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Bitter taste receptors (TAS2Rs) are not only expressed in the oral cavity but also in skin. Extraoral TAS2Rs are thought to be involved in non‐taste perception and tissue‐specific functions. Keratinocytes that express TAS2Rs in the skin provide a first‐line defense against external threats. However, the functional roles of these receptors in host defense remain unclear. Here, we demonstrated the sensory role of intracellularly located TAS2Rs against toxic substances in keratinocytes. Although many G protein‐coupled receptors elicit signals from the surface, TAS2Rs were found to localize intracellularly, possibly to the ER, in human keratinocytes and HaCaT cells. TAS2R38, one of the TAS2R members, activated the Gα12/13/RhoA/ROCK/p38 MAP kinase/NF‐κB pathway upon stimulation by phenylthiocarbamide (PTC), an agonist for this receptor, leading to the production of ABC transporters, such as ABCB1, in these cells. Notably, treatment with bitter compounds, such as PTC and saccharin, induced the upregulation of ABCB1 in HaCaT cells. Mechanistically, intracellular TAS2R38 and its downstream signaling Gα12/13/RhoA/ROCK/p38 MAP kinase/NF‐κB pathway were identified to be responsible for the above effect. Pretreatment with PTC prevented the accumulation of rhodamine 123 because of its excretion via ABCB1. Furthermore, pretreatment with PTC or saccharin counteracted the effect of the toxic compound, diphenhydramine, and pretreated HaCaT cells were found to proliferate faster than untreated cells. This anti‐toxic effect was suppressed by treatment with verapamil, an ABCB1 inhibitor, indicating that enhanced ABCB1 helps clear toxic substances. Altogether, harmless activators of TAS2Rs may be promising drugs that enhance the excretion of toxic substances from the human skin. [ABSTRACT FROM AUTHOR]

In 2004, we started the initial attempt to evaluate the efficacy of SLIT for Japanese cedar pollinosis (JCP) using Japanese cedar (JC) pollen extract solution through a multicenter, placebo-controlled, double-blind comparative study. Based on its success in demonstrating the substantial efficacy of SLIT, we next conducted a larger-scale study by administering JC pollen to all JCP patients recruited. It was because of aiming to ascertain the effectiveness and safety of SLIT and its underlying mechanisms by comparing high- and non-responder patients. Despite limitations posed by liquid medication, significant effectiveness and safety demonstrated by the 2-year treatment served as the foundation for launching the first SLIT medicine for JCP, in 2014. Furthermore, in addition to the clearer Th1/Th2-imbalanced property in the high-responders, the possible involvement of bitter taste receptors in CD4+ T cells, apoptosis pathways in CD4+ T cells and basophils, and inducing a mast cell degranulation inhibitory molecule in the effect of SLIT was demonstrated. To solve the limitations posed by liquid medication, clinical trials evaluating JC pollen sublingual tablets started in 2014. Due to the minimal side effects, ease of administration, and convenient storage, the sublingual tablet medicine was launched in 2018. Giving the ongoing rise in demand for SLIT and considering that more than 1% of JCP patients are currently undergoing SLIT, the practical use of this treatment for multiple allergens is becoming increasingly important. [ABSTRACT FROM AUTHOR]

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/m2). 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. [ABSTRACT FROM AUTHOR]

Bitter taste receptors, also known as type 2 taste receptors (T2Rs), are found not only in the mouth's taste bud cells but also in various tissues and cells, including macrophages. Macrophages, known for their remarkable plasticity, play a crucial role in regulating innate immunity, managing inflammation, and orchestrating immune responses to antigens, pathogens, and environmental factors. Recently, the study of the expression and function of bitter taste receptors within macrophages has garnered significant interest. This review summarizes the expression levels and distribution characteristics of bitter taste receptors in macrophages and examines their effects on macrophage polarization, phagocytosis, and chemotaxis, as well as their potential molecular mechanisms. The purpose of this review is to provide insight and perspectives for research on the regulatory role of T2Rs in macrophage functions. [ABSTRACT FROM AUTHOR]

In 2004, we started the initial attempt to evaluate the efficacy of SLIT for Japanese cedar pollinosis (JCP) using Japanese cedar (JC) pollen extract solution through a multicenter, placebo-controlled, double-blind comparative study. Based on its success in demonstrating the substantial efficacy of SLIT, we next conducted a larger-scale study by administering JC pollen to all JCP patients recruited. It was because of aiming to ascertain the effectiveness and safety of SLIT and its underlying mechanisms by comparing high- and non-responder patients. Despite limitations posed by liquid medication, significant effectiveness and safety demonstrated by the 2-year treatment served as the foundation for launching the first SLIT medicine for JCP, in 2014. Furthermore, in addition to the clearer Th1/Th2-imbalanced property in the high-responders, the possible involvement of bitter taste receptors in CD4+ T cells, apoptosis pathways in CD4+ T cells and basophils, and inducing a mast cell degranulation inhibitory molecule in the effect of SLIT was demonstrated. To solve the limitations posed by liquid medication, clinical trials evaluating JC pollen sublingual tablets started in 2014. Due to the minimal side effects, ease of administration, and convenient storage, the sublingual tablet medicine was launched in 2018. Giving the ongoing rise in demand for SLIT and considering that more than 1% of JCP patients are currently undergoing SLIT, the practical use of this treatment for multiple allergens is becoming increasingly important.

