From the genesis to the present: The evolution of sublingual immunotherapy for cedar pollinosis.

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.

Potential exacerbation of polycystic ovary syndrome by saccharin sodium Via taste receptors in a letrozole rat model.

The most common cause of anovulatory infertility is polycystic ovarian syndrome (PCOS), which is closely associated with obesity and metabolic syndrome. Artificial sweetener, notably saccharin sodium (SS), has been utilized in management of obesity in PCOS. However, accumulating evidence points towards SS deleterious effects on ovarian physiology, potentially through activation of ovarian sweet and bitter taste receptors, culminating in a phenotype reminiscent of PCOS. This research embarked on exploration of SS influence on ovarian functions within a PCOS paradigm. Rats were categorized into six groups: Control, Letrozole-model, two SS groups at 2 dose levels, and two groups receiving 2 doses of SS with Letrozole. The study underscored SS capability to potentiate PCOS-related anomalies. Elevated cystic profile with outer thin granulosa cells, were discernible. This owed to increased apoptotic markers as cleaved CASP-3, mirrored by high BAX and low BCL-2, with enhanced p38-MAPK/ERK1/2 pathway. This manifestation was accompanied by activation of taste receptors and disruption of steroidogenic factors; StAR, CYP11A1, and 17ß-HSD. Thus, SS showed an escalation in testosterone, progesterone, estrogen, and LH/FSH ratio, insinuating a perturbation in endocrine regulation. It is found that there is an impact of taste receptor downstream signaling on ovarian steroidogenesis and apoptosis instigating pathophysiological milieu of PCOS.

Bitter Taste Receptor 46 (hTAS2R46) Protects Monocytes/Macrophages from Oxidative Stress.

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.

Gastrointestinal delivery of bitter hop extract reduces appetite and food cravings in healthy adult women undergoing acute fasting.

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).

Intestinal Taste Receptor Expression and Its Implications for Health: An Integrative Analysis in Female Rats after Chronic Insect Supplementation.

Taste receptors are found in the gastrointestinal tract, where they are susceptible to dietary modulation, a key point that is crucial for diet-related responses. Insects are sustainable and good-quality protein sources. This study analyzed the impact of insect consumption on the modulation of taste receptor expression across various segments of the rat intestine under healthy or inflammatory conditions. Female Wistar rats were supplemented with Tenebrio molitor (T) or Alphitobius diaperinus (B), alongside a control group (C), over 21 days under healthy or LPS-induced inflammation. The present study reveals, for the first time, that insect consumption modulates taste receptor gene expression, mainly in the ascending colon. This modulation was not found under inflammation. Integrative analysis revealed colonic Tas1r1 as a key discriminator for insect consumption (C = 1.04 ± 0.32, T = 1.78 ± 0.72, B = 1.99 ± 0.82, p-value <0.05 and 0.01, respectively). Additionally, correlation analysis showed the interplay between intestinal taste receptors and metabolic and inflammatory responses. These findings underscore how insect consumption modulates taste receptors, influencing intestinal function and broader physiological mechanisms.

The taste for health: the role of taste receptors and their ligands in the complex food/health relationship.

Taste, food, and health are terms that have since always accompanied the act of eating, but the association was simple: taste serves to classify a food as good or bad and therefore influences food choices, which determine the nutritional status and therefore health. The identification of taste receptors, particularly, the G protein-coupled receptors that mediate sweet, umami, and bitter tastes, in the gastrointestinal tract has assigned them much more relevant tasks, from nutrient sensing and hormone release to microbiota composition and immune response and finally to a rationale for the gut-brain axis. Particularly interesting are bitter taste receptors since most of the times they do not mediate macronutrients (energy). The relevant roles of bitter taste receptors in the gut indicate that they could become new drug targets and their ligands new medications or components in nutraceutical formulations. Traditional knowledge from different cultures reported that bitterness intensity was an indicator for distinguishing plants used as food from those used as medicine, and many non-cultivated plants were used to control glucose level and treat diabetes, modulate hunger, and heal gastrointestinal disorders caused by pathogens and parasites. This concept represents a means for the scientific integration of ancient wisdom with advanced medicine, constituting a possible boost for more sustainable food and functional food innovation and design.

