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1

Luongo, Francesca Paola, Sofia Passaponti, Alesandro Haxhiu, Maryam Raeispour, Giuseppe Belmonte, Laura Governini, Livio Casarini, Paola Piomboni, and Alice Luddi. "Bitter Taste Receptors and Endocrine Disruptors: Cellular and Molecular Insights from an In Vitro Model of Human Granulosa Cells." International Journal of Molecular Sciences 23, no. 24 (December 8, 2022): 15540. http://dx.doi.org/10.3390/ijms232415540.

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Анотація:
Endocrine disrupting chemicals (EDCs) are compounds that interfere with the synthesis, transport and binding action of hormones responsible for reproduction and homeostasis. Some EDCs compounds are activators of Taste bitter Receptors, a subclass of taste receptors expressed in many extraoral locations, including sperm and follicular somatic cells. This makes TAS2Rs attractive molecules to study and investigate to shed light on the effect of EDCs on female reproduction and fertility. This study aims to assess the effect of selected EDCs [namely Biochanin A (BCA), caffeine, Daidzein, Genistein and Isoflavone] on hGL5, an immortalized cell line exhibiting characteristics coherent with primary follicular granulosa cells. After demonstrating that this model expresses all the TAS2Rs (TAS2R3, TAS2R4, TAS2R14, TAS2R19, TAS2R43) specifically expressed by the primary human granulosa cells, we demonstrated that BCA and caffeine significantly affect mitochondrial footprint and intracellular lipid content, indicating their contribution in steroidogenesis. Our results showed that bitter taste receptors may be involved in steroidogenesis, thus suggesting an appealing mechanism by which these compounds affect the female reproductive system.
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2

Kimura, Shunsuke, Ai Tsuruma, and Eisuke Kato. "Taste 2 Receptor Is Involved in Differentiation of 3T3-L1 Preadipocytes." International Journal of Molecular Sciences 23, no. 15 (July 23, 2022): 8120. http://dx.doi.org/10.3390/ijms23158120.

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Анотація:
Expression of taste 2 receptor (T2R) genes, also known as bitter taste receptor genes, has been reported in a variety of tissues. The white adipose tissue of mice has been shown to express Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, but the function of T2Rs in adipocytes remains unclear. Here, we show that fasting and stimulation by bitter compounds both increased Tas2r expression in mouse white adipose tissue, and serum starvation and stimulation by bitter compounds both increased the expression of Tas2r genes in 3T3-L1 adipocytes, suggesting that T2Rs have functional roles in adipocytes. RNA sequencing analysis of 3T3-L1 adipocytes stimulated by epicatechin, the ligand of Tas2r126, suggested that this receptor may play a role in the differentiation of adipocytes. Overexpression of Tas2r126 in 3T3-L1 preadipocytes decreases fat accumulation after induction of differentiation and reduces the expression of adipogenic genes. Together, these results indicate that Tas2r126 may be involved in adipocyte differentiation.
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3

Semplici, Bianca, Francesca Paola Luongo, Sofia Passaponti, Claudia Landi, Laura Governini, Giuseppe Morgante, Vincenzo De Leo, Paola Piomboni, and Alice Luddi. "Bitter Taste Receptors Expression in Human Granulosa and Cumulus Cells: New Perspectives in Female Fertility." Cells 10, no. 11 (November 11, 2021): 3127. http://dx.doi.org/10.3390/cells10113127.

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Анотація:
Bitter taste receptors (TAS2RS) expression is not restricted to the oral cavity and the presence of these receptors in the male reproductive system and sperm provides insights into their possible role in human reproduction. To elucidate the potential role of TAS2Rs in the female reproductive system, we investigated the expression and localization of bitter taste receptors and the components of signal transduction cascade involved in the pathway of taste receptors in somatic follicular cells obtained from women undergoing assisted reproductive techniques. We found that TAS2R genes are expressed in both cumulus (CCs) and granulosa (GCs) cells, with TAS2R14 being the most highly expressed bitter receptor subtype. Interestingly, a slight increase in the expression of TAS2R14 and TAS2R43 was shown in both GCs and CCs in young women (p < 0.05), while a negative correlation may be established between the number of oocytes collected at the pickup and the expression of TAS2R43. Regarding α-gustducin and α-transducin, two Gα subunits expressed in the taste buds on the tongue, we provide evidence for their expression in CCs and GCs, with α-gustducin showing two additional isoforms in GCs. Finally, we shed light on the possible downstream transduction pathway initiated by taste receptor activation in the female reproductive system. Our study, showing for the first time the expression of taste receptors in the somatic ovarian follicle cells, significantly extends the current knowledge of the biological role of TAS2Rs for human female fertility.
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4

Lipchock, Sarah V., Andrew I. Spielman, Julie A. Mennella, Corrine J. Mansfield, Liang-Dar Hwang, Jennifer E. Douglas, and Danielle R. Reed. "Caffeine Bitterness is Related to Daily Caffeine Intake and Bitter Receptor mRNA Abundance in Human Taste Tissue." Perception 46, no. 3-4 (January 24, 2017): 245–56. http://dx.doi.org/10.1177/0301006616686098.

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Анотація:
We investigated whether the abundance of bitter receptor mRNA expression from human taste papillae is related to an individual’s perceptual ratings of bitter intensity and habitual intake of bitter drinks. Ratings of the bitterness of caffeine and quinine and three other bitter stimuli (urea, propylthiouracil, and denatonium benzoate) were compared with relative taste papilla mRNA abundance of bitter receptors that respond to the corresponding bitter stimuli in cell-based assays ( TAS2R4, TAS2R10, TAS2R38, TAS2R43, and TAS2R46). We calculated caffeine and quinine intake from a food frequency questionnaire. The bitterness of caffeine was related to the abundance of the combined mRNA expression of these known receptors, r = 0.47, p = .05, and self-reported daily caffeine intake, t(18) = 2.78, p = .012. The results of linear modeling indicated that 47% of the variance among subjects in the rating of caffeine bitterness was accounted for by these two factors (habitual caffeine intake and taste receptor mRNA abundance). We observed no such relationships for quinine but consumption of its primary dietary form (tonic water) was uncommon. Overall, diet and TAS2R gene expression in taste papillae are related to individual differences in caffeine perception.
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5

Bertran, Laia, Marta Portillo-Carrasquer, Salomé Martínez, Carmen Aguilar, Miguel Lopez-Dupla, David Riesco, Jessica Binetti, et al. "Expression of Jejunal Taste Receptors in Women with Morbid Obesity." Nutrients 13, no. 7 (July 16, 2021): 2437. http://dx.doi.org/10.3390/nu13072437.

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Анотація:
Nutrient sensing plays important roles in promoting satiety and maintaining good homeostatic control. Taste receptors (TAS) are located through the gastrointestinal tract, and recent studies have shown they have a relationship with metabolic disorders. The aim of this study was to analyze the jejunal expression of TAS1R2, TAS1R3, TAS2R14 and TAS2R38 in women with morbid obesity, first classified according to metabolic syndrome presence (MetS; n = 24) or absence (non-MetS; n = 45) and then classified according to hepatic histology as normal liver (n = 28) or nonalcoholic fatty liver disease (n = 41). Regarding MetS, we found decreased expression of TAS2R14 in MetS patients. However, when we subclassified patients according to liver histology, we did not find differences between groups. We found negative correlations between glucose levels, triglycerides and MetS with TAS1R3 expression. Moreover, TAS2R14 jejunal expression correlated negatively with the presence of MetS and ghrelin levels and positively with the jejunal Toll-like receptor (TLR)4, peroxisome proliferator-activated receptor (PPAR)-γ, and interleukin (IL)-10 levels. Furthermore, TAS2R38 expression correlated negatively with TLR9 jejunal expression and IL-6 levels and positively with TLR4 levels. Our findings suggest that metabolic dysfunctions such as MetS trigger downregulation of the intestinal TASs. Therefore, taste receptors modulation could be a possible therapeutic target for metabolic disorders.
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6

Pulkkinen, Ville, Martijn L. Manson, Jesper Säfholm, Mikael Adner, and Sven-Erik Dahlén. "The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea." American Journal of Physiology-Lung Cellular and Molecular Physiology 303, no. 11 (December 1, 2012): L956—L966. http://dx.doi.org/10.1152/ajplung.00205.2012.

