, these observations are also confirmed for TAS2R14 and TAS1R2/TAS1R3 (the sweet taste receptor) stimulated by 12 bitter compounds and by sucralose and neotame, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

G protein-coupled receptors (GPCRs) regulate multiple cellular responses and represent highly successful therapeutic targets. The mechanisms by which agonists activate the G protein are unclear for many GPCR families, including the bitter taste receptors (TAS2Rs). We ascertained TAS2R5 properties by live cell-based functional assays, direct binding affinity measurements using optical resonators, and atomistic molecular dynamics simulations. We focus on three agonists that exhibit a wide range of signal transduction in cells despite comparable ligand-receptor binding energies derived from direct experiment and computation. Metadynamics simulations revealed that the critical barrier to activation is ligand-induced opening of the G protein between the α-helical (AH) and Ras-like domains of Gα subunit from a precoupled TAS2R5-G protein state to the fully activated state. A moderate agonist opens the AH-Ras cleft from 22 Å to 31 Å with an energy gain of -4.8 kcal mol -1 , making GDP water-exposed for signaling. A high-potency agonist had an energy gain of -11.1 kcal mol -1 . The low-potency agonist is also exothermic for Gα opening, but with an energy gain of only -1.4 kcal mol -1 . This demonstrates that TAS2R5 agonist-bound functional potencies are derived from energy gains in the transition from a precoupled complex at the level of Gα opening. Our experimental and computational study provides insights into the activation mechanism of signal transduction that provide a basis for rational design of new drugs., Competing Interests: Competing interests statement:The authors declare no competing interest.

Bitter taste perception is crucial for animal survival. By detecting potentially harmful substances, such as plant secondary metabolites, as bitter, animals can avoid ingesting toxic compounds. In vertebrates, this function is mediated by taste receptors type 2 (T2Rs), a family of G protein-coupled receptors (GPCRs) expressed on taste buds. Given their vital roles, T2Rs have undergone significant selective pressures throughout vertebrate evolution, leading to frequent gene duplications and deletions, functional changes, and intrapopulation differentiation across various lineages. Recent advancements in genomic and functional research have uncovered the repertoires and functions of bitter taste receptors in a wide range of vertebrate species, shedding light on their evolution in relation to dietary habits and other ecological factors. This review summarizes recent research on bitter taste receptors and explores the mechanisms driving the diversity of these receptors from the perspective of vertebrate ecology and evolution.

Bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs) expressed orally and extraorally, elicit signaling in response to a large set of tastants. Among 25 functional TAS2Rs encoded in the human genome, TAS2R14 is the most promiscuous, and responds to hundreds of chemically diverse ligands. Here we present the cryo-electron microscopy (cryo-EM) structure of the human TAS2R14 in complex with its signaling partner gustducin, and bound to flufenamic acid (FFA), a clinically approved nonsteroidal anti-inflammatory drug. The structure reveals an unusual binding mode, where two copies of FFA are bound at distinct pockets: one at the canonical receptor site within the trans-membrane bundle, and the other in the intracellular facet, bridging the receptor with gustducin. Together with a pocket-specific BRET-based ligand binding assay, these results illuminate bitter taste signaling and provide tools for a site-targeted compound design., Competing Interests: Competing interests The authors declare no competing interests, (© 2024. The Author(s).)

Various organisms produce several products to defend themselves from the environment and enemies. These natural products have pharmacological and biological activities and are used for therapeutic purposes, retaining bitter taste because of chemical defense mechanisms. Cnicin is a plant-derived bitter sesquiterpene lactone with pharmacological characteristics such as anti-bacterial, anti-myeloma, anti-cancer, anti-tumor, anti-oxidant, anti-inflammatory, allelopathic, and cytotoxic properties. Although many studies have focused on cnicin detection, they have limitations and novel cnicin-detecting strategies are required. In this study, we developed the bioelectronics for screening cnicin using its distinct taste. hTAS2R46 was produced using an Escherichia coli expression system and reconstituted into nanodiscs (NDs). The binding sites and energy between hTAS2R46 and cnicin were investigated using biosimulations. hTAS2R46-NDs were combined with a side-gated graphene micropatterned field-effect transistor (SGMFET) to construct hTAS2R46-NDs bioelectronics. The construction was examined by chemical and electrical characterization. The developed system exhibited unprecedented performance, 10 fM limit of detection, rapid response time (within 10 s), 0.1354 pM -1 equilibrium constant, and high selectivity. Furthermore, the system was stable as the sensing performance was maintained for 15 days. Therefore, the hTAS2R46-NDs bioelectronics can be utilized to screen cnicin from natural products and applied in the food and drug industries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Shegan-Mahuang Decoction (SMD) is a classical formula that has been used to effectively treat cold-induced asthma (CA) for 1800 years. Airway smooth muscle cells (ASMCs) play a crucial role in airway remodeling of CA and can be modulated through bitter taste-sensing type 2 receptors (TAS2Rs). Given that SMD contains numerous bitter herbs and TAS2R10 expression in ASMCs remains consistently high, it is pertinent to explore whether SMD regulates ASMCs via TAS2R10 to exert its CA mechanism., Aim of the Study: This study investigated the efficacy as well as the potential mechanism of SMD in CA., Materials and Methods: In this study, experiments in vivo were conducted using the CA rat model induced by ovalbumin (OVA) along with cold stimulation. The effects of SMD and TAS2R10 expression in CA rats were evaluated using the following methods: clinical symptoms, weights, pathological staining, immunofluorescence staining (IF), enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB). Assays in vitro including cell counting Kit-8 (CCK-8), ELISA, flow cytometry, TUNEL staining, RT-qPCR and WB were performed to investigate potential mechanism of SMD on the proliferation and apoptosis of ASMCs through upregulation of TAS2R10., Results: The administration of SMD resulted in a notable improvement in the symptoms, trends in weight, airway inflammation and airway remodeling observed in CA rats with upregulated TAS2R10. Mechanistically, we furtherly confirmed that SMD inhibits p70S6K/CyclinD1 pathway by upregulating TAS2R10. SMD furthermore blocked the G0/G1 phase, suppressed the proliferation and inducted apoptosis in ASMCs induced by platelet-derived growth factor-BB (PDGF-BB). Erythromycin (EM), a TAS2R10 agonist, can intensify these effects., Conclusions: SMD significantly ameliorates CA by upregulating TAS2R10 and inhibiting the p70S6K/CyclinD1 pathway, thereby modulating ASMCs' proliferation and apoptosis. Inspired by the Five Flavors Theory of Traditional Chinese Medicine, this study provides an updated treatment perspective for treating CA., Competing Interests: Declaration of competing interest Conflicts of interest are not disclosed by the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Scope: Inflorescences of the female hop plant (Humulus lupulus L.) contain biologically active compounds, most of which have a bitter taste. Given the rising global obesity rates, there is much increasing interest in bitter taste receptors (TAS2Rs). Intestinal TAS2Rs can have beneficial effects on obesity when activated by bitter agonists. This study aims to investigate the mechanism of action of a hydroalcoholic hop extract in promoting hormone secretion that reduces the sense of hunger at the intestinal level through the interaction with TAS2Rs., Methods and Results: The results demonstrate that the hop extract is a rich source of bitter compounds (mainly α-, β-acids) that stimulate the secretion of anorexigenic peptides (glucagon-like peptide 1 [GLP-1], cholecystokinin [CCK]) in a calcium-dependent manner while reducing levels of hunger-related hormones like ghrelin. This effect is mediated through interaction with TAS2Rs, particularly Tas2r138 and Tas2r120, and through the activation of downstream signaling cascades. Knockdown of these receptors using siRNA transfection and inhibition of Trpm5, Plcβ-2, and other calcium channels significantly reduces the hop-induced calcium response as well as GLP-1 and CCK secretion., Conclusions: This study provides a potential application of H. lupulus extract for the formulation of food supplements with satiating activity capable of preventing or combating obesity., (© 2024 The Author(s). Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