Activation of bitter taste receptors (TAS2R) protects against rotenone-induced neurotoxicity: Could ghrelin have a role?

AIMS: Bitter taste receptors (TAS2Rs) and their downstream signaling pathways are expressed not only in the oral tissues but also in extraoral tissues. Emerging data has demonstrated the beneficial effect of ghrelin in neurodegenerative diseases. Gaining more insight into the interaction between TAS2Rs and gut hormones may expand their therapeutic applications. Herein, we aimed to assess the possible effect of TAS2R activation by denatonium benzoate (DB) in modulating functional and neurobiochemical alterations in a model of Parkinson's disease (PD). MAIN METHODS: PD model was induced by daily injection of rotenone (2 mg/kg). Rats received DB (5 mg/kg), atenolol (10 mg/kg), or both concomitantly with rotenone, daily for 28 days. Evaluation of the motor abnormalities and histological examination of brain tissues were conducted. In addition, striatal dopamine contents, immunohistochemical expression of tyrosine hydroxylase, plasma ghrelin level, and biochemical analysis of markers of inflammation and oxidative stress were assessed. KEY FINDINGS: Treatment with DB increased serum levels of ghrelin and striatal dopamine contents with consequent amelioration of oxidative stress and attenuation of inflammatory cytokines. Moreover, DB treatment significantly ameliorated motor disturbance and histological abnormalities compared to untreated rats. Atenolol inhibited ghrelin release and abolished the positive effect of DB suggesting the involvement of ghrelin on such effects. SIGNIFICANCE: The current study suggests that TAS2Rs agonists are promising candidates for ameliorating rotenone-induced PD pathology in rats, an action that could be linked to the enhancement of ghrelin release with consequent antioxidant and anti-inflammatory activities.

A Pharmacological perspective on the temporal properties of sweeteners.

Several non-caloric sweeteners exhibit a delay in sweetness onset and a sweetness linger after sampling. These temporal properties are thought to be the result of non-specific interactions with cell membranes and proteins in the oral cavity. Data and analysis presented in this report also support the potential involvement of receptor affinity and binding kinetics to this phenomenon. In general, affected sweeteners exhibit distinctly higher binding affinity compared to carbohydrate sweeteners, which do not have temporal issues. In addition, binding kinetic simulations illustrate much slower receptor binding association and dissociation kinetics for a set of non-caloric sweeteners presenting temporal issues, in comparison to carbohydrate sweeteners. So, the higher affinity of some non-caloric sweeteners, dictating lower use levels, and affecting binding kinetics, could contribute to their delay and linger in sweetness perception. Simple pharmacology principles could explain, at least in part, some of the temporal issues of sweeteners.

Machine learning approaches to predict TAS2R receptors for bitterants.

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

Gastric digestion of the sweet-tasting plant protein thaumatin releases bitter peptides that reduce H. pylori induced pro-inflammatory IL-17A release via the TAS2R16 bitter taste receptor.

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.

[Sweet protein brazzein as a promising sweetener].

