Summary Human bitter taste is mediated by the hTAS2R family of G protein-coupled receptors [1-4]. The discovery of the hTAS2Rs enables the potential to develop specific bitter receptor antagonists that could be beneficial as chemical probes to examine the role of bitter receptor function in gustatory and non-gustatory tissues. In addition, they could have widespread utility in food and beverages fortified with vitamins, antioxidants and other nutraceuticals since many of these have unwanted bitter aftertastes. We employed a high-throughput screening approach to discover a novel bitter receptor antagonist (GIV3727) that inhibits activation of hTAS2R31 by saccharin and acesulfame K, two common artificial sweeteners. Pharmacological analyses revealed that GIV3727 likely acts as an orthosteric, insurmountable antagonist of hTAS2R31. Surprisingly, we also found that this compound could inhibit five additional hTAS2Rs, including the closely related receptor hTAS2R43. Molecular modeling and site-directed mutagenesis studies suggest that two residues in helix seven are important for antagonist activity in hTAS2R43/31. In human sensory trials, GIV3727 significantly reduced the bitterness associated with the two sulphonamide sweeteners, indicating that TAS2R antagonists are active in vivo. Our results demonstrate that small molecule bitter receptor antagonists can effectively reduce the bitter taste qualities of foods, beverages, and pharmaceuticals.
Sawyer CM, Iodi Carstens M, Simons CT, Slack J, McCluskey TS, Furrer S, Carstens E. Activation of lumbar spinal wide-dynamic range neurons by a sanshool derivative. J Neurophysiol 101: 1742-1748, 2009. First published January 21, 2009 doi:10.1152/jn.91311.2008. The enigmatic sensation of tingle involves the activation of primary sensory neurons by hydroxy-␣-sanshool, a tingly agent in Szechuan peppers, by inhibiting two-pore potassium channels. Central mechanisms mediating tingle sensation are unknown. We investigated whether a stable derivative of sanshool-isobutylalkenyl amide (IBA)-excites wide-dynamic range (WDR) spinal neurons that participate in transmission of chemesthetic information from the skin. In anesthetized rats, the majority of WDR and low-threshold units responded to intradermal injection of IBA in a dose-related manner over a Ͼ5-min time course and exhibited tachyphylaxis at higher concentrations (1 and 10%). Almost all WDR and low-threshold units additionally responded to the pungent agents mustard oil (allyl isothiocyanate) and/or capsaicin, prompting reclassification of the low-threshold cells as WDR. The results are discussed in terms of the functional role of WDR neurons in mediating tingle sensation. I N T R O D U C T I O NSzechuan pepper (sansho) from the plant genus Xanthoxylum piperitum is used as a spice because of the unique tingling paresthetic and numbing sensations imparted by the primary active chemical, hydroxy-␣-sanshool. The southern prickly ash (Xanthoxylum clava-herculis), indigenous to the southern United States, is called the "toothache tree" because of anesthetic properties of its bark (Jacobsen 1948). The tingling, buzzing, cooling, and numbing sensations elicited by hydroxy-␣-sanshool differ from the burning sensation elicited by capsaicin, the pungent chemical in chili peppers (Bryant and Mezine 1999; Sugai et al. 2005a,b;Yang 2008), suggesting that sanshool activates a different population of sensory receptors than does capsaicin, which acts via TRPV1 receptors expressed in the nerve endings of polymodal nociceptors. Hydroxy-␣-sanshool was shown to increase spontaneous firing in cool-sensitive fibers and to elicit responses in mechanosensitive fibers, cold nociceptors, and mechanically insensitive fibers recorded in rat lingual nerve (Bryant and Mezine 1999), suggesting that sanshool activates a variety of sensory receptors. It was recently reported that hydroxy-␣-sanshool excites cells expressing TRPV1 or TRPA1 (Koo et al. 2007), which are associated with nociception (Dhaka et al. 2006), although sanshool was reported to be much less effective than capsaicin in activating cells expressing TRPV1 receptors (Sugai et al. 2005a). A very recent study reported that hydroxy-␣-sanshool activates small-diameter sensory neurons expressing TRPV1 receptors (but not TRPA1), as well as large-diameter sensory neurons expressing TrkC, by inhibiting anesthetic-sensitive two-pore K ϩ channel subtypes KCNK3, KCNK9, and KCNK18 (Bautista et al. 2008). The available data suggest that san...
Background Hypersensitivity to metals as a cause of implant‐related complications has been a subject of controversy. Projections indicate an increase in the frequency of joint replacements of between 300% and 600% by the year 2030; therefore, this issue is of considerable interest. Objective To evaluate sensitization to implant materials in patients with implant‐related complications, to identify allergens, and to clarify whether hypersensitivity is a relevant cause. Methods Patients with implant‐related complications or a positive history of contact allergy and planned total joint replacements referred for allergological investigation between 2004 and 2017 were retrospectively analysed. Results In total, 311 patients were included. A positive patch test reaction to a metal was seen in 64.4% of preoperative patients and in 54.6% of patients with implant‐related complications. Common alloy metals such as cobalt, chromium and titanium gave positive reactions in up to 2.9% of patients with implant‐related complications. None of the patients with skin changes had a positive patch test reaction to an implant metal. Conclusion Other factors, such as the type of replaced joint and mechanical stress, seem to be more relevant for implant‐related complications. Sensitization to metals or other materials seems to rarely play a role, and is overestimated.
Cooling chemicals play a fundamental role in the flavor and fragrance industry. Traditional trial-and-error techniques led in the past to the discovery of several commercially successful cooling compounds. Over the years, the market needs became more complex requiring products with very specific profiles. These radical changes demanded a fresh research approach encompassing chem-
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.