Role of bitter contributors and bitter taste receptors:a comprehensive review of their sources,functions and future development

Bitterness,one of the 5“basic tastes”,is usually undesired by humans.However,abundant literature reported that bitter fruits and vegetables have beneficial health effects due to their bitter contributors.This review provided an updated overview of the main bitter contributors of typical bitter fruits and vegetables and their health benefits.The main bitter contributors,including phenolics,terpenoids,alkaloids,amino acids,nucleosides and purines,were summarized.The bioactivities and wide range of beneficial effects of them on anti-cancers,anti-inflammations,anti-microbes,neuroprotection,inhibiting chronic and acute injury in organs,as well as regulating behavior performance and metabolism were reported.Furthermore,not only did the bitter taste receptors(taste receptor type 2 family,T2Rs)show taste effects,but extra-oral T2Rs could also be activated by binding with bitter components,regulating physiological activities via modulating hormone secretion,immunity,metabolism,and cell proliferation.This review provided a new perspective on exploring and explaining the nutrition of bitter foods,revealing the relationship between the functions of bitter contributors from food and T2Rs.Future trends may focus on revealing the possibility of T2Rs being targets for the treatment of diseases,exploring the mechanism of T2Rs mediating the bioactivities,and making bitter foods more acceptable without getting rid of bitter contributors.

Etiopathogenesis of reproductive tract infections and the emerging role of bitter taste receptors:A scoping review

Reproductive tract infections pose an immense public health concern worldwide as over 600 million new cases are recorded annually along with several complications,including infertility,ectopic pregnancy,preterm delivery,and neonatal death.Despite improved understanding of the mechanisms of pathogenic invasion,the etiopathogenesis of reproductive tract infections is yet to be completely understood.Recent data has suggested a critical role of bitter taste receptors of the reproductive tract in etiopathogenesis of reproductive tract infections.Here,we review the literature on current etiopathogenesis of reproductive tract infections and the role of bitter taste receptors of the reproductive tract in etiopathogenesis of reproductive tract infections.Emerging evidence suggests a critical role of microbiota disorder of the reproductive tract in reproductive tract infections.Several bacterial,protozoan parasitic,helminthic parasitic and viral pathogens have been identified as causative agents of reproductive tract infections.These pathogens subvert host defenses and activate specific architectural units of the uroepithelium such as Toll-like receptors,which recognize conserved motifs on the pathogens.The activated Toll-like receptors mediate downstream signaling,stimulating nuclear factor-κB,which in turn activates the production of proinflammatory cytokines.This pathway is also associated with recruitment of immunocytes to the site of aggression and release of proteinases,which drive tissue damage in the reproductive tract.Defects in detection of pathogenic components by the bitter taste receptors of the reproductive tract may play a critical role in the etiopathogenesis of reproductive tract infections.This review provides important information for identification of novel frontiers for the treatment of reproductive tract infections.

Genetic mutation of Tas2r104/Tas2r105/Tas2r114 cluster leads to a loss of taste perception to denatonium benzoate and cucurbitacin B

Background:Bitter taste receptors(Tas2rs)are generally considered to sense various bitter compounds to escape the intake of toxic substances.Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo.Methods:To investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues,multiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene-editing technique.A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes.Then,T7EN1 assays and sequencing were used to screen genetic mutation at the target sites in founder mice.Quantitative real-time polymerase chain reaction(qRT-PCR)and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds.Perception to taste substance was also studied using twobottle preference tests.Results:We successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique.Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice.But qRT-PCR results revealed the changed expression profile of m Tas2rs gene in taste buds of these mutant mice.With two-bottle preference tests,these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105.In addition,these mutant mice showed a loss of taste perception to quinine dihydrochloride,denatonium benzoate,and cucurbitacin B(CuB).Gnat3-mediated taste receptor and its signal pathway contribute to CuB perception.Conclusions:These findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound-induced responses mediated by these TAS2Rs in many extraoral tissues.

