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      Hesperidin depolarizes the pacemaker potentials through 5-HT 4 receptor in murine small intestinal interstitial cells of Cajal

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          ABSTRACT

          Hesperidin, a citrus flavonoid, can exert numerous beneficial effects on human health. Interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal (GI) tract. In the present study, we investigated potential effects of hesperidin on pacemaker potential of ICC in murine small intestine and GI motility. A whole-cell patch-clamp configuration was used to record pacemaker potential in ICC, and GI motility was investigated in vivo by recording gastric emptying (GE) and intestinal transit rate (ITR). Hesperidin depolarized pacemaker potentials of ICC in a dose-dependent manner. Pre-treatment with methoctramine or 4-DAMP did not inhibit hesperidin-induced pacemaker potential depolarization. Neither a 5-HT 3 receptor antagonist (Y25130) nor a 5-HT 7 receptor antagonist (SB269970) reduced the effect of hesperidin on ICC pacemaker potential, whereas the 5-HT 4 receptor antagonist RS39604 was found to inhibit this effect. In the presence of GDP–β–S, hesperidin-induced pacemaker potential depolarization was inhibited. Moreover, in the presence of U73122 and calphostin C, hesperidin did not depolarize pacemaker potentials. Furthermore, hesperidin accelerated GE and ITR in vivo. These results imply that hesperidin depolarized ICC pacemaker potential via 5-HT 4 receptors, G protein, and PLC/PKC dependent pathways and that it increased GI motility. Therefore, hesperidin may be a promising novel drug to regulate GI motility.

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          Most cited references31

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          The burden of selected digestive diseases in the United States.

          Gastrointestinal (GI) and liver diseases inflict a heavy economic burden. Although the burden is considerable, current and accessible information on the prevalence, morbidity, and cost is sparse. This study was undertaken to estimate the economic burden of GI and liver disease in the United States for use by policy makers, health care providers, and the public. Data were extracted from a number of publicly available and proprietary national databases to determine the prevalence, direct costs, and indirect costs for 17 selected GI and liver diseases. Indirect cost calculations were purposefully very conservative. These costs were compared with National Institutes of Health (NIH) research expenditures for selected GI and liver diseases. The most prevalent diseases were non-food-borne gastroenteritis (135 million cases/year), food-borne illness (76 million), gastroesophageal reflux disease (GERD; 19 million), and irritable bowel syndrome (IBS; 15 million). The disease with the highest annual direct costs in the United States was GERD ($9.3 billion), followed by gallbladder disease ($5.8 billion), colorectal cancer ($4.8 billion), and peptic ulcer disease ($3.1 billion). The estimated direct costs for these 17 diseases in 1998 dollars were $36.0 billion, with estimated indirect costs of $22.8 billion. The estimated direct costs for all digestive diseases were $85.5 billion. Total NIH research expenditures were $676 million in 2000. GI and liver diseases exact heavy economic and social costs in the United States. Understanding the prevalence and costs of these diseases is important to help set priorities to reduce the burden of illness.
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            Chemistry and pharmacology of the Citrus bioflavonoid hesperidin.

            Hesperidin, a bioflavonoid, is an abundant and inexpensive by-product of Citrus cultivation. A deficiency of this substance in the diet has been linked with abnormal capillary leakiness as well as pain in the extremities causing aches, weakness and night leg cramps. No signs of toxicity have been observed with the normal intake of hesperidin or related compounds. Both hesperidin and its aglycone hesperetin have been reported to possess a wide range of pharmacological properties. This paper reviews various aspects of hesperidin and its related compounds, including their occurrence, physical and chemical properties, analysis, pharmacokinetics, safety and toxicity and the marketed products available. A special emphasis has been laid on the pharmacological properties and medicinal uses of these compounds. Copyright 2001 John Wiley & Sons, Ltd.
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              A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract.

              Electrical rhythmicity in gastrointestinal muscles has been studied for a century, but the pacemakers driving this phenomenon have been elusive. Anatomic studies suggest that interstitial cells of Cajal (ICC) may be pacemakers and conductors of electrical activity. ICC may also mediate neurotransmission from enteric neurons. Functional evaluations of ICC include the following. (1) Electrophysiology experiments on dissected muscle strips show that slow waves originate from specific sites. These pacemaker areas are populated by networks of ICC that make gap junctions with smooth muscle cells. Removal of pacemaker regions interferes with slow wave generation and propagation. (2) Chemicals that label ICC histochemically can damage ICC and abolish rhythmicity. (3) isolated ICC are spontaneously active, and several voltage-dependent ion channels, including a low-threshold Ca2+ conductance, are expressed. (4) ICC are innervated by enteric neurons, and they respond to neurotransmitters. ICC may produce nitric oxide and amplify inhibitory neurotransmission. (5) Some classes of ICC fall to develop in animals with mutations in c-kit or stem cell factor, the ligand for c-Kit receptors. Without ICC, electrical slow waves are absent. Many questions remain about the function of ICC, but modern technologies should now facilitate rapid progress toward determining the role of these cells in normal physiology and pathological conditions.
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                Author and article information

                Journal
                Anim Cells Syst (Seoul)
                Anim Cells Syst (Seoul)
                TACS
                tacs20
                Animal Cells and Systems
                Taylor & Francis
                1976-8354
                2151-2485
                2020
                26 March 2020
                : 24
                : 2
                : 84-90
                Affiliations
                [a ]Department of Sasang Constitutional Medicine, College of Korean Medicine, Kyung Hee University , Seoul, Republic of Korea
                [b ]Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine , Yangsan, Republic of Korea
                Author notes
                [CONTACT ] Byung Joo Kim vision@ 123456pusan.ac.kr Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine , 49 Busandaehakro, Mulgeum-eup, Yangsan 50612, Republic of Korea
                Article
                1746398
                10.1080/19768354.2020.1746398
                7241530
                ef08783c-3918-4dc4-8ba2-d8cf1fa2305e
                © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 02 December 2019
                : 04 March 2020
                : 19 March 2020
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 34, Pages: 7
                Categories
                Translational Medicine

                hesperidin,interstitial cells of cajal,gastrointestinal motility,pacemaker potential

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