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Анотація:
Activation of taste receptors (TAS2Rs) by bitter taste agonists has been reported to cause bronchodilation. The aim of this study was to extend the information on the effects of bitter taste agonists on responses induced by different contractile mediators in a standard airway physiology preparation. Isometric responses were assessed in guinea pig trachea (GPT). TAS2R agonists were administered either to segments precontracted with different agonists for contraction or given before challenge with the different contractile stimuli, including antigen in tissues from ovalbumin-sensitized animals. TAS2R mRNA expression on GPT epithelium and smooth muscle was measured with real-time PCR. Denatonium, chloroquine, thiamine, and noscapine induced concentration-dependent relaxations (Rmax: 98.3 ± 1.6, 100.0 ± 0.0, 100.0 ± 0.0, and 52.3 ± 1.1% of maximum, respectively, in the presence of indomethacin) in segments precontracted with carbachol. The receptors for denatonium (TAS2R4, TAS2R10) and chloroquine (TAS2R3, TAS2R10) were expressed in GPT. Whereas denatonium selectively inhibited contractions induced by carbachol, chloroquine uniformly inhibited contractions evoked by prostaglandin E2, the thromboxane receptor agonist U-46619, leukotriene D4, histamine, and antigen. The effects of denatonium, but not those of chloroquine, were partly inhibited by blockers of the large Ca2+-activated K+ channels and decreased by an increase of the level of precontraction. In conclusion, TAS2R agonists mediated strong relaxations and substantial inhibition of contractions in GPT. Chloroquine and denatonium had distinct patterns of activity, indicating different signaling mechanisms. The findings reinforce the hypothesis that TAS2Rs are potential targets for the development of a new class of more efficacious agonists for bronchodilation.
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7

Orlova, Ekaterina, Tom Dudding, Jonathan M. Chernus, Rasha N. Alotaibi, Simon Haworth, Richard J. Crout, Myoung Keun Lee, et al. "Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study." Genes 14, no. 1 (December 24, 2022): 59. http://dx.doi.org/10.3390/genes14010059.

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Анотація:
Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing ~3.9 million genetic variants and found suggestive evidence for association at genetic regions previously associated with caries in primary and permanent dentition, including the β-defensin anti-microbial proteins. We then integrated the meta-analysis results with gene expression data in a transcriptome-wide association study (TWAS). This approach identified four genes whose genetically predicted expression was associated with ECC (p-values < 3.09 × 10−6; CDH17, TAS2R43, SMIM10L1, TAS2R14). Some of the strongest associations were with genes encoding members of the bitter taste receptor family (TAS2R); other members of this family have previously been associated with caries. Of note, we identified the receptor encoded by TAS2R14, which stimulates innate immunity and anti-microbial defense in response to molecules released by the cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus. These findings provide insight into ECC genetic architecture, underscore the importance of host-microbial interaction in caries risk, and identify novel risk genes.
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8

Yuan, Yamei, Xiangming Fang, and Weidong Ye. "Acrid and Bitter Chinese Herbs in Decoction Effectively Relieve Lung Inflammation and Regulation of TRPV1/TAS2R14 Channels in a Rat Asthmatic Model." Evidence-Based Complementary and Alternative Medicine 2022 (August 22, 2022): 1–10. http://dx.doi.org/10.1155/2022/8061740.

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Анотація:
Background. Shegan Mahuang decoction (SGMHD) was widely used as a classic prescription of traditional Chinese medicine to treat asthma. However, there is no research on the acrid and bitter Chinese herbs in the SGMHD to treat asthma. This study aimed to investigate the effects of SGMHD and its acrid-bitter Chinese herbs composition on airway inflammation and the expression of TRPV1 and TAS2R14 genes and proteins in asthmatic rats. Methods. SD (Sprague Dawley) rats of asthma were induced by ovalbumin and aluminum hydroxide, then randomly divided into the Normal group, Model group, SGMHD group, Dexamethasone (Dex) group, Guilongkechuangning (GLKC) group, The Acrid Chinese Herbs group (ACH), and The Bitter Chinese Herbs group (BCH). The rats were given intragastric gavage after 21 days for 4 weeks. The bronchoalveolar lavage fluid (BALF) was collected, and the levels of IL-4, IL-13, nerve factors SP, CGRP, PGE2, and serum of IgE were determined by ELISA. Pathological changes in the lungs were determined by hematoxylin-eosin (HE) staining. The expression of TRPV1 and TAS2R14 in the rat lung group was detected by immunofluorescence (IF). The expression levels of TRPV1 and TAS2R14 were measured using western blotting. The mRNA levels of TRPV1 and TAS2R14 were measured using RT-qPCR. Results. The levels of serum IgE in treated rats and the cytokines IL-4, IL-13, SP, CGRP, and PGE2 were all decreased. HE-staining showed that significantly reduced inflammatory cell infiltration in lung tissue. IF-staining showed the expression levels except those of the normal group were enhanced. Acrid Chinese herbs inhibited TRPV1, and bitter Chinese herbs activated the gene and protein expression of TAS2R in the lung. Conclusion. The acrid Chinese herbs regulate TRPV1, and bitter Chinese herbs regulate the gene and protein expression of TAS2R14, through nerve and immune-inflammatory factors, reduced airway inflammation, reduced airway reactivity, promoted airway remodeling, and the combination of acrid-bitter Chinese herbs can enhance the above effects. This will lay a foundation for further in vivo study of specific compounds of acrid-bitter Chinese herbs.
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9

Taher, Shèdy, Yamilette Borja, Lucía Cabanela, Vincent J. Costers, Morgan Carson-Marino, Julie C. Bailes, Biswadeep Dhar, et al. "Cholecystokinin, gastrin, cholecystokinin/gastrin receptors, and bitter taste receptor TAS2R14: trophoblast expression and signaling." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 316, no. 5 (May 1, 2019): R628—R639. http://dx.doi.org/10.1152/ajpregu.00153.2018.

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We investigated expression of cholecystokinin (CCK) in humans and mice, and the bitter taste receptor TAS2R14 in the human placenta. Because CCK and gastrin activate the CCKBR receptor, we also explored placental gastrin expression. Finally, we investigated calcium signaling by CCK and TAS2R14. By RT-PCR, we found CCK/Cck and GAST/Gast mRNA expression in both normal human and mouse placentas, as well as in human trophoblast cell lines (TCL). Although both Cckar and – br mRNA were expressed in the mouse placenta, only CCKBR mRNA was detected in the human placenta and TCL. mRNA expression for TAS2R14 was also observed in the human placenta and TCL. Using immunohistochemistry, CCK protein was localized to the syncytiotrophoblast (ST) and extravillous trophoblast (EVT) in the human term placenta, and to trophoblast glycogen cells in mouse and human placentas. Gastrin and TAS2R14 proteins were also observed in ST and EVT of the human placenta. Both sulfated and nonsulfated CCK elicited a comparable rise in intracellular calcium in TCL, consistent with CCKBR expression. Three TAS2R14 agonists, flufenamic acid, chlorhexidine, and diphenhydramine, also evoked rises in intracellular calcium in TCL. These results establish CCK, gastrin, and their receptor(s) in both human and mouse placentas, and TAS2R14 in the human placenta. Both CCK and TAS2R14 agonists increased intracellular calcium in human TCL. Although the roles of these ligands and receptors, and their potential cross talk in normal and pathological placentas, are currently unknown, this study opens new avenues for placental research.
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10

Le Nevé, Boris, Martin Foltz, Hannelore Daniel, and Robin Gouka. "The steroid glycoside H.g.-12 from Hoodia gordonii activates the human bitter receptor TAS2R14 and induces CCK release from HuTu-80 cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 299, no. 6 (December 2010): G1368—G1375. http://dx.doi.org/10.1152/ajpgi.00135.2010.

