Search Results (81)

Background/Objectives: Sweeteners and sweetness enhancers (S&SEs) have been proposed to potentially impair appetite regulation by stimulating sweet taste receptors beyond the perception of sweetness, similar to caloric sweeteners. The evidence is, however, not clear. Methods: This sub-study investigated the acute effects of a mixture of acesulfame potassium and cyclamate (Ace-K/Cyc) versus water on postprandial appetite sensations and energy intake at baseline, after a two-month weight loss period, and after a four-month weight loss maintenance period, including (S&SE group) or excluding S&SEs (Sugar group) in the diet. A total of 26 participants (18–65 years; BMI ≥ 25.0 kg/m²) were recruited from the one-year randomized controlled SWEET trial. Subjective appetite sensations were measured using visual analogue scales while fasting and nine times during a 250-min postprandial period. During this period, a standardized breakfast (0–10 min) was served and, 2 h later, a test drink containing either Ace-K/Cyc or water (120–130 min) was given. After 265 min, an ad libitum test meal was served. Results: Of 26 participants enrolled, 22 completed test day 2 and 16 completed test day 3. The S&SEs group rated lower prospective consumption and desire to eat something sweet after the test drink with Ace-K/Cyc compared to the sugar group consuming water (p < 0.05), with effects persisting after adjusting for taste. Initial differences in hunger were explained by taste palatability. This was true for all three test days. Ad libitum energy intake did not differ (p > 0.05). Conclusions: Ace-K/Cyc compared to water reduced feelings of prospective consumption and desire to eat something sweet acutely, after two months of weight loss, and after four months of weight loss maintenance. Due to the low sample size and power, larger studies are warranted to confirm these results. Full article

Background/Objectives: Humans have at least 26 bitter taste receptors (T2Rs), and among these, bitter taste receptor 14 (T2R14) is highly expressed in both oral and extraoral tissues. Over 100 bitter ligands can activate T2R14, including hormones, vitamins, plant compounds, and peptides. Previous studies suggest that bitter tastants such as quinine and caffeine can inhibit G protein-coupled receptor kinases (GRKs) and delay T2R signal termination. Our earlier research showed that peptides from alcalase and chymotrypsin hydrolysates of beef proteins inhibited quinine-dependent calcium release through T2R4, with AGDDAPRAVF and ETSARHL showing the greatest effectiveness. However, the effect of these antagonistic peptides on other T2Rs, such as T2R14 signaling, remains unknown. This study aimed to evaluate the ability of these beef protein-derived peptides to activate or inhibit T2R14 signaling and the involvement of GRK2 in signal termination. Methods and Results: Our results indicate that the above two antagonist peptides significantly inhibit T2R14 activity. Furthermore, GRK2 knockout in HEK cells stably expressing T2R14 decreases intracellular calcium release, as measured by the area under the curve (AUC), and also delays the fall time (indication of desensitization) of the calcium response when exposed to the T2R14 agonist diphenhydramine (DPH) or beef protein-derived agonist peptide TMTL. Next, we measured the effects of these ligands on cAMP accumulation, and our results suggest no significant change in cAMP levels upon treatment with beef protein-derived peptides. Conclusions: Thus, this study showed that beef protein-derived peptides can function as both T2R inhibitors and mediate T2R14 desensitization through GRK2 signaling. These antagonistic food protein-derived peptides inform strategies to enhance nutrition, such as promoting healthier food choices by reducing bitterness and thereby improving the palatability of health-promoting bitter foods, such as fruit and vegetable extracts, as well as bitter medications. Full article

In our previous study, a taste sensor employing a lipid/polymer membrane modified with 2,6-dihydroxyterephthalic acid (2,6-DHTPA) enabled the detection of the umami substances monosodium glutamate (MSG) and inosinate monophosphate (IMP). The taste sensor was also able to evaluate the synergistic effect, an umami enhancement phenomenon that occurs between MSG and IMP. However, the structural requirements for modifiers capable of detecting IMP have not yet been clarified. In the present study, to elucidate these requirements, nine different modifiers were prepared, and taste sensor measurements for IMP were conducted in combination with ¹H-NMR analysis. As a result, three distinct patterns were observed: (1) modifiers that exhibited chemical shift changes and generated a potential response in the positive direction (i.e., a positive potential response); (2) modifiers that showed chemical shift changes but produced either an almost zero or a negative potential response; and (3) modifiers that exhibited neither chemical shift changes nor any potential response. For receptor membranes that did not exhibit a positive response, the corresponding modifiers either lacked two carboxyl groups or did not possess intramolecular hydrogen bonding involving hydroxyl groups. From these results, it was clarified that the essential conditions for obtaining a positive potential response to IMP are that the modifier (1) contains two carboxyl groups and (2) possesses intramolecular hydrogen bonding. Full article

