The role of TRPA1 and TRPV1 in the perception of astringency.

Astringency, commonly described as a drying, roughening, and/or puckering sensation associated with polyphenol-rich foods affects their palatability. While the compounds eliciting astringency are known, its mechanism of action is debated. This study investigated the role of transient receptor potential (TRP) channels A1 and V1 in astringency perception. If TRP A1 or V1 have a functional role in astringency perception, then desensitizing these receptors should decrease perceived astringency. Thirty-seven panelists underwent unilateral lingual desensitization of TRP A1 and V1 channels using mustard oil and capsaicin, respectively. Panelists then evaluated four astringent stimuli: epicatechin (EC), epigallocatechin gallate (EGCG), tannic acid (TA), and potassium alum (Alum), via 2-AFC and intensity ratings. When TRPA1 receptors were desensitized on one half of the tongue via mustard oil, no significant differences were observed between the treated and untreated sides for both 2-AFC and intensity ratings. Similarly, when TRPV1 receptors were desensitized on one half of the tongue via capsaicin, no significant differences were observed between the treated and untreated sides for both 2-AFC and intensity ratings. These findings challenge the notion that TRP channels play a pivotal role in astringency perception.

Taste Sensor Assessment of Bitterness in Medicines: Overview and Recent Topics.

In recent decades, taste sensors have been increasingly utilized to assess the taste of oral medicines, particularly focusing on bitterness, a major obstacle to patient acceptance and adherence. This objective and safe method holds promise for enhancing the development of patient-friendly medicines in pharmaceutical companies. This review article introduces its application in measuring the intensity of bitterness in medicine, confirming the achievement of taste masking, distinguishing taste differences between branded and generic medicines, and identifying substances to suppress bitterness in target medicines. Another application of the sensor is to predict a significant increase in bitterness when medicine is taken with certain foods/beverages or concomitant medication. Additionally, to verify the sensor's predictability, a significant correlation has been demonstrated between the output of a bitter-sensitive sensor designed for drug bitterness (BT0) and the bitterness responses of the human taste receptor hT2R14 from BitterDB (huji.ac.il). As a recent advancement, a novel taste sensor equipped with lipid/polymer membranes modified by 3-Br-2,6-dihydroxybenzoic acid (2,6-DHBA), based on the concept of allostery, is introduced. This sensor successfully predicts the bitterness of non-charged pharmaceuticals with xanthine skeletons, such as caffeine or related compounds. Finally, the future prospects of taste sensors are discussed.

Formulation and clinical evaluation of carbidopa/levodopa oral solution for the treatment of sepiapterin reductase deficiency.

BACKGROUND: sepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child's needs, as the splitting of the tablet into smaller portions or its dilution in water. It's essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients. MATERIALS AND METHODS: we described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD. RESULTS: we documented the stability for 28 days at 25 °C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance. CONCLUSIONS: in-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.

Unleashing the Potential of ß -cyclodextrin Inclusion Complexes in Bitter Taste Abatement: Development, Optimization and Evaluation of Taste Masked Anti-emetic Chewing Gum of Promethazine Hydrochloride.

Motion sickness also known as kinetosis is a condition in which there exists a disagreement between visually perceived movement and the vestibular system's sense of movement. Nausea, vomiting, dizziness, fatigue, and headache are the most common symptoms of motion sickness. This study mainly focuses on the taste masking of Promethazine Hydrochloride (PMZ) by inclusion complexation method, its formulation development in the chewing gum form by using directly compressible gum base HIG® and its quality and performance testing. Different molar ratios (1:1, 1:2, 1:3 and 1:4) of PMZ-cyclodextrin complexes were prepared by using ß-Cyclodextrin (ß-CD) as a taste masking agent. These complexes were evaluated for FTIR, DSC, % Entrapment Efficiency, % drug yield, and taste evaluation by E-Tongue. The optimized ratio was further evaluated by sophisticated analytical techniques such as Scanning Electron Microscopy (SEM) and X-Ray Diffraction (XRD). A central composite design (CCD) (3 ^2) was utilized to examine the effects of independent variables (amount of gum-X1 and amount of plasticizer-X2) on dependent variables (%CDRY1 and hardness Y2). The prepared gums were evaluated for drug content, organoleptic properties, in-vitro dissolution testing by fabricated disintegration apparatus, texture analysis, etc. The optimization statistics showed that on decreasing the amount of gum, in- vitro drug release increases and hardness decreases. The optimized batch MCG-2 of Promethazine MCG showed 92.34 ± 0.92% of drug release, whereas for marketed formulation (Phenergan®-25 mg) drug release value was 86.19 ± 1.88%. Results provided evidence that PMZ MCGs could be a better alternative to conventional tablet formulations with improved drug release, palatability and texture.