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Анотація:
Steroid glycosides extracted from the succulent plant Hoodia gordonii are suggested to have appetite-suppressant effects both in animals and humans. Yet, the mechanisms underlying the putative satiety action of Hoodia steroid glycosides are not fully understood. We found that H.g.-12, a steroid glycoside purified from H. gordonii extract, initiated cholecystokinin (CCK) secretion both ex vivo in rat intestine and in vitro in the human enteroendocrine (EC) cell line HuTu-80. CCK is known to exert central effects on appetite suppression via the vagus nerve which afferents terminate in the gut wall. Recent data show that G protein-coupled receptors signaling bitter taste (T2Rs) are expressed in both rodent and human gastrointestinal tract. It was further demonstrated that bitter sensing is functional in mouse STC-1 EC cells and leads to CCK secretion via increased intracellular Ca2+ concentrations. Based on the bitter taste of H. gordonii purified extracts, we assessed whether H.g.-12 could activate human bitter receptors. The steroid glycoside activated selectively TAS2R7 and TAS2R14, both heterologously expressed in HEK 293 cells. Removing an essential structural feature from the steroid glycoside inhibited H.g.-12-induced Ca2+ increase in TAS2R14-expressing HEK cells and abolished H.g.-12-induced CCK secretion from human EC cells. Similarly, a nonspecific bitter receptor antagonist abolished H.g.-12-induced CCK secretion in HuTu-80 cells. These results point to a potential route of action by which components of Hoodia might influence appetite control. Our data also provide additional evidence that bitter taste-sensing mechanisms are coupled to hormone release from EC cells in the intestine. Moreover, we identified a natural agonist of TAS2R7 and TAS2R14 for further studies on the role of bitter receptors in satiety control and food intake.
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11

Imai, Hiroo, Nami Suzuki, Yoshiro Ishimaru, Takanobu Sakurai, Lijie Yin, Wenshi Pan, Keiko Abe, Takumi Misaka, and Hirohisa Hirai. "Functional diversity of bitter taste receptor TAS2R16 in primates." Biology Letters 8, no. 4 (March 7, 2012): 652–56. http://dx.doi.org/10.1098/rsbl.2011.1251.

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Анотація:
In mammals, bitter taste is mediated by TAS2R genes, which belong to the large family of seven transmembrane G protein-coupled receptors. Because TAS2Rs are directly involved in the interaction between mammals and their dietary sources, it is likely that these genes evolved to reflect species-specific diets during mammalian evolution. Here, we investigated the sensitivities of TAS2R16s of various primates by using a cultured cell expression system, and found that the sensitivity of each primate species varied according to the ligand. Especially, the sensitivity of TAS2R16 of Japanese macaques to salicin was much lower than that of human TAS2R16, which was supported by behavioural tests. These results suggest the possibility that bitter-taste sensitivities evolved independently by replacing specific amino acid residues of TAS2Rs in different primate species to adapt to food items they use.
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12

Itoigawa, Akihiro, Takashi Hayakawa, Nami Suzuki-Hashido, and Hiroo Imai. "A natural point mutation in the bitter taste receptor TAS2R16 causes inverse agonism of arbutin in lemur gustation." Proceedings of the Royal Society B: Biological Sciences 286, no. 1904 (June 5, 2019): 20190884. http://dx.doi.org/10.1098/rspb.2019.0884.

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Анотація:
Bitter taste enables the detection of potentially harmful substances and is mediated by bitter taste receptors, TAS2Rs, in vertebrates. Few antagonists and inverse agonists of TAS2Rs have been identified, especially natural compounds. TAS2R16s in humans, apes and Old World monkeys (Catarrhini, Anthropoidea) recognize β-glucoside analogues as specific agonists. Here, we investigated responses of TAS2R16 to β-glucosides in non-anthropoid primates, namely lemurs (Lemuriformes, Strepsirrhini). Salicin acted as an agonist on lemur TAS2R16. Arbutin acted as an agonist in the ring-tailed lemur ( Lemur catta ) but as an inverse agonist in black lemur ( Eulemur macaco ) and black-and-white ruffed lemur ( Varecia variegata ). We identified a strepsirrhine-specific amino acid substitution responsible for the inverse agonism of arbutin. In a food preference test, salicin bitterness was inhibited by arbutin in the black lemur. Structural modelling revealed this locus was important for a rearrangement of the intracellular end of transmembrane helix 7 (TM7). Accordingly, arbutin is the first known natural inverse agonist of TAS2Rs, contributing to our understanding of receptor–ligand interactions and the molecular basis of the unique feeding habit diversification in lemurs. Furthermore, the identification of a causal point mutation suggests that TAS2R can acquire functional changes according to feeding habits and environmental conditions.
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13

Kaur, Kiranjit, Alexandria Turner, Patrice Jones, Dean Sculley, Martin Veysey, Mark Lucock, Janet Wallace, and Emma L. Beckett. "A Cross-Sectional Study of Bitter-Taste Receptor Genotypes, Oral Health, and Markers of Oral Inflammation." Oral 1, no. 2 (May 18, 2021): 122–38. http://dx.doi.org/10.3390/oral1020013.

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Анотація:
(1) Background: The aetiology of oral disease is multifactorial, involving genetic and environmental factors, including dietary ones. Bitter taste genetics may be related to oral health through dietary modulation or non-gustatory roles, including modulation of inflammation. Investigations of bitter taste and oral health associations to date have been restricted to specific polymorphisms, limited outcomes (caries), and age-groups (children), and links to inflammation remain to be elucidated. (2) Methods: A cross-sectional study (n = 65) investigated the correlations between bitter taste genotypes, oral health outcomes, and oral inflammation markers. Oral examinations were conducted, including saliva testing with evaluation of flow rate, pH, and buffering and antioxidant capacity (FRAP) and IL-1β, TNF-α, IL-6 levels. DNA was collected via buccal swabs and used to evaluate the presence of multiple bitter-taste receptor gene polymorphisms. (3) Results: The major allele for TAS2R4-rs2233998, TAS2R5-rs2227264, TAS2R50-rs1376251, and TAS2R9-rs3741845 was associated with a higher mean of unstimulated salivary flow rate, FRAP, TNF-α, IL-1β, and likelihood of filled teeth. Presence of the major allele for TAS2R4-rs2234001 and TAS2R9-rs3741845 was associated with lower means FRAP, TNF-α, IL-1β, DMFT index, and likelihood of missing teeth. (4) Conclusions: These findings suggest relationships between bitter-taste genotypes, oral health outcomes, and inflammatory markers. These findings justify the need for further studies that could help identify risk groups and develop novel agents for maintaining oral health.
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14

Mikołajczyk-Stecyna, Joanna, Anna M. Malinowska, and Agata Chmurzynska. "Polymorphism of TAS2R3, TAS2R5, TAS2R19, and TAS2R50 genes and bitter food intake frequency inelderly woman." Acta Scientiarum Polonorum Technologia Alimentaria 19, no. 1 (March 30, 2020): 109–22. http://dx.doi.org/10.17306/j.afs.0729.

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15

Mikołajczyk-Stecyna, Joanna, Anna M. Malinowska, and Agata Chmurzynska. "Polymorphism of TAS2R3, TAS2R5, TAS2R19, and TAS2R50 genes and bitter food intake frequency inelderly woman [pdf]." Acta Scientiarum Polonorum Technologia Alimentaria 19, no. 1 (March 30, 2020): 109–22. http://dx.doi.org/10.17306/j.afs.2020.0729.

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16

Lund, Troy, Diane Lidke, Amanda Kobs, Bruce R. Blazar, and Jakub Tolar. "“Tasting the Microenvironment”: Human Bone Marrow Stromal Cells Have Microenvironment Chemosensory Capacity Via Taste Receptor Expression." Blood 116, no. 21 (November 19, 2010): 938. http://dx.doi.org/10.1182/blood.v116.21.938.938.