Abstract Bitter taste receptors (TAS2Rs) are not only expressed in the oral cavity but also in skin. Extraoral TAS2Rs are thought to be involved in non‐taste perception and tissue‐specific functions. Keratinocytes that express TAS2Rs in the skin provide a first‐line defense against external threats. However, the functional roles of these receptors in host defense remain unclear. Here, we demonstrated the sensory role of intracellularly located TAS2Rs against toxic substances in keratinocytes. Although many G protein‐coupled receptors elicit signals from the surface, TAS2Rs were found to localize intracellularly, possibly to the ER, in human keratinocytes and HaCaT cells. TAS2R38, one of the TAS2R members, activated the Gα12/13/RhoA/ROCK/p38 MAP kinase/NF‐κB pathway upon stimulation by phenylthiocarbamide (PTC), an agonist for this receptor, leading to the production of ABC transporters, such as ABCB1, in these cells. Notably, treatment with bitter compounds, such as PTC and saccharin, induced the upregulation of ABCB1 in HaCaT cells. Mechanistically, intracellular TAS2R38 and its downstream signaling Gα12/13/RhoA/ROCK/p38 MAP kinase/NF‐κB pathway were identified to be responsible for the above effect. Pretreatment with PTC prevented the accumulation of rhodamine 123 because of its excretion via ABCB1. Furthermore, pretreatment with PTC or saccharin counteracted the effect of the toxic compound, diphenhydramine, and pretreated HaCaT cells were found to proliferate faster than untreated cells. This anti‐toxic effect was suppressed by treatment with verapamil, an ABCB1 inhibitor, indicating that enhanced ABCB1 helps clear toxic substances. Altogether, harmless activators of TAS2Rs may be promising drugs that enhance the excretion of toxic substances from the human skin.

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. [ABSTRACT FROM AUTHOR]

Background: Dietary restrictions or reductions such as fasting for weight loss are often difficult to adhere to due to increased appetite and food cravings. Recently, gastrointestinal delivery of bitter hops has been shown to be effective at reducing appetite in men. Our aim was to determine the effect of a bitter hop extract on appetite and cravings in women, using a 24 h, water-only fast. Methods: This was a randomized, double-blind, cross-over treatment study. Thirty adult women were recruited and required to fast for 24 h from 1800 h to 1800 h on three occasions and given an ad libitum meal to break each fast. Treatments of either a placebo or one of two doses (high dose; HD: 250 mg or low dose; LD: 125 mg) of a bitter hop-based appetite suppressant (Amarasate®) were given twice per day at 16 and 20 h into the fast. Results: The HD and LD treatment groups exhibited a significant (p

Type 2 taste receptors (TAS2Rs), traditionally known for their role in bitter taste perception, are present in diverse reproductive tissues of both sexes. This review explores our current understanding of TAS2R functions with a particular focus on reproductive health. In males, TAS2Rs are believed to play potential roles in processes such as sperm chemotaxis and male fertility. Genetic insights from mouse models and human polymorphism studies provide some evidence for their contribution to male infertility. In female reproduction, it is speculated that TAS2Rs influence the ovarian milieu, shaping the functions of granulosa and cumulus cells and their interactions with oocytes. In the uterus, TAS2Rs contribute to uterine relaxation and hold potential as therapeutic targets for preventing preterm birth. In the placenta, they are proposed to function as vigilant sentinels, responding to infection and potentially modulating mechanisms of fetal protection. In the cervix and vagina, their analogous functions to those in other extraoral tissues suggest a potential role in infection defense. In addition, TAS2Rs exhibit altered expression patterns that profoundly affect cancer cell proliferation and apoptosis in reproductive cancers. Notably, TAS2R agonists show promise in inducing apoptosis and overcoming chemoresistance in these malignancies. Despite these advances, challenges remain, including a lack of genetic and functional studies. The application of techniques such as single‐cell RNA sequencing and clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR‐associated endonuclease 9 gene editing could provide deeper insights into TAS2Rs in reproduction, paving the way for novel therapeutic strategies for reproductive disorders. [ABSTRACT FROM AUTHOR]

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/m2). 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.

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Bone marrow microenvironmental stimuli profoundly impact hematopoietic stem cell fate and biology. As G protein-coupled receptors, the bitter taste receptors (TAS2Rs) are key in transmitting extracellular stimuli into an intracellular response, within the oral cavity but also in extraoral tissues. Their expression in the bone marrow (BM)-derived cells suggests their involvement in sensing the BM microenvironmental fluctuation. In the present study, we demonstrated that umbilical cord blood (UCB)-derived CD34+ cells express fully functional TAS2Rs along with the signal transduction cascade components and their activation by the prototypical agonist, denatonium benzoate, significantly modulated genes involved in stemness maintenance and regulation of cell trafficking. The activation of these specific pathways was confirmed in functional in vitro experiments. Denatonium exposure exerted an antiproliferative effect on UCB-derived CD34+ cells, mainly affecting the most undifferentiated progenitor frequency. It also reduced their clonogenicity and repopulating potential in vitro. In addition, the TAS2R signaling activation impaired the UCB-derived CD34+ cell trafficking, mainly reducing the migration toward the chemoattractant agent CXCL12 and modulating the expression of the adhesion molecules CD62L, CD49d, and CD29. In conclusion, our results in UCB-derived CD34+ cells expand the observation of TAS2R expression in the setting of BM-resident cells and shed light on the role of TAS2Rs in the extrinsic regulation of hematopoietic stem cell functions. [ABSTRACT FROM AUTHOR]

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.

Ziwen Mao,1,2 Weyland Cheng,1,2 Zhenwei Li,2 Manye Yao,2 Keming Sun2 1Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of China; 2Department of Orthopaedic Surgery, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Weyland Cheng, Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, 33 Longhu Waihuan East Road, Zhengzhou, Henan, People’s Republic of China, Tel +86 18502758200, Email wey_c@hotmail.comAbstract: Bitter taste receptors (T2Rs) consist of 25 functional receptors that can be found in various types of cells throughout the human body with responses ranging from detecting bitter taste to suppressing pathogen-induced inflammation upon activation. Numerous studies have observed clinical associations with genetic or phenotypic variants in bitter taste receptors, most notably that of the receptor isoform T2R38. With genetic variants playing a role in the response of the body to bacterial quorum-sensing molecules, bacterial metabolites, medicinal agonists and nutrients, we examine how T2R polymorphisms, expression levels and bitter taste perception can lead to varying clinical associations. From these genetic and phenotypic differences, healthcare management can potentially be individualized through appropriately administering drugs with bitter masking to increase compliance; optimizing nutritional strategies and diets; avoiding the use of T2R agonists if this pathway is already activated from bacterial infections; adjusting drug regimens based on differing prognoses; or adjusting drug regimens based on T2R expression levels in the target cell type and bodily region.Keywords: bitter taste receptors, TAS2R38, chronic rhinosinusitis, obesity, oral health, cancer

