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      Advanced Glycation End-Products Can Activate or Block Bitter Taste Receptors

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          Abstract

          Bitter taste receptors (T2Rs) are expressed in several tissues of the body and are involved in a variety of roles apart from bitter taste perception. Advanced glycation end-products (AGEs) are produced by glycation of amino acids in proteins. There are varying sources of AGEs, including dietary food products, as well as endogenous reactions within our body. Whether these AGEs are T2R ligands remains to be characterized. In this study, we selected two AGEs, namely, glyoxal-derived lysine dimer (GOLD) and carboxymethyllysine (CML), based on their predicted interaction with the well-studied T2R4, and its physiochemical properties. Results showed predicted binding affinities ( K d ) for GOLD and CML towards T2R4 in the nM and μM range, respectively. Calcium mobilization assays showed that GOLD inhibited quinine activation of T2R4 with IC 50 10.52 ± 4.7 μM, whilst CML was less effective with IC 50 32.62 ± 9.5 μM. To characterize whether this antagonism was specific to quinine activated T2R4 or applicable to other T2Rs, we selected T2R14 and T2R20, which are expressed at significant levels in different human tissues. A similar effect of GOLD was observed with T2R14; and in contrast, GOLD and CML activated T2R20 with an EC 50 of 79.35 ± 29.16 μM and 65.31 ± 17.79 μM, respectively. In this study, we identified AGEs as novel T2R ligands that caused either activation or inhibition of different T2Rs.

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          Most cited references47

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          Motile cilia of human airway epithelia are chemosensory.

          Cilia are microscopic projections that extend from eukaryotic cells. There are two general types of cilia; primary cilia serve as sensory organelles, whereas motile cilia exert mechanical force. The motile cilia emerging from human airway epithelial cells propel harmful inhaled material out of the lung. We found that these cells express sensory bitter taste receptors, which localized on motile cilia. Bitter compounds increased the intracellular calcium ion concentration and stimulated ciliary beat frequency. Thus, airway epithelia contain a cell-autonomous system in which motile cilia both sense noxious substances entering airways and initiate a defensive mechanical mechanism to eliminate the offending compound. Hence, like primary cilia, classical motile cilia also contain sensors to detect the external environment.
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            Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells.

            Although a role for the gastric and intestinal mucosa in molecular sensing has been known for decades, the initial molecular recognition events that sense the chemical composition of the luminal contents has remained elusive. Here we identified putative taste receptor gene transcripts in the gastrointestinal tract. Our results, using reverse transcriptase-PCR, demonstrate the presence of transcripts corresponding to multiple members of the T2R family of bitter taste receptors in the antral and fundic gastric mucosa as well as in the lining of the duodenum. In addition, cDNA clones of T2R receptors were detected in a rat gastric endocrine cell cDNA library, suggesting that these receptors are expressed, at least partly, in enteroendocrine cells. Accordingly, expression of multiple T2R receptors also was found in STC-1 cells, an enteroendocrine cell line. The expression of alpha subunits of G proteins implicated in intracellular taste signal transduction, namely Galpha(gust), and Galpha(t)-(2), also was demonstrated in the gastrointestinal mucosa as well as in STC-1 cells, as revealed by reverse transcriptase-PCR and DNA sequencing, immunohistochemistry, and Western blotting. Furthermore, addition of compounds widely used in bitter taste signaling (e.g., denatonium, phenylthiocarbamide, 6-n-propil-2-thiouracil, and cycloheximide) to STC-1 cells promoted a rapid increase in intracellular Ca(2+) concentration. These results demonstrate the expression of bitter taste receptors of the T2R family in the mouse and rat gastrointestinal tract.
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              Role of advanced glycation end products in cardiovascular disease.

              Advanced glycation end products (AGEs) are produced through the non enzymatic glycation and oxidation of proteins, lipids and nucleic acids. Enhanced formation of AGEs occurs particularly in conditions associated with hyperglycaemia such as diabetes mellitus (DM). AGEs are believed to have a key role in the development and progression of cardiovascular disease in patients with DM through the modification of the structure, function and mechanical properties of tissues through crosslinking intracellular as well as extracellular matrix proteins and through modulating cellular processes through binding to cell surface receptors [receptor for AGEs (RAGE)]. A number of studies have shown a correlation between serum AGE levels and the development and severity of heart failure (HF). Moreover, some studies have suggested that therapies targeted against AGEs may have therapeutic potential in patients with HF. The purpose of this review is to discuss the role of AGEs in cardiovascular disease and in particular in heart failure, focussing on both cellular mechanisms of action as well as highlighting how targeting AGEs may represent a novel therapeutic strategy in the treatment of HF.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                12 June 2019
                June 2019
                : 11
                : 6
                : 1317
                Affiliations
                [1 ]Manitoba Chemosensory Biology Research Group, Department of Oral Biology, University of Manitoba, Children’s Hospital Research Institute of Manitoba (CHRIM), Winnipeg, MB R3E 0W4, Canada; Appalaraju.Jaggupilli@ 123456umanitoba.ca (A.J.); umhowarr@ 123456myumanitoba.ca (R.H.)
                [2 ]Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada; Rotimi.Aluko@ 123456umanitoba.ca
                Author notes
                [* ]Correspondence: Prashen.Chelikani@ 123456umanitoba.ca ; Tel.: +204-789-3539; Fax: +204-789-3913
                Author information
                https://orcid.org/0000-0002-1718-8551
                https://orcid.org/0000-0002-9025-2513
                https://orcid.org/0000-0003-1129-7957
                Article
                nutrients-11-01317
                10.3390/nu11061317
                6628017
                31212814
                66e92f84-7927-4bb8-826a-a053ba01ac64
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 22 May 2019
                : 10 June 2019
                Categories
                Article

                Nutrition & Dietetics
                bitter taste receptor,advanced glycation end-products,bitter blockers,gpcr,calcium mobilization

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