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Анотація:
Abstract Abstract 938 The ability of cells to detect molecules in the microenvironment is important in cell signaling and cell responsiveness to environmental changes. Through an isobaric tag for relative and absolute quantitation (iTRAQ) based proteomic screen of human bone marrow stroma-derived cells (MSC) at the third passage we identified the novel expression of a bitter taste receptor, TAS2R46 in undifferentiated MSC and MSC differentiated into osteocytes, adipocytes, and cartilage. The relative amount of the receptor by iTRAQ and qRT-PCR was equivalent in all cell types. TAS2R46 expression was verified by flow cytometry, immunohistochemistry, and RT-PCR. Expression of TAS2R46 was also found in freshly obtained bone marrow mononuclear cells, and sorting by flow cytometry showed that the taste receptor positive cells had the ability to become MSC in vitro, while significantly fewer cells became MSC in the taste receptor negative/low fraction. Other members of the bitter taste receptor family including TAS2R4, TAS2R5, TAS2R1, TAS2R38 were negative by flow cytometry and iTRAQ. Bitter compounds, of which the prototypical molecule is denatonium, were found to increase intracellular human MSC calcium levels in a dose-responsive manner up to a level of 200% above baseline in fluorescent intracellular calcium detection assays. Other bitter compounds tested were caffeine, thujone, and salicin, and quinine gave rise to increased intracellular calcium levels. The specificity of the calcium response was verified through transgenic overexpression experiments, antibody inhibition, and a novel newly developed direct labeling method in which we were to directly label denatonium and show binding to the cell surface. Evaluation of downstream signaling events showed that interaction with this receptor caused a decrease in cAMP levels of 40% with exposure to 3 mM denatonium. Finally, to reveal the potential that this receptor may have, a native physiologically relevant function related to small peptide binding, a casein hydrosylate was used as a substrate. Remarkably, casein hydrosylate caused a similar increase in intracellular calcium as denatonium. Furthermore, this effect was augmented when TAS2R46 was overexpressed as a transgene. Current studies are working towards revealing the specific peptide that binds to this receptor. This is the first description of chemosensory detection by MSC. Our data show that this environmental detection occurs through a novel expression of a bitter taste receptor, TAS2R46. This ability may allow MSC to sample changes in their microenvironment triggered by small molecules, which could include either toxins or hormones as true natural ligands of this receptor class. The expression of bitter taste receptors may influence the response of MSCs to noxious materials or pathological insults to the organism that are detected as bitter substrates. Future studies will examine the directed mobility of MSCs to such stimuli which may offer new insights as to how MSCs sense organism injury. Disclosures: No relevant conflicts of interest to declare.
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17

Governini, Laura, Bianca Semplici, Valentina Pavone, Laura Crifasi, Camilla Marrocco, Vincenzo De Leo, Elisabeth Arlt, et al. "Expression of Taste Receptor 2 Subtypes in Human Testis and Sperm." Journal of Clinical Medicine 9, no. 1 (January 18, 2020): 264. http://dx.doi.org/10.3390/jcm9010264.

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Taste receptors (TASRs) are expressed not only in the oral cavity but also throughout the body, thus suggesting that they may play different roles in organ systems beyond the tongue. Recent studies showed the expression of several TASRs in mammalian testis and sperm, indicating an involvement of these receptors in male gametogenesis and fertility. This notion is supported by an impaired reproductive phenotype of mouse carrying targeted deletion of taste receptor genes, as well as by a significant correlation between human semen parameters and specific polymorphisms of taste receptor genes. To better understand the biological and thus clinical significance of these receptors for human reproduction, we analyzed the expression of several members of the TAS2Rs family of bitter receptors in human testis and in ejaculated sperm before and after in vitro selection and capacitation. Our results provide evidence for the expression of TAS2R genes, with TAS2R14 being the most expressed bitter receptor subtype in both testis tissue and sperm cells, respectively. In addition, it was observed that in vitro capacitation significantly affects both the expression and the subcellular localization of these receptors in isolated spermatozoa. Interestingly, α-gustducin and α-transducin, two Gα subunits expressed in taste buds on the tongue, are also expressed in human spermatozoa; moreover, a subcellular redistribution of both G protein α-subunits to different sub-compartments of sperm was registered upon in vitro capacitation. Finally, we shed light on the possible downstream transduction pathway initiated upon taste receptor activation in the male reproductive system. Performing ultrasensitive droplets digital PCR assays to quantify RNA copy numbers of a distinct gene, we found a significant correlation between the expression of TAS2Rs and TRPM5 (r = 0.87), the cation channel involved in bitter but also sweet and umami taste transduction in taste buds on the tongue. Even if further studies are needed to clarify the precise functional role of taste receptors for successful reproduction, the presented findings significantly extend our knowledge of the biological role of TAS2Rs for human male fertility.
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18

Jain, Krishan, Sangita Bhattacharyya, Afreen Sayed, David Standing, Kathy Benich, Shahid Umar, Shrikant Anant, Scott Weir, Roy Jansen, and Prasad Ravindra Dandawate. "Abstract 1529: Role of bitter taste receptor in colon cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1529. http://dx.doi.org/10.1158/1538-7445.am2022-1529.

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Abstract Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the US with 53,200 deaths projected in 2020. Although the disease affects older people, recent statistics show an increase in the younger population. CRC is a major problem in veterans and every year ~4,000 veterans are diagnosed with CRC within VA facilities. Hence, there is a dire need to identify novel signaling pathways as targets for therapy. Based on a bedside discovery in CRC patients, we observed that CRC patients complained about dysgeusia or taste alterations. There are 25 bitter taste receptors (TAS2R1-50, TAS2R60). Taste receptors utilize G-protein coupled receptors (GPCRs) and signal through calcium release. In preliminary studies, mining the Cancer Genome Atlas (TCGA) database, we have determined that TAS2R38 is upregulated in multiple cancers, including CRC. Moreover, the higher expression of TAS2R38 transcript in CRC compared to other cancers. Furthermore, we confirmed overexpression of TAS2R38 in CRC tissues and cell lines by immunohistochemistry and RT-PCR. Moreover, N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), a TAS2R38 agonist, treatment activated calcium mobilization in HCT116 and DLD1 cells suggesting the functionality of the receptor. OdDHL also enhanced mRNA of interleukin (IL)-6 and IL-8 levels in the CRC cells. To determine whether expression of the receptor is affected in vivo, we conducted the dextran sodium sulfate (DSS)-induced acute colitis and colitis-associated cancer model (azoxymethane (AOM)-DSS) in C57BL/6 mice. TAS2R138, the mouse homolog of human TAS2R38 is overexpressed in crypt epithelial cells in the colitis and tumor tissues. These observations suggest that TAS2R38 is overexpressed in the CRC and may play a critical role in disease progression. Citation Format: Krishan Jain, Sangita Bhattacharyya, Afreen Sayed, David Standing, Kathy Benich, Shahid Umar, Shrikant Anant, Scott Weir, Roy Jansen, Prasad Ravindra Dandawate. Role of bitter taste receptor in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1529.
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19

Lu, Ping, Mai K. ElMallah, Zeyu Liu, Chan Wu, Jun Chen, Lawrence M. Lifshitz, and Ronghua ZhuGe. "Genetic deletion of the Tas2r143 / Tas2r135 / Tas2r126 cluster reveals that TAS2Rs may not mediate bitter tastant‐induced bronchodilation." Journal of Cellular Physiology 236, no. 9 (February 8, 2021): 6407–23. http://dx.doi.org/10.1002/jcp.30315.

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20

Woo, Jung A., Maria Castaño, Ashley Goss, Donghwa Kim, Eric M. Lewandowski, Yu Chen, and Stephen B. Liggett. "Differential long‐term regulation of TAS2R14 by structurally distinct agonists." FASEB Journal 33, no. 11 (August 20, 2019): 12213–25. http://dx.doi.org/10.1096/fj.201802627rr.

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21

Szczepaniak, Oskar, Maria Jokiel, Kinga Stuper-Szablewska, Daria Szymanowska, Marcin Dziedziński, and Joanna Kobus-Cisowska. "Can cornelian cherry mask bitter taste of probiotic chocolate? Human TAS2R receptors and a sensory study with comprehensive characterisation of new functional product." PLOS ONE 16, no. 2 (February 8, 2021): e0243871. http://dx.doi.org/10.1371/journal.pone.0243871.