Type 2 diabetes (T2D) is a major global healthcare challenge and burden on the quality of life in affected individuals. While lifestyle management is the mainstay treatment for T2D, the advent of gut-incretin-based therapies with powerful effects on metabolic health, appetite and weight regulation has focussed attention on the role of the gut in the risk, progression and management of T2D. Beyond the tongue, intestinal sweet taste receptors (STRs) are increasingly being identified and functionally characterised. Growing evidence now supports a role for nutrient-activated (e.g., sugars) intestinal STRs in the release of gut hormones from enteroendocrine cells (EECs) and the control of blood glucose and body weight. However, the specific STR pathway and mechanisms linking STRs to these homeostatic controls are poorly understood, with a notable gap existing between evidence from preclinical studies and clinical validation. This review explores intestinal STR-EEC functions and the evidence on how these functions regulate glucose metabolism and energy homeostasis. We further discuss the impact of environmental and dietary factors on these signalling pathways. Full knowledge of the signalling and regulation of intestinal STR-EEC and integrated neural pathways will bridge the current knowledge gap, with a high potential to develop new novel strategies targeting STRs or EECs that preserve hedonic taste rewards and reduce cravings, as well as improve the management of individuals with metabolic diseases. Full article

Oral cancer is a leading cause of cancer-related deaths and significantly affects the quality of life of patients. However, many of its mechanisms remain unclear, and its treatment needs improvement. The G-protein-coupled receptor taste receptor type 2 member 14 (T2R14 or TAS2R14) is expressed in various cancer types. However, few studies have investigated its roles in oral cancer, and its effects on oral cancer cell proliferation and growth are unknown. This study aimed to examine T2R14’s impact on proliferation and cell population growth (CPG) of oral cancer cells. TAS2R14 gene knockout was performed, and cell numbers, cell viability, and colony formation were measured. This study showed that TAS2R14 knockout in oral cancer cells significantly decreased calcium mobilization, increased cell numbers, colony formation, the proliferation marker proliferating cell nuclear antigen, and the phosphorylation of mechanistic target of rapamycin, but did not affect cell viability. These observations are consistent with the clinical data that higher TAS2R14 mRNA expression is associated with better survival of patients with oral cancer. Therefore, T2R14 downregulation increased oral cancer CPG, suggesting a tumor-suppressor-like role. The study’s findings could improve our understanding of T2R14 mechanisms and help develop strategies to advance oral cancer treatment by targeting T2R14. Full article

Clinical reports have shown that administration of Nauclea officinalis (Danmu in Chinese, DM) preparations may cause significant gastrointestinal discomfort. This study aimed to systematically evaluate the adverse effects of DM and its primary active constituent, strictosamide, on gastrointestinal motility, intestinal barrier integrity, and gut microbiota homeostasis. Furthermore, we sought to investigate the potential role of the bitter taste receptor (T2R) signaling pathway in mediating these effects. In vitro cell cultures and ex vivo intestinal tissues were employed to assess cell viability and molecular alterations. In vivo studies involved short-term (2 weeks) gavage of DM (0.54 and 1.08 g/kg) and long-term (16 weeks) intervention (0.4, 0.8, and 1.2 g/kg) in rodents. Evaluations included histopathological examination, serum levels of cytokines and oxidative stress markers (ELISA), expression of tight junction proteins (Western blot and qPCR), and 16S rDNA sequencing of cecal microbiota. Mechanistic analyses focused on α-defensin secretion and T2R-associated gene and protein expression. Administration of DM resulted in significant gastrointestinal dysfunction, characterized by delayed intestinal propulsion and increased gastric retention. Dose-dependent histopathological damage, disruption of the intestinal barrier (reduced occludin and claudin-1 expression), and elevated levels of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), oxidative stress markers (MDA, SOD, and GSH-Px), and immune mediators (IFN-γ) were observed. Gut microbiota analysis revealed dysbiosis, marked by a decline in beneficial genera (e.g., Mucispirillum, Butyricicoccus, Roseburia) and an increase in potentially pathogenic bacteria (e.g., Citrobacter, Helicobacter). Mechanistically, DM suppressed α-defensin secretion and downregulated the expression of TAS2R108, TAS2R138, and Gα-gustducin both in vitro and in vivo. DM and strictosamide disrupt gut microbiota composition and compromise intestinal barrier function, likely through inhibition of the T2R/α-defensin pathway. These findings provide important mechanistic insights into drug-induced gastrointestinal toxicity and underscore the potential risks associated with prolonged use of DM-containing preparations. Full article

