Paul Breslin - Profile on Academia.edu (original) (raw)

Papers by Paul Breslin

Pharmaceutical Research, Jul 1, 2002

2002-07, Modifying the bitterness of selected oral pharmaceuticals with cation and anion series o... more 2002-07, Modifying the bitterness of selected oral pharmaceuticals with cation and anion series of salts, Bitterness inhibition of pseudoephedrine, ranitidine, acetaminophen 2

Chemical Senses, 2003

The aim of this study was to determine if taste interactions occur when bitter stimuli are mixed.... more The aim of this study was to determine if taste interactions occur when bitter stimuli are mixed. Eight bitter stimuli were employed: denatonium benzoate (DB), quinine-HCl (QHCl), sucrose octaacetate (SOA), urea, L-tryptophan (L-trp), L-phenylalanine (L-phe), ranitidine-HCl, and Tetralone. The first experiment constructed individual psychophysical curves for each subject (n = 19) for each compound to account for individual differences in sensitivities when presenting bitter compounds in experiment 2. Correlation analysis revealed two groupings of bitter compounds at low intensity (1, L-trp, L-phe, and ranitidine; 2, SOA and QHCl), but the correlations within each group decreased as the perceived intensity increased. In experiment 2, intensity ratings and two-alternative forced-choice discrimination tasks showed that bitter compounds generally combine additively in mixture and do not show interactions with a few specific exceptions. The methods employed detected synergy among sweeteners, but could not detect synergy among these eight bitter compounds. In general, the perceived bitterness of these binary bitter-compound mixtures was an additive function of the total bitter-inducing stimuli in the mouth.

Chemical Senses, 2004

We investigated the ability of zinc sulfate (5, 25, 50 mM) to inhibit the sweetness of 12 chemica... more We investigated the ability of zinc sulfate (5, 25, 50 mM) to inhibit the sweetness of 12 chemically diverse sweeteners, which were all intensity matched to 300 mM sucrose [800 mM glucose, 475 mM fructose, 3.25 mM aspartame, 3.5 mM saccharin, 12 mM sodium cyclamate, 14 mM acesulfame-K, 1.04 M sorbitol, 0.629 mM sucralose, 0.375 mM neohesperidin dihydrochalcone (NHDC), 1.5 mM stevioside and 0.0163 mM thaumatin]. Zinc sulfate inhibited the sweetness of most compounds in a concentration dependent manner, peaking with 80% inhibition by 50 mM. Curiously, zinc sulfate never inhibited the sweetness of Na-cyclamate. This suggests that Na-cyclamate may access a sweet taste mechanism that is different from the other sweeteners, which were inhibited uniformly (except thaumatin) at every concentration of zinc sulfate. We hypothesize that this set of compounds either accesses a single receptor or multiple receptors that are inhibited equally by zinc sulfate at each concentration.

Utilisation d'oleocanthal principal d'irrigation dans l'huile d'olive et composants structuralement et fonctionnellement semblables

Chemical Senses, Sep 1, 2001

The human tongue is a relatively symmetrical anatomical structure and is generally assumed functi... more The human tongue is a relatively symmetrical anatomical structure and is generally assumed functionally equivalent on both sides. Experimental evaluation of this assumption is complicated by the fact that psychophysical measurements tend to vary considerably across testing sessions. To address functional laterality, we determined the detection thresholds of six right-handed and six left-handed subjects for Na saccharin, NaCl, citric acid and quinine HCl. Five pairs of interwoven, left and right unilateral thresholds were obtained for each taste stimulus in 12 subjects (n = 480 separate thresholds). In most cases mean sensitivity based on multiple measurements was found to be laterally symmetrical, however, we observed a few cases of lateral asymmetry of both general and compound-specific sensitivity. Threshold values were found to vary considerably across sessions, consistent with the test-retest variability previously reported for whole mouth thresholds. We conclude that taste threshold sensitivity is equivalent on the left and right anterior tongue for most individuals. Given the occasional exceptions to this rule, however, it is advisable to employ a counterbalanced design for any experimental or clinical testing protocol in which treatments are applied asymmetrically to the tongue.

Chimia International Journal For Chemistry, Apr 30, 2001

Excessive bitterness is an ongoing taste problem for both the pharmaceutical and food industries.... more Excessive bitterness is an ongoing taste problem for both the pharmaceutical and food industries. This paper reports on how salts (NaCl, NaAcetate, NaGluconate, LiCl, KCl) and bitter compounds (urea, quinine-HCl, caffeine, amiloride-HCl, magnesium sulfate, KCl) interact to influence bitter perception. Sodium salts differentially suppress bitterness of these compounds; for example urea bitterness was suppressed by over 70% by sodium salts, while MgSO 4 bitterness was not reduced. This study indicates that lithium ions had the same bitter suppressing ability as sodium ions, however the potassium cation had no bitter suppression ability. Changing the anion attached to the sodium didn't affect bitter suppression however as the anion increased in size, perceived saltiness decreased. This indicates that sodium's mode of action is at the peripheral taste level, rather than a cognitive affect. We speculate on potential sites of action of the sodium cation in the peripheral taste system.