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Cornelian cherry (Cornus mas L.) fruits are a valuable source of bioactive compounds that are responsible for the perception of bitter taste of chocolate products. The aim of the study was to validate the inhibitory effect of Cornus mas on the TAS2R3 and TAS2R13 bitter taste receptors and to assess the effect of masking the bitter taste of dark chocolate with the help of the sensory panel. Dark chocolate was prepared with an addition of 5% of freeze-dried cornelian cherry fruits and 108 CFU/g of Bacillus coagulans probiotic strains. Effect on the TAS2R receptors was evaluated in specially transfected HEK293T cells, and the inhibition ratio was measured using the calcium release test. Moreover, the total polyphenol content, antioxidant activity and simulated intestinal in vitro digestion were determined for the samples. The tested chocolate products were rich in chlorogenic, caffeic and sinapic acids. The addition of cornelian cherry positively affected the antioxidant activity. The phytochemicals of Cornus mas decreased the TAS2R13 activity by 132% after a 2-minute interaction and, % at the same time, inhibited the TAS2R3 activity by 11.5. Meanwhile, chocolate with the addition of fruit was less bitter according to the sensory panel.
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Wang, Zhi-Xin, Yu-Xin Zhang, Yan-Ling Zeng, Xi Li, Zhao Chen, Jia-Ming Luo, Yang Zhang, Yan-Ling Zhang, and Yan-Jiang Qiao. "Discovery of TAS2R14 Agonists from Platycodon grandiflorum Using Virtual Screening and Affinity Screening Based on a Novel TAS2R14-Functionalized HEMT Sensor Combined with UPLC–MS Analysis." Journal of Agricultural and Food Chemistry 66, no. 44 (September 27, 2018): 11663–71. http://dx.doi.org/10.1021/acs.jafc.8b04455.

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23

Wölfle, Ute, Birgit Haarhaus, and Christoph M. Schempp. "Amarogentin Displays Immunomodulatory Effects in Human Mast Cells and Keratinocytes." Mediators of Inflammation 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/630128.

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Keratinocytes express the bitter taste receptors TAS2R1 and TAS2R38. Amarogentin as an agonist for TAS2R1 and other TAS2Rs promotes keratinocyte differentiation. Similarly, mast cells are known to express bitter taste receptors. The aim of this study was to assess whether bitter compounds display immunomodulatory effects on these immunocompetent cells in the skin, so that they might be a target in chronic inflammatory diseases such as atopic dermatitis and psoriasis. Here, we investigated the impact of amarogentin on substance P-induced release of histamine and TNF-αfrom the human mast cell line LAD-2. Furthermore, the effect of amarogentin on HaCaT keratinocytes costimulated with TNF-αand histamine was investigated. Amarogentin inhibited in LAD-2 cells substance P-induced production of newly synthesized TNF-α, but the degranulation and release of stored histamine were not affected. In HaCaT keratinocytes histamine and TNF-αinduced IL-8 and MMP-1 expression was reduced by amarogentin to a similar extent as with azelastine. In conclusion amarogentin displays immunomodulatory effects in the skin by interacting with mast cells and keratinocytes.
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24

Turner, Alexandria, Martin Veysey, Simon Keely, Christopher J. Scarlett, Mark Lucock, and Emma L. Beckett. "Genetic Variation in the Bitter Receptors Responsible for Epicatechin Detection Are Associated with BMI in an Elderly Cohort." Nutrients 13, no. 2 (February 9, 2021): 571. http://dx.doi.org/10.3390/nu13020571.

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Globally, more than one-third of adults are overweight. Overweight and obesity are complex and multifaceted conditions, associated with an increased risk of chronic illness and early mortality. While there are known risk factors, these alone do not fully explain the varying outcomes between individuals. Recently, taste receptors have been proposed to have a role in the risk for obesity. These receptors are expressed throughout the gastrointestinal tract. In this system, they may be involved in modulating dietary intake and metabolic processes. The taste 2 family of receptors (T2Rs) detects bitter compounds. Receptors T2R4 and T2R5 detect (-)-epicatechin (epicatechin), an antioxidant polyphenol, which may have protective effects against obesity. However, the potential role for taste receptors in this association has not been explored. This study assessed whether polymorphisms in TAS2R4 (rs2233998 and rs2234001) and TAS2R5 (rs2227264) were associated with body mass index (BMI). Genotyping (Taqman qPCR assays) was performed on DNA extracted from blood samples (n = 563) from an elderly cohort. Homozygosity for the minor allele of all polymorphisms was significantly associated with a lower BMI in males. The TAS2R4-rs2233998 CC genotype, the TAS2R4-rs2234001 CC genotype and the TAS2R5-rs2227264 TT genotype were associated with lower BMI (2.1, 2.1 and 2.2 units; p = 0.002, 0.003 and 0.001, respectively). Epicatechin intake was not associated with BMI and genotype was not associated with epicatechin intake. This suggests that the association between TAS2R genotype and elevated BMI risk occurs through altered extra-oral responses and not directly via altered epicatechin intake.
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25

Hayashi, Misa, Akihiko Inaba, Miho Hakukawa, Ken Iwatsuki, Hiroo Imai, and Katsuyoshi Masuda. "Expression of TAS2R14 in the intestinal endocrine cells of non-human primates." Genes & Genomics 43, no. 3 (February 20, 2021): 259–67. http://dx.doi.org/10.1007/s13258-021-01054-7.

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26

Liu, Lianyong, Qingyun Zhu, Hong Du, Chao Shi, Mingjun Gu, and Xiangqi Li. "New values of a type 2 taste receptor TAS2R14 in thyroid cancer." Acta Biochimica et Biophysica Sinica 54, no. 4 (March 15, 2022): 587–89. http://dx.doi.org/10.3724/abbs.2022026.

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27

Levit, Anat, Stefanie Nowak, Maximilian Peters, Ayana Wiener, Wolfgang Meyerhof, Maik Behrens, and Masha Y. Niv. "The bitter pill: clinical drugs that activate the human bitter taste receptor TAS2R14." FASEB Journal 28, no. 3 (November 27, 2013): 1181–97. http://dx.doi.org/10.1096/fj.13-242594.

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28

Nowak, Stefanie, Antonella Di Pizio, Anat Levit, Masha Y. Niv, Wolfgang Meyerhof, and Maik Behrens. "Reengineering the ligand sensitivity of the broadly tuned human bitter taste receptor TAS2R14." Biochimica et Biophysica Acta (BBA) - General Subjects 1862, no. 10 (October 2018): 2162–73. http://dx.doi.org/10.1016/j.bbagen.2018.07.009.

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29

Roelse, Margriet, Ron Wehrens, Maurice Gl Henquet, Renger F. Witkamp, Robert D. Hall, and Maarten A. Jongsma. "The Effect of Calcium Buffering and Calcium Sensor Type on the Sensitivity of an Array-Based Bitter Receptor Screening Assay." Chemical Senses 44, no. 7 (July 5, 2019): 497–505. http://dx.doi.org/10.1093/chemse/bjz044.

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Abstract The genetically encoded calcium sensor protein Cameleon YC3.6 has previously been applied for functional G protein–coupled receptor screening using receptor cell arrays. However, different types of sensors are available, with a wide range in [Ca2+] sensitivity, Hill coefficients, calcium binding domains, and fluorophores, which could potentially improve the performance of the assay. Here, we compared the responses of 3 structurally different calcium sensor proteins (Cameleon YC3.6, Nano140, and Twitch2B) simultaneously, on a single chip, at different cytosolic expression levels and in combination with 2 different bitter receptors, TAS2R8 and TAS2R14. Sensor concentrations were modified by varying the amount of calcium sensor DNA that was printed on the DNA arrays prior to reverse transfection. We found that ~2-fold lower concentrations of calcium sensor protein, by transfecting 4 times less sensor-coding DNA, resulted in more sensitive bitter responses. The best results were obtained with Twitch2B, where, relative to YC3.6 at the default DNA concentration, a 4-fold lower DNA concentration increased sensitivity 60-fold and signal strength 5- to 10-fold. Next, we compared the performance of YC3.6 and Twitch2B against an array with 11 different bitter taste receptors. We observed a 2- to 8-fold increase in sensitivity using Twitch2B compared with YC3.6. The bitter receptor arrays contained 300 spots and could be exposed to a series of 18 injections within 1 h resulting in 5400 measurements. These optimized sensor conditions provide a basis for enhancing receptomics calcium assays for receptors with poor Ca2+ signaling and will benefit future high-throughput receptomics experiments.
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30

Di Pizio, Antonella, Lukas A. W. Waterloo, Regine Brox, Stefan Löber, Dorothee Weikert, Maik Behrens, Peter Gmeiner, and Masha Y. Niv. "Rational design of agonists for bitter taste receptor TAS2R14: from modeling to bench and back." Cellular and Molecular Life Sciences 77, no. 3 (June 24, 2019): 531–42. http://dx.doi.org/10.1007/s00018-019-03194-2.