Preparation and Evaluation of Clarithromycin Taste-Masking Dry Suspension Using Hot Melt Extrusion Based on Solid Dispersion Technology.

Clarithromycin (CLA) is the preferred drug for treating respiratory infections in pediatric patients, but it has the drawbacks of extreme bitterness and poor water solubility. The purpose of this study was to improve solubility and mask the extreme bitterness of CLA. We use Hot Melt Extrusion (HME) to convert CLA and Eudragit® E100 into Solid Dispersion (SD). Differential scanning calorimetry (DSC) and Powder X-ray diffraction (PXRD) were used to identify the crystalline form of the prepared SDs, which showed that the crystalline CLA was converted to an amorphous form. At the same time, an increase in dissolution rate was observed, which is one of the properties of SD. The results showed that the prepared SD significantly increased the dissolution rate of crystalline CLA. Subsequently, the SD of CLA was prepared into a dry suspension with excellent suspending properties and a taste-masking effect. The bitterness bubble chart and taste radar chart showed that the SD achieved the bitter taste masking of CLA. Principal components analysis (PCA) of the data generated by the electronic tongue showed that the bitter taste of CLA was significantly suppressed using the polymer Eudragit® E100. Subsequently, a dry suspension was prepared from the SD of CLA. In conclusion, this work illustrated the importance of HME for preparing amorphous SD of CLA, which can solve the problems of bitterness-masking and poor solubility. It is also significant for the development of compliant pediatric formulations.

Artificial and Natural Sweeteners Biased T1R2/T1R3 Taste Receptors Transactivate Glycosylated Receptors on Cancer Cells to Induce Epithelial-Mesenchymal Transition of Metastatic Phenotype.

Understanding the role of biased taste T1R2/T1R3 G protein-coupled receptors (GPCR) agonists on glycosylated receptor signaling may provide insights into the opposing effects mediated by artificial and natural sweeteners, particularly in cancer and metastasis. Sweetener-taste GPCRs can be activated by several active states involving either biased agonism, functional selectivity, or ligand-directed signaling. However, there are increasing arrays of sweetener ligands with different degrees of allosteric biased modulation that can vary dramatically in binding- and signaling-specific manners. Here, emerging evidence proposes the involvement of taste GPCRs in a biased GPCR signaling crosstalk involving matrix metalloproteinase-9 (MMP-9) and neuraminidase-1 (Neu-1) activating glycosylated receptors by modifying sialic acids. The findings revealed that most natural and artificial sweeteners significantly activate Neu-1 sialidase in a dose-dependent fashion in RAW-Blue and PANC-1 cells. To confirm this biased GPCR signaling crosstalk, BIM-23127 (neuromedin B receptor inhibitor, MMP-9i (specific MMP-9 inhibitor), and oseltamivir phosphate (specific Neu-1 inhibitor) significantly block sweetener agonist-induced Neu-1 sialidase activity. To assess the effect of artificial and natural sweeteners on the key survival pathways critical for pancreatic cancer progression, we analyzed the expression of epithelial-mesenchymal markers, CD24, ADLH-1, E-cadherin, and N-cadherin in PANC-1 cells, and assess the cellular migration invasiveness in a scratch wound closure assay, and the tunneling nanotubes (TNTs) in staging the migratory intercellular communication. The artificial and natural sweeteners induced metastatic phenotype of PANC-1 pancreatic cancer cells to promote migratory intercellular communication and invasion. The sweeteners also induced the downstream NFκB activation using the secretory alkaline phosphatase (SEAP) assay. These findings elucidate a novel taste T1R2/T1R3 GPCR functional selectivity of a signaling platform in which sweeteners activate downstream signaling, contributing to tumorigenesis and metastasis via a proposed NFκB-induced epigenetic reprogramming modeling.

