Flavanoids and related polyphenols, among them hesperitin, have been shown to modulate cellular glucose transport by targeting SGLT-1 and GLUT-2 transport proteins. We aimed to investigate whether ...homoeriodictyol, which is structurally related to hesperitin, affects glucose uptake in differentiated Caco-2 cells as a model for the intestinal barrier. The results revealed that, in contrast to other polyphenols, the flavanon homoeriodictyol promotes glucose uptake by 29.0 ± 3.83% at a concentration of 100 μM. The glucose uptake stimulating effect was sensitive to phloridzin, but not to phloretin, indicating an involvement of the sodium-coupled glucose transporter SGLT-1, but not of sodium-independent glucose transporters (GLUT). In addition, in contrast to the increased extracellular serotonin levels by stimulation with 500 mM D-(+)-glucose, treatment with 100 μM homoeriodictyol decreased serotonin release by -48.8 ± 7.57% in Caco-2 cells via a phloridzin-sensitive signaling pathway. Extracellular serotonin levels were also reduced by -57.1 ± 5.43% after application of 0.01 μM homoeriodictyol to human neural SH-SY5Y cells. In conclusion, we demonstrate that homoeriodictyol affects both the glucose metabolism and the serotonin system in Caco-2 cells via a SGLT-1-meditated pathway. Furthermore, the results presented here support the usage of Caco-2 cells as a model for peripheral serotonin release. Further investigations may address the value of homoeriodictyol in the treatment of anorexia and malnutrition through the targeting of SGLT-1.
A modified aroma extract dilution approach (AEDA), followed by the determination of flavor dilution (FD) factors, a quantitative analysis and calculation of the relative flavor activity (RFA) and ...odor activity values (OAVs) as well as recombination experiments were conducted to evaluate the odor- and taste-relevant components of cold-pressed Citrus latifolia peel oil. A 2-fold concentration by distillation and reanalysis, compared with the original oil, revealed relevant components. Partition of the odor-active substances into four reconstitution groups according to their respective FD factors, followed by a recombination, allowed for a better understanding of the contribution of each FD-factor group to the overall aroma. Especially α-pinene, limonene, γ-terpinene, and 7-methoxycoumarin contribute significantly to the distinct aroma profile of C. latifolia. Heptadecanal (CAS 629-90-3) was described for the first time as an odor-active substance in an enriched C. latifolia peel oil. Campherenyl acetate (CAS 18530-07-9) was identified in nature for the first time and described with a herbal, minty and citrus-like odor. The odor profile of the final recombinant mixture, containing 36 components, was similar to cold-pressed C. latifolia peel oil for most descriptors, whereas the taste profile was described as more aldehydic and citral-like.
This study aimed at identifying whether the bitter-tasting amino acids l-arginine (l-ARG) and l-isoleucine (l-ILE) differentially regulate mechanisms of gastric acid secretion in human parietal cells ...(HGT-1 cells) via activation of bitter taste sensing receptors (T2Rs). In a first set of experiments, involvement of T2Rs in l-ARG and l-ILE-modulated proton secretion was demonstrated by co-treatment of HGT-1 cells with T2R antagonists. Subsequent whole genome screenings by means of cDNA arrays revealed T2R1 as a prominent target for both amino acids. Next, the functional role of T2R1 was verified by means of a T2R1 CRISPR-Cas9 knock-out approach. Here, the effect of l-ARG on proton secretion decreased by 65.7 ± 21.9% and the effect of l-ILE increased by 93.2 ± 24.1% in HGT-1 T2R1 ko versus HGT-1 wt cells (p < 0.05). Overall, our results indicate differential effects of l-ARG and l-ILE on proton secretion in HGT-1 cells and our molecular docking studies predict distinct binding for these amino acids in the binding site of T2R1. Further studies will elucidate whether the mechanism of differential effects involves structure-specific ligand-biased signaling of T2R1 or additional cellular targets.