Citrus is an important source of flavonoids in our daily diet. Citrus flavonoids have antioxidant, anticancer, anti‐inflammatory, and cardiovascular disease prevention functions. Studies have shown that some pharmaceutical values of flavonoids may be related to their binding to bitter taste receptors, thus activating downstream signal transduction pathways; however, the underlying mechanism has not been systematically elucidated. In this paper, the biosynthesis pathway and the absorption and metabolism of citrus flavonoids were briefly reviewed, and the relationship between flavonoid structure and bitter taste intensity was investigated. In addition, the pharmacological effects of bitter flavonoids and the activation of bitter taste receptors in combating various diseases were discussed. This review provides an important basis for the targeted design of citrus flavonoid structures to make them more biologically active and more attractive as powerful drugs for the effective treatment of chronic diseases such as obesity, asthma, and neurological diseases. [ABSTRACT FROM AUTHOR]

Abstract The chemical senses of olfaction and taste are well developed in fish and play a vital role in its various activities such as navigation, mate recognition, and food detection. The small teleost fish Astyanax mexicanus consists of interfertile river‐dwelling and cave‐dwelling populations, referred to as “surface fish” and “cavefish” respectively. An important anatomical feature of cavefish is the lack of eyes leading them to be referred to as blind fish and suggesting an enhanced functional role for other senses such as taste. In this study, we characterize the expression of bitter taste receptors (T2Rs or Tas2Rs) in A. mexicanus and investigate their functionality in a heterologous expression system. The genome database of A. mexicanus (ensemble and NCBI) showed 7 Tas2Rs, among these Tas2R1, Tas2R3, Tas2R4, and Tas2R114 are well characterized in humans and mice but not in A. mexicanus. Therefore, the 4 Tas2Rs were selected for further analysis and their expression in A. mexicanus was confirmed by in situ hybridization and RT‐PCR in early developmental stages. These Tas2Rs are expressed in various oral and extraoral organs (liver, fins, jaws, and gills) in A. mexicanus, and Tas2R1 has maximum expression and is localized throughout the fish body. Using the heterologous expression of A. mexicanus T2Rs in HEK293T cells coupled with cell‐based calcium mobilization assays, we show that A. mexicanus T2Rs are activated by commonly used fish food and known bitter agonists, including quinine. This study provides novel insights into the extraoral expression of T2Rs in A. mexicanus and suggests their importance in extraoral food detection.

Simple Summary: Weaning is a stressful period for pigs that causes gastrointestinal disruption and low growth rates. For a long time, zinc oxide at pharmacological doses, along with different antibiotics, has been used prophylactically during this phase to reduce the incidence of these gastrointestinal problems. Nowadays, the increasing concern about the environment, along with the global and constant growth of bacterial resistance to antibiotics, has led to the prohibition of the prophylactic use of zinc oxide in diets for piglets in the EU, along with the implementation of new regulations on the use of antibiotics. Consequently, the pig sector faces the important challenge that supposes developing alternatives to the classical system based on the use of these antimicrobial compounds. This study is the first step to achieving this goal by minimizing the use of various antibiotics and zinc oxide in weanling pigs by supplementing citrus flavonoids and only one antibiotic (amoxicillin). Accordingly, the influence of zinc oxide plus antibiotics and citrus flavonoids plus amoxicillin in weaned pigs has been investigated and its impact on growth performance, gut microbiology profile, gut signaling, intestinal architecture, and serum biomarkers indicative of stress and inflammatory responses have been evaluated. Citrus flavonoids plus amoxicillin improved growth performance and gut health, evidencing a positive microbial modulation, stress status reduction, and a positive effect on the gastrointestinal barrier, and other digestive functions. Additionally, the expression of some bitter taste receptors in the intestine has been increased when supplementing both dietary strategies, the one based on zinc oxide or the one based on citrus flavonoids supplementation. Consequently, the present study shows that in weanling piglets, the supplement of citrus flavonoids with amoxicillin might be a promising alternative to the dietary use of pharmacological doses of zinc oxide with more than two antibiotics, therefore minimizing the use of antimicrobial compounds without detrimental effects on performance. Since citrus flavonoids have antioxidant and anti-inflammatory properties, it was hypothesized that these compounds would become a suitable alternative to the use of therapeutic doses of zinc oxide at weaning. A total of 252 weaned pigs ([LargeWhite × Landrace] × Pietrain) were distributed according to BW (5.7 kg ± 0.76) into 18 pens (6 pens per diet, 14 pigs/pen). Three experimental diets for the prestarter (0–14 d postweaning) and starter (15–35 d postweaning) period were prepared: (i) a nonmedicated (CON) diet, (ii) a CON diet supplemented with zinc oxide at 2500 mg/kg, amoxicillin at 0.3 mg/kg and apramycin at 0.1 mg/kg (ZnO), and (iii) CON diet with the addition of a commercial citrus flavonoid extract at 0.3 mg/kg and amoxicillin at 0.3 mg/kg (FLAV). Pig BW, ADG, ADFI, and FCR were assessed on d7, d14, and d35. Samples of intestinal tissue, cecal content, and serum were collected on day seven (18 piglets). FLAV treatment achieved greater BW and ADG during the starter and for the entire experimental period compared with the CON diet (p < 0.05), whereas ZnO pigs evidenced intermediate results. Jejunum tissue analysis showed that pigs fed the FLAV diet overexpressed genes related to barrier function, digestive enzymes, and nutrient transport compared to those pigs fed the CON diet (p < 0.05). An increase in the abundance of bacterial genera such as Succinivibrio, Turicibacter, and Mitsuokella (p < 0.05) was observed in the FLAV compared with the CON and ZnO piglets. ZnO and FLAV increased the expression of TAS2R39, while ZnO pigs also expressed greater TAS2R16 than CON (p < 0.05) in the intestine. FLAV treatment improved the gut function, possibly explaining a higher performance at the end of the nursery period. Consequently, citrus flavonoids supplementation, together with amoxicillin, is a promising alternative to the use of zinc oxide plus amoxicillin and apramycin in weanling pigs, minimizing the use of antibiotics. [ABSTRACT FROM AUTHOR]