Background: Non-syndromic cleft lip/palate (NCL/P) is a prevalent congenital anomaly. Despite an unclear epidemiological link between orofacial clefts and dental caries, genetic studies suggest that polymorphisms in taste receptor genes may influence caries risk. Objectives: This study had two primary objectives: (1) to compare SNPs in NCL/P-associated genes (IRF6, FOXE1) between Kuwaiti NCL/P cases and controls, and (2) to explore whether variants in caries-associated (KLK4, DSPP) and taste receptor (TAS1R2, TAS2R38) genes are associated with dental caries susceptibility in individuals with NCL/P, independent of overall caries prevalence. Methods: A case–control design was employed, with 25 NCL/P cases and 25 unaffected controls recruited from a Dental Craniofacial Clinic in Kuwait. Genomic DNA was extracted from buccal swabs, and SNP genotyping was performed using real-time PCR for genes related to NCL/P, dental caries, and taste perception. Caries status was assessed using the dmft/DMFT scoring system. The genotyped genes included NCL/P-related (IRF6, FOXE1), caries-related (KLK4, DSPP), and taste receptor genes (TAS1R2, TAS2R38). Results: At nominal significance, KLK4, DSPP, and TAS1R2 showed associations with NCL/P status, while IRF6 and FOXE1 did not. After applying Benjamini–Hochberg FDR correction across 10 SNPs, no allele- or genotype-level association remained significant (q < 0.05). The strongest signal was KLK4 rs2235091 (allele-level p = 0.016; q = 0.159). An exploratory age- and sex-adjusted logistic model for KLK4 suggested a possible effect (aOR 0.40; 95% CI 0.18–0.87; p = 0.021). Within-group analyses of caries burden revealed no associations that survived FDR control (lowest q = 0.056 for FOXE1 in controls). Conclusions: After controlling for multiple testing, no SNP showed a statistically significant association with NCL/P or caries burden. Nominal signals for KLK4, DSPP, and TAS1R2 did not survive FDR correction; an exploratory adjusted model suggested a possible KLK4 effect, but this requires cautious interpretation. The small sample size is a key limitation, and the findings highlight the need for larger, well-powered studies to clarify genetic contributions to NCL/P and caries risk. Full article

Taste receptor type 1 member 3 (TAS1R3) is a class C G protein-coupled receptor (GPCR) traditionally associated with taste perception. While its role in insulin secretion is established, its contribution to skeletal muscle glucose uptake, a process responsible for 70–80% of postprandial glucose disposal, remains unclear. TAS1R3 expression was assessed in skeletal muscle biopsies from non-diabetic and type 2 diabetes (T2D) donors using qPCR and immunoblotting. Functional studies in human LHCN-M2 myotubes involved TAS1R3 inhibition with lactisole or siRNA-mediated knockdown, followed by the measurement of insulin-stimulated glucose uptake using radiolabeled glucose assays. Rac1 activation and phospho-cofilin were analyzed by G-LISA and Western blotting, and Gαq/11 involvement was tested using YM-254890. TAS1R3 mRNA and protein levels were significantly reduced in T2D skeletal muscle. Pharmacological inhibition or the knockdown of TAS1R3 impaired insulin-stimulated glucose uptake in myotubes. TAS1R3 regulates skeletal muscle glucose uptake through a non-canonical insulin signaling pathway involving Rac1 and phospho-cofilin, independent of IRS1-AKT and Gαq/11 signaling. These findings identify TAS1R3 as a key determinant of Rac1-mediated glucose uptake and a potential therapeutic target for improving insulin sensitivity in T2D. Full article

