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Taste receptors in the gastrointestinal tract. IV. Functional implications of bitter taste receptors in gastrointestinal chemosensing.

Changes in the luminal contents of the gastrointestinal tract modulate gastrointestinal functions, including absorption of nutrients, food intake, and protection against harmful substances. The current notion is that mucosal enteroendocrine cells act as primary chemoreceptors by releasing signaling molecules in response to changes in the luminal environment, which in turn activate nerve terminals. The recent discovery that taste receptors and G protein subunits alpha-gustducin and alpha-transducin, involved in gustatory signal transduction, are expressed in the gastrointestinal mucosa supports the concept of a chemosensory machinery in the gastrointestinal tract. An understanding of luminal sensing processes responsible for the generation of the appropriate functional response to specific nutrients and nonnutrients is of clinical importance since aberrant or unsteady responses to changes in luminal contents might result in disease states ranging from intoxication to feeding disorders and inflammation. The purpose of this theme article is to discuss the functional implications of bitter taste signaling molecules in the gastrointestinal tract deduced by their localization in selected populations of epithelial cells and their relationship with neural pathways responsible for the generation of specific responses to luminal contents.

Animals↗

Sweet and bitter taste discrimination in primates: scaling effects across species.

The adaptive nature of taste discrimination has been questioned on the basis that marked differences in taste thresholds for soluble sugars across mammals may not correspond to distinct dietary tendencies and further imply inaccurate prediction of the energetic value of food. Appropriate models of the evolution of taste, however, require not only consideration of adaptations to diet but also recognition of phylogenetic and allometric effects. Here, we analyse these factors in primates exhibiting various diets and covering a wide range of body weights. Taste thresholds for sucrose and fructose are negatively related to body weight overall but are commonly similar in closely related species irrespective of dietary specialisations. By contrast, major interspecific differences in the discrimination of quinine hydrochloride are observed in the absence of any allometric effect. We propose that this asymmetrical differentiation of sweet and bitter taste discrimination reflects divergent evolutionary trends for meeting energy requirements and for avoiding noxious substances.

Animals↗

Humulon, a bitter in the hop, inhibits tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin.

Humulon, one of the bitters in the hop, was isolated from the female flowers of Humulus lupulus. This component has inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation. At 1 mg/mouse, humulon inhibited markedly the tumor-promoting effect of TPA (1 microgram/mouse) on skin tumor formation following initiation with 7,12-dimethylbenz[a]anthracene (50 micrograms/mouse). Furthermore, humulon inhibited arachidonic acid-induced inflammatory ear edema in mice.

9,10-Dimethyl-1,2-benzanthracene↗

Influence of bitter taste on mastication pattern.

Mastication is a rhythmic activity that can be modified by peripheral information generated in the mouth. To study whether taste cognition could influence the way in which a food is broken down in the mouth, subjects masticated firm, sugar-based gelatine gels with differing concentrations of quinine, up to 1500 micromol/kg, while electromyography (EMG) of masticatory muscles was recorded. Taste intensity and composition of saliva were measured. With increasing quinine concentration, the average number of chews for nine subjects decreased from 30 to 22, and their average clearance time increased from 7 to 14 sec. Quinine concentration had no effect on chewing frequency (1.3 Hz) or on the rate of salivation (5.5 g/min). Bitterness increased, while acceptability and sweetness decreased, with increasing concentration of quinine in the gel and in saliva. Taste cognition could therefore modify food breakdown in the mouth.

Adult↗

Role of low-substituted hydroxypropylcellulose in dissolution and bioavailability of novel fine granule system for masking bitter taste.

Coated fine granules with water-insoluble film composed primarily of ethylcellulose, containing 20% of sparfloxacin (SPFX) and various amounts of low-substituted hydroxypropylcellulose (L-HPC) (0-52%) in the cores and which masked the bitter taste of SPFX, were orally administered to fasting rats to determine the effect of L-HPC on bioavailability. The release of SPFX in water from four kinds of these coated fine granules containing 0, 25, 40 and 52% of L-HPC showed the pseudo first order kinetics, followed by the second phase, with refractive points between 0.25 and 0.5 h. The rate constant (K1) up to 0.25 h increased with an increase [corrected] of the amount of L-HPC in the core, and the rate constant (K2) in subsequent release (the second phase) was lower than K1 in each fine granule. Areas under plasma concentration-time curves (AUC) of SPFX and the peak plasma SPFX levels (Cmax) after oral administration of coated fine granules lacking L-HPC to fasting rats were suppressed to one-eighth and one-ninth, respectively, of those obtained from the core granules that rapidly released SPFX. However, AUC and Cmax from the coated fine granules increased linearly with an increase in the amount of L-HPC in the cores, and nearly equaled those from the core fine granules when the content of L-HPC was 52%. These results confirmed that the addition of L-HPC to the cores increases not only the dissolution rate but also the bioavailability of SPFX.