Extraoral bitter taste receptors offer intriguing potential for modulating metabolism and the gut-brain axis through dietary interventions. Our understanding of these receptors is limited, and data on their effects on ageing are scarce. The complexity conveyed by their high diversity, low expression levels and species-dependent variability challenges our comprehension. We used real-time PCR to examine the relative abundance of multiple TAS2R across different segments of gastrointestinal mucosa in four human cohorts and related them to enteroendocrine secretions at the colon site. TAS2R14 exhibited the highest expression levels in all analyzed tissues. In contrast, TAS2R39, -38 and -42 consistently exhibited lower expression levels. Ageing was found to upregulate TAS2R4, -5, -13, -20 and GLP-1 mRNA in the descending colon. Stimulating TAS2R14 in Hutu-80 cells induced GLP-1 secretion, while stimulating TAS2R5 modulated GLP-1 and PYY secretion. Given the modifications TAS2R agonists may undergo along the GIT, as well as the distinctive expression patterns and possible functional roles of TAS2R receptors along the intestinal tract, our findings suggest the viability of a targeted strategy aimed at enhancing specific functions to improve health outcomes. This study offers valuable insights into the intricate interplay between bitter taste receptors, gut physiology and potential dietary interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jalševac, Descamps-Solà, Grau-Bové, Segú, Auguet, Avilés-Jurado, Balaguer, Jorba, Beltrán-Debón, Blay, Terra Barbadora, Pinent and Ardévol.)

Objective: Primary ciliary dyskinesia (PCD) severity has been related to genotype and levels of nasal nitric oxide (nNO). The most common TAS2R38 haplotypes (PAV/PAV, PAV/AVI, AVI/AVI) encoding the bitter taste receptor can affect nNO levels and thus could play a role in the susceptibility to respiratory infections. We assessed the impact of these polymorphisms on nNO production and Pseudomonas aeruginosa ( P.a .) infections in different PCD genotypes., Methods: Prospective, longitudinal, single-centre study in patients with PCD with known genotype and one of three TAS2R38 haplotypes evaluated for up to 10 years. We related nNO values to TAS2R38 haplotypes in all patients, and in the three most frequent genotypes ( CCDC39/CCDC40 , DNAH5 , DNAH11 ). In the genetic group(s) with different mean trends of nNO in relation to the polymorphism, we evaluated longitudinal lung function as a clinical outcome measure. We also studied any associations between the prevalence of chronic P.a . infection and PAV alleles. Linear mixed-effects models were used to evaluate longitudinal associations., Results: 119 patients with PCD underwent 1116 study visits. Only in the DNAH11 mutations group was there a mean trend of nNO production which was significantly higher in PAV/PAV than AVI/AVI haplotype (p=0.033), with a better trend in spirometric and plethysmographic parameters. In patients with DNAH11 mutations the PAV allele was also associated with a significantly reduced prevalence of chronic P.a ., Conclusion: TAS2R38 may be a modifier gene for PCD severity, but only in mild phenotype disease. Further study of TAS2R38 polymorphisms might enable new management strategies to prevent chronic P.a ., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Theacrine, a purine alkaloid derived from Camellia assamica var. kucha, has a distinct bitter taste. Our previous study found the lower recognition threshold of theacrine at 25 °C than 45 °C. This study aims to investigate the bitterness characterizations of theacrine at aforementioned temperatures and its taste perception mechanism. Sensory analysis exhibited higher bitterness intensity for theacrine at 25 °C than 45 °C. Subsequently, flow cytometry was performed to verify the above characterization at the cellular level. It revealed that theacrine could activated the bitter receptor hTAS2R14 and the calcium signal at 25 °C was higher than 45 °C. Ultimately, the interaction mechanism was studied by molecular dynamics simulations, indicating that the conformation of theacrine-hTAS2R14 had a higher binding capacity and better stability at 25 °C. Overall, temperature affected the binding of theacrine to the bitter receptor hTAS2R14, resulting in the stronger bitterness intensity of theacrine at 25 °C than 45 °C., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Although bitter receptors, known as Tas2Rs, have been identified in the testes and mature sperm, their expression in testicular Sertoli cells (SCs) and their role in recognizing harmful substances to maintain the immune microenvironment remain unknown. To explore their potential function in spermatogenesis, this study utilized TM4 cells and discovered the high expression of the bitter receptor Tas2R143 in the cells. Interestingly, when the Tas2R143 gene was knocked down for 24 and 48 h, there was a significant downregulation (P < 0.05) in the expression of tight junction proteins (occludin and ZO-1) and NF-κB. Additionally, Western blot results demonstrated that the siRNA-133+NF-κB co-treatment group displayed a significant downregulation (P < 0.05) in the expression of occludin and ZO-1 compared to both the siRNA-133 transfection group and the NF-κB inhibitors treatment group. These findings suggest that Tas2R143 likely regulates the expression of occludin and ZO-1 through the NF-κB signaling pathway and provides a theoretical basis for studying the regulatory mechanism of bitter receptors in the reproductive system, aiming to attract attention to the chemical perception mechanism of spermatogenesis., Competing Interests: Declaration of competing interest The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Experimental and clinical research has reported beneficial effects of polyphenol intake on high prevalent diseases such as type 2 diabetes and obesity. These phytochemicals are ligands of taste 2 receptors (T2Rs) that have been recently located in a variety of organs and extra-oral tissues. Therefore, the interaction between polyphenol and T2Rs in brain structures can play a direct effect on appetite/satiety regulation and food intake. T2Rs are also expressed along the digestive tract, and their interaction with polyphenols can induce the release of gastrointestinal hormones (e.g., ghrelin, GLP-1, CCK) influencing appetite, gastrointestinal functionally, and glycemia control. Intestinal microbiota can also influence on network effects of polyphenols-T2Rs interaction and vice versa, impacting innate immune responses and consequently on gut functionally. Furthermore, polyphenols binding to T2Rs present important effects on adipose tissue metabolism. Interestingly, T2R polymorphism could, at least partially, explain the inter-individual variability of the effects of polyphenols on glucose and body weight homeostasis. Together, these factors can contribute to understand the beneficial effects of polyphenol-rich diets but also might aid in identifying new pharmacological pathway targets for the treatment of diabetes and obesity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: To investigate associations between Single Nucleotide Polymorphisms (SNPs) in the TAS1R and TAS2R taste receptors and diet quality, intake of alcohol, added sugar, and fat, using linear regression and machine learning techniques in a highly admixed population., Methods: In the ISA-Capital health survey, 901 individuals were interviewed and had socioeconomic, demographic, health characteristics, along with dietary information obtained through two 24-h recalls. Data on 12 components related to food groups, nutrients, and calories was combined into a diet quality score (BHEI-R). BHEI-R, SoFAAs (calories from added sugar, saturated fat, and alcohol) and Alcohol use were tested for associations with 255 TAS2R SNPs and 73 TAS1R SNPs for 637 individuals with regression analysis and Random Forest. Significant SNPs were combined into Genetic taste scores (GTSs)., Results: Among 23 SNPs significantly associated either by stepwise linear/logistic regression or random forest with any possible biological functionality, the missense variants rs149217752 in TAS2R40, for SoFAAs, and rs2233997 in TAS2R4, were associated with both BHEI-R (under 4% increase in Mean Squared Error) and SoFAAs. GTSs increased the variance explanation of quantitative phenotypes and there was a moderately high AUC for alcohol use., Conclusions: The study provides insights into the genetic basis of human taste perception through the identification of missense variants in the TAS2R gene family. These findings may contribute to future strategies in precision nutrition aimed at improving food quality by reducing added sugar, saturated fat, and alcohol intake., Competing Interests: Declaration of competing interest None., (Copyright © 2024 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