The role of bitter and sweet taste receptors in upper airway innate immunity: Recent advances and future directions

Bitter(T2R)and sweet(T1R)taste receptors have been implicated in sinonasal innate immunity and in the pathophysiology of chronic rhinosinusitis(CRS).Taste receptors are expressed on several sinonasal cell types including ciliated epithelial cells and solitary chemosensory cells.Bitter agonists released by pathogenic microbes elicit a T2R dependent signaling cascade which induces the release of bactericidal nitric oxide,increases mucociliary clearance,and promotes secretion of antimicrobial peptides.Genetic variation conferred by polymorphisms in T2R related genes is associated with differential CRS susceptibility,symptomatology and post-treatment outcomes.More recently,based on our understanding of T1R and T2R function,investigators have discovered novel potential therapeutics in T2R agonists and T1R antagonists.This review will discuss bitter and sweet taste receptor function in sinonasal immunity,explore the emerging diagnostic and therapeutic implications stemming from the most recent findings,and suggest directions for future research.

口腔外甜味受体生物学作用的研究进展

甜味受体(STR)是1型味觉受体的一种主要类型,可感知甜味并与不同的糖类和人工甜味剂相结合。虽然它最初被发现于口腔味蕾,但近来许多研究表明其在心脏、肾脏、胰腺、胃肠道、呼吸道和大脑等口腔外组织中均有表达,并发挥多种口外味觉效应,如参与摄食活动、能量稳态调节、内分泌代谢调节、内皮通透性调节、免疫防御调控和认知功能调节等。对此,本文综述STR的信号途径及其在口外组织中生物学作用的研究进展,旨在为STR相关的深入研究提供参考。

Molecular mechanisms of bitterness and astringency in the oral cavity induced by soyasaponin

The interaction mechanism between soyasaponin(Ssa)and bitter receptors/mucin,as well as the saliva interface behavior of Ssa,were investigated to explore the presentation mechanism of Ssa bitterness and astringency(BA).Strong bitterness arising from high Ssa concentrations(0.5–1.5 mg/mL)had a masking effect on astringency.At Ssa concentrations of 1.0–1.5 mg/mL,Ssa micelles altered the structure of mucin,exposing its internal tryptophan to a more polar environment.At Ssa concentrations of 0.05–1.50 mg/mL,its reaction with mucin increased the aggregation of particles in artificial saliva,which reduced the frictional lubricating properties of oral saliva.Ssa-mucin interactions affected the salivary interfacial adsorption layer,and their complexes synergistically reduced the interfacial tension.Ssa monomers and soyasapogenols bind to bitter receptors/mucin via hydrogen bonding and hydrophobic interactions.Class A Ssa binds more strongly than class B Ssa,and thus likely presents a higher BA.In conclusion,Ssa interacts with bitter receptors/mucin causing conformational changes and aggregation of salivary mucin,resulting in diminished frictional lubricating properties of oral saliva.This,in turn,affects taste perception and gustatory transmission.

Comparing the difference in enhancement of kokumi-tastingγ-glutamyl peptides on basic taste via molecular modeling approaches and sensory evaluation

γ-Glutamyl peptides can enhance basic taste sensations such as saltiness,sweetness,and umaminess,while the molecular mechanism and the difference in taste enhancement remain elusive.Thus,two complex conformations:taste type 1 receptor 1(T1 R1)-MSG and taste type 1 receptor 2(T1 R2)-sucrose were constructed to form binding receptors.These peptides showed affinity for the two receptors,but a higher affi nity scores and more binding amino acid residues for the T1 R1-MSG receptor,implying that they may exhibit a higher umami-enhancing effect.Thereinto,γ-glutamyl alanine(γ-EA)displayed the highest affi nity for the two receptors through mobilizing multiple amino acid residues to form hydrophobic and hydrogen bonds,indicating it had the highest enhancement for umaminess and sweetness among these peptides.Sensory evaluation demonstrated the enhancement ofγ-EA on umaminess was superior to that of sweetness.Generally,γ-glutamyl peptides could enhance basic taste sensation via activating taste receptor,and exhibited a highest umami-enhancing effect.

