Taste Perception of Antidesma bunius Fruit and Its Relationships to Bitter Taste Receptor Gene Haplotypes.

It was shown more than 40 years ago that the ability to perceive the bitterness of the fruit of the Antidesma bunius tree is inversely correlated with the ability to perceive the well-studied bitter tastant phenylthiocarbamide (PTC). To determine if variants of the TAS2R38 gene, which encodes the PTC taste receptor, or variants in any of the other TAS2R bitter or TAS1R sweet receptor genes account for Antidesma taste perception, we recruited an independent subject sample and examined associations between these taste receptor gene haplotypes and Antidesma perception. Consistent with previous findings, almost none of our subjects who reported Antidesma juice as bitter was a PTC "responder" by previous definitions (i.e. a PTC taster). In our study, of the 132 individuals who perceived PTC as bitter, 15 perceived Antidesma as bitter, although these 15 subjects had very weak bitterness perception scores. Examination of TAS2R38 gene haplotypes showed that, of the subjects who perceive Antidesma as bitter, all carried at least one copy of the TAS2R38 AVI (PTC non-taster) haplotype. However, 86 subjects carried at least one AVI haplotype and failed to perceive Antidesma as bitter. No other TAS2R or TAS1R gene variants showed an association with Antidesma bitter, sweet, or sour perception. Our results show that TAS2R38 haplotypes are associated with differential perception of Antidesma berry juice bitterness, and that all those who perceive this bitterness carry at least one AVI haplotype. This indicates that the AVI haplotype is necessary for this perception, but that additional variable factors are involved.

Relationship of Phenylthiocarbamide (PTC) Taster Status to Olfactory and Gustatory Function in Patients with Chemosensory Disturbances.

Poor sensitivity to the bitter taste of phenylthiocarbamide (PTC) and related substances has been associated with a number of diseases. We determined, in patients with chemosensory dysfunction from multiple etiologies, whether PTC "tasters" (n = 511) exhibit less smell and taste dysfunction than their non-PTC-tasting counterparts (n = 432) on a comprehensive battery of olfactory and gustatory tests. The proportion of tasters (54%) in our study population was much lower than that calculated from 11 North American population studies (76.5%; P < 0.0001). This taster/nontaster ratio was maintained across a range of etiologic categories. More women (60.7%) than men (45.5%) were PTC tasters (P < 0.0001). Although PTC tasting status was unrelated to scores on the olfactory tests (which included tests of odor identification, detection threshold, and odor memory/discrimination), tasters significantly outperformed nontasters on suprathreshold identification and intensity taste tests employing both bitter (caffeine) and nonbitter (sucrose, citric acid, sodium chloride) tasting stimuli. Regardless of PTC taster status, women outperformed men on the taste tests. Our findings suggest the possibility that the T2R38 gene may protect against significant olfactory dysfunction, but once such dysfunction becomes manifest at a level where professional help is sought, such protection is not evident. However, other hypotheses for this phenomenon are possible. This study demonstrates that patients with chemosensory disturbances who are PTC tasters outperform their non-PTC taster counterparts in both identifying and perceiving the intensity of a range of suprathreshold tastants, including ones that do not taste bitter.

Phenylthiocarbamide taste perception as a possible genetic association marker for nutritional habits and obesity tendency of people.

Ability to taste Phenylthiocarbamide (PTC) a bitter molecule, is usually used to know the heritable characteristic in both genetic and physiological studies. So far, no research has yet attested whether PTC blindness relation with obesity and some nutrition behaviors of human. This study is the first attempt on a large scale to examine PTC sensitivity in healthy and overweight people in Turkish population to define in the perception of bitter senses which is associated with nutrition habits, body mass index, age, gender, and to be in stable weight. PTC taste perception was measured by tasting PTC solution filtered in a paper. The results showed that tasters were significantly more frequent (81,8%) than nontasters (18,2%) in all population. A higher proportion of nontasters were observed in the quite fat individual group (BMI >40kg/m(2)). Alterations explained these differences in basic taste sensitivity, age, gender, BMI, individuals' family obesity situations, vegetarian nourishment. Increased frequency of nontasters allele is evident with obesity condition. This could be due to lack of preference for nutrition among nontasters. So the phenotypic variation in PTC sensitivity is genetic in origin; it may represent an association with obesity, dietary habits, regular weight, gender, and age.

Mechanism of N-Acylthiourea-mediated activation of human histone deacetylase 8 (HDAC8) at molecular and cellular levels.