Chemical Senses, 2002

A previous study investigating individuals' bitterness sensitivities found a close association am... more A previous study investigating individuals' bitterness sensitivities found a close association among three compounds: L-tryptophan (L-trp), L-phenylalanine (L-phe) and urea (Delwiche et al., 2001, Percept. Psychophys. 63, 761-776). In the present experiment, psychophysical cross-adaptation and bitterness inhibition experiments were performed on these three compounds to determine whether the bitterness could be differentially affected by either technique. If the two experimental approaches failed to differentiate L-trp, L-phe and urea's bitterness, then we may infer they share peripheral physiological mechanisms involved in bitter taste. All compounds were intensity matched in each of 13 subjects, so the judgments of adaptation or bitterness inhibition would be based on equal initial magnitudes and, therefore, directly comparable. In the first experiment, cross-adaptation of bitterness between the amino acids was high (>80%) and reciprocal. Urea and quinine-HCl (control) did not cross-adapt with the amino acids symmetrically. In a second experiment, the sodium salts, NaCl and Na gluconate, did not differentially inhibit the bitterness of L-trp, L-phe and urea, but the control compound, MgSO4, was differentially affected. The bitter inhibition experiment supports the hypothesis that L-trp, L-phe and urea share peripheral bitter taste mechanisms, while the adaptation experiment revealed subtle differences between urea and the amino acids indicating that urea and the amino acids activate only partially overlapping bitter taste mechanisms.

Alzheimer's-associated A oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal

Toxicol Appl Pharmacol, 2009

It now appears likely that soluble oligomers of amyloid-β1–42 peptide, rather than insoluble fibr... more It now appears likely that soluble oligomers of amyloid-β1–42 peptide, rather than insoluble fibrils, act as the primary neurotoxin in Alzheimer's disease (AD). Consequently, compounds capable of altering the assembly state of these oligomers (referred to as ADDLs) may have potential for AD therapeutics. Phenolic compounds are of particular interest for their ability to disrupt Aβ oligomerization and reduce pathogenicity. This study has focused on oleocanthal (OC), a naturally-occurring phenolic compound found in extra-virgin olive oil. OC increased the immunoreactivity of soluble Aβ species, when assayed with both sequence- and conformation-specific Aβ antibodies, indicating changes in oligomer structure. Analysis of oligomers in the presence of OC showed an upward shift in MW and a ladder-like distribution of SDS-stable ADDL subspecies. In comparison with control ADDLs, oligomers formed in the presence of OC (Aβ-OC) showed equivalent colocalization at synapses but exhibited greater immunofluorescence as a result of increased antibody recognition. The enhanced signal at synapses was not due to increased synaptic binding, as direct detection of fluorescently-labeled ADDLs showed an overall reduction in ADDL signal in the presence of OC. Decreased binding to synapses was accompanied by significantly less synaptic deterioration assayed by drebrin loss. Additionally, treatment with OC improved antibody clearance of ADDLs. These results indicate oleocanthal is capable of altering the oligomerization state of ADDLs while protecting neurons from the synaptopathological effects of ADDLs and suggest OC as a lead compound for development in AD therapeutics.

Use of the irritating principal oleocanthal in olive oil, as well as structurally and functionally similar compounds

Sodium specificity of salt appetite in Fischer-344 and Wistar rats is impaired by chorda tympani nerve transection

American Journal of Physiology Regulatory Integrative and Comparative Physiology, Sep 1, 1995

Unlike other rat strains, the sodium-replete Fischer-344 (F344) strain shows no innate preference... more Unlike other rat strains, the sodium-replete Fischer-344 (F344) strain shows no innate preference for NaCl and displays more aversive and fewer ingestive oral motor responses to orally infused NaCl when tested in sodium balance. Despite these differences, F344 rats show an increase in preference for NaCl in response to sodium depletion. The present study was designed to determine whether the salt appetite of sodium-depleted F344 rats is cation specific and whether such selectivity is mediated in part by an intact chorda tympani nerve. Sodium-depleted (10 mg furosemide) F344 (n = 13) and Wistar (n = 16) rats were permitted repeated access to nine stimuli (water, and 0.05 and 0.3 M NaCl, KCl, NH4Cl, and CaCl2), presented randomly in 10-s trials. One-half of the rats had their chorda tympani nerve sectioned (CTX). Under conditions of sodium depletion, both strains discriminated NaCl from other chloride salts. CTX significantly impaired the selectivity of the licking behavior in both strains, suggesting that sodium-specific licking is partially mediated by anterior tongue taste receptors. These findings suggest that both sodium-depleted F344 and Wistar rats are comparable in their abilities to recognize NaCl, to distinguish it from other salts, and to respond selectively to it, despite the fact that sodium-replete F344 and Wistar rats differ greatly in their NaCl preference.