Taste of common prebiotic oligosaccharides: impact of molecular structure.

Prebiotic oligosaccharides are naturally occurring nondigestible carbohydrates with demonstrated health benefits. They are also a chemically diverse class of nutrients, offering an opportunity to investigate the impact of molecular structure on oligosaccharide taste perception. Accordingly, a relevant question is whether these compounds are detected by the human gustatory system, and if so, whether they elicit sweet or "starchy" taste. Here, in 3 psychophysical experiments, we investigated the taste perception of 3 commercially popular prebiotics [fructooligosaccharides (FOS), galactooligosaccharides (GOS), xylooligosaccharides (XOS)] in highly pure form. Each of these classes of prebiotics differs in the type of glycosyl residue, and position and type of bond between those residues. In experiments I and II, participants were asked to discriminate a total of 9 stimuli [FOS, GOS, XOS; degree of polymerization (DP) of 2, 3, 4] prepared at 75 mM in the presence and absence of lactisole, a sweet receptor antagonist. We found that all 9 compounds were detectable (P < 0.05). We also found that GOS and XOS DP 4 were discriminable even with lactisole, suggesting that their detection was not via the canonical sweet receptor. Accordingly, in experiment III, the taste of GOS and XOS DP 4 were directly compared with that of MOS (maltooligosaccharides) DP 4-6, which has been reported to elicit "starchy" taste. We found that GOS and MOS were perceived similarly although narrowly discriminable, while XOS was easily discriminable from both GOS and MOS. The current findings suggest that the molecular structure of oligosaccharides impacts their taste perception in humans.

Topical application of a P2X2/P2X3 purine receptor inhibitor suppresses the bitter taste of medicines and other taste qualities.

BACKGROUND AND PURPOSE: Many medications taste intensely bitter. The innate aversion to bitterness affects medical compliance, especially in children. There is a clear need to develop bitter blockers to suppress the bitterness of vital medications. Bitter taste is mediated by TAS2R receptors. Because different pharmaceutical compounds activate distinct sets of TAS2Rs, targeting specific receptors may only suppress bitterness for certain, but not all, bitter-tasting compounds. Alternative strategies are needed to identify universal bitter blockers that will improve the acceptance of every medication. Taste cells in the mouth transmit signals to afferent gustatory nerve fibres through the release of ATP, which activates the gustatory nerve-expressed purine receptors P2X2/P2X3. We hypothesized that blocking gustatory nerve transmission with P2X2/P2X3 inhibitors (e.g. 5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine [AF-353]) would reduce bitterness for all medications and bitter compounds. EXPERIMENTAL APPROACH: Human sensory taste testing and mouse behavioural analyses were performed to determine if oral application of AF-353 blocks perception of bitter taste and other taste qualities but not non-gustatory oral sensations (e.g. tingle). KEY RESULTS: Rinsing the mouth with AF-353 in humans or oral swabbing it in mice suppressed the bitter taste and avoidance behaviours of all compounds tested. We further showed that AF-353 suppressed other taste qualities (i.e. salt, sweet, sour and savoury) but had no effects on other oral or nasal sensations (e.g, astringency and oral tingle). CONCLUSION AND IMPLICATIONS: This is the first time a universal, reversible taste blocker in humans has been reported. Topical application of P2X2/P2X3 inhibitor to suppress bitterness may improve medical compliance.

Bitter taste TAS2R14 activation by intracellular tastants and cholesterol.

Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents1,2. TAS2R14 is also widely expressed in extragustatory tissues, suggesting its extra roles in diverse physiological processes and potential therapeutic applications3. Here we present cryogenic electron microscopy structures of TAS2R14 in complex with aristolochic acid, flufenamic acid and compound 28.1, coupling with different G-protein subtypes. Uniquely, a cholesterol molecule is observed occupying what is typically an orthosteric site in class A G-protein-coupled receptors. The three potent agonists bind, individually, to the intracellular pockets, suggesting a distinct activation mechanism for this receptor. Comprehensive structural analysis, combined with mutagenesis and molecular dynamic simulation studies, elucidate the broad-spectrum ligand recognition and activation of the receptor by means of intricate multiple ligand-binding sites. Our study also uncovers the specific coupling modes of TAS2R14 with gustducin and Gi1 proteins. These findings should be instrumental in advancing knowledge of bitter taste perception and its broader implications in sensory biology and drug discovery.