Citrus fruits have been known and valued for their aroma in food and perfume ever since humans have maintained written records. Often described as the “champagne” of citrus oils, especially cold ...pressed lime peel oils have raised attention. Particularly peel oils of Citrus latifolia exhibit a pleasant coumarinic, sweet, and balsamic aroma in comparison to its close relative, the Citrus aurantifolia. Those coumarinic notes have not been completely understood until today. Thus, this study aimed to identify the responsible substances and elucidate their contribution and impact on the aroma of cold-pressed lime oil. By combining distillation, fractionation, olfactory detection, and structure elucidation, the responsible key aroma components were identified. A combination of coumarins and their corresponding saturated analogs have been identified to significantly contribute to the typical coumarinic-like aroma, including three new flavor compounds that have not yet been described in the literature as lime oil constituents: 7-methoxy-2-chromanone (3,4-dihydro-7-methoxy-2H-1-benzopyran-2-one; CAS 20921-02-2), 5,7-dimethoxy-2-chromanone (3,4-dihydro-5,7-dimethoxy-2H-1-benzopyran-2-one; CAS 82243-01-4) and 5,6-dihydrobergaptene (5,6-dihydro-4-methoxy-7H-furo3,2-g1benzopyran-7-one; CAS 29050-61-1). The sensorial evaluation of the impact of these components on the lime aroma profile has shown flavor-modulating effects and the ability to enhance aldehydic-peely, juicy, and fruity notes as well as their importance in reproducing the authentic, typical coumarin-like notes.
Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs). TAS2Rs are expressed in the mouth ...and in several extraoral sites, e.g., in the gastrointestinal tract, in which their functional role still needs to be clarified. We hypothesized that caffeine evokes effects on GAS by activation of oral and gastric TAS2Rs and demonstrate that caffeine, when administered encapsulated, stimulates GAS, whereas oral administration of a caffeine solution delays GAS in healthy human subjects. Correlation analysis of data obtained from ingestion of the caffeine solution revealed an association between the magnitude of the GAS response and the perceived bitterness, suggesting a functional role of oral TAS2Rs in GAS. Expression of TAS2Rs, including cognate TAS2Rs for caffeine, was shown in human gastric epithelial cells of the corpus/fundus and in HGT-1 cells, a model for the study of GAS. In HGT-1 cells, various bitter compounds as well as caffeine stimulated proton secretion, whereby the caffeine-evoked effect was (i) shown to depend on one of its cognate receptor, TAS2R43, and adenylyl cyclase; and (ii) reduced by homoeriodictyol (HED), a known inhibitor of caffeine’s bitter taste. This inhibitory effect of HED on caffeine-induced GAS was verified in healthy human subjects. These findings (i) demonstrate that bitter taste receptors in the stomach and the oral cavity are involved in the regulation of GAS and (ii) suggest that bitter tastants and bittermasking compounds could be potentially useful therapeutics to regulate gastric pH.
Background Canakinumab is a fully human anti-interleukin IL-1beta monoclonal antibody, being investigated for the treatment of rheumatoid arthritis (RA). This multicenter, phase II, randomized, ...double-blind, placebo-controlled, parallel-group, dose-finding study investigated the efficacy and safety of canakinumab in patients with active RA despite ongoing therapy at stable doses of methotrexate. Methods Patients were randomized to receive one of four regimens, in addition to methotrexate, for 12 weeks: canakinumab 150 mg subcutaneously (SC) every 4 weeks (q4wk), canakinumab 300 mg SC (2 injections of 150 mg SC) every 2 weeks, a 600 mg intravenous loading dose of canakinumab followed by 300 mg SC every 2 weeks', or placebo SC every 2 weeks. Results Among 274 patients with evaluable efficacy data, the percentage of responders according to American College of Rheumatology 50 criteria (the primary endpoint, based on a 28-joint count) was significantly higher with canakinumab 150 mg SC q4wk than with placebo (26.5% vs. 11.4%, respectively; p = 0.028). Compared to placebo, this dosage of canakinumab was also associated with significantly more favorable responses at week 12 with respect to secondary endpoints including the Disease Activity Score 28, scores on the Health Assessment Questionnaire and Functional Assessment of Chronic Illness Therapy-Fatigue, swollen 28-joint count, and patient's and physician's global assessments of disease activity. No safety concerns were raised with canakinumab therapy, particularly with regard to infections. Few injection-site reactions occurred. Conclusion The addition of canakinumab 150 mg SC q4wk improves therapeutic responses among patients who have active RA despite stable treatment with methotrexate. Trial Registration (ClinicalTrials.gov identifier: NCT00784628)
Secretion of gastric acid, aimed at preventing bacterial growth and aiding the digestion of foods in the stomach, is chiefly stimulated by dietary intake of protein and amino acids (AAs). However, ...AAs’ key structural determinants responsible for their effects on mechanisms regulating gastric acid secretion (GAS) have not been identified yet. In this study, AAs have been tested in the parietal cell model HGT-1 on GAS and on mRNA expression of genes regulating GAS. AAs’ taste intensities from 0 (not bitter at all) to 10 (very bitter) were assessed in a sensory study, in which ARG (l: 6.42 ± 0.41; d: 4.62 ± 0.59) and ILE (l: 4.21 ± 0.43; d: 2.28 ± 0.33) were identified as bitter-tasting candidates in both isomeric forms. Pearson correlation showed that GAS in HGT-1 cells is directly associated with the bitter taste quality (r: −0.654) in combination with the molecular weight of l-AA (r: −0.685).