Maternal antibiotic treatment affects offspring gastric sensing for umami taste and ghrelin regulation in the pig

Background:Scarce is knowledge on the process regulating the development of acid secretion,orexigenic signaling,and chemosensing in the stomach of young pigs.Changes of early microbial encounters by suckling pigs can interact with the gut maturation,by the induction of different molecular signaling.Our goal was to assess if the age of offspring and the maternal environment,influenced by sow antibiotic treatment peripartum,could affect gastric morphology and the expression of genes involved in the control of hydrochloric secretion,feed intake,taste,and inflammation in offspring stomach.Methods:84 pigs from sows fed a diet with amoxicillin(on-d10 to+d21 from farrowing,ANT)or without(CON)were sacrificed at d14,d21,d28(weaning)or d42.Samples of oxyntic(OXY),pyloric(PY)and cardiac mucosae close to OXY were collected and parietal and enteroendocrine cells(EECs)were counted.Relative gene expression of a set of 11 key genes(ATP4A,SSTR2,GAST,GHRL,MBOAT4,PCSK1,GNAT1,TAS1R1,TAS1R3,IL8 and TNF)was assessed by qRT-PCR.In addition,40 offspring obtained from the same ANT and CON sows were offered a normal or a fatenriched diet for 4 weeks between 140 and 169 d of age,and then OXY and PY were sampled.Results:The number of parietal and EECs increased with age(P<0.001).ATP4A increased with age(within suckling,P=0.043,post-weaning vs.suckling,P<0.001),SSTR2 increased only after weaning(P<0.001).In OXY,GHRL increased during suckling(P=0.012),and post-weaning as a trend(P=0.088).MBOAT4 tended to increase during suckling(P=0.062).TAS1R1 increased from suckling to post-weaning period(P=0.001)and was lower in ANT offspring(P=0.013).GNAT1 in PY was higher in ANT offspring(P=0.041).Antibiotic treatment of sows peripartum increased expression of GHRL and MBOAT4 in OXY of growing-finishing offspring aged 5 months.Conclusions:Data show that sensing for umami taste and ghrelin regulation can be affected by maternal environment,but the development of acid secretion,orexigenic signaling and taste perception in the stomach are mostly developmentally controlled.

Bitter components related to alleviating intestinal obstruction in traditional Mongolian medicine

Intestinal obstruction is a blockage that keeps digesta from passing through upper or lower intestine.Traditional Mongolian medicine(TMM)has been proven to be efficacious in the clinical treatment of intestinal obstruction.However,the mechanism of its treatment has not been studied.The bitter taste receptors(T2Rs)are highly expressed in the extra-oral digestive system,such as gastrointestinal tract,which can regulate gastrointestinal peristalsis and contraction of gastrointestinal smooth muscle.In the respiratory system,T2Rs can relax the airway smooth muscle and effectively alleviate asthma symptoms.In this review,the theory and clinical applications of bitter herbs in TMM were discussed and the functional expression of T2Rs and bitter taste signal transduction pathway were analyzed to investigate whether bitter Mongolian medicine may play an effective role in promoting gastrointestinal peristalsis.Therefore,the scientific connotation of the theory of bitter medicinal property of TMM was interpreted by combining T2Rs research and application of modern technology.This new research approach may enrich and improve the basic theory and accelerate the modernization of TMM.