Animals↗

New bitter-tasting hemiterpene glycosides from the Japanese fern Hymenophyllum barbatum.

Hymenosides G--J were newly isolated from the Japanese fern Hymenophyllum barbatum, in addition to hymenosides A--F. The structures of hymenosides were elucidated by extensive two-dimensional nuclear magnetic resonance and/or chemical evidence. The structures of those aglycones were divided into three types, 1,4-dihydroxy-2-hydroxymethyl-but-2-ene, 1,4-dihydroxy-2-methyl-but-2-ene, and 3-hydroxy-5-hexanolide. The sugar moieties were also established by chemical and spectroscopic methods, which were acylated by phenylacetic acid derivatives. These glycosides had a bitter or weakly pungent taste.

Acetylation↗

The complete amino acid sequence of momordin-a, a ribosome-inactivating protein from the seeds of bitter gourd (Momordica charantia).

The complete amino acid sequence of momordin-a, a ribosome-inactivating protein from the seeds of bitter gourd, has been analyzed. Twenty-two peptides were isolated from the tryptic digest of momordin-a and sequenced by the DABITC/PITC double coupling method. The alignment of these tryptic peptides was done by analyzing the amino acid sequences of the peptides derived from chymotryptic digestion and cyanogen bromide cleavage of momordin-a as well as V8 protease-digestion of the CNBr fragment. Momordin-a consisted of 250 amino acid residues and carbohydrate residues attached to Asn227, and its molecular mass was calculated to be 28,690 Da. The sequence comparison with ricin A-chain shows that 33% of the residues of momordin-a are identical to those of ricin A-chain and that the residues involved in the catalytic site of the ricin A-chain are conserved in momordin-a.

Amino Acid Sequence↗

Antioxidative activity of hop bitter acids and their analogues.

Hop bitter acids, humulones (1) and lupulones (2), were shown to have potent DPPH radical scavenging activity (RSA) and lipid peroxidation inhibitory activity (LIA). Furthermore, 5-acetyl lupulones (3) and 4-methyl lupulones (4) had more potent LIA than native lupulones but no RSA. This result indicates that the beta, beta'-triketone moiety of the lupulones has LIA.

Antioxidants↗

Expression and mutational analysis of amino acid residues involved in catalytic activity in a ribonuclease MC1 from the seeds of bitter gourd.

The ribonuclease MC1 (RNase MC1) from seeds of bitter gourd (Momordica charantia) consists of 190 amino acids and belongs to the RNase T2 family, including fungal RNases typified by RNase Rh from Rhizopus niveus. We expressed RNase MC1 in Escherichia coli cells and made use of site-directed mutagenesis to identify essential amino acid residues for catalytic activity. Mutations of His34 and His88 to Ala completely abolished the enzymatic activity, and considerable decreases in the enzymatic activity were observed in cases of mutations of His83, Glu84, and Lys87, when yeast RNA was used as a substrate. Kinetic parameters for the enzymatic activity of the mutants of His83, Glu84, and Lys87 were analyzed using a dinucleoside monophosphate CpU. Km values for the mutants were approximately like that for wild-type, while k(cat) values were decreased by about 6 to 25-fold. These results suggest that His34, His83, Glu84, Lys87, and His88 in RNase MC1 may be involved in the catalytic function. These observation suggests that RNase MC1 from a plant catalyzes RNA degradation in a similar manner to that of fungal RNases.

Amino Acids↗

Stimulation of insulin secretion by denatonium, one of the most bitter-tasting substances known.