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31

Duarte, Ana C., Tiago Rosado, Ana R. Costa, José Santos, Eugénia Gallardo, Telma Quintela, Hiroshi Ishikawa, et al. "The bitter taste receptor TAS2R14 regulates resveratrol transport across the human blood-cerebrospinal fluid barrier." Biochemical Pharmacology 177 (July 2020): 113953. http://dx.doi.org/10.1016/j.bcp.2020.113953.

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32

Di Pizio, Antonella, and Alessandro Nicoli. "In Silico Molecular Study of Tryptophan Bitterness." Molecules 25, no. 20 (October 11, 2020): 4623. http://dx.doi.org/10.3390/molecules25204623.

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Tryptophan is an essential amino acid, required for the production of serotonin. It is the most bitter amino acid and its bitterness was found to be mediated by the bitter taste receptor TAS2R4. Di-tryptophan has a different selectivity profile and was found to activate three bitter taste receptors, whereas tri-tryptophan activated five TAS2Rs. In this work, the selectivity/promiscuity profiles of the mono-to-tri-tryptophans were explored using molecular modeling simulations to provide new insights into the molecular recognition of the bitter tryptophan. Tryptophan epitopes were found in all five peptide-sensitive TAS2Rs and the best tryptophan epitope was identified and characterized at the core of the orthosteric binding site of TAS2R4.
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33

Li, Yan, and Yajuan Zhang. "To Determine Pivotal Genes Driven by Methylated DNA in Obstructive Sleep Apnea Hypopnea Syndrome." Computational and Mathematical Methods in Medicine 2021 (March 29, 2021): 1–9. http://dx.doi.org/10.1155/2021/5520325.

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Obstructive sleep apnea syndrome (OSAHS) is a widespread respiratory dysfunction that has attracted more and more attention in recent years. Recently, a large number of studies have shown that abnormal DNA methylation epigenetically silences genes necessary for the pathogenesis of human diseases. However, the exact mechanism of abnormal DNA methylation in OSAHS is still elusive. In this study, we downloaded the OSAHS data from the GEO database. Our data for the first time revealed 520 hypermethylated genes and 889 hypomethylated genes in OSAHS. Bioinformatics analysis revealed that these abnormal methylated genes exhibited an association with the regulation of angiogenesis, apoptosis, Wnt, and ERBB2 signaling pathways. PPI network analysis displayed the interactions among these genes and validated several hub genes, such as GPSM2, CCR8, TAS2R20, TAS2R4, and TAS2R5, which were related to regulating liganded Gi-activating GPCR and the transition of mitotic metaphase/anaphase. In conclusion, our study offers a new hint of understanding the molecular mechanisms in OSAHS progression and will provide OSAHS with newly generated innovative biomarkers.
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34

Kour, Aneet, Saket Kumar Niranjan, Mohan Malayaperumal, Utsav Surati, Martina Pukhrambam, Jayakumar Sivalingam, Amod Kumar, and Mihir Sarkar. "Genomic Diversity Profiling and Breed-Specific Evolutionary Signatures of Selection in Arunachali Yak." Genes 13, no. 2 (January 28, 2022): 254. http://dx.doi.org/10.3390/genes13020254.

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Arunachali yak, the only registered yak breed of India, is crucial for the economic sustainability of pastoralist Monpa community. This study intended to determine the genomic diversity and to identify signatures of selection in the breed. Previously available double digest restriction-site associated DNA (ddRAD) sequencing data of Arunachali yak animals was processed and 99,919 SNPs were considered for further analysis. The genomic diversity profiled based on nucleotide diversity, π (π = 0.041 in 200 bp windows), effective population size, Ne (Ne = 83) and Runs of homozygosity (ROH) (predominance of shorter length ROHs) was found to be optimum. Subsequently, 207 regions were identified to be under selective sweeps through de-correlated composite of multiple signals (DCMS) statistic which combined three individual test statistics viz. π, Tajima’s D and |iHS| in non-overlapping 100 kb windows. Mapping of these regions revealed 611 protein-coding genes including KIT, KITLG, CDH12, FGG, FGA, FGB, PDGFRA, PEAR1, STXBP3, olfactory receptor genes (OR5K3, OR5H6 and OR1E1) and taste receptor genes (TAS2R1, TAS2R3 and TAS2R4). Functional annotation highlighted that biological processes like platelet aggregation and sensory perception were the most overrepresented and the associated regions could be considered as breed-specific signatures of selection in Arunachali yak. These findings point towards evolutionary role of natural selection in environmental adaptation of Arunachali yak population and provide useful insights for pursuing genome-wide association studies in future.
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35

Karaman, Rafik, Stefanie Nowak, Antonella Di Pizio, Hothaifa Kitaneh, Alaa Abu-Jaish, Wolfgang Meyerhof, Masha Y. Niv, and Maik Behrens. "Probing the Binding Pocket of the Broadly Tuned Human Bitter Taste Receptor TAS2R14 by Chemical Modification of Cognate Agonists." Chemical Biology & Drug Design 88, no. 1 (February 17, 2016): 66–75. http://dx.doi.org/10.1111/cbdd.12734.

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36

Zehentner, Sofie, Agnes T. Reiner, Christoph Grimm, and Veronika Somoza. "The Role of Bitter Taste Receptors in Cancer: A Systematic Review." Cancers 13, no. 23 (November 23, 2021): 5891. http://dx.doi.org/10.3390/cancers13235891.

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Background: Since it is known that bitter taste receptors (TAS2Rs) are expressed and functionally active in various extra-oral cells, their genetic variability and functional response initiated by their activation have become of broader interest, including in the context of cancer. Methods: A systematic research was performed in PubMed and Google Scholar to identify relevant publications concerning the role of TAS2Rs in cancer. Results: While the findings on variations of TAS2R genotypes and phenotypes and their association to the risk of developing cancer are still inconclusive, gene expression analyses revealed that TAS2Rs are expressed and some of them are predominately downregulated in cancerous compared to non-cancerous cell lines and tissue samples. Additionally, receptor-specific, agonist-mediated activation induced various anti-cancer effects, such as decreased cell proliferation, migration, and invasion, as well as increased apoptosis. Furthermore, the overexpression of TAS2Rs resulted in a decreased tumour incidence in an in vivo study and TAS2R activation could even enhance the therapeutic effect of chemotherapeutics in vitro. Finally, higher expression levels of TAS2Rs in primary cancerous cells and tissues were associated with an improved prognosis in humans. Conclusion: Since current evidence demonstrates a functional role of TAS2Rs in carcinogenesis, further studies should exploit their potential as (co-)targets of chemotherapeutics.
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Yu, Zhipeng, Yingxue Wang, Wenzhu Zhao, Jianrong Li, David Shuian, and Jingbo Liu. "Identification of Oncorhynchus mykiss nebulin-derived peptides as bitter taste receptor TAS2R14 blockers by in silico screening and molecular docking." Food Chemistry 368 (January 2022): 130839. http://dx.doi.org/10.1016/j.foodchem.2021.130839.

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38

Kurshed, Ali Abbas Mohammad, Ferenc Vincze, Péter Pikó, Zsigmond Kósa, János Sándor, Róza Ádány, and Judit Diószegi. "Taste Preference-Related Genetic Polymorphisms Modify Alcohol Consumption Behavior of the Hungarian General and Roma Populations." Genes 14, no. 3 (March 7, 2023): 666. http://dx.doi.org/10.3390/genes14030666.