We reported previously that an N-acylthiourea derivative (TM-2-51) serves as a potent and isozyme-selective activator for human histone deacetylase 8 (HDAC8). To probe the molecular mechanism of the enzyme activation, we performed a detailed account of the steady-state kinetics, thermodynamics, molecular modeling, and cell biology studies. The steady-state kinetic data revealed that TM-2-51 binds to HDAC8 at two sites in a positive cooperative manner. Isothermal titration calorimetric and molecular modeling data conformed to the two-site binding model of the enzyme-activator complex. We evaluated the efficacy of TM-2-51 on SH-SY5Y and BE(2)-C neuroblastoma cells, wherein the HDAC8 expression has been correlated with cellular malignancy. Whereas TM-2-51 selectively induced cell growth inhibition and apoptosis in SH-SY5Y cells, it showed no such effects in BE(2)-C cells, and this discriminatory feature appears to be encoded in the p53 genotype of the above cells. Our mechanistic and cellular studies on HDAC8 activation have the potential to provide insight into the development of novel anticancer drugs.

The relationship between taste sensitivity to phenylthiocarbamide and anhedonia.

It has been proposed that taste sensitivity to bitter compounds such as, phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), represents a genetic marker for an increased vulnerability to depressive illness. Previous explorations of this idea have proven equivocal. This study refines and further explores this idea by focusing specifically on anhedonia (diminished hedonic capacity), a key symptom in some depressive illness, linked also with sensory pleasure. It is hypothesized that diminished PTC taste sensitivity will be associated with more general decrements in hedonic capacity (anhedonia). An opportunity sample of 198 university students were assessed using paper strips impregnated with PTC, the same participants also completed a widely used assessment of hedonic capacity, the Snaith-Hamilton Pleasure Scale (SHAPS). Hedonic capacity scores positively correlated with PTC taste sensitivity; specifically, heightened hedonic capacity was associated with heightened sensitivity to the bitter taste of PTC. Furthermore, modest differences were observed between those least (non-tasters) and most (supertasters) sensitive to PTC, with non-tasters reporting significantly lower hedonic capacity scores than supertasters. PTC taste sensitivity may represent a peripheral risk factor for anhedonia.

Isoxyl assays in plasma.

Isoxyl is an effective drug to treat multi-drug resistant (MDR) tuberculosis but was abandoned due to failure in some clinical outcomes. The aim of this study was to develop and validate a reverse-phase high-performance liquid chromatographic (HPLC) method for determination of isoxyl concentrations in plasma, a prerequisite for understanding poor in vivo behavior of the drug. In the method, isoxyl was extracted from guinea pig plasma with acetonitrile and quantified by a Hewlett Packard 1100 series HPLC coupled with a Spherisorb 5 µm ODS2 (2 × 100 mm) column and UV detection at 270 nm. The mobile phase was 70% ACN in 20 mM ammonium acetate buffer. The isoxyl peak was eluted at 4.8 min with no interference with the peaks of impurities from plasma and internal standard. Recovery of isoxyl from guinea pig plasma was >68%, and LOQ (Limit of Quantification) was 0.25 µg/ml which was 8 times lower than the reported minimal inhibitory concentration (MIC, 2 µg/ml). The HPLC method was sensitive, reproducible, and accurate for quantification of isoxyl in guinea pig plasma according to FDA guidance for bioanalytical method validation. The method was utilized to quantify isoxyl plasma concentrations following oral administration of the drug to guinea pigs. The results suggest that the poor clinical outcomes of the drug may have been caused by the extremely low isoxyl plasma concentrations which were far below the MIC for action on Mycobacterium tuberculosis.

Management of severe thyrotoxicosis when the gastrointestinal tract is compromised.

BACKGROUND: The management of patients with severe thyrotoxicosis in the absence of a functional gastrointestinal tract represents an uncommon but significant clinical challenge associated with a high mortality rate. This article offers a literature review and discussion of the available management options in this setting. SUMMARY: Treatment of severe thyrotoxicosis in patients unable to ingest medications by the oral route should focus on normalization of thyroid hormone levels utilizing conventional medical therapy for thyrotoxicosis, administered via non-oral routes. This includes thionamides, beta-blockers, iodine containing solutions, and glucocorticoids. When conventional medical therapy fails, plasmapheresis should be considered as a temporary therapeutic bridge until conventional therapies can be instituted effectively or emergent surgery performed. CONCLUSION: Although a rare scenario, the management of patients with severe thyrotoxicosis in the absence of a functional gastrointestinal tract represents a challenging clinical situation. Endocrinologists and critical care physicians should be apprised of the available treatment modalities which must be instituted swiftly in order to avoid a catastrophic outcome.

Isoxyl particles for pulmonary delivery: In vitro cytotoxicity and potency.