Effects of nano zinc oxide and nano chitosan on the taste masking paracetamol granules.

OBJECTIVE: The purpose of this study is to investigate the taste masking of Paracetamol granules in the range of 250-850 µm, coated by two nanocomposites prepared from Eudragit® E100, nanozinc oxide, and nanochitosan, respectively, from 1 to 5% by the weight of the granules. METHODS: In this study, Paracetamol granules were coated in several formulas with two different types of nanocomposites (polymeric and mineral) on two sizes of granules to reduce bitter taste and with the FBC method and pH-sensitive polymers (Eudragit® E100). RESULTS: The effect of nanoparticles (Nano zinc oxide and Nanochitosan) on taste-masking Paracetamol was studied with dissolution-coated granules in vitro by simulating in the oral (pH 6.8) range. Based on the results of the studies, the rate of drug release was confirmed by the taste test, and the formulated granule with 5% nano-chitosan (F14) had the best bitter taste mask function of all samples. These results were also confirmed by scanning electron microscopy (SEM) analysis, which showed a smoother and more stable surface than the samples obtained from other formulations. CONCLUSION: In the comparison of the release of two types of nanocomposites in the dissolution test, it was shown that the type B granules of Paracetamol's 5% nano-chitosan-coated granule (F14) were released 99% less than Paracetamol's 5% nano-ZnO-coated granule (F11). and Paracetamol's 1% nano-chitosan-coated granule (F12) was released 91% less than Paracetamol's 1% nano-ZnO-coated granule (F9). The results showed that nano-chitosan-coated granules have better coverage of bitter taste instead of nano-ZnO.

Sodium Bicarbonate Decreases Alcohol Consumption in Mice.

We previously reported that mice with low neuronal pH drink more alcohol, demonstrating the importance of pH for alcohol reward and motivation. In this study, we tested whether systemic pH affects alcohol consumption and if so, whether it occurs by changing the alcohol reward. C57BL/6J mice were given NaHCO3 to raise their blood pH, and the animals' alcohol consumption was measured in the drinking-in-the-dark and two-bottle free choice paradigms. Alcohol consumption was also assessed after suppressing the bitterness of NaHCO3 with sucrose. Alcohol reward was evaluated using a conditioned place preference. In addition, taste sensitivity was assessed by determining quinine and sucrose preference. The results revealed that a pH increase by NaHCO3 caused mice to decrease their alcohol consumption. The decrease in high alcohol contents (20%) was significant and observed at different ages, as well as in both males and females. Alcohol consumption was also decreased after suppressing NaHCO3 bitterness. Oral gavage of NaHCO3 did not alter quinine and sucrose preference. In the conditioned place preference, NaHCO3-treated mice spent less time in the alcohol-injected chamber. Conclusively, the results show that raising systemic pH with NaHCO3 decreases alcohol consumption, as it decreases the alcohol reward value.

Pharmacodynamics, pharmacokinetics and CYP3A4 interaction potential of the selective P2X3 receptor antagonist filapixant: A randomized multiple ascending-dose study in healthy young men.