The excessive consumption of sugar-containing foods contributes to the development of a number of diseases, including obesity, diabetes mellitus, etc. As a substitute for sugar, people with diabetes mellitus and obesity most often use sweeteners. Sweet proteins, in particular brazzein, are an alternative to synthetic sweeteners that have natural origin, are broken down in the intestines along with food proteins, and do not affect blood sugar and insulin levels. The purpose of the review was to analyze the available data on the sweet protein brazzein, its physical and chemical properties, existing biotechnological methods of production, and prospects for application in the food industry in order to further develop an optimized heterologous expression system. Material and methods. Google Scholar, Scopus, Web of Science, PubMed, RSCI and eLibrary.ru databases were used for collecting and analyzing literature. Search depth - 30 years. Results. Numerous studies of the physical and chemical properties of brazzein have demonstrated its high potential for use in the food industry. In particular, a short amino acid sequence, thermal stability, the ability to maintain its structure and sweet properties in a wide pH range, hypoallergenicity, lack of genotoxicity, and an extremely high level of sweetness compared to sucrose allow us to conclude that its use is promising. Mutant variants of brazzein have been generated, the sweetest of which (with three amino acid substitutions H31R/E36D/E41A) exceeds sucrose sweetness by 22 500 times. To date, various systems for the expression of recombinant brazzein have already been developed, in which bacteria (Escherichia coli, Lactococcus lactis, Bacillus licheniformis), yeast (Komagataella phaffii, Kluyveromyces lactis, Saccharomyces cerevisiae), plants (Zea mays, Oryza sativa, Lactuca sativa, Nicotiana tabacum, Daucus carota) and animals (Mus musculus) have been used. Conclusion. Due to its high sweetness, organoleptic properties and long history of human consumption, brazzein can be considered as a promising natural sweetener. Despite the short peptide sequence, the production of the recombinant protein faced a number of problems, including low protein yield (for example, it could only be detected in mouse milk by Western blot hybridization) and loss of sweetness. Thus, further optimization of the process is necessary for widespread brazzein use in the food industry, which includes the selection of an adequate producer and the use of extracellular expression systems to reduce the final cost of the product.

Identification of mozambioside roasting products and their bitter taste receptor activation.

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-ß-d-glucosyl-11-hydroxycafestol-2-on, 11-O-ß-d-glucosyl-16-desoxycafestol-2-on, 11-O-ß-d-glucosyl-(S)-16-desoxy-17-oxocafestol-2-on, 11-O-ß-d-glucosyl-15,16-dehydrocafestol-2-on, and 11-O-ß-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-ß-d-glucosyl-(S)-16-desoxy-17-oxocafestol-2-on, 11-O-ß-d-glucosyl-15,16-dehydrocafestol-2-on, and 11-O-ß-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-ß-d-glucosyl-15,16-dehydrocafestol-2-on and 11-O-ß-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-ß-d-glucosyl-11-hydroxycafestol-2-on, 11-O-ß-d-glucosyl-(S)-16-desoxy-17-oxocafestol-2-on, 11-O-ß-d-glucosyl-15,16-dehydrocafestol-2-on, and 11-O-ß-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.

Food bioactive peptides: functionality beyond bitterness.

Bitter taste is an aversive taste because it is unconsciously associated with toxic compounds. However, a considerable variability in bitter sensitivity exists in those who have the genetic polymorphism for bitter taste receptors (TAS2Rs). Besides the oral cavity, TAS2Rs are present in many body tissues, including the gastrointestinal tract; therefore, they are crucial players both in the gustatory/hedonic system and in the homeostatic system, triggering numerous biological responses, including adipogenesis, carcinogenesis, or immunity. Bitter-tasting compounds are widely distributed in plant and animal foods and belong to many chemical classes. In this study, the evidence was reviewed on bitter peptides, considering the food sources, their formation in food under different processing and storage conditions and in the gastrointestinal tract during digestion, as well as their biological activities. Bitterness associated with peptides is due to the presence of hydrophobic amino acids in the C-terminus. The current literature mainly explores the enzymes and hydrolysis conditions, with the aim of reducing the formation of bitter peptides in hydrolysate preparation or food. Few studies highlight the bioactivity (namely, antihypertensive, antidiabetic, antioxidant, or immunity boosting), besides the bitterness. However, encapsulation of bitter peptides has been tentatively used to develop antihypertensive and antidiabetic supplements. In the era of personalized nutrition and precision medicine, the evidence available suggests the opportunity to use bitter bioactive peptides as functional ingredients in food. Such types of food may modulate a plethora of physiological mechanisms by targeting TAS2Rs in the gastrointestinal tract, thus modulating appetite sensations or gastrointestinal motility and discomfort according to individual nutritional needs and goals. More studies are needed to optimize the technological strategies to target TAS2Rs by bitter bioactive peptides, improve their stability in food, and validate the biological efficacy through well-designed in vivo studies.