Pulmonary delivery of isoxyl may increase drug efficacy by targeting alveolar macrophages which are host cells for Mycobacteria. Isoxyl microparticles (1-2microm) were obtained by antisolvent precipitation and simultaneous spray drying method. The controls were made by mixing isoxyl solution in DMSO with cell culture media. Depending on the drug concentration, either isoxyl solution or nanosuspension was obtained in these controls. In the study, MTT (methylthiazol tetrazolium) and LDH (lactose dehydrogenase) assays were utilized to test cytotoxicity of these particle suspensions or solutions toward macrophages. Isoxyl microparticles and controls in concentrations up to 100microg/ml were not toxic to macrophages. Both isoxyl microparticle suspensions and controls showed bactericidal activity, as estimated by death of mycobacteria inside the macrophages, at a concentration of 5microg/ml.

Role of CCK1 and Y2 receptors in activation of hindbrain neurons induced by intragastric administration of bitter taste receptor ligands.

G-protein-coupled receptors signaling bitter taste (T2Rs) in the oral gustatory system and the alpha-subunit of the taste-specific G-protein gustducin are expressed in the gastrointestinal (GI) tract. alpha-Subunit of the taste-specific G-protein gustducin colocalizes with markers of enteroendocrine cells in human and mouse GI mucosa, including peptide YY. Activation of T2Rs increases cholecystokinin (CCK) release from the enteroendocrine cell line, STC-1. The aim of this study was to determine whether T2R agonists in the GI tract activate neurons in the nucleus of the solitary tract (NTS) and whether this activation is mediated by CCK and peptide YY acting at CCK(1) and Y(2) receptors. Immunocytochemistry for the protooncogene c-Fos protein, a marker for neuronal activation, was used to determine activation of neurons in the midregion of the NTS, the region where vagal afferents from the GI tract terminate. Intragastric administration of the T2R agonist denatonium benzoate (DB), or phenylthiocarbamide (PTC), or a combination of T2R agonists significantly increased the number of Fos-positive neurons in the mid-NTS; subdiaphragmatic vagotomy abolished the NTS response to the mixture of T2R agonists. Deletion of CCK(1) receptor gene or blockade of CCK(1) receptors with devazepide abolishes the activation of NTS neurons in response to DB, but had no effect on the response to PTC. Administration of the Y(2) receptor antagonist BIIE0246 blocks the activation of NTS neurons to DB, but not PTC. These findings suggest that activation of neurons in the NTS following administration of T2R agonists to the GI tract involves CCK(1) and Y(2) receptors located on vagal afferent terminals in the gut wall. T2Rs may regulate GI function via release of regulatory peptides and activation of the vagal reflex pathway.

Biological evaluation of 1-alkyl-3-phenylthioureas as orally active HDL-elevating agents.

A series of 1-alkyl-3-phenylthiourea analogues were prepared and evaluated as HDL- and Apo A-I-elevating and triglyceride-lowering agents. Several derivatives were superior to gemfibrozil. The optimal analogue (HDL376) was shown to raise HDL cholesterol in the rat, hamster, dog, and monkey models.

The relationship between phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) taster status and taste thresholds for sucrose and quinine.

OBJECTIVE: The aim of this study was to investigate the relationship of taster status with taste detection and recognition thresholds for sucrose and quinine. DESIGN: Sixty-nine subjects (35 men and 34 women; mean age, 23.9+/-1.2 years) were included. Stimulus fluids were prepared, one each for phenylthiocarbamide (PTC), 6-n-propylthiouracil (PROP), sucrose and quinine HCl. In each series, successive solutions, which comprised a total of 15 grades, differed by 0.25log units of the molar concentration. Two concentrations of NaCl (0.32 and 1.0 M) were prepared. The subjects were classified as nontasters and tasters using their PTC and PROP perceptions. Tasters were classified as medium-tasters and supertasters by the ratio of perceived bitterness of above-threshold PROP relative to the perceived saltiness of NaCl (PROP ratio). Taste detection and recognition thresholds for sucrose and quinine were determined by standard two-alternative forced choice trials. A Student's t-test, a Pearson's correlation analysis and linear contrasts in a one-way analysis of variance (ANOVA) were used. RESULTS: The percentages of nontaster, medium-taster and supertaster were 13, 70 and 17%, respectively. There were no significant gender differences in the taste detection and recognition thresholds for sucrose and quinine. The threshold for PTC and PROP showed significant correlations with taste threshold for quinine. Linear contrast in one-way ANOVA showed that the greater the value of PROP ratio, the more sensitive to sweet and bitter tastes (p<0.001). CONCLUSION: The PTC and PROP taster status is closely related with taste detection and recognition thresholds for sucrose and quinine.