How do moth and butterfly taste?——Molecular basis of gustatory receptors in Lepidoptera

Insect gustatory system plays a central role in guiding insect feeding behaviors,insect-plant interactions and coevolutions.Gustatory receptors(GRs)form the interface between the insect taste system and their environment.Previously,most studies on insect GRs are focused on Drosophila;much less attention has been paid to Lepidoptera species,which consist of a large number of serious agricultural crop pests.With the exceptional advances in the next generation sequencing(NGS),cellular biology,RNA interference(RNAi),and clustered regularly interspaced short palindromic repeats(CRISPR)technologies in recent years,extraordinary progresses have been achieved elucidating the molecular mechanisms of Lepidopteran GRs.In this review,we highlighted these advances,discussed what these advances have revealed and provide our new insights into this field.

A NOVEL BITTER DETECTION BIOSENSOR BASED ON LIGHT ADDRESSABLE POTENTIOMETRIC SENSOR

This paper presents a novel biosensor for bitter substance detection on the basis of light addressable potentiometric sensor(LAPS).Taste receptor cells(TRCs)were used as sensitive elements,which can respond to different bitter stimuli with extreme high sensitivity and speci-ficity.TRCs were isolated from the taste buds of rats and cultured on the surface of LAPS chip.Due to the unique advantages such as single-cell recording,light addressable capability,and noninvasiveness,LAPS chip was used as secondary transducer to monitor the responses of TRCs by recording extracelluar potential changes.The results indicate LAPS chip can effectively record the responses of TRCs to different bitter substances used in this study in a real-time manner for a long-term.In addition,by performing principal component analysis on the LAPS recording data,different bitter substances tested can be successfully discriminated.It is suggested this TRCs
LAPS hybrid biosensor could be a valuable tool for bitter substance detection.With further improvement and novel design,it has great potentials to be applied in both basic research and practical applications related to bitter taste detection.

Identification of the material basis of the medicinal properties in Curcuma Longa L. to enhance targeted clinical application

Objective:To identify the relationship between the active compounds in turmeric(Curcuma Longa L.,C.Longa)and their medicinal properties,and clarify the chemical material basis of the medicinal properties in C.Longa.Methods:High throughput screening models of the thermo-transient receptor potentials(thermo-TRPs)and human taste type 2 receptors(hTAS2Rs)were established to evaluate the activity of the active compounds in C.Longa.The biological processes and distributions of the related targets of the active compounds were acquired by data mining.The above results were then used as basic data to comprehensively analyze the material basis of the medicinal properties of turmeric.Results:Curcumin inhibited TRPV1,TRPV2,TRPV3,and TRPA1,while demethoxycurcumin(DMC)inhibited TRPV3,TRPA1,and TRPM8.In terms of the 21 hTAS2Rs,the response values of hTAS2R38,hTAS2R16,and hTAS2R44 intervened by curcumin were ranked top three;the response values of hTAS2R3,hTAS2R1,and hTAS2R9 by DMC were in top three;the response values of hTAS2R47,hTAS2R39,and hTAS2R43 by bisdemethoxycurcumin(BDMC)were in top three.The biological processes related to active compounds primarily involved blood circulation,ossification,and regulation of the inflammatory response.Conclusion:Curcumin,DMC,and BDMC were identified as the material basis of the property of Chinese materia medica of C.Longa.Among these,curcumin and DMC may contribute to its warming effect in the four qi.Curcumin,DMC,and BDMC may lead to its bitter flavor,and the three active compounds were consistent with the meridian entry of C.Longa.Although different compounds play diverse roles in the four qi,five flavors,and meridian entry,they all were relevant to the efficacy of C.Longa.It is helpful to further understand the important role of the property of Chinese materia medica for the clinical application of traditional Chinese medicine.