Objectives: Chronic rhinosinusitis (CRS) is a major hallmark of primary ciliary dyskinesia (PCD). We investigated the possible correlation between some severity markers of CRS and several clinical features of the disease. We further studied the bitter taste receptor TAS2R38 polymorphisms to identify the genotypes associated with more severe disease. Methods: We included 39 adult PCD patients with (CRSwNP) and without nasal polyposis (CRSsNP); a sample for nasal cytology was obtained and clinical cytological grading (CCG) was determined. The SNOT‐22 and Lund‐Mackay scores were recorded. A sample of DNA was extracted from peripheral blood to investigate TAS2R38 polymorphisms. Results: CRSwNP patients had features of more severe disease: indeed, they had statistically significantly higher frequency of previous sinus surgery, higher SNOT‐22, LM scores, and CCG than CRSsNP patients. Upon genotyping of TAS2R38 polymorphisms, we observed that the AVI–AVI genotype, associated to homozygous nonfunctional bitter TAS2R38 receptor, was more prevalent among CRSwNP (100%) than in CRSsNP patients (0%); furthermore, AVI–AVI subjects showed statistically significantly worse SNOT‐22 and CCG scores than PAV–PAV and PAV–AVI subjects. The group of AVI–AVI patients also had more frequent respiratory exacerbations, Gram‐negative infections, and Pseudomonas aeruginosa colonization than PAV–PAV and PAV–AVI patients. Conclusion: Our findings indicate for the first time that PCD patients with CRSwNP display a more severe disease than those with CRSsNP. Genotyping of TAS2R38 polymorphisms demonstrated that in PCD patients, the AVI–AVI genotype is strikingly more prevalent among CRSwNP than in CRSsNP, while the PAV–PAV genotype might be protective against Gram‐negative infections and respiratory exacerbations. Level of Evidence: 3 Laryngoscope, 133:248–254, 2023 [ABSTRACT FROM AUTHOR]

Lopinavir and ritonavir (LPV/r) are the primary anti-human immunodeficiency virus (HIV) drugs recommended by the World Health Organization for treating children aged 3 years and above who are infected with the HIV. These drugs are typically available in liquid formulations to aid in dosing for children who cannot swallow tablets. However, the strong bitter taste associated with these medications can be a significant obstacle to adherence, particularly in young children, and can jeopardize the effectiveness of the treatment. Studies have shown that poor palatability can affect the survival rate of HIV-infected children. Therefore, developing more child-friendly protease inhibitor formulations, particularly those with improved taste, is critical for children with HIV. The molecular mechanism by which lopinavir and ritonavir activate bitter taste receptors, TAS2Rs, is not yet clear. In this study, we utilized a calcium mobilization assay to characterize the activation of bitter taste receptors by lopinavir and ritonavir. We discovered that lopinavir activates TAS2R1 and TAS2R13, while ritonavir activates TAS2R1, TAS2R8, TAS2R13, and TAS2R14. The development of bitter taste blockers that target these receptors with a safe profile would be highly desirable in eliminating the unpleasant bitter taste of these anti-HIV drugs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). 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. 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. 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. • Ghrelin displays neuroprotective effect in neurodegenerative diseases including PD. • Denatonium benzoate, a TAS2Rs agonist, displayed neuroprotective effect in rotenone-induced model of PD. • Activation of TAS2Rs could be a promising target for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Sweet-tasting thaumatin is cleaved into bitter peptides during gastric digestion. • Bitter peptides stimulate the proton secretion of immortalized human partial cells. • Native proteins of H. pylori induce increased IL-17A release in HGT-1 cells. • Bitter peptides reduce the release of IL-17A induced by H. pylori. • Stimulation of H+ secretion and reduction of IL-17A release are TAS2R16-mediated. [ABSTRACT FROM AUTHOR]

The chemical senses of olfaction and taste are well developed in fish and play a vital role in its various activities such as navigation, mate recognition, and food detection. The small teleost fish Astyanax mexicanus consists of interfertile river‐dwelling and cave‐dwelling populations, referred to as "surface fish" and "cavefish" respectively. An important anatomical feature of cavefish is the lack of eyes leading them to be referred to as blind fish and suggesting an enhanced functional role for other senses such as taste. In this study, we characterize the expression of bitter taste receptors (T2Rs or Tas2Rs) in A. mexicanus and investigate their functionality in a heterologous expression system. The genome database of A. mexicanus (ensemble and NCBI) showed 7 Tas2Rs, among these Tas2R1, Tas2R3, Tas2R4, and Tas2R114 are well characterized in humans and mice but not in A. mexicanus. Therefore, the 4 Tas2Rs were selected for further analysis and their expression in A. mexicanus was confirmed by in situ hybridization and RT‐PCR in early developmental stages. These Tas2Rs are expressed in various oral and extraoral organs (liver, fins, jaws, and gills) in A. mexicanus, and Tas2R1 has maximum expression and is localized throughout the fish body. Using the heterologous expression of A. mexicanus T2Rs in HEK293T cells coupled with cell‐based calcium mobilization assays, we show that A. mexicanus T2Rs are activated by commonly used fish food and known bitter agonists, including quinine. This study provides novel insights into the extraoral expression of T2Rs in A. mexicanus and suggests their importance in extraoral food detection. [ABSTRACT FROM AUTHOR]