The dark sides of the GPCR tree - research progress on understudied GPCRs.

A large portion of the human GPCRome is still in the dark and understudied, consisting even of entire subfamilies of GPCRs such as odorant receptors, class A and C orphans, adhesion GPCRs, Frizzleds and taste receptors. However, it is undeniable that these GPCRs bring an untapped therapeutic potential that should be explored further. Open questions on these GPCRs span diverse topics such as deorphanisation, the development of tool compounds and tools for studying these GPCRs, as well as understanding basic signalling mechanisms. This review gives an overview of the current state of knowledge for each of the diverse subfamilies of understudied receptors regarding their physiological relevance, molecular mechanisms, endogenous ligands and pharmacological tools. Furthermore, it identifies some of the largest knowledge gaps that should be addressed in the foreseeable future and lists some general strategies that might be helpful in this process.

The importance of taste on swallowing function.

The world's population is aging. Pneumonia is the leading cause of death among the older adults, with aspiration pneumonia being particularly common. Aspiration pneumonia is caused by a decline in swallowing function. Causes can include age-related sarcopenia of swallowing muscles, cognitive decline, cerebrovascular and other diseases or even changes in individual taste preference. Currently, the main treatment approach for dysphagia is resistance training of swallowing-related muscles. This approach has not been effective and establishment of novel methods are required. In this review, we introduce and discuss the relationship between taste, taste preference, carbonation and swallowing function. Taste and preference improve swallowing function. Recently, it has been shown that a carbonated beverage that combines the functionality of a thickening agent, the appeal of taste, and the stimulation of carbonation improves swallowing function. This may be very useful in the recovery of swallowing function. It is important to note that deliciousness is based not only on taste and preference, but also on visual information such as food form. Umami taste receptors are expressed not only in taste buds but also in skeletal muscle and small intestine. These receptors may be involved in homeostasis of the amino acid metabolic network, i.e., the process of amino acid ingestion, intestine absorption, and storage in skeletal muscle. Proper stimulation of umami receptors in organs other than taste buds may help maintain nutritional status and muscle mass. Umami receptors are therefore a potential therapeutic target for dysphagia.

Sodium-Permeable Ion Channels TRPM4 and TRPM5 are Functional in Human Gastric Parietal Cells in Culture and Modulate the Cellular Response to Bitter-Tasting Food Constituents.

Gastric parietal cells secrete chloride ions and protons to form hydrochloric acid. Besides endogenous stimulants, e.g., acetylcholine, bitter-tasting food constituents, e.g., caffeine, induce proton secretion via interaction with bitter taste receptors (TAS2Rs), leading to increased cytosolic Ca2+ and cAMP concentrations. We hypothesized TAS2R activation by bitter tastants to result in proton secretion via cellular Na+ influx mediated by transient receptor potential channels (TRP) M4 and M5 in immortalized human parietal HGT-1 cells. Using the food-derived TAS2R agonists caffeine and l-arginine, we demonstrate both bitter compounds to induce a TRPM4/M5-mediated Na+ influx, with EC50 values of 0.65 and 10.38 mM, respectively, that stimulates cellular proton secretion. Functional involvement of TAS2Rs in the caffeine-evoked effect was demonstrated by means of the TAS2R antagonist homoeriodictyol, and stably CRISPR-Cas9-edited TAS2R43ko cells. Building on previous results, these data further support the suitability of HGT-1 cells as a surrogate cell model for taste cells. In addition, TRPM4/M5 mediated a Na+ influx after stimulating HGT-1 cells with the acetylcholine analogue carbachol, indicating an interaction of the digestion-associated cholinergic pathway with a taste-signaling pathway in parietal cells.

BitterDB database analysis plus cell stiffness screening identify flufenamic acid as the most potent TAS2R14-based relaxant of airway smooth muscle cells for therapeutic bronchodilation.