Importance: The coronavirus disease 2019 (COVID-19) was the third leading cause of mortality in the United States for three years in a row. The genetic contributions to disease severity remain unclear and many previously identified single nucleotide polymorphisms (SNPs) have not been replicated nor linked with functional significance. Objective: To identify SNPs associated with mortality among hospitalized COVID-19 patients supplemented by expression quantitative trait loci (eQTL) evidence to infer plausible functional mechanisms related to COVID-19 severity. Design: A quality-controlled genome-wide association study (GWAS) supported by robust gene-level omnibus kernel association tests (SKAT-O), functional prediction, and eQTL analyses of the top GWAS signal. Setting: Massachusetts General Hospital (MGH). Participants: 370 adult ICU patients with SARS-CoV-2 infection and acute hypoxemic respiratory failure and floor patients with mild hypoxemia managed with supplemental oxygen consecutively admitted to MGH between March and June 2020 (Surge 1), and January and March 2021 (Surge 2) with baseline clinical characteristics and demographics collected. Exposures: Low-pass genotyped SNPs from whole blood and aggregated SNP-sets of potential disease susceptibility loci with $\pm$500 kb flanking regions. Main Outcomes & Measures: Genome-wide individual SNP associations and SNP-set associations with mortality outcomes from 370 severe COVID-19 cases. Results: After LD pruning (<0.8) and false discovery rate adjustment (<0.05), we identified rs7420371 G>A of the receptor transporter protein 5 (RTP5) gene as the top independent signal significantly associated with 30- and 60-day mortality among severe COVID-19 patients (OR, 2.32; 95% CI, 1.59–3.39; p = 4.92 × 10⁻⁹ and OR, 2.06; 95% CI, 1.43–2.97; p = 5.43 × 10⁻⁸, respectively). SKAT-O analyses on the RTP5 SNP-set showed associations with both mortality outcomes (p = 5.90 × 10⁻⁵ and 6.17 × 10⁻⁵, respectively). eQTL analysis showed rs7420371 A allele significantly upregulated the mRNA expression of RTP5 in 266 cerebellum tissues, in 277 cerebellar hemisphere tissues, and in 270 cerebral cortex samples. Conclusions & Relevance: We discovered a novel, independent, and potentially functional SNP RTP5 rs7420371 G>A to be significantly associated with COVID-19 mortality. The A allele is significantly associated with elevated mRNA expression of RTP5 in the brain, an important protein coding gene that modulates olfactory binding and taste perceptions in response to SARS-CoV-2 infection. Full article

Background/Objectives: Fat, a newly researched taste, has been associated with the cluster of differentiation 36 (CD36) gene, which codes for the CD36 receptor protein. The rs1761667 variant has been associated with fat taste sensitivity. Furthermore, umami is a well-established taste with known receptors. The combination of these tastes is common in food; nevertheless, they have not been extensively investigated together. This study aimed to assess whether CD36 rs1761667 is associated with food liking and the perception of fat and umami foods. Methods: Two studies were conducted: A field study on 235 individuals from Italy and a laboratory study on 49 individuals from the UK. Data includes demographics, anthropometrics, a food liking questionnaire or a fat and umami food flavour test, dietary intake assessment, and rs1761667 genotyping. Results: Study 1: The rs1761667 A-allele was associated with a reduced liking for fatty and umami foods in individuals with BMI ≥ 25. Study 2: The rs1761667 A-allele was associated with an increased intensity of the umami food samples, and a significant positive association of rs1761667 with BMI and DQS was found. Conclusions: This study is the first to address the potential links between rs1761667, fat, umami, diet, and BMI. Further research is required to confirm these findings. Full article