Preclinical studies in animal models of obesity and inflammation have shown that oral administration of ARD‐101, a potential TAS2R agonist, reduced food intake and body weight and downregulated inflammatory cytokines. We present results from a first‐in‐human phase 1 randomized, placebo‐controlled trial that evaluated safety, pharmacokinetics, and pharmacodynamics of single or multiple ascending doses of oral ARD‐101 (40, 100, and 240 mg) in healthy adults. A total of 43 subjects were randomly assigned and dosed to ARD‐101 or placebo with 42 subjects completing the study treatment. ARD‐101 was found to be >99% restricted to the gut with minimal systemic exposure, demonstrated a favorable safety profile, and was well tolerated at all dose levels. Blood samples taken 1 hour after administration showed that subjects dosed with 240 mg of ARD‐101 had elevated circulating levels of several gut peptide hormones. It is postulated that ARD‐101 activates enteroendocrine cells to achieve its effects regulating metabolism and inflammation. The phase 1 clinical results demonstrated safety of ARD‐101 and indicated activation of gut peptide hormone release in healthy adults. Further clinical trials will evaluate ARD‐101 in patients with metabolic and inflammatory disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: Today, the commitment of beef production systems is to enhance their sustainability. Therefore, improving animal welfare and improving feed efficiency are both important challenges. Citrus flavonoids are polyphenols that have previously shown promising effects on reducing feed intake and modulating animal behavior in bulls fattened under commercial conditions. Moreover, increasing fat during the finishing phase in beef cattle diets has been used to increase dietary energy content and to reduce the risk of rumen acidosis. Therefore, the present study supports the hypothesis that a high dietary fat content does not interfere in the mode of action of these flavonoids and that the positive effects on feed efficiency and animal behaviors should be observed. Nevertheless, the mode of action of flavonoids is not known; it is speculated that digestive tract health (rumen) and changes in the expression of behavior- and inflammation-related genes (rumen and duodenum) may be involved, and dietary fat supplementation may also affect, antagonistic to flavonoids, these mechanisms. However, the present study data support that citrus flavonoid supplementation in high dietary fat diets may be a good strategy to face current beef production system challenges such as improving feed efficiency and animal welfare. One hundred and forty-six bulls (178.2 ± 6.64 kg BW and 146.0 ± 0.60 d of age) were randomly allocated to one of eight pens and assigned to control (C) or citrus flavonoid (BF) treatments (Citrus aurantium, Bioflavex CA, HTBA, S.L.U., Barcelona, Spain, 0.4 kg per ton of Bioflavex CA). At the finishing phase, the dietary fat content of the concentrate was increased (58 to 84 g/kg DM). Concentrate intake was recorded daily, and BW and animal behavior by visual scan, fortnightly. After 168 d, bulls were slaughtered, carcass data were recorded, and rumen and duodenum epithelium samples were collected. Performance data were not affected by treatment, except for the growing phase where concentrate intake (p < 0.05) was lesser in the BF compared with the C bulls. Agonistic and sexual behaviors were more frequent (p < 0.01) in the C than in the BF bulls. In the rumen epithelium, in contrast to duodenum, gene expression of some bitter taste receptors (7, 16, 39) and other genes related to behavior and inflammation was higher (p < 0.05) in the BF compared with the C bulls. Supplementing citrus flavonoids in high-fat finishing diets to Holstein bulls reduces growing concentrate consumption and improves animal welfare. [ABSTRACT FROM AUTHOR]

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.

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

Studies have shown differences in TAS2R38 receptor expression in patients with chronic rhinosinusitis (CRS) compared to healthy controls. Known agonists of TAS2R38 stimulate epithelial cells, leading to robust intracellular nitric oxide (NO) production, which damages bacterial membranes, enzymes, and DNA, but also increases ciliary beat frequency. In this study we examined, using qRT-PCR, the expression of TAS2R38 receptor in nasal polyps (NP) of patients with CRS (N = 107) and in inferior turbinate mucosa (ITM) of patients with CRS and controls (N = 39), and confronted it with clinical features and the severity of the disease. The expression was shown in 43 (50.00%) samples of ITM in the study group (N = 107), in 28 (71.79%) in the control group (N = 39) (p = 0.037), and in 43 (46.24%) of NP. There were no differences in levels of the expression in all analyzed tissues. Patients who rated their symptoms at 0–3 showed higher TAS2R38 expression in ITM in comparison to the patients with 8–10 points on the VAS scale (p = 0.020). A noticeable, however not significant, correlation between the TAS2R38 expression in ITM and the Lund–Mackay CT score was shown (p = 0.068; R = −0.28). Patients with coexisting asthma had significantly higher receptor expression in the NP (p = 0.012). Our study is the first to confirm the presence of the TAS2R38 receptor in NP. Expression of the TAS2R38 receptor is reduced in the sinonasal mucosa in patients with more advanced CRS with NP. [ABSTRACT FROM AUTHOR]

Bitter taste receptors (T2Rs) are G protein-coupled receptors (GPCRs) expressed in various cell types including ciliated airway epithelial cells and macrophages. T2Rs in these two innate immune cell types are activated by bitter products, including those secreted by Pseudomonas aeruginosa, leading to Ca2+-dependent activation of endothelial nitric oxide (NO) synthase (eNOS). NO enhances mucociliary clearance and has direct antibacterial effects in ciliated epithelial cells. NO also increases phagocytosis by macrophages. Using biochemistry and live-cell imaging, we explored the role of heat shock protein 90 (HSP90) in regulating T2R-dependent NO pathways in primary sinonasal epithelial cells, primary monocyte-derived macrophages, and a human bronchiolar cell line (H441). Immunofluorescence showed that H441 cells express eNOS and T2Rs and that the bitter agonist denatonium benzoate activates NO production in a Ca2+- and HSP90-dependent manner in cells grown either as submerged cultures or at the air–liquid interface. In primary sinonasal epithelial cells, we determined that HSP90 inhibition reduces T2R-stimulated NO production and ciliary beating, which likely limits pathogen clearance. In primary monocyte-derived macrophages, we found that HSP-90 is integral to T2R-stimulated NO production and phagocytosis of FITC-labeled Escherichia coli and pHrodo-Staphylococcus aureus. Our study demonstrates that HSP90 serves as an innate immune modulator by regulating NO production downstream of T2R signaling by augmenting eNOS activation without impairing upstream Ca2+ signaling. These findings suggest that HSP90 plays an important role in airway antibacterial innate immunity and may be an important target in airway diseases such as chronic rhinosinusitis, asthma, or cystic fibrosis. [ABSTRACT FROM AUTHOR]