The objective of this study is to review the association of TAS2R38 polymorphisms and taste phenotypes to bitter compounds (phenylthiocarbamide [PTC]/propylthiouracil [PROP]), and its association among persons who drink alcohol and individuals with smoking behavior. A literature search was carried out in PubMed, ScienceDirect, Cochrane, and Wiley online library databases using the keyword "(Bitter taste receptor genes OR TAS2R38) AND (PROP OR propylthiouracil) AND (PTC OR phenylthiocarbamide)," "(Bitter taste receptor genes OR TAS2R38) AND (alcohol)," "(Bitter taste receptor genes OR TAS2R38) AND (tobacco OR smoker)" to find articles evaluating the association of taste phenotypes and TAS2R38 polymorphisms, and its association among persons who drink alcohol and individuals with smoking behavior. The analysis show that TAS2R38 taster genotype (proline-alanine-valine [PAV] allele) was significantly (OR, 5.88; CI [3.87, 8.95], p < .001) associated with taster phenotype for bitter compounds (PTC/PROP), and TAS2R38 nontaster genotype (alanine-valine-isoleucine allele) was significantly (OR, 6.73; CI [4.57, 9.90], p < .001) associated with nontaster phenotype for bitter compounds. Further, TAS2R38 taster genotypes (PAV homozygotes and heterozygotes) were significantly associated with higher alcohol intake (OR, 5.15; 95% CI [2.66, 9.98]; p < .001) and among individuals with smoking behavior (OR, 1.73; 95% CI [1.24, 2.42]; p = .001). This suggests that TAS2R38 single nucleotide polymorphisms can be identified by clinically assessing taste phenotype status for bitter compounds and can be used as a potential therapeutic target in the prevention and treatment of harmful higher alcohol intake and smoking behavior. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Masking the bitter taste of foods is one of the key strategies to improve their taste and palatability, particularly in the context of clean labeling, where natural compounds are preferred. Despite the demand, the availability of natural bitter-masking compounds remains limited. Here, we identified the bitter-masking compound 4'-demethyl-3,9-dihydroeucomin ( DMDHE ) isolated from the resin of Daemonorops draco by means of an activity-guided in vivo (sensory bitterness rating of quinine) and in vitro (cell-based bitter response assays) approach. First, a mean bitter-masking effect of -29.6 ± 6.30% on the bitterness perceived from quinine [10 ppm] was demonstrated for an organic solvent extract of the resin of D. draco (= DD [500 ppm]) in a sensory trial. The results were verified in a cell-based bitter assay in which the bitter taste receptor (TAS2R)-dependent proton secretion serves as an outcome measure of the cellular bitter response in parietal HGT-1 cells. By means of preparative RP-18 high-performance liquid chromatography (HPLC) analysis combined with activity-guided sensory evaluations, the most potent bitter-masking fractions were identified. Subsequent quantitative liquid chromatography/high-resolution mass spectrometry/charged aerosol detection/ultraviolet (LC-HRMS/CAD/UV), NMR analysis, followed by gram-scale synthesis, led to the characterization of DMDHE as bitter-masking homoisoflavanone. DMDHE decreased the sensory bitterness of quinine by 14.8 ± 5.00%. Functional involvement of TAS2R14 was demonstrated by means of a CRISPR-Cas9 approach, which revealed a reduction of the DMDHE -evoked bitter-masking effect by 40.4 ± 9.32% in HGT-1 TAS2R14ko versus HGT-1 wt cells.

Aims: Bitter taste receptors (TAS2Rs) and their downstream signaling pathways are expressed not only in the oral tissues but also in extraoral tissues. Emerging data has demonstrated the beneficial effect of ghrelin in neurodegenerative diseases. Gaining more insight into the interaction between TAS2Rs and gut hormones may expand their therapeutic applications. Herein, we aimed to assess the possible effect of TAS2R activation by denatonium benzoate (DB) in modulating functional and neurobiochemical alterations in a model of Parkinson's disease (PD)., Main Methods: PD model was induced by daily injection of rotenone (2 mg/kg). Rats received DB (5 mg/kg), atenolol (10 mg/kg), or both concomitantly with rotenone, daily for 28 days. Evaluation of the motor abnormalities and histological examination of brain tissues were conducted. In addition, striatal dopamine contents, immunohistochemical expression of tyrosine hydroxylase, plasma ghrelin level, and biochemical analysis of markers of inflammation and oxidative stress were assessed., Key Findings: Treatment with DB increased serum levels of ghrelin and striatal dopamine contents with consequent amelioration of oxidative stress and attenuation of inflammatory cytokines. Moreover, DB treatment significantly ameliorated motor disturbance and histological abnormalities compared to untreated rats. Atenolol inhibited ghrelin release and abolished the positive effect of DB suggesting the involvement of ghrelin on such effects., Significance: The current study suggests that TAS2Rs agonists are promising candidates for ameliorating rotenone-induced PD pathology in rats, an action that could be linked to the enhancement of ghrelin release with consequent antioxidant and anti-inflammatory activities., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Genetic variation in the bitter taste receptor gene taste receptor type 2, member 38 (TAS2R38) is associated with an individual's bitter taste sensitivity, food preference and consumption, which may also influence overall diet quality. This study aims to determine whether the TAS2R38 bitter taste receptor genetic variation is associated with overall diet quality using the Korean Healthy Eating Index (KHEI). A total of 41,839 individuals from the Korean Genome and Epidemiology Study were analyzed for their TAS2R38 diplotypes (rs713598, rs1726866, and rs10246939), general characteristics, and KHEI scores by obesity status. Results revealed that in the non-obese group, individuals with the AVI/AVI diplotype had a significantly higher score of 'ratio of white meat to red meat' than individuals with the PAV/* diplotype (3.89 ± 3.23 vs. 3.79 ± 3.18, adjusted p = 0.029). However, obese individuals with the PAV/* diplotype showed a significantly higher level of the mean score of 'moderation' (19.32 ± 5.82 vs. 18.92 ± 5.80, adjusted p = 0.026) and total KHEI score (61.07 ± 12.19 vs. 60.52 ± 12.29, adjusted p = 0.008) than those with the AVI/AVI diplotype. Finally, an interactive effect between bitterness genetic variation and obesity level was observed in those scores of 'ratio of white meat to red meat' (adjusted p = 0.007), 'moderation' (adjusted p = 0.013), and total KEHI (adjusted p = 0.007). In conclusion, TAS2R38 genetic variation is associated with overall diet quality in Koreans, which is more evident in the obese group., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeong-hwa Choi reports financial support was provided by National Research Foundation of Korea. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Bitter taste receptors, also known as taste 2 receptors (T2R), are expressed throughout the body and are involved in regulating different physiological processes. T2R expression in the intestinal tract regulates orexigenic and anorexigenic peptide secretion, thus becoming potential a potential target for controlling food intake and the prevalence of obesity and overweight. The present study aims to investigate the implication of hop bitter compounds such as α-acids, β-acids, and xanthohumol in the secretion of anorexigenic hormones and T2R expression in intestinal STC-1 cells. The tested bitter compounds induced the secretion of the anorexigenic hormones glucagon-like peptide 1 and cholecystokinin concurrently with a selective increase of murine Tas2r expression. Xanthohumol and α-acids selectively increase Tas2r 138 and Tas2r 130- Tas2r 138 expression, respectively, in STC-1 cells, while β-acids increased the expression of all bitter receptors studied, including Tas2r 119, Tas2r 105, Tas2r 138, Tas2r 120, and Tas2r 130. Increased intracellular calcium levels confirmed this activity. As all investigated bitter molecules increased Tas2r 138 expression, computational studies were performed on Tas2r 138 and its human orthologue T2R38 for the first time. Molecular docking experiments showed that all molecules might be able to bind both bitter receptors, providing an excellent basis for applying hop bitter molecules as lead compounds to further design gastrointestinal-permeable T2R agonists.