AIMS: We report on investigations exploring the P2X3-receptor antagonist filapixant's effect on taste perception and cough-reflex sensitivity and describe its pharmacokinetics, including its CYP3A4-interaction potential. METHODS: In a randomized, placebo-controlled, double-blind study, 3 × 12 healthy men (18-45 years) were assigned (3:1) to filapixant (20, 80 or 250 mg by mouth) or placebo twice daily over 2 weeks. A single dose of midazolam (1 mg), a CYP3A4 substrate, was administered with and without filapixant. Assessments included a taste-strips test, a taste questionnaire, cough challenge with adenosine triphosphate, adverse event reports and standard safety assessments. RESULTS: Taste disturbances were observed mainly in the 250-mg group: six of nine participants (67%) in this group reported hypo- or dysgeusia in the questionnaire; eight participants (89%) reported taste-related adverse events. Five participants (56%) had a decrease in overall taste-strips-test scores ≥2 points (point estimate -1.1 points, 90% confidence interval [-3.3; 1.1]). Cough counts increased with adenosine triphosphate concentration but without major differences between treatments. Filapixant exposure increased proportionally to dose. Co-administration of filapixant had no clinically relevant effect on midazolam pharmacokinetics. Area under the concentration-time curve ratios and 90% confidence intervals were within 80-125%. No serious or severe adverse events were reported. CONCLUSIONS: Overall, filapixant was safe and well tolerated, apart from mild, transient taste disturbances. Such disturbances occurred more frequently than expected based on (in vitro) receptor-selectivity data, suggesting that other factors than P2X3:P2X2/3 selectivity might also play an important role in this context. The cough-challenge test showed no clear treatment effect. Filapixant has no clinically relevant CYP3A4 interaction potential.

Taste alteration and its relationship with nutritional status among cancer patients receiving chemotherapy, cross-sectional study.

The aim of this study is to determine the prevalence of taste alterations (TAs) during chemotherapy and their association with nutritional status and malnutrition. In addition to the associated factors with TA, including sociodemographic health-related factors and clinical status, and to investigate coping strategies to manage TA. A multicenter cross-sectional design study was conducted on 120 cancer patients aged at least 18 who had been undergoing at least one round of chemotherapy. TAs were evaluated using the chemotherapy-induced taste alteration scale (CiTAS), the malnutrition universal screening tool (MUST) was used for nutritional screening, the antineoplastic side effects scale (ASES) was used for subjective assessment of chemotherapy side effects, and the Charlson comorbidity index (CCI) was used for comorbidity assessment. SPSS21 software was used to analyze the data, and the independent T-test and one-way ANOVA test were used to determine the association between TAs and a variety of related variables. The prevalence of TAs was 98.3%. Among participants, 48.3% were at low risk of malnutrition, 20% at medium risk, and 31.7% at high risk. Malnutrition risk was associated with taste disorders (p<0.05). Patients' age, gender, educational level, and physical status were associated with TAs (p<0.05). Type of cancer, chemotherapy regimen, and number of chemotherapy cycles were also associated with TAs (p<0.05). A variety of antineoplastic side effects were associated with TAs (p<0.05), including nausea, vomiting, dry mouth, sore mouth and throat, excessive thirst, swallowing difficulty, appetite changes, weight loss, dizziness, lack of energy, disturbed sleep, anxiety, and difficulty concentrating. TAs were associated with an increased number of comorbidities, and individuals with diabetes, pulmonary diseases, and hypertension were associated with TAs (P<0.05). Patients in this study rarely practice self-management strategies to cope with TAs. A high prevalence (98.3%) of TAs in cancer patients receiving chemotherapy was found, and it was linked to a variety of negative outcomes. Chemotherapy-induced TAs are an underestimated side effect that requires more attention from patients and health care providers.

Neural responses to oral administration of erythritol vs. sucrose and sucralose explain differences in subjective liking ratings.

