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      Endogenous salivary citrate is associated with enhanced rheological properties following oral capsaicin stimulation

      research-article
      1 , 2 , 3 , , 1
      Experimental Physiology
      John Wiley and Sons Inc.
      metabolomics, rheology, saliva

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          Abstract

          New Findings

          • What is the central question of this study?

            What are the relationships between physical properties of saliva, protein composition and metabolite composition?

          • What is the main finding and its importance?

            Salivary citrate, one of the major endogenous metabolites in saliva, increased upon capsaicin stimulation and was associated with improved physical properties measured by extensional rheology. This suggests salivary gland citrate transporters might be a valuable area of future study.

          Abstract

          Saliva displays viscoelastic properties which enable coating, lubrication and protection of the oral mucosa and hard tissues. Individuals lacking saliva or perceiving oral dryness can manage their symptoms using artificial saliva preparations, but these often fail to mimic the sensation and functionality of natural saliva. It is widely acknowledged that mucins (MUC7 and MUC5B) confer saliva's rheological properties, but artificial saliva containing purified mucins is still often an inadequate substitute. This work aimed to explore salivary components that influence salivary extensional rheology to better understand how natural saliva could be replicated. Saliva was stimulated via control and capsaicin solutions in healthy volunteers. Extensional rheology was analysed using a CaBER‐1 (capillary breakup) extensional rheometer. Protein composition, including mucins, was measured by gel‐electrophoresis band densitometry and metabolites were measured by 1H nuclear magnetic resonance spectroscopy. Capsaicin stimulation significantly increased capillary breakup time, extensional viscosity and the abundance of most major salivary proteins. Stimulation also increased salivary citrate and choline concentrations. Significant correlations were found between capillary breakup time and amylase ( r = 0.67, P < 0.05), statherin ( ρ = 0.66, P < 0.05) and citrate ( ρ = 0.81, P < 0.01). The relationship between citrate and salivary rheology was subsequently investigated in vitro. These results suggest that citrate and non‐mucin proteins are stronger predictors of salivary rheology than the more often studied mucin glycoproteins. Potential mechanisms are discussed and future work in this area could help formulate more effective saliva substitutes, more closely resembling natural saliva.

          Abstract

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          Most cited references32

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          The physiology of salivary secretion.

          Saliva in the mouth is a biofluid produced mainly by three pairs of major salivary glands--the submandibular, parotid and sublingual glands--along with secretions from many minor submucosal salivary glands. Salivary gland secretion is a nerve-mediated reflex and the volume of saliva secreted is dependent on the intensity and type of taste and on chemosensory, masticatory or tactile stimulation. Long periods of low (resting or unstimulated) flow are broken by short periods of high flow, which is stimulated by taste and mastication. The nerve-mediated salivary reflex is modulated by nerve signals from other centers in the central nervous system, which is most obvious as hyposalivation at times of anxiety. An example of other neurohormonal influences on the salivary reflex is the circadian rhythm, which affects salivary flow and ionic composition. Cholinergic parasympathetic and adrenergic sympathetic autonomic nerves evoke salivary secretion, signaling through muscarinic M3 and adrenoceptors on salivary acinar cells and leading to secretion of fluid and salivary proteins. Saliva gland acinar cells are chloride and sodium secreting, and the isotonic fluid produced is rendered hypotonic by salivary gland duct cells as it flows to the mouth. The major proteins present in saliva are secreted by salivary glands, creating viscoelasticity and enabling the coating of oral surfaces with saliva. Salivary films are essential for maintaining oral health and regulating the oral microbiome. Saliva in the mouth contains a range of validated and potential disease biomarkers derived from epithelial cells, neutrophils, the microbiome, gingival crevicular fluid and serum. For example, cortisol levels are used in the assessment of stress, matrix metalloproteinases-8 and -9 appear to be promising markers of caries and periodontal disease, and a panel of mRNA and proteins has been proposed as a marker of oral squamous cell carcinoma. Understanding the mechanisms by which components enter saliva is an important aspect of validating their use as biomarkers of health and disease.
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            • Article: not found

            SLC Transporters: Structure, Function, and Drug Discovery.