Disorders of gallbladder motility can lead to serious pathology. Bitter tastants acting upon bitter taste receptors (TAS2R family) have been proposed as a novel class of smooth muscle relaxants to combat excessive contraction in the airways and other organs. To explore whether this might also emerge as an option for gallbladder diseases, we here tested bitter tastants for relaxant properties and profiled Tas2r expression in the mouse gallbladder. In organ bath experiments, the bitter tastants denatonium, quinine, dextromethorphan, and noscapine, dose-dependently relaxed the pre-contracted gallbladder. Utilizing gene-deficient mouse strains, neither transient receptor potential family member 5 (TRPM5), nor the Tas2r143/Tas2r135/Tas2r126 gene cluster, nor tuft cells proved to be required for this relaxation, indicating direct action upon smooth muscle cells (SMC). Accordingly, denatonium, quinine and dextromethorphan increased intracellular calcium concentration preferentially in isolated gallbladder SMC and, again, this effect was independent of TRPM5. RT-PCR revealed transcripts of Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, and analysis of gallbladders from mice lacking tuft cells revealed preferential expression of Tas2r108 and Tas2r137 in tuft cells. A TAS2R143-mCherry reporter mouse labeled tuft cells in the gallbladder epithelium. An in silico analysis of a scRNA sequencing data set revealed Tas2r expression in only few cells of different identity, and from in situ hybridization histochemistry, which did not label distinct cells. Our findings demonstrate profound tuft cell- and TRPM5-independent relaxing effects of bitter tastants on gallbladder smooth muscle, but do not support the concept that these effects are mediated by bitter receptors., (© 2024. The Author(s).)

Several chronic respiratory diseases could be risk factors for acquiring SARS-CoV-2 infection: among them, Primary Ciliary Dyskinesia (PCD) is a rare (about 1:10.000) inherited ciliopathy (MIM 242650) characterized by recurrent upper and lower respiratory tract infections due to a dysfunction of the respiratory cilia. In this study, we aimed to investigate whether PCD subjects are more susceptible to infection by SARS-CoV-2 and whether some polymorphisms of the TAS2R38 bitter taste receptor correlate with an increased prevalence of SARS-CoV-2 infection and severity of symptoms. Patients answered several questions about possible SARS-CoV-2 infection, experienced symptoms, and vaccinations; in the case of infection, they also filled out a SNOT-22 questionnaire and ARTIQ. Forty PCD adult patients (mean age, 36.6 ± 16.7 years; 23 females, 17 males) participated in this study, out of which 30% had tested positive for COVID-19 during the last four years; most of them reported a mildly symptomatic disease. We found no differences in age or sex, but a statistically significant difference ( p = 0.03) was observed in body mass index (BMI), which was higher in the COVID-acquired group (23.2 ± 3.3 vs. 20.1 ± 4.1 kg/m 2 ). Genotyping for TAS2R38 polymorphisms showed a prevalence of 28.6% PAV/PAV, 48.6% PAV/AVI, and 22.8% AVI/AVI individuals in our cohort. In contrast to our hypothesis, we did not observe a protective role of the PAV allele towards SARS-CoV-2 infection. Conclusions: Our findings suggest that subjects with PCD may not be at increased risk of severe outcomes from COVID-19 and the TAS2R38 bitter taste receptor genotype does not affect SARS-CoV-2 infection.

Yeast extracts (YEs) are used in foods because of their flavour properties and ability to reduce bitterness. The adenosine 5'-monophosphate (AMP) found in YEs is known to decrease the bitterness of some compounds. This study aimed to investigate the ability of YEs to inhibit bitter taste receptors (TAS2Rs) using in vitro cell-based assays. A screen of TAS2Rs activated by AMP and YEs revealed that AMP and the AMP-rich YE activated more TAS2Rs. The inhibitory effect of the AMP-rich YE on seven TAS2Rs activated by bitter agonists was studied. YE reduced TAS2R activation, increased the EC 50 value and decreased the maximum amplitude, demonstrating competitive and non-competitive inhibitions. Amongst the nineteen TAS2Rs tested, seven showed 40 % or greater inhibition after treatment of AMP-rich YE. Our data provide a better understanding of the TAS2R inhibition mechanism of AMP-rich YEs and promote their use as a strategy to reduce bitterness in foods and medicines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BRIAND reports financial support was provided by Biospringer by Lesaffre. THOMAS and MENIN are employees of Biospringer by Lessafre which manufactures and supplies YEs. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Bitter taste receptors (TAS2Rs) Tas2r108 gene possesses a high abundance in mouse kidney; however, the biological functions of Tas2r108 encoded receptor TAS2Rs member 4 (TAS2R4) are still unknown. In the present study, we found that mouse TAS2R4 (mTAS2R4) signaling was inactivated in chronic high glucose-stimulated mouse podocyte cell line MPC, evidenced by the decreased protein expressions of mTAS2R4 and phospholipase C β2 (PLCβ2), a key downstream molecule of mTAS2R4 signaling. Nonetheless, agonism of mTAS2R4 by quinine recovered mTAS2R4 and PLCβ2 levels, and increased podocyte cell viability as well as protein expressions of ZO-1 and nephrin, biomarkers of podocyte slit diaphragm, in high glucose-cultured MPC cells. However, blockage of mTAS2R4 signaling with mTAS2R4 blockers γ-aminobutyric acid and abscisic acid, a Gβγ inhibitor Gallein, or a PLCβ2 inhibitor U73122 all abolished the effects of quinine on NLRP3 inflammasome and p-NF-κB p65 as well as the functional podocyte proteins in MPC cells in a high glucose condition. Furthermore, knockdown of mTAS2R4 with lentivirus-carrying Tas2r108 shRNA also ablated the effect of quinine on the key molecules of the above inflammatory signalings and podocyte functions in high glucose-cultured MPC cells. In summary, we demonstrated that activation of TAS2R4 signaling alleviated the podocyte injury caused by chronic high glucose, and inhibition of NF-κB p65 and NLRP3 inflammasome mediated the protective effects of TAS2R4 activation on podocytes. Moreover, activation of TAS2R4 signaling could be an important strategy for prevention and treatment of diabetic kidney disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