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Harmful alcohol consumption has been considered a major public health issue globally, with the amounts of alcohol drunk being highest in the WHO European Region including Hungary. Alcohol consumption behaviors are complex human traits influenced by environmental factors and numerous genes. Beyond alcohol metabolization and neurotransmitter gene polymorphisms, taste preference-related genetic variants may also mediate alcohol consumption behaviors. Applying the Alcohol Use Disorders Identification Test (AUDIT) we aimed to elucidate the underlying genetic determinants of alcohol consumption patterns considering taste preference gene polymorphisms (TAS1R3 rs307355, TAS2R38 rs713598, TAS2R19 rs10772420 and CA6 rs2274333) in the Hungarian general (HG) and Roma (HR) populations. Alcohol consumption assessment was available for 410 HG and 387 HR individuals with 405 HG and 364 HR DNA samples being obtained for genotyping. No significant associations were found between TAS1R3 rs307355, TAS2R19 rs10772420, and CA6 rs2274333 polymorphisms and alcohol consumption phenotypes. Significant associations were identified between TAS2R38 rs713598 and the number of standard drinks consumed in the HG sample (genotype GG negatively correlated with the number of standard drinks; coef: −0.136, p = 0.028) and the prevalence of having six or more drinks among Roma (a negative correlation was identified in the recessive model; genotype GG, coef: −0.170, p = 0.049), although, none of these findings passed the Bonferroni-corrected probability criterion (p > 0.05). Nevertheless, our findings may suggest that alcohol consumption is partially driven by genetically determined taste preferences in our study populations. Further studies are required to strengthen the findings and to understand the drivers of alcohol consumption behavior in more depth.
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39

Xu, Weixiu, Lijie Wu, Shenhui Liu, Xiao Liu, Xiaoling Cao, Cui Zhou, Jinyi Zhang, et al. "Structural basis for strychnine activation of human bitter taste receptor TAS2R46." Science 377, no. 6612 (September 16, 2022): 1298–304. http://dx.doi.org/10.1126/science.abo1633.

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Taste sensing is a sophisticated chemosensory process, and bitter taste perception is mediated by type 2 taste receptors (TAS2Rs), or class T G protein–coupled receptors. Understanding the detailed molecular mechanisms behind taste sensation is hindered by a lack of experimental receptor structures. Here, we report the cryo–electron microscopy structures of human TAS2R46 complexed with chimeric mini–G protein gustducin, in both strychnine-bound and apo forms. Several features of TAS2R46 are disclosed, including distinct receptor structures that compare with known GPCRs, a new “toggle switch,” activation-related motifs, and precoupling with mini–G protein gustducin. Furthermore, the dynamic extracellular and more-static intracellular parts of TAS2R46 suggest possible diverse ligand-recognition and activation processes. This study provides a basis for further exploration of other bitter taste receptors and their therapeutic applications.
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40

Huang, Ting-Ting, Pan-Pan Gu, Ting Zheng, Ling-Shan Gou, and Yao-Wu Liu. "Piperine, as a TAS2R14 agonist, stimulates the secretion of glucagon-like peptide-1 in the human enteroendocrine cell line Caco-2." Food & Function 13, no. 1 (2022): 242–54. http://dx.doi.org/10.1039/d1fo02932k.

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41

Purba, Laurentia Henrieta Permita Sari, Kanthi Arum Widayati, Kei Tsutsui, Nami Suzuki-Hashido, Takashi Hayakawa, Sarah Nila, Bambang Suryobroto, and Hiroo Imai. "Functional characterization of the TAS2R38 bitter taste receptor for phenylthiocarbamide in colobine monkeys." Biology Letters 13, no. 1 (January 2017): 20160834. http://dx.doi.org/10.1098/rsbl.2016.0834.

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Анотація:
Bitterness perception in mammals is mostly directed at natural toxins that induce innate avoidance behaviours. Bitter taste is mediated by the G protein-coupled receptor TAS2R, which is located in taste cell membranes. One of the best-studied bitter taste receptors is TAS2R38, which recognizes phenylthiocarbamide (PTC). Here we investigate the sensitivities of TAS2R38 receptors to PTC in four species of leaf-eating monkeys (subfamily Colobinae). Compared with macaque monkeys (subfamily Cercopithecinae), colobines have lower sensitivities to PTC in behavioural and in vitro functional analyses. We identified four non-synonymous mutations in colobine TAS2R38 that are responsible for the decreased sensitivity of the TAS2R38 receptor to PTC observed in colobines compared with macaques. These results suggest that tolerance to bitterness in colobines evolved from an ancestor that was sensitive to bitterness as an adaptation to eating leaves.
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42

Talmon, Maria, Federica Pollastro, and Luigia Grazia Fresu. "The Complex Journey of the Calcium Regulation Downstream of TAS2R Activation." Cells 11, no. 22 (November 16, 2022): 3638. http://dx.doi.org/10.3390/cells11223638.

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Bitter taste receptors (TAS2Rs) have recently arisen as a potential drug target for asthma due to their localization in airway cells. These receptors are expressed in all cell types of the respiratory system comprising epithelial, smooth muscle and immune cells; however, the expression pattern of the subtypes is different in each cell type and, accordingly, so is their role, for example, anti-inflammatory or bronchodilator. The most challenging aspect in studying TAS2Rs has been the identification of the downstream signaling cascades. Indeed, TAS2R activation leads to canonical IP3-dependent calcium release from the ER, but, alongside, there are other mechanisms that differ according to the histological localization. In this review, we summarize the current knowledge on the cytosolic calcium modulation downstream of TAS2R activation in the epithelial, smooth muscle and immune cells of the airway system.
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43

Liszt, Kathrin Ingrid, Jakob Peter Ley, Barbara Lieder, Maik Behrens, Verena Stöger, Angelika Reiner, Christina Maria Hochkogler, et al. "Caffeine induces gastric acid secretion via bitter taste signaling in gastric parietal cells." Proceedings of the National Academy of Sciences 114, no. 30 (July 10, 2017): E6260—E6269. http://dx.doi.org/10.1073/pnas.1703728114.

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Анотація:
Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs). TAS2Rs are expressed in the mouth and in several extraoral sites, e.g., in the gastrointestinal tract, in which their functional role still needs to be clarified. We hypothesized that caffeine evokes effects on GAS by activation of oral and gastric TAS2Rs and demonstrate that caffeine, when administered encapsulated, stimulates GAS, whereas oral administration of a caffeine solution delays GAS in healthy human subjects. Correlation analysis of data obtained from ingestion of the caffeine solution revealed an association between the magnitude of the GAS response and the perceived bitterness, suggesting a functional role of oral TAS2Rs in GAS. Expression of TAS2Rs, including cognate TAS2Rs for caffeine, was shown in human gastric epithelial cells of the corpus/fundus and in HGT-1 cells, a model for the study of GAS. In HGT-1 cells, various bitter compounds as well as caffeine stimulated proton secretion, whereby the caffeine-evoked effect was (i) shown to depend on one of its cognate receptor,TAS2R43,and adenylyl cyclase; and (ii) reduced by homoeriodictyol (HED), a known inhibitor of caffeine’s bitter taste. This inhibitory effect of HED on caffeine-induced GAS was verified in healthy human subjects. These findings (i) demonstrate that bitter taste receptors in the stomach and the oral cavity are involved in the regulation of GAS and (ii) suggest that bitter tastants and bitter-masking compounds could be potentially useful therapeutics to regulate gastric pH.
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44

Deng, Mengyan, Noriko Hida, Taigi Yamazaki, Ryo Morishima, Yuka Kato, Yoshiaki Fujita, Akihiro Nakamura, and Tsutomu Harada. "Comparison of Bitterness Intensity between Prednisolone and Quinine in a Human Sensory Test Indicated Individual Differences in Bitter-Taste Perception." Pharmaceutics 14, no. 11 (November 14, 2022): 2454. http://dx.doi.org/10.3390/pharmaceutics14112454.