            The human Solute Carrier (SLC) transporters are important targets for drug development. Structure-based drug discovery for SLC transporters requires the description of their structure, dynamics, and mechanism of interaction with small molecule ligands and ions. The recent determination of atomic structures of human SLC transporters and their homologs, combined with improved computational power and prediction methods have led to an increased applicability of structure-based drug design methods for human SLC members. In this review, we provide an overview of the SLC transporters' structures and transport mechanisms. We then describe computational techniques, such as homology modeling and virtual screening that are emerging as key tools to discover chemical probes for human SLC members. We illustrate the utility of these methods by presenting case studies in which rational integration of computation and experiment was used to characterize SLC members that transport key nutrients and metabolites, including the amino acid transporters LAT-1 and ASCT2, the SLC13 family of citric acid cycle intermediate transporters, and the glucose transporter GLUT1. We conclude with a brief discussion about future directions in structure-based drug discovery for the human SLC superfamily, one of the most structurally and functionally diverse protein families in human.
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              • Article: not found

              Role of salivary mucins in the protection of the oral cavity.

              Mucins are the principal organic constituents of mucus, the slimy visco-elastic material that coats all mucosal surfaces. Compelling evidence suggests that they play an integral role in non-immune protection of the oral cavity. Specific protective functions include: 1) protection against desiccation and environmental insult, 2) lubrication, and 3) antimicrobial effects against potential pathogens. Biosynthesis of mucin is regulated by both intrinsic ("cooperative sequential specificity") and extrinsic ("structural modulation") controls. These controls form the basis by which mucin's structure can be modified to meet a dynamically changing biological need.
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                Author and article information

                Contributors
                po-wah.so@kcl.ac.uk
                Journal
                Exp Physiol
                Exp. Physiol
                10.1111/(ISSN)1469-445X
                EPH
                expphysiol
                Experimental Physiology
                John Wiley and Sons Inc. (Hoboken )
                0958-0670
                1469-445X
                09 December 2019
                01 January 2020
                : 105
                : 1 ( doiID: 10.1113/eph.v105.1 )
                : 96-107
                Affiliations
                [ 1 ] Salivary Research, Centre for Host‐Microbiome Interactions Faculty of Dental, Oral & Craniofacial Sciences King's College London London UK
                [ 2 ] Department of Restorative Dentistry, Dental Hospital and School University of Dundee Dundee UK
                [ 3 ] Department of Neuroimaging, Institute of Psychiatry Psychology and Neuroscience, King's College London Maurice Wohl Clinical Neuroscience Institute London UK
                Author notes
                [*] [* ] Correspondence

                Po‐Wah So, Office K0.25/Ground Floor, Maurice Wohl Clinical Neuroscience Institute, London, SE5 9RT, UK.

                Email: po-wah.so@ 123456kcl.ac.uk

                Author information
                https://orcid.org/0000-0001-8618-9622
                https://orcid.org/0000-0003-3449-8532
                Article
                EPH12629
                10.1113/EP088166
                6973168
                31705555
                caaa6a32-3b45-4dd8-8bd0-b16c5ab49ffc
                © 2019 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 September 2019
                : 04 November 2019
                Page count
                Figures: 10, Tables: 3, Pages: 12, Words: 7162
                Funding
                Funded by: Diageo plc
                Funded by: Biotechnology and Biological Sciences Research Council , open-funder-registry 10.13039/501100000268;
                Award ID: BB/M015211/1
                Categories
                Research Paper
                Research Papers
                GI & Epithelial
                Custom metadata
                2.0
                1 January 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:21.01.2020

                Anatomy & Physiology
                metabolomics,rheology,saliva
                Anatomy & Physiology
                metabolomics, rheology, saliva

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