About half of the world's population is infected with the bacterium Helicobacter pylori. For colonization, the bacterium neutralizes the low gastric pH and recruits immune cells to the stomach. The immune cells secrete cytokines, i.e., the pro-inflammatory IL-17A, which directly or indirectly damage surface epithelial cells. Since (I) dietary proteins are known to be digested into bitter tasting peptides in the gastric lumen, and (II) bitter tasting compounds have been demonstrated to reduce the release of pro-inflammatory cytokines through functional involvement of bitter taste receptors (TAS2Rs), we hypothesized that the sweet-tasting plant protein thaumatin would be cleaved into anti-inflammatory bitter peptides during gastric digestion. Using immortalized human parietal cells (HGT-1 cells), we demonstrated a bitter taste receptor TAS2R16-dependent reduction of a H. pylori-evoked IL-17A release by up to 89.7 ± 21.9% (p ≤ 0.01). Functional involvement of TAS2R16 was demonstrated by the study of specific antagonists and siRNA knock-down experiments., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Phil Richter (co-author), Veronika Somoza (corresp. author) reports financial support, administrative support, article publishing charges, and equipment, drugs, or supplies were provided by Leibniz-Institute for Food Systems Biology at the Technical University of Munich. Veronika Somoza reports a relationship with Leibniz-Institute for Food Systems Biology at the Technical University of Munich that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Bitterness, as one of the most important physiological sensations in animals, is primarily recognized through the mediation of bitter taste receptors. In recent years, it has been found that these receptors are not only expressed in taste bud cells on the tongue but also in the respiratory, cardiovascular, digestive, reproductive, and nervous systems. They are involved in regulating various fundamental physiological processes and are now considered important targets for the treatment of various diseases. This paper reviewed the structure, classification, distribution, and signaling pathways of bitter taste receptors, their relationship with different diseases, and the role of bitter taste receptors agonists, aiming to provide a basis for scientific research on bitter taste receptors.

G-protein-coupled receptors (GPCRs) belonging to the type 2 taste receptors (TAS2Rs) family are predominantly present in taste cells to allow the perception of bitter-tasting compounds. TAS2Rs have also been shown to be expressed in human airway smooth muscle (ASM), and TAS2R agonists relax ASM cells and bronchodilate airways despite elevating intracellular calcium. This calcium "paradox" (calcium mediates contraction by pro-contractile Gq-coupled GPCRs) and the mechanisms by which TAS2R agonists relax ASM remain poorly understood. To gain insight into pro-relaxant mechanisms effected by TAS2Rs, we employed an unbiased phosphoproteomic approach involving dual-mass spectrometry to determine differences in the phosphorylation of contractile-related proteins in ASM following the stimulation of cells with TAS2R agonists, histamine (an agonist of the Gq-coupled H1 histamine receptor) or isoproterenol (an agonist of the Gs-coupled β 2 -adrenoceptor) alone or in combination. Our study identified differential phosphorylation of proteins regulating contraction, including A-kinase anchoring protein (AKAP)2, AKAP12, and RhoA guanine nucleotide exchange factor (ARHGEF)12. Subsequent signaling analyses revealed RhoA and the T853 residue on myosin light chain phosphatase (MYPT)1 as points of mechanistic divergence between TAS2R and Gs-coupled GPCR pathways. Unlike Gs-coupled receptor signaling, which inhibits histamine-induced myosin light chain (MLC)20 phosphorylation via protein kinase A (PKA)-dependent inhibition of intracellular calcium mobilization, HSP20 and ERK1/2 activity, TAS2Rs are shown to inhibit histamine-induced pMLC20 via inhibition of RhoA activity and MYPT1 phosphorylation at the T853 residue. These findings provide insight into the TAS2R signaling in ASM by defining a distinct signaling mechanism modulating inhibition of pMLC20 to relax contracted ASM., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

A microfluidic tongue-on-a-chip platform has been evaluated relative to the known sensory properties of various sweeteners. Analogous metrics of typical sensory features reported by human panels such as sweet taste thresholds, onset, and lingering, as well as bitter off-flavor and blocking interactions were deduced from the taste receptor activation curves and then compared. To this end, a flow cell containing a receptor cell array bearing the sweet and six bitter taste receptors was transiently exposed to pure and mixed sweetener samples. The sample concentration gradient across time was separately characterized by the injection of fluorescein dye. Subsequently, cellular calcium responses to different doses of advantame, aspartame, saccharine, and sucrose were overlaid with the concentration gradient. Parameters describing the response kinetics compared to the gradient were quantified. Advantame at 15 μM recorded a significantly faster sweetness onset of 5 ± 2 s and a longer lingering time of 39 s relative to sucrose at 100 mM with an onset of 13 ± 2 s and a lingering time of 6 s. Saccharine was shown to activate the bitter receptors TAS2R8, TAS2R31, and TAS2R43, confirming its known off-flavor, whereas addition of cyclamate reduced or blocked this saccharine bitter response. The potential of using this tongue-on-a-chip to bridge the gap with in vitro assays and taste panels is discussed.

Bitter taste receptors (TAS2Rs) expressed in extraoral tissues represent a whole-body sensory system, whose role and mechanisms could be of interest for the identification of new therapeutic targets. It is known that TAS2R46s in pre-contracted airway smooth muscle cells increase mitochondrial calcium uptake, leading to bronchodilation, and that several SNPs have been identified in its gene sequence. There are very few reports on the structure-function analysis of TAS2Rs. Thus, we delved into the subject by using mutagenesis and in silico studies. We generated a cellular model that expresses native TAS2R46 to evaluate the influence of the four most common SNPs on calcium fluxes following the activation of the receptor by its specific ligand absinthin. Then, docking studies were conducted to correlate the calcium flux results to the structural mutation. The analysed SNPs differently modulate the TAS2R46 signal cascade according to the altered protein domain. In particular, the SNP in the sixth transmembrane domain of the receptors did not modulate calcium homeostasis, while the SNPs in the sequence coding for the fourth transmembrane domain completely abolished the mitochondrial calcium uptake. In conclusion, these results indicate the fourth transmembrane domain of TAS2R46 is critical for the intrinsic receptor activity.

Cornelian cherry fruits contain a wide range of phenolic acids, flavonoids, and other secondary metabolites. Selected flavonoids may inhibit the perceiving of bitterness, however, the full mechanism with all TAS2R bitter taste receptors is not known. The aim of the study was to determine the inhibitory effect of Cornus mas phenolics against the bitterness receptors TAS2R13 and TAS2R3 through functional in vitro assays and coupling studies. The overall effect was validated by analysing the inhibition of the receptors activity in cells treated with tested cornelian cherry extracts. The strength of interaction with both TAS2R receptors varied between studied compounds with different binding affinity. Most compounds bonded with the TAS2R3 receptor through a long-distant hydrophobic interaction with Trp89A and π-π orbital overlapping-between phenolic and tryptophane aromatic rings. For TAS2R13 observed were various mechanisms of interaction with the compounds. Nonetheless, naringin and quercetin had most similar binding affinity to chloroquine and denatonium-the model agonists for the receptor., (© 2024. The Author(s).)