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Prednisolone is a frequently prescribed steroid with a bitter, unpalatable taste that can result in treatment refusal. Oral suspensions or powder dosage forms are often prescribed, particularly to pediatric patients, as they improve swallowability and ease of dose adjustment. Consequently, the bitterness of prednisolone is more apparent in these dosage forms. Few studies have investigated prednisolone’s bitterness. Thus, in this study, 50 adults evaluated the bitterness of prednisolone using the generalized Labeled Magnitude Scale (gLMS), in comparison with quinine, a standard bitter substance. Overall, prednisolone-saturated solution demonstrated the same extent (mean gLMS score: 46.8) of bitterness as 1 mM quinine solution (mean gLMS score: 40.1). Additionally, large individual differences were observed in the perception of the bitterness of prednisolone and quinine. Perceived flavors of some drugs are reportedly associated with bitter-taste receptor (TAS2Rs) polymorphisms. Therefore, we investigated the relationship between subjects’ genetic polymorphisms of TAS2R19, 38, and 46, and their sensitivity to bitterness. Although a relationship between TAS2R19 polymorphisms and the perception of quinine bitterness was observed, no significant relationship was found between the perceived bitterness of prednisolone and the investigated genes. Ultimately, the results show that despite individual differences among subjects, the cause of prednisolone’s strong bitterness is yet to be elucidated.
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45

Pan, Shi, Pawan Sharma, Sushrut D. Shah, and Deepak A. Deshpande. "Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 313, no. 1 (July 1, 2017): L154—L165. http://dx.doi.org/10.1152/ajplung.00106.2017.

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Airway remodeling, including increased airway smooth muscle (ASM) mass, is a hallmark feature of asthma and COPD. We previously identified the expression of bitter taste receptors (TAS2Rs) on human ASM cells and demonstrated that known TAS2R agonists could promote ASM relaxation and bronchodilation and inhibit mitogen-induced ASM growth. In this study, we explored cellular mechanisms mediating the antimitogenic effect of TAS2R agonists on human ASM cells. Pretreatment of ASM cells with TAS2R agonists chloroquine and quinine resulted in inhibition of cell survival, which was largely reversed by bafilomycin A1, an autophagy inhibitor. Transmission electron microscope studies demonstrated the presence of double-membrane autophagosomes and deformed mitochondria. In ASM cells, TAS2R agonists decreased mitochondrial membrane potential and increased mitochondrial ROS and mitochondrial fragmentation. Inhibiting dynamin-like protein 1 (DLP1) reversed TAS2R agonist-induced mitochondrial membrane potential change and attenuated mitochondrial fragmentation and cell death. Furthermore, the expression of mitochondrial protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) and mitochondrial localization of DLP1 were significantly upregulated by TAS2R agonists. More importantly, inhibiting Bnip3 mitochondrial localization by dominant-negative Bnip3 significantly attenuated cell death induced by TAS2R agonist. Collectively the TAS2R agonists chloroquine and quinine modulate mitochondrial structure and function, resulting in ASM cell death. Furthermore, Bnip3 plays a central role in TAS2R agonist-induced ASM functional changes via a mitochondrial pathway. These findings further establish the cellular mechanisms of antimitogenic effects of TAS2R agonists and identify a novel class of receptors and pathways that can be targeted to mitigate airway remodeling as well as bronchoconstriction in obstructive airway diseases.
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46

Tsutsui, Kei, Masahiro Otoh, Kodama Sakurai, Nami Suzuki-Hashido, Takashi Hayakawa, Filippo Aureli, Colleen M. FedSchaffner, Linda M. Fedigan, Shoji Kawamura, and Hiroo Imai. "2P225 Functional diversity of bitter taste receptors TAS2R1 and TAS2R4 in New World monkeys(14. Chemoreception,Poster)." Seibutsu Butsuri 53, supplement1-2 (2013): S196. http://dx.doi.org/10.2142/biophys.53.s196_2.

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47

Jeruzal-Świątecka, Joanna, Wojciech Fendler, and Wioletta Pietruszewska. "Clinical Role of Extraoral Bitter Taste Receptors." International Journal of Molecular Sciences 21, no. 14 (July 21, 2020): 5156. http://dx.doi.org/10.3390/ijms21145156.

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Анотація:
Humans can recognise five basic tastes: sweet, sour, salty, bitter and umami. Sour and salty substances are linked to ion channels, while sweet, bitter and umami flavours are transmitted through receptors linked to the G protein (G protein-coupled receptors; GPCRs). There are two main types of GPCRs that transmit information about sweet, umami and bitter tastes—the Tas1r and TAS2R families. There are about 25 functional TAS2R genes coding bitter taste receptor proteins. They are found not only in the mouth and throat, but also in the intestines, brain, bladder and lower and upper respiratory tract. The determination of their purpose in these locations has become an inspiration for much research. Their presence has also been confirmed in breast cancer cells, ovarian cancer cells and neuroblastoma, revealing a promising new oncological marker. Polymorphisms of TAS2R38 have been proven to have an influence on the course of chronic rhinosinusitis and upper airway defensive mechanisms. TAS2R receptors mediate the bronchodilatory effect in human airway smooth muscle, which may lead to the creation of another medicine group used in asthma or chronic obstructive pulmonary disease. The discovery that functionally compromised TAS2R receptors negatively impact glucose homeostasis has produced a new area of diabetes research. In this article, we would like to focus on what facts have been already established in the matter of extraoral TAS2R receptors in humans.
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48

Wölfle, Ute, Floriana A. Elsholz, Astrid Kersten, Birgit Haarhaus, Walter E. Müller, and Christoph M. Schempp. "Expression and Functional Activity of the Bitter Taste Receptors TAS2R1 and TAS2R38 in Human Keratinocytes." Skin Pharmacology and Physiology 28, no. 3 (2015): 137–46. http://dx.doi.org/10.1159/000367631.

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49

An, Steven S., Wayne C. H. Wang, Cynthia J. Koziol-White, Kwangmi Ahn, Danielle Y. Lee, Richard C. Kurten, Reynold A. Panettieri та Stephen B. Liggett. "TAS2R activation promotes airway smooth muscle relaxation despite β2-adrenergic receptor tachyphylaxis". American Journal of Physiology-Lung Cellular and Molecular Physiology 303, № 4 (15 серпня 2012): L304—L311. http://dx.doi.org/10.1152/ajplung.00126.2012.

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Анотація:
Recently, bitter taste receptors (TAS2Rs) were found in the lung and act to relax airway smooth muscle (ASM) via intracellular Ca2+ concentration signaling generated from restricted phospholipase C activation. As potential therapy, TAS2R agonists could be add-on treatment when patients fail to achieve adequate bronchodilation with chronic β-agonists. The β2-adrenergic receptor (β2AR) of ASM undergoes extensive functional desensitization. It remains unknown whether this desensitization affects TAS2R function, by cross talk at the receptors or distal common components in the relaxation machinery. We studied intracellular signaling and cell mechanics using isolated human ASM, mouse tracheal responses, and human bronchial responses to characterize TAS2R relaxation in the context of β2AR desensitization. In isolated human ASM, magnetic twisting cytometry revealed >90% loss of isoproterenol-promoted decrease in cell stiffness after 18-h exposure to albuterol. Under these same conditions of β2AR desensitization, the TAS2R agonist chloroquine relaxation response was unaffected. TAS2R-mediated stimulation of intracellular Ca2+ concentration in human ASM was unaltered by albuterol pretreatment, in contrast to cAMP signaling, which was desensitized by >90%. In mouse trachea, β2AR desensitization by β-agonist amounted to 92 ± 6.0% ( P < 0.001), while, under these same conditions, TAS2R desensitization was not significant (11 ± 3.5%). In human lung slices, chronic β-agonist exposure culminated in 64 ± 5.7% ( P < 0.001) desensitization of β2AR-mediated dilation of carbachol-constricted airways that was reversed by chloroquine. We conclude that there is no evidence for physiologically relevant cross-desensitization of TAS2R-mediated ASM relaxation from chronic β-agonist treatment. These findings portend a favorable therapeutic profile for TAS2R agonists for the treatment of bronchospasm in asthma or chronic obstructive lung disease.
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50

Purnell, Phillip R., Benjamin L. Addicks, Habib G. Zalzal, Scott Shapiro, Sijin Wen, Hassan H. Ramadan, Vincent Setola, and David P. Siderovski. "Single Nucleotide Polymorphisms in Chemosensory Pathway Genes GNB3, TAS2R19, and TAS2R38 Are Associated with Chronic Rhinosinusitis." International Archives of Allergy and Immunology 180, no. 1 (2019): 72–78. http://dx.doi.org/10.1159/000499875.

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