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

[Display omitted] • Arabica-specific bitter tastant mozambioside degrades during coffee roasting. • Previously unknown pyrolysis products with higher bitter intensity are generated. • The structures of the new compounds are elucidated by NMR and HR-MS. • The new compounds are potent agonists for TAS2R43 and TAS2R46 (HEK 293T-Gα16gust44). • Molecular Docking simulations reveal their orientation within the bitter receptor. Arabica coffee contains the bitter-tasting diterpene glycoside mozambioside , which degrades during coffee roasting, leading to yet unknown structurally related degradation products with possibly similar bitter-receptor-activating properties. The study aimed at the generation, isolation, and structure elucidation of individual pyrolysis products of mozambioside and characterization of bitter receptor activation by in vitro analysis in HEK 293T-Gα16gust44 cells. The new compounds 17- O - β - d -glucosyl-11-hydroxycafestol-2-on, 11- O - β - d -glucosyl-16-desoxycafestol-2-on, 11- O -β- d -glucosyl- (S) -16-desoxy-17-oxocafestol-2-on, 11- O - β - d -glucosyl-15,16-dehydrocafestol-2-on, and 11- O - β - d -glucosyl- (R) -16-desoxy-17-oxocafestol-2-on were isolated from pyrolyzed mozambioside by HPLC and identified by NMR and UHPLC-ToF-MS. Roasting products 11- O -β- d -glucosyl- (S) -16-desoxy-17-oxocafestol-2-on, 11- O - β - d -glucosyl-15,16-dehydrocafestol-2-on, and 11- O - β - d -glucosyl- (R) -16-desoxy-17-oxocafestol-2-on had lower bitter receptor activation thresholds compared to mozambioside. Molecular docking simulations revealed the binding modes of the compounds 11- O - β - d -glucosyl-15,16-dehydrocafestol-2-on and 11- O - β - d -glucosyl- (R) -16-desoxy-17-oxocafestol-2-on and their aglycone 11-hydroxycafestol-2-on in the two cognate receptors TAS2R43 and TAS2R46. The newly discovered roasting products 17- O - β - d -glucosyl-11-hydroxycafestol-2-on, 11- O -β- d -glucosyl- (S) -16-desoxy-17-oxocafestol-2-on, 11- O - β - d -glucosyl-15,16-dehydrocafestol-2-on, and 11- O - β - d -glucosyl- (R) -16-desoxy-17-oxocafestol-2-on were detected in authentic roast coffee brew by UHPLC-ToF-MS and could contribute to coffee's bitter taste impression. [ABSTRACT FROM AUTHOR]

Since citrus flavonoids have antioxidant and anti-inflammatory properties, it was hypothesized that these compounds would become a suitable alternative to the use of therapeutic doses of zinc oxide at weaning. A total of 252 weaned pigs ([LargeWhite × Landrace] × Pietrain) were distributed according to BW (5.7 kg ± 0.76) into 18 pens (6 pens per diet, 14 pigs/pen). Three experimental diets for the prestarter (0–14 d postweaning) and starter (15–35 d postweaning) period were prepared: (i) a nonmedicated (CON) diet, (ii) a CON diet supplemented with zinc oxide at 2500 mg/kg, amoxicillin at 0.3 mg/kg and apramycin at 0.1 mg/kg (ZnO), and (iii) CON diet with the addition of a commercial citrus flavonoid extract at 0.3 mg/kg and amoxicillin at 0.3 mg/kg (FLAV). Pig BW, ADG, ADFI, and FCR were assessed on d7, d14, and d35. Samples of intestinal tissue, cecal content, and serum were collected on day seven (18 piglets). FLAV treatment achieved greater BW and ADG during the starter and for the entire experimental period compared with the CON diet (p < 0.05), whereas ZnO pigs evidenced intermediate results. Jejunum tissue analysis showed that pigs fed the FLAV diet overexpressed genes related to barrier function, digestive enzymes, and nutrient transport compared to those pigs fed the CON diet (p < 0.05). An increase in the abundance of bacterial genera such as Succinivibrio, Turicibacter, and Mitsuokella (p < 0.05) was observed in the FLAV compared with the CON and ZnO piglets. ZnO and FLAV increased the expression of TAS2R39, while ZnO pigs also expressed greater TAS2R16 than CON (p < 0.05) in the intestine. FLAV treatment improved the gut function, possibly explaining a higher performance at the end of the nursery period. Consequently, citrus flavonoids supplementation, together with amoxicillin, is a promising alternative to the use of zinc oxide plus amoxicillin and apramycin in weanling pigs, minimizing the use of antibiotics.

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

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

Bitter taste receptors serve as a vital component in the defense system against toxin intake by animals, and the family of genes encoding these receptors has been demonstrated, usually by family size variance, to correlate with dietary preference. However, few systematic studies of specific Tas2R to unveil their functional evolution have been conducted. Here, we surveyed Tas2R16 across all major clades of primates and reported a rare case of a convergent change to increase sensitivity to β-glucopyranosides in human and a New World monkey, the white-faced saki. Combining analyses at multiple levels, we demonstrate that a parallel amino acid substitution (K172N) shared by these two species is responsible for this functional convergence of Tas2R16. Considering the specialized feeding preference of the white-faced saki, the K172N change likely played an important adaptive role in its early evolution to avoid potentially toxic cyanogenic glycosides, as suggested for the human TAS2R16 gene. [ABSTRACT FROM AUTHOR]

The aims of this review were to understand the roles of bitter taste genes in humans. Some of the peoples have the capacity to taste some chemical substance such as phenylthiocarbamide (PTC) while others cant not based on the dietary hazards and food preferences. There are two alleles responsible to express these phenotypes which are homozygous recessive. In human TAS2R38 genes located on the chromosome number 7 and consist of different nucleotide polymorphism that related to detection of the phenotype of different chemical compounds such as 6-n-propylthiouracil (PROP) and phenylthiocarbamide bitterness and this Gene is the member of the TAS2R genes which are eleven pseudogenes and twenty that has roles in many biological processes. There are many factors that affect the bitter taste such as food, age, sex, and different diseases. The mechanism of food bitter taste and genotype of TAS2R38 until know not well understood due to that the proof of relation between bitter taste sensitivity and food is harmful. there are many different diseases can impact the influence of taste such as neoplasm and lifestyle such as consumption of alcohol along with the use of medication, head trauma, upper tract infections. On the other hand, A relation between TAS2R38 genotype and meal preferences has been observed among children, however, no associations have been mentioned among older adults. Some previous research proved some vital points that show an association between type 1 of diabetes and phenylthiocarbamide (PTC) but other studies cannot demonstrate that. However, of other disease such as obesity is controversial but other studies reported to the relationship between them.