INTRODUCTION: High sugar intake is associated with many chronic diseases. However, non-caloric sweeteners (NCSs) might fail to successfully replace sucrose due to the mismatch between their rewarding sweet taste and lack of caloric content. The natural NCS erythritol has been proposed as a sugar substitute due to its satiating properties despite being non-caloric. We aimed to compare brain responses to erythritol vs. sucrose and the artificial NCS sucralose in a priori taste, homeostatic, and reward brain regions of interest (ROIs). METHODS: We performed a within-subject, single-blind, counterbalanced fMRI study in 30 healthy men (mean ± SEM age:24.3 ± 0.8 years, BMI:22.3 ± 0.3 kg/m2). Before scanning, we individually matched the concentrations of both NCSs to the perceived sweetness intensity of a 10% sucrose solution. During scanning, participants received 1 mL sips of the individually titrated equisweet solutions of sucrose, erythritol, and sucralose, as well as water. After each sip, they rated subjective sweetness liking. RESULTS: Liking ratings were significantly higher for sucrose and sucralose vs. erythritol (both pHolm = 0.0037); water ratings were neutral. General Linear Model (GLM) analyses of brain blood oxygen level-depended (BOLD) responses at qFDR<0.05 showed no differences between any of the sweeteners in a priori ROIs, but distinct differences were found between the individual sweeteners and water. These results were confirmed by Bayesian GLM and machine learning-based models. However, several brain response patterns mediating the differences in liking ratings between the sweeteners were found in whole-brain multivariate mediation analyses. Both subjective and neural responses showed large inter-subject variability. CONCLUSION: We found lower liking ratings in response to oral administration of erythritol vs. sucrose and sucralose, but no differences in neural responses between any of the sweeteners in a priori ROIs. However, differences in liking ratings between erythritol vs. sucrose or sucralose are mediated by multiple whole-brain response patterns.

Effect of lozenge surface texture, taste and acidity on salivary flow rate: A crossover preclinical trial in healthy subjects.

Dry mouth is a multifaceted condition which is caused by reduced salivary secretion. This study aimed to evaluate and compare the effects of different lozenge surface textures, tastes and acidity levels on stimulated salivary secretion for increased oral moistening in participants without hyposalivation. This randomized, double-blind, clinical crossover trial with before and after comparison involved 33 healthy volunteers. Five lozenges, including a baseline control (C), apple (A), sour (S), sour apple (SA) and granular pectin (P) were tested on five different days with all the subjects. Salivary flow, pH value, and subjective feeling (visual analog scale) were measured before and after consuming the lozenge each day. Throughout all trial days the unstimulated whole salivary flow (UWSF) averaged 0.65 ± 0.26 ml/min. Lozenges S, SA, and P showed higher stimulated whole salivary flow (SWSF) than C (P < 0.001) by more than 0.5 ml/min. Lozenge P, with a rough surface, demonstrated the highest difference between UWSF and SWSF, 2.41 ± 0.69 ml/min. The stimulated saliva with the lozenges containing acidifiers (S, SA and P) was more than 1.4 pH units lower compared to lozenges C and A (P < 0.001). Subjects reported the strongest subjective feeling of increased saliva with lozenges SA and P. Overall lozenges SA and P provided the best objective results in enhancing salivary flow rate and subjective feeling of increased salivary flow.

The Effects of Fingolimod (FTY720) on Leukocyte Subset Circulation cannot be Behaviourally Conditioned in Rats.

Suppression of immune functions can be elicited by behavioural conditioning using drugs such as cyclosporin A or rapamycin. Nevertheless, little is known about the underlying mechanisms and generalisability of this phenomenon. Against this background, the present study investigated whether the pharmacological properties of fingolimod (FTY720), an immunosuppressive drug widely applied to treat multiple sclerosis, can be conditioned in rats by means of taste-immune associative learning. For this purpose, a conditioned taste avoidance paradigm was used, pairing the presentation of a novel sweet drinking solution (saccharin or sucrose) as conditioned stimulus (CS) with therapeutically effective doses of FTY720 as unconditioned stimulus (US). Subsequent re-exposure to the CS at a later time point revealed that conditioning with FTY720 induced a mild conditioned taste avoidance only when saccharin was employed as CS. However, on an immunological level, neither re-exposure with saccharin nor sucrose altered blood immune cell subsets or splenic cytokine production. Despite the fact that intraperitonally administered FTY720 could be detected in brain regions known to mediate neuro-immune interactions, the present findings show that the physiological action of FTY720 is not inducible by mere taste-immune associative learning. Whether conditioning generalises across all small-molecule drugs with immunosuppressive properties still needs to be investigated with modified paradigms probably using distinct sensory CS. Moreover, these findings emphasize the need to further investigate the underlying mechanisms of conditioned immunomodulation to assess the generalisability and usability of associative learning protocols as supportive therapies in clinical contexts.

Bitter taste receptors: Key target to understand the effects of polyphenols on glucose and body weight homeostasis. Pathophysiological and pharmacological implications.