Beyond the key bitter compound kaempferol 3- O -(2‴- O -sinapoyl-β-d-sophoroside) previously described in the literature ( 1 ), eight further bitter and astringent-tasting kaempferol glucosides ( 2 - 9 ) have been identified in rapeseed protein isolates ( Brassica napus L.). The bitterness and astringency of these taste-active substances have been described with taste threshold concentrations ranging from 3.3 to 531.7 and 0.3 to 66.4 μmol/L, respectively, as determined by human sensory experiments. In this study, the impact of 1 and kaempferol 3- O -β-d-glucopyranoside ( 8 ) on TAS2R-linked proton secretion by HGT-1 cells was analyzed by quantification of the intracellular proton index. mRNA levels of bitter receptors TAS2R3, 4, 5, 13, 30, 31, 39, 40, 43, 45, 46, 50 and TAS2R8 were increased after treatment with compounds 1 and 8 . Using quantitative UHPLC-MS/MS MRM measurements, the concentrations of 1 - 9 were determined in rapeseed/canola seeds and their corresponding protein isolates. Depending on the sample material, compounds 1 , 3 , and 5 - 9 exceeded dose over threshold (DoT) factors above one for both bitterness and astringency in selected protein isolates. In addition, an increase in the key bitter compound 1 during industrial protein production (apart from enrichment) was observed, allowing the identification of the potential precursor of 1 to be kaempferol 3- O -(2‴- O -sinapoyl-β-d-sophoroside)-7- O -β-d-glucopyranoside ( 3 ). These results may contribute to the production of less bitter and astringent rapeseed protein isolates through the optimization of breeding and postharvest downstream processing.

Bitter taste receptors (TAS2Rs) are not only responsible for taste perception in the oral cavity, but are spread throughout the body, generating a widespread chemosensory system. In humans, 25 subtypes have been identified and are differentially expressed in tissues and organs, including in the immune system. In fact, several TAS2R subtypes have been detected in neutrophils, lymphocytes, B and T cells, NK cells, and monocytes/macrophages, in which they regulate various protective functions of the innate immune system. Given its recognized anti-inflammatory and antioxidant activity, and the generally protective role of bitter taste receptors, in this work, we studied TAS2R46's potential in the protection of human monocyte/macrophage DNA from stress-induced damage. Through both direct and indirect assays and a single-cell gel electrophoresis assay, we demonstrated that absinthin, a specific TAS2R46 agonist, counteracts the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and reduces DNA damage in both cell types. Even though the release of ROS from monocytes/macrophages is fundamental for contrast pathogen agents, supraphysiological ROS production impairs their function, finally leading to cell death. Our results highlight TAS2R46 as a novel player involved in the protection of monocytes and macrophages from oxidative stress damage, while simultaneously supporting their antimicrobial activity.

Bitter taste perception is important in preventing animals from ingesting potentially toxic compounds. Whole-genome assembly (WGA) data have revealed that bitter taste receptor genes (TAS2Rs) comprise a multigene family with dozens of intact and disrupted genes in primates. However, publicly available WGA data are often incomplete, especially for multigene families. In this study, we employed a targeted capture (TC) approach specifically probing TAS2Rs for ten species of cercopithecid primates with diverse diets, including eight omnivorous cercopithecine species and two folivorous colobine species. We designed RNA probes for all TAS2Rs that we modeled to be intact in the common ancestor of cercopithecids ("ancestral-cercopithecid TAS2R gene set"). The TC was followed by short-read and high-depth massive-parallel sequencing. TC retrieved more intact TAS2R genes than found in WGA databases. We confirmed a large number of gene "births" at the common ancestor of cercopithecids and found that the colobine common ancestor and the cercopithecine common ancestor had contrasting trajectories: four gene "deaths" and three gene births, respectively. The number of intact TAS2R genes was markedly reduced in colobines (25-28 detected via TC and 20-26 detected via WGA analysis) as compared with cercopithecines (27-36 via TC and 19-30 via WGA). Birth or death events occurred at almost every phylogenetic-tree branch, making the composition of intact genes variable among species. These results show that evolutionary change in intact TAS2R genes is a complex process, refute a simple general prediction that herbivory favors more TAS2R genes, and have implications for understanding dietary adaptations and the evolution of detoxification abilities., (© 2024. The Author(s).)

Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents 1,2 . TAS2R14 is also widely expressed in extragustatory tissues, suggesting its extra roles in diverse physiological processes and potential therapeutic applications 3 . Here we present cryogenic electron microscopy structures of TAS2R14 in complex with aristolochic acid, flufenamic acid and compound 28.1, coupling with different G-protein subtypes. Uniquely, a cholesterol molecule is observed occupying what is typically an orthosteric site in class A G-protein-coupled receptors. The three potent agonists bind, individually, to the intracellular pockets, suggesting a distinct activation mechanism for this receptor. Comprehensive structural analysis, combined with mutagenesis and molecular dynamic simulation studies, elucidate the broad-spectrum ligand recognition and activation of the receptor by means of intricate multiple ligand-binding sites. Our study also uncovers the specific coupling modes of TAS2R14 with gustducin and G i1 proteins. These findings should be instrumental in advancing knowledge of bitter taste perception and its broader implications in sensory biology and drug discovery., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

In the realm of colon carcinoma, significant genetic and epigenetic diversity is observed, underscoring the necessity for tailored prognostic features that can guide personalized therapeutic strategies. In this study, we explored the association between the type 2 bitter taste receptor (TAS2Rs) family-related genes and colon cancer using RNA-sequencing and clinical datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Our preliminary analysis identified seven TAS2Rs genes associated with survival using univariate Cox regression analysis, all of which were observed to be overexpressed in colon cancer. Subsequently, based on these seven TAS2Rs prognostic genes, two colon cancer molecular subtypes (Cluster A and Cluster B) were defined. These subtypes exhibited distinct prognostic and immune characteristics, with Cluster A characterized by low immune cell infiltration and less favorable outcomes, while Cluster B was associated with high immune cell infiltration and better prognosis. Finally, we developed a robust scoring system using a gradient boosting machine (GBM) approach, integrated with the gene-pairing method, to predict the prognosis of colon cancer patients. This machine learning model could improve our predictive accuracy for colon cancer outcomes, underscoring its value in the precision oncology framework.

Dietary intake and alcohol consumption might be influenced by genetic variations in taste receptor genes. The objectives of this study were to examine the relationship between polymorphisms in the bitter taste receptor genes TAS2R13 (rs1015443) and TAS2R38 (rs1726866, rs10246939, and rs713598) as well as alcohol consumption and body fat percentage in college students. Four hundred and two students with a mean age of 20.2 years participated in this study. An NIH Diet History Questionnaire (DHQ II) was used to collect data on their dietary intake, while an AUDIT survey was used to determine their level of alcohol consumption. Bitter taste receptor gene polymorphisms were assessed by TaqMan allelic discrimination assays. Despite significant associations between TAS2R13 (rs1015443) and certain aspects of alcohol consumption, including the frequency of alcohol intake, no significant associations were found between TAS2R13 (rs1015443) and alcohol consumption after accounting for confounding variables in the regression model. Neither association was found regarding percent of body fat. In contrast, ethnicity and gender significantly influenced percent of body fat ( p < 0.001), while no significant association was observed between TAS2R13 (rs1015443) and percent of body fat. Likewise, TAS2R38 (rs1726866, rs10246939, and rs713598) demonstrated no significant association with alcohol consumption and percent of body fat. These results were controlled for confounding factors, such as ethnicity and gender. Body fat percentage and alcohol consumption may be influenced by ethnicity, gender, and age rather than SNPs of TAS2R13 and TAS2R38 genes. Assessing taste genes' interactions with diet and body composition might be useful in identifying human disease risk.