Knowledge regarding the involvement of sweetness perception on energy intake is scarce. Here, the impact of glucose and sucrose sweetness, beyond their caloric load, on subsequent food intake and ...biomarkers of satiation was evaluated by co-administration of the sweet taste receptor inhibitor lactisole. A total of 27 healthy, male subjects received solutions of either 10% glucose
/
60 ppm lactisole or 10% sucrose
/
60 ppm lactisole. Subsequent food intake from a standardized breakfast was evaluated 2 h after receiving the respective test solution. Changes in postprandial plasma concentrations of cholecystokinin, ghrelin, and serotonin were determined over a period of 120 min, as was the body temperature. Administration of lactisole to the sucrose solution increased the energy intake from the subsequent standardized breakfast by 12.9 ± 5.8% (
= 0.04), led to a decreased Δ AUC of the body core temperature by 46 ± 20% (
= 0.01), and time-dependently reduced Δ serotonin plasma concentrations (-16.9 ± 6.06 ng/mL vs. -0.56 ± 3.7 ng/mL after sucrose administration,
= 0.03). The present study shows that lactisole increases energy intake and decreases plasma serotonin concentrations as well as body core temperature induced by sucrose, but not glucose. This finding may be associated with the different binding affinities of sucrose and glucose to the sweet taste receptor.
Scope
Inflammation‐related diseases are a worldwide problem. The counteraction of inflammation with compounds activating the trigeminal nerve is one strategy to fight these diseases. Known ...trigeminally active compounds found in black or red pepper are the tingling t‐pellitorine, the pungent capsaicin, and the less pungent nonivamide. The presented study compares the anti‐inflammatory potential of nonivamide to the two known anti‐inflammatory compounds, elucidating the mechanism of action and the role of transient receptor protein (TRP) channels.
Methods and results
Primary peripheral blood mononuclear cells (PBMCs) and U‐937 macrophages were stimulated with 1 μg/mL LPS from Escherichia coli (EC‐LPS) to induce inflammation. Nonivamide attenuated the EC‐LPS induced release of IL‐6 and TNF‐α in PBMCs and U‐937 macrophages determined by magnetic bead kit analysis. This anti‐inflammatory mechanism was independent from nuclear factor‐kappa B pathway but mitogen‐activated protein kinase (MAPK) pathway may be involved. In addition, cotreatment of U‐937 with the trigeminally active compound and an antagonist of TRPV1 or TRPA1 abolished the anti‐inflammatory activity.
Conclusions
Nonivamide possessed similar anti‐inflammatory potential as capsaicin and t‐pellitorine. In U‐937 macrophages, the tested compounds exploited an anti‐inflammatory effect by inhibiting the EC‐LPS induced activation of the MAPK pathway. In addition, the TRP channel activation plays a role in the anti‐inflammatory capacity of capsaicin and nonivamide.
Trigeminally active compounds, namely nonivamide, capsaicin, and t‐pellitorine, possess anti‐inflammatory activities in macrophages by inhibiting LPS‐induced ERK1/2 phosphorylation, cytokine mRNA expression and release, but not by inhibition of NF‐κB signaling
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