Background: Dietary restrictions or reductions such as fasting for weight loss are often difficult to adhere to due to increased appetite and food cravings. Recently, gastrointestinal delivery of bitter hops has been shown to be effective at reducing appetite in men. Our aim was to determine the effect of a bitter hop extract on appetite and cravings in women, using a 24 h, water-only fast., Methods: This was a randomized, double-blind, cross-over treatment study. Thirty adult women were recruited and required to fast for 24 h from 1800 h to 1800 h on three occasions and given an ad libitum meal to break each fast. Treatments of either a placebo or one of two doses (high dose; HD: 250 mg or low dose; LD: 125 mg) of a bitter hop-based appetite suppressant (Amarasate®) were given twice per day at 16 and 20 h into the fast., Results: The HD and LD treatment groups exhibited a significant ( p  < 0.05) reduction in appetite and cravings for food when compared to the placebo control. Two participants reported loose stools and one reported heartburn while on the HD treatment, and one participant reported loose stools while on the LD treatment., Conclusion: These data suggest that appetite suppressant co-therapy may be useful in reducing hunger during fasting in women and shows that gastrointestinal delivery of bitter compounds may also be an effective method of reducing cravings for food.This trial received ethical approval from the Northen B New Zealand Human Disability and Ethics committee (Northern B Health and Disability Ethics Committee (2022 EXP 10995) and was prospectively registered with the Australian New Zealand Clinical Trial Registry (ACTRN12622000107729)., Competing Interests: The authors themselves declare no competing financial interests. The New Zealand Institute for Plant and Food Research Limited, a New Zealand government-owned Crown Research Institute, has licensed a hop extract as a dietary supplement to Calocurb Ltd to commercialize and currently holds a minor shareholding in this company., (© 2024 The Authors.)

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.

The exopolysaccharide preparation of Bacillus amyloliquefaciens amy-1 (EPS) regulates glycemic levels and promotes glucagon-like peptide 1 (GLP-1) secretion in vivo and in vitro. This study aimed to identify the molecular mechanism underlying EPS-induced GLP-1 secretion. HEK293T cells stably expressing human Gα-gustducin were used as a heterologous system for expressing the genes of human bitter taste receptor (T2R) 10, 14, 30, 38 (PAV), 38 (AVI), 43, and 46, which were expressed as recombinant proteins with an N-terminal tag composed of a Lucy peptide and a human somatostatin receptor subtype 3 fragment for membrane targeting and a C-terminal red fluorescent protein for expression monitoring. EPS induced a dose-dependent calcium response from the human NCI-H716 enteroendocrine cell line revealed by fluorescent calcium imaging, but inhibitors of the G protein–coupled receptor pathway suppressed the response. EPS activated heterologously expressed T2R14 and T2R38 (PAV). shRNAs of T2R14 effectively inhibited EPS-induced calcium response and GLP-1 secretion in NCI-H716 cells, suggesting the involvement of T2R14 in these effects. The involvement of T2R38 was not characterized because NCI-H716 cells express T2R38 (AVI). In conclusion, the activation of T2Rs mediates EPS-induced GLP-1 secretion from enteroendocrine cells, and T2R14 is a critical target activated by EPS in these cells. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the presence of bitter taste receptors (T2Rs) in the middle ear and to examine their relationship with chronic ear infections. Study Design: Cross-sectional study. Setting: Tertiary care hospital. Methods: This study enrolled 84 patients being evaluated for otologic surgery: 40 for chronic otitis media (COM) and 44 for other surgical procedures (controls). We collected a small piece of mucosa from 14 patients for mRNA analysis and from 23 patients for immunohistochemistry. A total of 55 patients underwent a double-blind taste test to gauge sensitivity to phenylthiocarbamide, denatonium, quinine, sucrose, and sodium chloride; 47 patients gave a salivary sample for single-nucleotide polymorphism analysis of rs1376251 (TAS2R50) and rs1726866 (TAS2R38). Results: Bitter taste receptors were found in all samples, but the repertoire varied among patients. T2R50 was the most consistently identified receptor by mRNA analysis. Its rs1376251 allele was related to susceptibility to COM but not the expression pattern of T2R50. Ratings of bitterness intensity of phenylthiocarbamide, a ligand for T2R38, differed significantly between the COM and control groups. Conclusion: T2Rs were found within the middle ear of every patient sampled; the rs1376251 allele of TAS2R50 appears to be related to chronic ear infections. These receptors are an intriguing target for future research and possible drug targeting. [ABSTRACT FROM AUTHOR]

One hundred and forty-six bulls (178.2 ± 6.64 kg BW and 146.0 ± 0.60 d of age) were randomly allocated to one of eight pens and assigned to control (C) or citrus flavonoid (BF) treatments (Citrus aurantium, Bioflavex CA, HTBA, S.L.U., Barcelona, Spain, 0.4 kg per ton of Bioflavex CA). At the finishing phase, the dietary fat content of the concentrate was increased (58 to 84 g/kg DM). Concentrate intake was recorded daily, and BW and animal behavior by visual scan, fortnightly. After 168 d, bulls were slaughtered, carcass data were recorded, and rumen and duodenum epithelium samples were collected. Performance data were not affected by treatment, except for the growing phase where concentrate intake (p < 0.05) was lesser in the BF compared with the C bulls. Agonistic and sexual behaviors were more frequent (p < 0.01) in the C than in the BF bulls. In the rumen epithelium, in contrast to duodenum, gene expression of some bitter taste receptors (7, 16, 39) and other genes related to behavior and inflammation was higher (p < 0.05) in the BF compared with the C bulls. Supplementing citrus flavonoids in high-fat finishing diets to Holstein bulls reduces growing concentrate consumption and improves animal welfare.