The rise in diabetes and obesity worldwide has created an urgent demand for low-sugar, nutrient-dense foods with appealing flavors. This study established an endogenous and “rapid validation–stable production” platform to enhance the flavor of edible tomato fruits by integrating two key technologies in the MicroTom cherry tomato: (1) TRV viral vector-mediated transient expression and (2) Agrobacterium-mediated stable genetic transformation. We employed the human sweet taste receptor TAS1R2 for in vitro functional validation and objectively demonstrated that tomato-derived recombinant thaumatin II exhibits receptor-binding activity equivalent to that of the native protein, overcoming the limitations of traditional sensory evaluation. Non-targeted metabolomic analysis (covering 1236 metabolites) confirmed that thaumatin II expression did not significantly alter the profiles of sugars, organic acids, or key flavor compounds in tomato fruits. This provides safety data supporting the development of “ready-to-eat sugar-substitute fruits.” Our strategy offers a solution and theoretical technical support for the development of low-sugar, high-nutrient foods. Full article

Background/Objectives: Dysgeusia is a taste disorder commonly associated with chronic inflammation, reducing the quality of life, particularly in ageing populations or individuals with non-communicable chronic diseases. This study aimed to evaluate the effect of β-Caryophyllene, a natural sesquiterpene and agonist of the cannabinoid receptor 2 (CB2), on dysgeusia through an analysis of inflammation, Renin–Angiotensin System (RAS) and taste perception. Methods: Male BALB/c mice were subjected to a dysgeusia model induced by molecular mimicry with lipopolysaccharide. Animals received intraperitoneal injections of lipopolysaccharide in a chronic–persistent regimen, starting at a dose of 35 μg/100 g body weight for 7 days until reaching a final concentration of 250 μg/100 g and a daily oral administration of β-Caryophyllene at a dose of 10 mg/kg. The effect of β-Caryophyllene on taste perception, inflammatory biomarkers, RAS key-elements, CB2 expression and physiological parameters was evaluated. Results: Data indicate that β-Caryophyllene attenuates systemic inflammation by decreasing IL-1β and IL-6 and increasing ACE2 enzymatic activity in lingual tissue. Also, it was shown that the sesquiterpene reduced taste cell apoptosis and improved sucrose preference, suggesting a feasible restoration of taste dysfunction. Conclusions: These findings demonstrate that β-Caryophyllene could be a potential candidate for treating dysgeusia due to its putative anti-inflammatory and angiotensinergic effects. Full article

Background/Objectives: Bitter Taste Receptors (encoded by TAS2R genes) are expressed in mucosal and bronchial epithelia, as well as in immune cells, contributing to defense against airborne pathogens such as SARS-CoV-2. Data on single-nucleotide polymorphisms (SNPs) in TAS2R genes or pseudogenes in COVID-19 are limited. This study examined the association between TAS2R SNPs and COVID-19 infection and seroconversion in European individuals participating in the Canadian Longitudinal Study on Aging. Methods: Data from the Genome-wide Genetic Data, Comprehensive Baseline (version 7.0), Follow-up 2 (version 1.1), COVID-19 Questionnaire Study (4-2020 to 12-2020), and COVID-19 Seroprevalence (Antibody) Study (11-2020 to 7-2021) datasets were accessed. Associations of TAS2R SNPS with COVID-19 infection or seroconversion were determined using logistic regression adjusted for sociodemographics, genetic principal components, smoking, vaccine doses, and chronic medical conditions (diabetes, immune-mediated inflammatory diseases (IMIDs), respiratory disease, and cardiovascular disease). Results: In the COVID-19 Questionnaire Study (N = 14,073), the rs117458236 (C) variant in TAS2R20 showed a trend toward an association with COVID-19 infection (OR = 1.95; 95% Confidence Interval (CI): 0.98, 3.51). In the COVID-19 Antibody Study (N = 8313), the rs2234235(G) variant in TAS2R1 was associated with anti-nucleocapsid (OR = 1.55; CI: 1.06, 2.20) and anti-spike response (OR = 0.74; CI: 0.57, 0.98); the rs2234010(A) variant in TAS2R5 was associated with anti-nucleocapsid (OR = 1.56; CI: 1.08, 2.19); and the rs34039200(A) variant in TAS2R62P was associated with anti-spike (OR = 0.86; CI: 0.77, 0.97). In a subgroup analysis, the rs2234235(G) variant in TAS2R1 was associated with a decreased anti-spike response to infection or vaccination in individuals with IMIDs or respiratory disease and an increased risk of SARS-CoV-2 infection. Conclusions: TAS2R variants are associated with COVID-19 infection and vaccine response. These data may inform personalized management and vaccination strategies. Full article