Denatonium, one of the most bitter-tasting substances known, stimulated insulin secretion in clonal HIT-T15 beta-cells and rat pancreatic islets. Stimulation of release began promptly after exposure of the beta-cells to denatonium, reached peak rates after 4-5 min, and then declined to near basal values after 20-30 min. In islets, no effect was observed at 2.8 mmol/;l glucose, whereas a marked stimulation was observed at 8.3 mmol/;l glucose. No stimulation occurred in the absence of extracellular Ca(2+) or in the presence of the Ca(2+)-channel blocker nitrendipine. Stimulated release was inhibited by alpha(2)-adrenergic agonists. Denatonium had no direct effect on voltage-gated calcium channels or on cyclic AMP levels. There was no evidence for the activation of gustducin or transducin in the beta-cell. The results indicate that denatonium stimulates insulin secretion by decreasing KATP channel activity, depolarizing the beta-cell, and increasing Ca(2+) influx. Denatonium did not displace glybenclamide from its binding sites on the sulfonylurea receptor (SUR). Strikingly, it increased glybenclamide binding by decreasing the K(d). It is concluded that denatonium, which interacts with K(+) channels in taste cells, most likely binds to and blocks Kir6.2. A consequence of this is a conformational change in SUR to increase the SUR/glybenclamide binding affinity.

Animals↗

The effects of bitter melon (Momordica charantia) extracts on serum and liver lipid parameters in hamsters fed cholesterol-free and cholesterol-enriched diets.

The hypolipidemic effect of dietary methanol fraction (BMMF) extracted from bitter melon (Koimidori variety), at the levels of 0.5% and 1.0%, was examined in male golden Syrian hamsters fed diets supplemented with and without cholesterol. The feeding of BMMF at 0.5% and 1.0% levels in the diets for 4 wk tended to reduce food intake and growth, although there was no difference in food efficiency (weight gain/food intake). An effect of dietary BMMF on serum triglyceride was not seen in hamsters fed diets free of cholesterol, while hypertriglyceridemia induced by dietary cholesterol was significantly lowered in a dose-dependent manner in those fed diets containing the BMMF Serum total cholesterol concentration also tended to decrease in a dose-dependent manner following feeding of increasing amounts of BMMF in the presence and absence of cholesterol in the diet. The effects of dietary BMMF on liver triglyceride and total cholesterol levels were marginal, although dietary cholesterol caused a marked accumulation of these lipid molecules in the liver. These results suggest that the BMMF contains some components that could ameliorate lipid disorders such as hyperlipidemia.

Animals↗

[Analysis of constituents in Jamaica quassia extract, a natural bittering agent].

Jamaica quassia extract, a natural bittering agent, is described as "a substance extracted from bark of Jamaica quassia (Quassia excelsa Sw.)" in the List of Existing Food Additives in Japan. The constituents in Jamaica quassia extract product were investigated as a part of an ongoing study to evaluate its quality and safety as a food additive. The main constituents of the extract were identified as quassin and two isomers of neoquassin by using LC/MS. The main constituent, quassin, was isolated and the structure was determined by spectral means. The quantification of their main constituents was performed by HPLC using quassin as a standard, and the concentrations of quassin and total of neoquassin isomers were 21.4% and 55.5%. In addition, it was confirmed that Jamaica quassia extract was different from quassia extract, which is extracted from bark of Picrasma quassioides Benn. belonging to the same family as Q. excelsa, by comparing their HPLC profiles.

Chromatography, High Pressure Liquid↗

Genetic sensitivity to the bitter taste of 6-n propylthiouracil: a new risk determinant for dental caries in children.

The aims of the present study were to contrast the prevalence of dental caries in children with different genetic sensitivity levels to the bitter taste of 6-n-propylthiouracil (PROP) and to determine the taste quality and taste intensity preferences of food products among the taster and nontaster groups. Overall caries experience (dmfs/DMFS) was significantly higher for nontasters than tasters. Caries experience on the available surfaces (dfs/DFS) was found to be significantly higher in nontasters than in medium tasters and in medium tasters than in supertasters (r=-0.41, P < 0.001). Majority of the nontasters were sweet likers and preferred strong tasting food products, while majority of the supertasters were sweet dislikers and preferred weak tastes. There was a significant increase in the overall caries experience in the population, as the genetic ability to detect PROP taste decreased ( P < 0.001). After all associated factors (age, gender, race, number of teeth and OHI-S) were controlled; multiple linear regression analyses revealed that taste was the only variable significantly related to overall caries experience.