(-)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization

Molecular & cellular oncology

(-)-Oleocanthal (OC), a phenolic compound present in extra-virgin olive oil (EVOO), has been impl... more (-)-Oleocanthal (OC), a phenolic compound present in extra-virgin olive oil (EVOO), has been implicated in the health benefits associated with diets rich in EVOO. We investigated the effect of OC on human cancer cell lines in culture and found that OC induced cell death in all cancer cells examined as rapidly as 30 minutes after treatment in the absence of serum. OC treatment of non-transformed cells suppressed their proliferation but did not cause cell death. OC induced both primary necrotic and apoptotic cell death via induction of lysosomal membrane permeabilization (LMP). We provide evidence that OC promotes LMP by inhibiting acid sphingomyelinase (ASM) activity, which destabilizes the interaction between proteins required for lysosomal membrane stability. The data presented here indicate that cancer cells, which tend to have fragile lysosomal membranes compared to non-cancerous cells, are susceptible to cell death induced by lysosomotropic agents. Therefore, targeting lysosomal membrane stability represents a novel approach for the induction of cancer-specific cell death.

Pharmaceutical research, 2002

NaCl has proven to be an effective bitterness inhibitor, but the reason remains unclear. The purp... more NaCl has proven to be an effective bitterness inhibitor, but the reason remains unclear. The purpose of this study was to examine the influence of a variety of cations and anions on the bitterness of selected oral pharmaceuticals and bitter taste stimuli: pseudoephedrine, ranitidine, acetaminophen, quinine, and urea. Human psychophysical taste evaluation using a whole mouth exposure procedure was used. The cations (all associated with the acetate anion) inhibited bitterness when mixed with pharmaceutical solutions to varying degrees. The sodium cation significantly (P < 0.003) inhibited bitterness of the pharmaceuticals more than the other cations. The anions (all associated with the sodium cation) also inhibited bitterness to varying degrees. With the exception of salicylate, the glutamate and adenosine monophosphate anions significantly (P < 0.001) inhibited bitterness of the pharmaceuticals more than the other anions. Also, there were several specific inhibitory interaction...

Chorda tympani section decreases the cation specificity of depletion-induced sodium appetite in rats

The American journal of physiology, 1993

Rats depleted of sodium by diuretic treatment were tested for their ability to respond selectivel... more Rats depleted of sodium by diuretic treatment were tested for their ability to respond selectively to NaCl after chorda tympani nerve (CTn) section (CTX). A variety of chloride salts (NaCl, KCl, NH4Cl, CaCl2) at two concentrations (0.05 and 0.3 M) were presented semirandomly to sodium-deplete rats in repeated single-stimulus trials (10 s). The responses of sodium-depleted surgical control rats (n = 8) were highly cation specific. These rats licked substantially more for both sodium stimuli than for any other chloride salt. On the other hand, the licking responses of CTX sodium-depleted rats (n = 8) were less cation selective. These rats licked NaCl and 0.05 M KCl at comparable rates. For both NaCl concentrations, CTX rats had significantly lower lick rates than controls. In addition, the difference between the lick rate for NaCl and that for the other salts was much greater for control rats than for CTX rats. Although CTn section did not entirely eliminate the high levels of respons...

It now appears likely that soluble oligomers of amyloid-β 1–42 peptide, rather than insoluble fib... more It now appears likely that soluble oligomers of amyloid-β 1–42 peptide, rather than insoluble fibrils, act as the primary neurotoxin in Alzheimer's disease (AD). Consequently, compounds capable of altering the assembly state of these oligomers (referred to as ADDLs) may have potential for AD therapeutics. Phenolic compounds are of particular interest for their ability to disrupt Aβ oligomerization and reduce pathogenicity. This study has focused on oleocanthal (OC), a naturally-occurring phenolic compound found in extra-virgin olive oil. OC increased the immunoreactivity of soluble Aβ species, when assayed with both sequence-and conformation-specific Aβ antibodies, indicating changes in oligomer structure. Analysis of oligomers in the presence of OC showed an upward shift in MW and a ladder-like distribution of SDS-stable ADDL subspecies. In comparison with control ADDLs, oligomers formed in the presence of OC (Aβ-OC) showed equivalent colocalization at synapses but exhibited greater immunofluorescence as a result of increased antibody recognition. The enhanced signal at synapses was not due to increased synaptic binding, as direct detection of fluorescently-labeled ADDLs showed an overall reduction in ADDL signal in the presence of OC. Decreased binding to synapses was accompanied by significantly less synaptic deterioration assayed by drebrin loss. Additionally, treatment with OC improved antibody clearance of ADDLs. These results indicate oleocanthal is capable of altering the oligomerization state of ADDLs while protecting neurons from the synaptopathological effects of ADDLs and suggest OC as a lead compound for development in AD therapeutics.