Experimental and clinical research has reported beneficial effects of polyphenol intake on high prevalent diseases such as type 2 diabetes and obesity. These phytochemicals are ligands of taste 2 receptors (T2Rs) that have been recently located in a variety of organs and extra-oral tissues. Therefore, the interaction between polyphenol and T2Rs in brain structures can play a direct effect on appetite/satiety regulation and food intake. T2Rs are also expressed along the digestive tract, and their interaction with polyphenols can induce the release of gastrointestinal hormones (e.g., ghrelin, GLP-1, CCK) influencing appetite, gastrointestinal functionally, and glycemia control. Intestinal microbiota can also influence on network effects of polyphenols-T2Rs interaction and vice versa, impacting innate immune responses and consequently on gut functionally. Furthermore, polyphenols binding to T2Rs present important effects on adipose tissue metabolism. Interestingly, T2R polymorphism could, at least partially, explain the inter-individual variability of the effects of polyphenols on glucose and body weight homeostasis. Together, these factors can contribute to understand the beneficial effects of polyphenol-rich diets but also might aid in identifying new pharmacological pathway targets for the treatment of diabetes and obesity.

Bitter taste receptor activation by cholesterol and an intracellular tastant.

Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors1. Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants2-6, although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with Ggust (also known as gustducin) and Gi1. Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of Ggust and Gi1. Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants.

A taste alteration-related scale assesses megestrol to improve chemotherapy-induced anorexia.

PURPOSE: We evaluated the efficacy of megestrol in improving chemotherapy-related anorexia by analyzing the related scales of taste alteration. METHODS: We conducted the current study on a group of advanced patients with cancer with two or more chemotherapy cycles. The chemotherapy-induced taste alteration scale (CiTAs) scale helped assess the megestrol effects on basic taste perception, aversive taste changes, unpleasant symptoms, and associated concerns. Furthermore, the Short Nutritional Assessment Questionnaire scale (SNAQ) helped measure the impact of megestrol on malnutrition likelihood in patients experiencing chemotherapy-induced anorexia. The World Health Organization Quality of Life (WHOQOL)-BREF Scale was used to evaluate the quality of life of participants, producing scores related to physical health, psychological well-being, environmental factors, and social relationships. RESULTS: The CiTAs scale assessment indicated that administering megestrol significantly enhanced taste perception among advanced patients with cancer undergoing chemotherapy. Notably, the megestrol group patients showed significantly higher Short Nutritional Assessment Questionnaire (SNAQ) scores than the control group. The megestrol group patients also exhibited higher physiological (PHYS) scores than their control group counterparts. However, this distinction was not statistically significant. The study findings indicate that patients who received megestrol demonstrated significantly higher scores in psychological (PSYCH) and environmental(ENVIR) domains than the control group. Furthermore, megestrol administration was associated with significantly elevated SOCIL and ENVIR levels in patients. CONCLUSION: The proficient efficacy evaluation of megestrol in enhancing appetite, mitigating malnutrition likelihood, and improving the quality of life of chemotherapy-induced anorexic patients can be achieved through taste-related scales.

Experience-Dependent Behavioral Plasticity in Avoiding Epigallocatechin Gallate (EGCG) Requires DAF-16/FOXO in the AIY Interneurons of Caenorhabditis elegans.

Bitterness and astringency are the aversive tastes in mammals. In humans, aversion to bitterness and astringency may be reduced depending on the eating experience. However, the cellular and molecular mechanisms underlying plasticity in preference to bitter and astringent tastants remain unknown. This study aimed to investigate the preference plasticity to bitter and astringent tea polyphenols, including catechins and tannic acids, in the model animal Caenorhabditis elegans. C. elegans showed avoidance behavior against epigallocatechin gallate (EGCG), tannic acid, and theaflavin. However, they displayed diminishing avoidance against EGCG depending on their EGCG-feeding regime at larval stages. Additionally, the behavioral plasticity in avoiding EGCG required the transcription factor DAF-16/FOXO. Isoform-specific deletion mutant analysis and cell-specific rescue analysis revealed that the function of daf-16 isoform b in AIY interneurons is necessary for experience-dependent behavioral plasticity to EGCG.