Rationale: Bitter taste receptors (TAS2Rs) are abundantly expressed in airway smooth muscle cells (ASMCs), which have been recognized as promising targets for bitter agonists to initiate relaxation and thereby prevent excessive airway constriction as the main characteristic of asthma. However, due to the current lack of tested safe and potent agonists functioning at low effective concentrations, there has been no clinically approved TAS2R-based drug for bronchodilation in asthma therapy. This study thus aimed at exploring TAS2R agonists with bronchodilator potential by BitterDB database analysis and cell stiffness screening. Methods: Bitter compounds in the BitterDB database were retrieved and analyzed for their working subtype of TAS2R and effective concentration. Compounds activating TAS2R5, 10, and 14 at < 100 µM effective concentration were identified and subsequently screened by cell stiffness assay using optical magnetic twisting cytometry (OMTC) to identify the most potent to relax ASMCs. Then the compound identified was further characterized for efficacy on various aspects related to relaxation of ASMCs, incl. but not limited to traction force by Fourier transform traction force microscopy (FTTFM), [Ca2+]i signaling by Fluo-4/AM intensity, cell migration by scratch wound healing, mRNA expression by qPCR, and protein expressing by ELISA. The compound identified was also compared to conventional ß-agonist (isoproterenol and salbutamol) for efficacy in reducing cell stiffness of cultured ASMCs and airway resistance of ovalbumin-treated mice. Results: BitterDB analysis found 18 compounds activating TAS2R5, 10, and 14 at < 100 µM effective concentration. Cell stiffness screening of these compounds eventually identified flufenamic acid (FFA) as the most potent compound to rapidly reduce cell stiffness at 1 µM. The efficacy of FFA to relax ASMCs in vitro and abrogate airway resistance in vivo was equivalent to that of conventional ß-agonists. The FFA-induced effect on ASMCs was mediated by TAS2R14 activation, endoplasmic reticulum Ca2+ release, and large-conductance Ca2+-activated K+ (BKCa) channel opening. FFA also attenuated lipopolysaccharide-induced inflammatory response in cultured ASMCs. Conclusions: FFA as a potent TAS2R14 agonist to relax ASMCs while suppressing cytokine release might be a favorite drug agent for further development of TAS2R-based novel dual functional medication for bronchodilation and anti-inflammation in asthma therapy.

The effect of bariatric surgery on the expression of gastrointestinal taste receptors: A systematic review.

Gastrointestinal nutrient sensing via taste receptors may contribute to weight loss, metabolic improvements, and a reduced preference for sweet and fatty foods following bariatric surgery. This review aimed to investigate the effect of bariatric surgery on the expression of oral and post-oral gastrointestinal taste receptors and associations between taste receptor alterations and clinical outcomes of bariatric surgery. A systematic review was conducted to capture data from both human and animal studies on changes in the expression of taste receptors in oral or post-oral gastrointestinal tissue following any type of bariatric surgery. Databases searched included Medline, Embase, Emcare, APA PsychInfo, Cochrane Library, and CINAHL. Two human and 21 animal studies were included. Bariatric surgery alters the quantity of many sweet, umami, and fatty acid taste receptors in the gastrointestinal tract. Changes to the expression of sweet and amino acid receptors occur most often in intestinal segments surgically repositioned more proximally, such as the alimentary limb after gastric bypass. Conversely, changes to fatty acid receptors were observed more frequently in the colon than in the small intestine. Significant heterogeneity in the methodology of included studies limited conclusions regarding the direction of change in taste receptor expression induced by bariatric surgeries. Few studies have investigated associations between taste receptor expression and clinical outcomes of bariatric surgery. As such, future studies should look to investigate the relationship between bariatric surgery-induced changes to gut taste receptor expression and function and the impact of surgery on taste preferences, food palatability, and eating behaviour.Registration code in PROSPERO: CRD42022313992.

Phenanthroline relaxes uterine contractions induced by diverse contractile agents by decreasing cytosolic calcium concentration.

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.

Bitter taste receptors in the reproductive system: Function and therapeutic implications.

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.