Journal of Neuroscience, 2011

Oleocanthal, a major phenolic compound in extra-virgin olive oil with antiinflammatory properties... more Oleocanthal, a major phenolic compound in extra-virgin olive oil with antiinflammatory properties, elicits an unusual oral pungency sensed almost exclusively in the throat. This contrasts with most other common oral irritants, such as cinnamaldehyde, capsaicin, and alcohol, which irritate mucus membranes throughout the oral cavity. Here, we show that this rare irritation pattern is a consequence of both the specificity of oleocanthal for a single sensory receptor and the anatomical restriction of this sensory receptor to the pharynx, within the oral cavity. We demonstrate, in vitro, that oleocanthal selectively activates the hTRPA1 channel in HEK 293 cells and that its ability to excite the trigeminal nervous system in rodents requires a functional TRPA1. Moreover, we similarly demonstrate that the over-the-counter analgesic, ibuprofen, which elicits the same restricted pharyngeal irritation as oleocanthal, also specifically excites rodent sensory neurons via TRPA1. Using human sensory psychophysical studies and immunohistochemical TRPA1 analyses of human oral and nasal tissues, we observe an overlap of the anatomical distribution of TRPA1 and the regions irritated by oleocanthal in humans. These results suggest that a TRPA1 (ANKTM1) gene product mediates the tissue sensitivity to oleocanthal within the oral cavity. Furthermore, we demonstrate that, despite the fact that oleocanthal possesses the classic electrophilic reactivity of many TRPA1 agonists, it does not use the previously identified activation mechanism via covalent cysteine modification. These findings provide an anatomical and molecular explanation for a distinct oral sensation that is elicited by oleocanthal and ibuprofen and that is commonly experienced around the world when consuming many extra-virgin olive oils.

Cough is a vital protective reflex that is triggered by both mechanical and chemical stimuli. The... more Cough is a vital protective reflex that is triggered by both mechanical and chemical stimuli. The current experiments explored how chemosensory stimuli modulate this important reflex. Cough thresholds were measured using a single-inhalation capsaicin challenge. Experiment 1 examined the impact of sweet taste: Cough thresholds were measured after rinsing the mouth with a sucrose solution (sweet) or with water (control). Experiment 2 examined the impact of menthol: Cough thresholds were measured after inhaling headspace above a menthol solution (menthol vapor) or headspace above the mineral oil solvent (control). Experiment 3 examined the impact of rinsing the mouth with a (bitter) sucrose octaacetate solution. Rinsing with sucrose and inhaling menthol vapor significantly increased measured cough thresholds. Rinsing with sucrose octaacete caused a non-significant decrease in cough thresholds, an important demonstration of specificity. Decreases in cough reflex sensitivity from sucrose or menthol could help explain why cough syrups without pharmacologically active ingredients are often almost as effective as formulations with an added drug. Further, the results support the idea that adding menthol to cigarettes might make tobacco smoke more tolerable for beginning smokers, at least in part, by reducing the sensitivity of an important airway defense mechanism.

Pharmaceutical Research, 2005

2005-11, Bitterness suppression with zinc sulfate and na-cyclamate: a model of combined periphera... more 2005-11, Bitterness suppression with zinc sulfate and na-cyclamate: a model of combined peripheral and central neural approaches to flavor modification, Bitterness inhibition using zinc 2

Synthesis and Assignment of Absolute Configuration of (−)-Oleocanthal: A Potent, Naturally Occurring Non-steroidal Anti-inflammatory and Anti-oxidant Agent Derived from Extra Virgin Olive Oils

Organic Letters, 2005

Induction of olfactory sensitivity in humans was first illustrated when men and women who were in... more Induction of olfactory sensitivity in humans was first illustrated when men and women who were initially unable to smell the volatile steroid androstenone (5α-androst-16-en-3-one) developed that ability after repeated, brief exposures 1 . Because this finding has not been replicated with other compounds in humans, it has been assumed that olfactory induction is a narrowly constrained phenomenon, occurring only in individuals with specific anosmias, perhaps only to androstenone (compare ref.