Lineage-specific evolution of bitter taste receptor genes in the giant and red pandas implies dietary adaptation

Taste 2 receptors(TAS2R)mediate bitterness perception in mammals,thus are called bitter taste receptors.It is believed that these genes evolved in response to species-specific diets.The giant panda(Ailuropoda melanoleuca)and red panda(Ailurus fulgens styani)in the order Carnivora are specialized herbivores with an almost exclusive bamboo diet(>90%bamboo).Because bamboo is full of bitter tasting compounds,we hypothesized that adaptive evolution has occurred at TAS2R genes in giant and red pandas throughout the course of their dietary shift.Here,we characterized 195 TAS2R genes in 9 Carnivora species and examined selective pressures on these genes.We found that both pandas harbor more putative functional TAS2R genes than other carnivores,and pseudogenized TAS2R genes in the giant panda are different from the red panda.The purifying selection on TAS2R1,TAS2R9 and TAS2R38 in the giant panda,and TAS2R62 in the red panda,has been strengthened throughout the course of adaptation to bamboo diet,while selective constraint on TAS2R4 and TAS2R38 in the red panda is relaxed.Remarkably,a few positively selected sites on TAS2R42 have been specifically detected in the giant panda.These results suggest an adaptive response in both pandas to a dietary shift from carnivory to herbivory,and TAS2R genes evolved independently in the 2 pandas.Our findings provide new insight into the molecular basis of mammalian sensory evolution and the process of adaptation to new ecological niches.

FET-based nanobiosensors for the detection of smell and taste

Various nanobiosensors composed of biomaterials and nanomaterials have been developed,due to their demonstrated advantage of showing high performance.Among various biomaterials for biological recognition elements of the nanobiosensor,sensory receptors,such as olfactory and taste receptors,are promising biomaterials for developing nanobiosensors,because of their high selectivity to target molecules.Field-effect transistors(FET)with nanomaterials such as carbon nanotube(CNT),graphene,and conducting polymer nanotube(CPNT),can be combined with the biomaterials to enhance the sensitivity of nanobiosensors.Recently,many efforts have been made to develop nanobiosensors using biomaterials,such as olfactory receptors and taste receptors for detecting various smells and tastes.This review focuses on the biomaterials and nanomaterials used in nanobiosensor systems and studies of various types of nanobiosensor platforms that utilize olfactory receptors and taste receptors which could be applied to a wide range of industrial fields,including the food and beverage industry,environmental monitoring,the biomedical field,and anti-terrorism.

Exploring the potential for an evolutionarily conserved role of the taste 1 receptor gene family in gut sensing mechanisms of fish

In this study,we investigated the transcriptional spatio-temporal dynamics of the taste 1 receptor(T1R)gene family repertoire in seabream(Sparus aurata[sa]),during larval ontogeny and in adult tissues.In early larval development,sa T1R expression arises heterochronously,i.e.the extraoral taste-related perception in the gastrointestinal tract(GIT)anticipates first exogenous feeding(at 9 days post hatching[dph]),followed by the buccal/intraoral perception from 14 dph onwards,supporting the hypothesis that the early onset of the molecular machinery underlying sa T1R expression in the GIT is not induced by food but rather genetically hardwired.During adulthood,we characterized the expression patterns of sa T1R within specific tissues(n=4)distributed in oropharingeal,GIT and brain regions substantiating their functional versatility as chemosensory signaling players to a variety of biological functions beyond oral taste sensation.Further,we provided for the first time direct evidences in fish for m RNA coexpression of a subset of sa T1R genes(mostly sa T1R3,i.e.the common subunit of the heterodimeric T1R complexes for the detection of“sweet”and“umami”substances),with the selected gut peptides ghrelin(ghr),cholecystokinin(cck),hormone peptide yy(pyy)and proglucagon(pg).Each peptide defines the enteroendocrine cells(ECCs)identity,and establishes on morphological basis,a direct link for T1R chemosensing in the regulation of fish digestive processes.Finally,we analyzed the spatial gene expression patterns of 2 taste signaling components functionally homologous to the mammalian G(i)a subunit gustducin,namely sa G(i)a1 and sa G(i)a2,and demonstrated their co-localization with the sa T1R3in EECs,thus validating their direct involvement in taste-like transduction mechanisms of the fish GIT.In conclusion,data provide new insights in the evolutionary conservation of gut sensing in fish suggesting a conserved role for nutrient sensors modulating entero-endocrine secretion.