Field efficacy and baseline toxicities of pyriproxifen, acetamiprid, and diafenthiuron against Bemisia tabaci Gennadius (Homoptera: Aleyrodidae) in Burkina Faso (West Africa).

Bioassays were conducted in 2001 and 2002 to estimate toxicities and dose-response relationships of 24 Bemisica tabaci Gennadius populations to pyriproxifen, acemitaprid, and diafenthiuron. LC50s ranging from 0.014 to 0.096 mgL(-1), 0.60 to 1.3 mgL(-1), and 3.5 to 6.7 mgL(-1) were observed respectively for pyriproxifen, acemitaprid, and diafenthiuron. These LC50s much lower than the field doses recommended for each compound. A fast increase in rates of mortality within a narrow range of lethal concentrations was observed for each compound. indicating that all three compounds were highly effective at killing whiteflies. In a separate experiment, pyriproxifen, acemitaprid, and diafenthiuron were tested in 2001 and 2002 to compare their effectiveness and assess their impact on parasitism in the field. In both years all three compounds significantly prevented B. tabaci populations from reaching economic injury levels in cotton and minimized adverse effects on parasitism. Our results provide for the first time baseline toxicological, field efficacy, and effect on parasitism data for pyriproxifen, acemitaprid, and diafenthiuron against B. tabaci in West Africa. These compounds should be included in a resistance management program of the cotton pest complex and their use should be restricted to prevent the building of resistance in B. tabaci populations.

Insensitivity to the bitter taste of chloramphenicol: an autosomal recessive trait.

Sensitivity to the bitter taste of chloramphenicol was studied in 860 students, 620 males and 240 females. About 8.6% of them were insensitive to this bitter taste. Familial lineage studies were carried out on a subset of these students, and the results suggested that the sensitivity or insensitivity was controlled by a pair of autosomal Mendelian genes, with the sensitive gene being dominant over the insensitive.

Distribution of non-tasters for phenylthiocarbamide and high sensitivity to quinine hydrochloride of the non-tasters in Japanese.

The percentage of non-tasters for phenylthiocarbamide in 915 Japanese students was 9.4%. The thresholds of the edge and back of the tongue to quinine hydrochloride were significantly smaller in the non-tasters than in the tasters. The thresholds of any tongue portions to NaCl, acetic acid or sucrose did not differ between the tasters and the non-tasters.

[A comparative study of the taste sensitivity to phenylthiocarbamide in rats differing by the threshold of nervous system excitability]. / Sravnitel'noe izuchenie vkusovoi chuvstvitel'nosti k feniltiokarbamidu u krys, razlichaiushchikhsia po progu vozbudimosti nervnoi sistemy.

Taste sensitivity to a bitter substance, phenylthiocarbamide (PTC) was studied in rat strains selected for the threshold of excitability of the nervous system. In the period of 17 days the drinking behaviour of the rats was estimated after giving them a series of PTC solutions with increasing concentrations and water as a control. The interstrain differences were found in the mean level of this index and its dynamics during the experimental period. Rats of the strain with high excitability showed the rhythmical changes of taste sensitivity to PTC related to the phases of moon rhythm. The obtained evidence points to relation between the sign under study and individual characteristics of the nervous system, namely, its excitability, and suggests the differences in activity of the second messenger system (Ca++, c-AMP and others) in the studied rat strains.

Field trials in sheep with the anthelmintic thiophanate.

Productivity and tolerance trials were conducted with the anthelmintic thiophanate (Nemafax; May & Baker) in sheep in the United Kingdom. Tolerance studies, conducted in sheep of various types under several management systems, in which thiophanate was given orally at recommended dosage (50 to 100 mg/kg), or multiples thereof, in single or repeated doses showed that treatment was in all cases well tolerated. Thiophanate administered at 75 mg per kg or 250 mg per kg to groups of growing lambs with low faecal egg counts produced no post treatment depression of weight gain. When breeding ewes were treated with thiophanate at 150 mg per kg on days 14, 21 and 28 after introduction of rams to the flock, the anthelmintic produced no adverse effect on lambing performance. Trials to assess the beneficial effects of treatment were conducted in weaned lambs naturally infected with gastrointestinal nematodes. Groups of lambs were treated monthly with either thiophanate or tetramisole at recommended dosages. The two anthelmintics produced similar weight gains in the lambs and these were significantly better than those of untreated controls. In untreated controls faecal egg counts increased markedly and the clinical condition of these animals deteriorated.

Variability in response to drugs.

Variability in the response to drugs is due to three principal components-the disease, the responsiveness of tissues, and the concentration of the drug at its site of action (as reflected by its plasma concentration). The relative contributions of these components will differ not only for different drugs but also for different effects of the same drug. Rational drug therapy depends on knowledge of all three factors.