Bitter taste involves the detection of diverse chemical compounds by a family of G protein-coupled receptors, known as taste receptor type 2 (TAS2R). It is often linked to toxins and harmful compounds and in particular bitter taste receptors participate in the regulation of glucose homeostasis, modulation of immune and inflammatory responses, and may have implications for various diseases. Human TAS2Rs are characterized by their polymorphism and differ in localization and function. Different receptors can activate various signaling pathways depending on the tissue and the ligand. However, in vitro screening of possible TAS2R ligands is costly and time-consuming. For this reason, in silico methods to predict bitterant-TAS2R interactions could be powerful tools to help in the selection of ligands and targets for experimental studies and improve our knowledge of bitter receptor roles. Machine learning (ML) is a branch of artificial intelligence that applies algorithms to large datasets to learn from patterns and make predictions. In recent years, there has been a record of numerous taste classifiers in literature, especially on bitter/non-bitter or bitter/sweet classification. However, only a few of them exploit ML to predict which TAS2R receptors could be targeted by bitter molecules. Indeed, the shortage and incompleteness of data on receptor-ligand associations in literature make this task non-trivial. In this work, we provide an overview of the state of the art dealing with this specific investigation, focusing on three ML-based models, namely BitterX (2016), BitterSweet (2019) and BitterMatch (2022). This review aims to establish the foundation for future research endeavours focused on addressing the limitations and drawbacks of existing models., (© 2024 Wiley Periodicals LLC.)

Background: Bitter taste receptors (Tas2rs) are generally considered to sense various bitter compounds to escape the intake of toxic substances. Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo., Methods: To investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues, multiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene-editing technique. A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes. Then, T7EN1 assays and sequencing were used to screen genetic mutation at the target sites in founder mice. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds. Perception to taste substance was also studied using two-bottle preference tests., Results: We successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique. Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice. But qRT-PCR results revealed the changed expression profile of mTas2rs gene in taste buds of these mutant mice. With two-bottle preference tests, these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105. In addition, these mutant mice showed a loss of taste perception to quinine dihydrochloride, denatonium benzoate, and cucurbitacin B (CuB). Gnat3-mediated taste receptor and its signal pathway contribute to CuB perception., Conclusions: These findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound-induced responses mediated by these TAS2Rs in many extraoral tissues., (© 2023 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

In the past, taste interactions between sodium chloride (NaCl) and bitter tastants were investigated in human sensory studies, and the suppression of bitterness by sodium was observed. It is currently not clear if this phenomenon occurs predominantly peripherally or centrally and if the effect is general or only particular bitter compounds are blocked. Therefore, the influence of NaCl at the receptor level was tested by functional expression assays using four out of ∼25 human bitter taste receptors together with prototypical agonists. It was observed that NaCl affected only the responses of particular bitter taste receptor-compound pairs, whereas other bitter responses remained unchanged upon variations of the sodium concentrations. Among the tested receptors, TAS2R16 showed a reduction in signaling in the presence of NaCl. This demonstrates that for some receptor-agonist pairs, NaCl reduces the activation at the receptor level, whereas central effects may dominate the NaCl-induced bitter taste inhibition for other substances.

Bitter taste perception plays a critical role in deterring animals from consuming harmful and toxic substances. To characterize the evolution of primate Tas2r, test the generality of Tas2r duplication in Cercopithecidae species, and examine whether dietary preferences have shaped the Tas2r repertoire of primate species, we identified Tas2r in the genomes of 35 primate species, including 16 Cercopithecidae, 6 Hominidae, 4 Cebidae, 3 Lemuridae, and 6 other species. The results showed that the total number of primate Tas2r ranged from 27 to 51, concentrating on 2 to 4 scaffolds of each species. Closely related genes were tandemly duplicated in the same scaffold. Phylogenetic construction revealed that Tas2r can be divided into 21 clades, including anthropoid-, Strepsirrhini-, and Cercopithecidae-specific Tas2r duplications. Phylogenetically independent contrast analysis revealed that the number of intact Tas2r significantly correlated with feeding preferences. Altogether, our data support diet as a driver of primate Tas2r evolution, and Cercopithecidae species have developed some specific Tas2r duplication during evolution. These results are probably because most Cercopithecidae species feed on plants containing many toxins, and it is necessary to develop specialized Tas2r to protect them from poisoning., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Bitterness is one of the five basic tastes generally considered undesirable. The widespread presence of bitter compounds can negatively affect the palatability of foods. The classification and sensory evaluation of bitter compounds have been the focus in recent research. However, the rigorous identification of bitter tastes and further studies to effectively mask or remove them have not been thoroughly evaluated. The present paper focuses on identification of bitter compounds in foods, structural-based activation of bitter receptors, and strategies to reduce bitter compounds in foods. It also discusses the roles of metabolomics and virtual screening analysis in bitter taste. The identification of bitter compounds has seen greater success through metabolomics with multivariate statistical analysis compared to conventional chromatography, HPLC, LC-MS, and NMR techniques. However, to avoid false positives, sensory recognition should be combined. Bitter perception involves the structural activation of bitter taste receptors (TAS2Rs). Only 25 human TAS2Rs have been identified as responsible for recognizing numerous bitter compounds, showcasing their high structural diversity to bitter agonists. Thus, reducing bitterness can be achieved through several methods. Traditionally, the removal or degradation of bitter substances has been used for debittering, while the masking of bitterness presents a new effective approach to improving food flavor. Future research in food bitterness should focus on identifying unknown bitter compounds in food, elucidating the mechanisms of activation of different receptors, and developing debittering techniques based on the entire food matrix., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Bitterness from phenylthiocarbamide and 6-n-propylthiouracil (PROP) varies with polymorphisms in the TAS2R38 gene. Three SNPs form two common (AVI, PAV) and four rare haplotypes (AAI, AAV, PVI, and PAI). AVI homozygotes exhibit higher detection thresholds and lower suprathreshold bitterness for PROP compared to PAV homozygotes and heterozygotes, and these differences may influence alcohol and vegetable intake. Within a diplotype, substantial variation in suprathreshold bitterness persists, and some AVI homozygotes report moderate bitterness at high concentrations. A second receptor encoded by a gene containing a functional polymorphism may explain this. Early work has suggested that PROP might activate TAS2R4 in vitro, but later work did not replicate this. Here, we identify three TAS2R4 SNPs that result in three diplotypes-SLN/SLN, FVS/SLN, and FVS/FVS-which make up 25.1%, 44.9%, and 23.9% of our sample. These TAS2R4 haplotypes show minimal linkage disequilibrium with TAS2R38, so we examined the suprathreshold bitterness as a function of both. The participants ( n = 243) rated five PROP concentrations in duplicate, interleaved with other stimuli. As expected, the TAS2R38 haplotypes explained ~29% ( p < 0.0001) of the variation in the bitterness ratings, with substantial variation within the haplotypes (AVI/AVI, PAV/AVI, and PAV/PAV). Notably, the TAS2R4 diplotypes (independent of the TAS2R38 haplotypes) explained ~7-8% of the variation in the bitterness ratings ( p = 0.0001). Given this, we revisited if PROP could activate heterologously expressed TAS2R4 in HEK293T cells, and calcium imaging indicated 3 mM PROP is a weak TAS2R4 agonist. In sum, our data are consistent with the second receptor hypothesis and may explain the recovery of the PROP tasting phenotype in some AVI homozygotes; further, this finding may potentially help explain the conflicting results on the TAS2R38 diplotype and food intake.

Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors 1 . Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants 2-6 , although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with G gust (also known as gustducin) and G i1 . Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of G gust and G i1 . Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The TAS2R38 gene is well known for its function in bitter taste sensitivity, but evidence also suggests a role in innate immunity. TAS2R38 may be relevant in coronavirus disease 2019 (COVID-19), but research findings are inconsistent. The objective of this study was to explore whether common TAS2R38 haplotypes are associated with COVID-19 infection and symptomatology in the Canadian Longitudinal Study on Aging (CLSA). Data from the CLSA COVID-19 Questionnaire and Seroprevalence sub-studies were utilized with CLSA genetic data for common TAS2R38 haplotypes related to bitter taste sensitivity. Haplotypes were categorized into three diplotype groups: [P]AV homozygotes, [P]AV/[A]VI heterozygotes, and [A]VI homozygotes. No significant differences were observed between diplotypes and COVID-19 infection frequency. Among self-reported COVID-19 cases (n = 76), and in uncorrected exploratory analyses, heterozygotes were less likely to report experiencing sinus pain compared to [P]AV homozygotes. Among seroprevalence-confirmed cases (n = 177), [A]VI homozygotes were less likely to report experiencing a sore/scratchy throat compared to [P]AV homozygotes. However, both observations were non-significant upon correction for multiple testing. In this study, TAS2R38 haplotypes were not significantly associated with COVID-19 infection or symptomatology. Nevertheless, in light of some exploratory patterns and conflicting evidence, additional research is warranted to evaluate links between TAS2R38 and innate immunity., (© 2024. The Author(s).)

Background: The aim of this study is to determine the association of TAS2R16 (rs860170, rs978739, rs1357949) gene polymorphisms and TAS2R16 serum levels in patients with the occurrence of age-related macular degeneration (AMD)., Methods: Subjects with early AMD, subjects with exudative AMD, and healthy controls participated in the study. DNA was isolated by salting out leukocytes from peripheral venous blood. Single nucleotide polymorphisms (SNPs) were analysed by RT-PCR. TAS2R16 levels were determined by enzyme-linked immunosorbent assay (ELISA) using the Abbexa Human Taste Receptor Type 2 Member 16 (TAS2R16) ELISA kit. Statistical data analysis was performed using "IBM SPSS Statistics 27.0" and SNPstats statistical data analysis programmes., Results: The TAS2R16 rs860170 TT genotype is statistically significantly less frequent in the exudative AMD group than in the control group, whereas the TAS2R16 rs860170 C allele gene is statistically significantly more frequent in the exudative AMD group. Each C allele of TAS2R16 rs860170 is associated with a 2.8-fold increased probability of occurrence of exudative AMD. The C allele of TAS2R16 rs860170 is statistically significantly more frequent in men and women with exudative AMD than in the control group. The C allele of TAS2R16 rs860170 is associated with a 2.8-fold increased odds of occurrence of exudative AMD in women and a 2.9-fold increased odds of occurrence of exudative AMD in men. In TAS2R16 (rs860170, rs978739, and rs1357949), the T-T-A haplotype is associated with a 2.6-fold decreased likelihood of developing early AMD and the T-T-A haplotype is associated with a 3.2-fold decreased likelihood of developing early AMD in women. For TAS2R16 (rs860170, rs978739, and rs1357949), carriers of the T-T-G and T-T-A haplotypes are associated with a 2.2- and 3.2-fold decreased probability of exudative AMD, respectively. Individuals with the C-C-A haplotype are 9.2-fold more likely to develop exudative AMD. Specifically, the C-C-A haplotype is associated with a 9.3-fold increased likelihood of exudative AMD in men. In contrast, women with the T-T-A haplotype are 5.6-fold less likely to develop exudative AMD., Conclusion: TAS2R16 plays an important role in the development of AMD.

Background: Variation in common taste receptor type 2 member 38 (TAS2R38) haplotypes is associated with bitter-taste sensitivity, but associations with dietary intake and risk factors for chronic disease are inconsistent., Objectives: To determine whether common TAS2R38 haplotypes are associated with dietary intake and risk factors for chronic disease using cross-sectional data from the Canadian Longitudinal Study on Aging (n = 26,090). Outcomes were assessed among the full sample and stratified by sex., Methods: Taster status was determined from TAS2R38 haplotypes, and the respondents were classified as supertasters, tasters, and nontasters. Primary outcome variables were the consumption frequencies of vegetables, sweet-tasting foods, alcoholic beverages, and visceral adiposity index (VAI). Secondary outcome variables were the individual VAI components. Multivariable regression models adjusted for sociodemographic and lifestyle factors were used to assess associations between the taster status and outcome variables., Results: Among the sample, 5655, 12,821, and 7614 respondents were classified as supertasters, tasters, and nontasters, respectively. Vegetable consumption was significantly higher among nontasters than among supertasters (1.23 ± 0.26 and 1.20 ± 0.22, respectively, P = 0.02). Among males, the consumption of sweet-tasting foods (0.40 ± 8.80 and 0.38 ± 7.55, P = 0.02) and green salad (0.35 ± 0.31 and 0.33 ± 0.27, P = 0.02) was also higher for nontasters than supertasters. Nontasters were more likely to be regular alcohol consumers compared with supertasters among the full sample (odds ratio [95% confidence interval]: 1.12 [1.03, 1.22]; P = 0.01) and among females (OR: 1.13; 95% CI: 1.01, 1.27; P = 0.04). No significant associations were observed between TAS2R38 haplotypes and VAI, although high-density lipoprotein cholesterol was significantly lower among supertasters than nontasters (1.45 ± 0.59 and 1.47 ± 0.63, respectively; P = 0.04)., Conclusions: Among middle- to older-aged adults, minor associations are observed between TAS2R38 haplotypes, dietary intake, and high-density lipoprotein cholesterol. Genetic predisposition to bitter-taste sensitivity is linked to diet; however, further research is needed to understand the relevance for chronic disease risk., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

TAS2Rs (bitter taste receptors) are GPCRs (G protein-coupled receptors) expressed on human airway smooth muscle (HASM) cells; when activated by receptor agonists they evoke marked airway relaxation. In both taste and HASM cells, TAS2Rs activate a canonical G βγ -mediated stimulation of Ca 2+ release from intracellular stores by activation of PLCβ (phospholipase Cβ). Alone, this [Ca 2+ ] i signaling does not readily account for relaxation, particularly since bronchoconstrictive agonists acting at G q -coupled receptors also increase [Ca 2+ ] i . We established that TAS2R14 activation in HASM promotes relaxation through F-actin (filamentous actin) severing. This destabilization of actin was from agonist-promoted activation (dephosphorylation) of cofilin, which was pertussis toxin sensitive. Cofilin dephosphorylation was due to TAS2R-mediated deactivation of LIM domain kinase. The link between early receptor action and the distal cofilin dephosphorylation was found to be the polarity protein partitioning defective 3 (Par3), a known binding partner with PLCβ that inhibits LIM kinase. The physiologic relevance of this pathway was assessed using knock-downs of cofilin and Par3 in HASM cells and in human precision-cut lung slices. Relaxation by TAS2R14 agonists was ablated with knock-down of either protein as assessed by magnetic twisting cytometry in isolated cells or intact airways in the slices. Blocking [Ca 2+ ] i release by TAS2R14 inhibited agonist-promoted cofilin dephosphorylation, confirming a role for [Ca 2+ ] i in actin-modifying pathways. These results further elucidate the mechanistic basis of TAS2R-mediated HASM relaxation and point toward nodal points that may act as asthma or chronic obstructive pulmonary disease response modifiers or additional targets for novel bronchodilators.