Background: Sweet taste adaptation, the decline in perceived sweetness with repeated exposure, may influence dietary behavior and differs across sweeteners. Low-calorie sweeteners (LCSs) such as sucralose strongly activate the T1R2+T1R3 receptor and are generally associated with greater adaptation than sugars, although this effect can be reduced with sweetener blends. Aim: We investigated whether habitual LCS consumption affects sweet taste perception and whether blending sucralose with small amounts of sugars attenuates adaptation using sensory tests in humans and in vivo calcium imaging in a rodent model. Methods: In study 1, habitual (HC; n = 39) and non-habitual (NHC; n = 42) LCS consumers rate sweetness of sucralose (0.6 mM), glucose (800 mM), fructose (475 mM), and blends with low glucose (111 mM) or fructose (45 mM) across repeated trials (1–10) using a generalized labeled magnitude scale. In study 2, a microfluidic-based intravital tongue imaging system was used to assess in vivo responses to sweet adaptation in genetically modified C57BL/6 mice (n = 8) expressing a calcium indicator in type II/III cells of taste buds. Results: Habitual LCS use was not associated with differences in sweetness perception or adaptation (all p-values > 0.6). Sucralose alone produced stronger adaptation than when blended with sugars in both humans (p-values < 0.002) and mice (p < 0.001). Glucose and fructose alone showed adaptation (relative decrease reached on final trial compared to the first trial: −27% ± 4% for glucose, −38% ± 5% for fructose, both p-values < 0.002) but to a lower degree compared with sucralose (−66% ± 5%). Conclusions: Sweetener composition, rather than habitual LCS use, drives sweet taste adaptation. Blending sucralose with small amounts of sugars reduces adaptation at both perceptual and cellular levels, providing mechanistic insights relevant to the formulation of LCS products. Full article

This study was designed to systematically identify novel umami peptides in lager beer, clarify their molecular interactions with the T1R1/T1R3 receptor, and determine their specific effects on multidimensional sensory attributes. The peptides were characterized by LC-MS/MS combined with de novo sequencing, and 906 valid sequences were obtained. Machine-learning models (UMPred-FRL, Tastepeptides-Meta, and Umami-MRNN) predicted 76 potential umami peptides. These candidates were docked to T1R1/T1R3 with the CDOCKER protocol, producing 57 successful complexes. Six representative peptides—KSTEL, DELIK, DIGISSK, IEKYSGA, DEVR, and PVPL—were selected for 100 ns molecular-dynamics simulations and MM/GBSA binding-energy calculations. All six peptides stably occupied the narrow cleft at the T1R1/T1R3 interface. Their binding free energies ranked as DEVR (−44.09 ± 5.47 kcal mol⁻¹) < KSTEL (−43.21 ± 3.45) < IEKYSGA (−39.60 ± 4.37) ≈ PVPL (−39.53 ± 2.52) < DELIK (−36.14 ± 3.11) < DIGISSK (−26.45 ± 4.52). Corresponding taste thresholds were 0.121, 0.217, 0.326, 0.406, 0.589, and 0.696 mmol L⁻¹ (DEVR < KSTEL < IEKYSGA < DELIK < PVPL < DIGISSK). TDA-based sensory validation with single-factor additions showed that KSTEL, DELIK, DEVR, and PVPL increased umami scores by ≈21%, ≈22%, ≈17%, and ≈11%, respectively, while DIGISSK and IEKYSGA produced marginal changes (≤2%). The short-chain peptides thus bound with high affinity to T1R1/T1R3 and improved core taste and mouthfeel but tended to amplify certain off-flavors, and the long-chain peptides caused detrimental impacts. Future formulation optimization should balance flavor enhancement and off-flavor suppression, providing a theoretical basis for targeted brewing of umami-oriented lager beer. Full article