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Background: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP), and aspirin‐exacerbated respiratory disease (AERD) have varying levels of inflammation and disease severity. Solitary chemosensory cells (SCCs) are enriched in nasal polyps, are the primary source of interleukin 25 (IL‐25) in upper airways, leading to type 2 inflammation, and are activated by bitter‐tasting denatonium benzoate (DB). Thus, we sought to evaluate DB taste perception at a range of concentrations in order to identify 1 that most differentiates CRS subgroups from controls. Methods: CRSsNP (n = 25), CRSwNP (n = 26), and AERD (n = 27) patients as well as controls (n = 25) tasted 6 DB concentrations in a fixed, random order, rating on a category scale of 0 (no intensity) to 12 (extremely intense). Sinonasal epithelial cultures were treated with and without denatonium and analyzed for IL‐25 via flow cytometry. Results: CRSsNP patients rated DB as significantly less intense than did controls at all concentrations: 5.62 × 10–9M, 1.00 × 10–8M, 1.78 × 10–8M, 3.16 × 10–8M, 5.62 × 10–8M, and 1.00 × 10–7M (all p < 0.0083). CRSwNP patients did not show significant differences from controls. AERD patients rated DB as significantly more intense than did controls at concentrations of 1.00 × 10–8M and 3.16 × 10–8M (p < 0.0083). In vitro data demonstrated significant increase in IL‐25–positive cells after denatonium stimulation (n = 5), compared to control (n = 5) (p = 0.012). Conclusion: Our findings link in vitro DB stimulation of sinonasal tissue with increased IL‐25 and show differential DB taste perception in CRS subgroups relative to the control group, with CRSsNP being hyposensitive and AERD being hypersensitive. We propose a concentration of 3.16 × 10–8M for future study of clinical utility. [ABSTRACT FROM AUTHOR]

The airway smooth muscle (ASM) cell plays a central role in the pathogenesis of asthma and constitutes an important target for treatment. These cells control muscle tone and thus regulate the opening of the airway lumen and air passage. Evidence indicates that ASM cells participate in the airway hyperresponsiveness as well as the inflammatory and remodeling processes observed in asthmatic subjects. Therapeutic approaches require a comprehensive understanding of the structure and function of the ASM in both the normal and disease states. This review updates current knowledge about ASM and its effects on airway narrowing, remodeling, and inflammation in asthma. [ABSTRACT FROM AUTHOR]

Background: Bitter and sweet taste receptors are present in the human upper airway, where they have roles in innate immunity. Previous studies have shown that 1 of the 25 bitter receptors, TAS2R38, responds to specific bacterial signaling molecules and evokes 1 type of a defense response in the upper airway, whereas ligands of sweet receptors suppress other types of defense responses. Methods: We examined whether other bitter taste receptors might also be involved in innate immunity by using sensory responses to bitter compounds that are not ligands of TAS2R38 (quinine and denatonium benzoate) to assess the sensitivity of other bitter receptors in chronic rhinosinusitis (CRS) patients. CRS patients with (n = 426) and without (n = 226) nasal polyps and controls (n = 356) rated the intensity of quinine, denatonium benzoate, phenylthiocarbamide (PTC; a ligand for TAS2R38), sucrose, and salt. Results: CRS patients rated the bitter compounds denatonium benzoate and quinine as less intense and sucrose as more intense than did controls (false discovery rate [FDR] <0.05) and CRS patients and controls did not differ in their ratings of salt (FDR >0.05). PTC bitter taste intensity differed between patient and control groups but were less marked than those previously reported. Though differences were statistically significant, overall effect sizes were small. Conclusion: CRS patients report bitter stimuli as less intense but sweet stimuli as more intense than do control subjects. We speculate that taste responses may reflect the competence of sinonasal innate immunity mediated by taste receptor function, and thus a taste test may have potential for clinical utility in CRS patients. [ABSTRACT FROM AUTHOR]

Uterine contractions during labor and preterm labor are influenced by a complex interplay of factors, including hormones and inflammatory mediators. This complexity may contribute to the limited efficacy of current tocolytics for preterm labor, a significant challenge in obstetrics with 15 million cases annually and approximately 1 million resulting deaths worldwide. We have previously shown that the myometrium expresses bitter taste receptors (TAS2Rs) and that their activation leads to uterine relaxation. Here, we investigated whether the selective TAS2R5 agonist phenanthroline can induce relaxation across a spectrum of human uterine contractions and whether the underlying mechanism involves changes in intracellular Ca2+ signaling. We performed experiments using samples from pregnant women undergoing scheduled cesarean delivery, assessing responses to various inflammatory mediators and oxytocin with and without phenanthroline. Our results showed that phenanthroline concentration-dependently inhibited contractions induced by PGF2α, U46619, 5-HT, endothelin-1 and oxytocin. Furthermore, in hTERT-infected human myometrial cells exposed to uterotonics, phenanthroline effectively suppressed the increase in intracellular Ca2+ concentration induced by PGF2α, U46619, oxytocin, and endothelin-1. These results suggest that the selective TAS2R5 agonist may not only significantly reduce uterine contractions but also decrease intracellular Ca2+ levels. This study highlights the potential development of TAS2R5 agonists as a new class of uterine relaxants, providing a novel avenue for improving the management of preterm labor. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Innate immunity utilizes components of sensory signal transduction such as bitter and sweet taste receptors. In fact, empirical evidence has shown bitter and sweet taste receptors to be an integral component of antimicrobial immune response in upper respiratory tract infections. Since an efficient immune response plays a key role in the attainment of longevity, it is not surprising that the rs978739 polymorphism of the bitter taste receptor TAS2R16 gene has been shown to be associated with longevity in a population of 941 individuals ranging in age from 20 to 106 years from Calabria (Italy). There are many possible candidate genes for human longevity, however of the many genes tested, only APOE and FOXO3 survived to association in replication studies. So, it is necessary to validate in other studies genes proposed to be associated with longevity. Thus, we analysed the association of the quoted polymorphism in a population of long lived individuals (LLIs) and controls from another Italian population from Cilento. Methods The analysis has been performed on data previously obtained with genome-wide association study on a population of LLIs (age range 90–109 years) and young controls (age range 18–45 years) from Cilento (Italy). Results Statistical power calculations showed that the analysed cohort represented by 410 LLIs and 553 young controls was sufficiently powered to replicate the association between rs978739 and the longevity phenotype according to the effect size and frequencies described in the previous paper, under a dominant and additive genetic model. However, no evidence of association between rs978739 and the longevity phenotype was observed according to the additive or dominant model. Conclusion There are several reasons for the failure of the confirmation of a previous study. However, the differences between the two studies in terms of environment of the population adopted and of the criteria of inclusion have made difficult the replication of the findings.