Age Factors↗

Stabilization of cucurbitacin E-glycoside, a feeding stimulant for diabroticite beetles, extracted from bitter Hawkesbury watermelon.

Cucurbitacins are feeding stimulants for diabroticite beetles, including corn rootworms and cucumber beetles, which can be added to a bait containing an insecticide thereby reducing the levels of other insecticide treatments needed to control these pests. One of them, cucurbitacin E-glycoside, is water soluble and easily processed from mutant bitter Hawkesbury watermelons (BHW) that express elevated levels of cucurbitacin. Storage of BHW extract at room temperature resulted in a 92% reduction of cucurbitacin E-glycoside over two months, while refrigeration or freezing resulted in a 60% loss of the active ingredient during this time. The loss of the active ingredient was correlated with an increase in BHW extract pH from 5 to greater than 9. The increase in pH of the BHW extracts at room temperature appeared to be due to the growth of certain bacteria, especially Bacillusspp. In refrigerated extracts, the pH remained relatively constant, and bacterial growth was dominated by bacteria such as Lactobacilli. An alternative to refrigeration is concentration of BHW extract. One means of concentration is spray drying, but the high sugar content of the BHW extract (20mg/ml glucose, 40mg/ml fructose) makes this technique impractical. Fermentation of the BHW extract by the yeast, Saccharomyces boulardii, eliminated the sugars and did not raise the pH nor alter the cucurbitacin E-glycoside content of the extract. Elimination of the sugars by fermentation produced an extract that could be successfully spray dried. BHW extract fermented by S. boulardii produced a higher level of feeding stimulation for spotted cucumber beetles in laboratory choice tests. When applied to cucumbers, there was no difference in control of spotted and striped cucumber beetles between baits of fresh or fermented juices combined with the same insecticide.

Animals↗

Bitter cassava poisoning in eight children: a case report.

Bitter cassava poisoning in 8 children is reported. The incidence of bright cherry-red blood is emphasized. These patients were in bad condition, but they survived although they received different therapies. Four of them were treated with sodium nitrite and thiosulfate and the remainder with hydroxocobalamin alone. This latter drug may be useful in less severe circumstances.

Antidotes↗

Purification and amino acid sequence of a bitter gourd inhibitor against an acidic amino acid-specific endopeptidase of Streptomyces griseus.

An inhibitor (BGIA) against an acidic amino acid-specific endopeptidase of Streptomyces griseus (Glu S. griseus protease) was isolated from seeds of the bitter gourd Momordica charantia L., and its amino acid sequence was determined. The molecular weight of BGIA based on the amino acid sequence was calculated to be 7419. BGIA competitively inhibited Glu S. griseus protease with an inhibition constant (Ki) of 70 nM, and gel filtration analyses suggested that BGIA forms a 1:1 complex with this protease. However, two other acidic amino acid-specific endopeptidases, protease V8 from Staphylococcus aureus and Bacillus subtilis proteinase (Glu B. subtilis protease), were not inhibited by BGIA. BGIA had no inhibitory activity against chymotrypsin, trypsin, porcine pancreatic elastase, and papain, although subtilisin Carlsberg was strongly inhibited. The amino acid sequence of BGIA shows similarity to potato chymotrypsin inhibitor, barley subtilisin-chymotrypsin inhibitor CI-1 and CI-2, and leech eglin C, especially around the reactive site. Although the residue at the putative reactive site of these inhibitors is leucine or methionine, the corresponding amino acid in BGIA is alanine.

Amino Acid Sequence↗

The total alkaloid and anagyrine contents of some bitter and sweet selections of lupin species used as food.

The total alkaloid and anagyrine contents of bitter and sweet Lupinus luteus, Lupinus angustifolius, Lupinus albus, Lupinus mutabilis, Lupinus polyphyllus, and Lupinus perennis were analyzed by gas chromatography (GC) and mass spectrometry. No anagyrine was detected in any of the samples. The GC peak in some of the samples which corresponded to anagyrine in retention of time seems to be identical to 17-oxolupanine. The alkaloid content of samples ranged from 3.17 to 0.003 percent.

Alkaloids↗