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Zhang M, Chen X, Zhang L, Li J, Sun C, Zhou G, Wan H, Lu W, Dong H. Zinc pyrithione ameliorates colitis in mice by interacting on intestinal epithelial TRPA1 and TRPV4 channels. Life Sci 2024; 358:123090. [PMID: 39384148 DOI: 10.1016/j.lfs.2024.123090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 09/26/2024] [Accepted: 09/28/2024] [Indexed: 10/11/2024]
Abstract
AIMS Although zinc pyrithione (ZPT) has been studied as topical antimicrobial and cosmetic consumer products, little is known about its pharmacological actions in gastrointestinal (GI) health and inflammation. Our aims were to investigate the effects of ZPT on transient receptor potential (TRP) channels and Ca2+ signaling in intestinal epithelial cells (IECs) and its therapeutic potential for colitis. MAIN METHODS Digital Ca2+ imaging and patch-clamp electrophysiology were performed on human colonic epithelial cells (HCoEpiC) and rat small intestinal epithelial cells (IEC-6). The transcription levels of proinflammatory cytokines such as IL-1β were detected by RTq-PCR. Dextran sulfate sodium (DSS) was used to induce colitis in mice. KEY FINDINGS ZPT dose-dependently induced Ca2+ signaling and membrane currents in IECs, which were attenuated by selective blockers of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 4 (TRPV4) channels, respectively. Interestingly, Ca2+ entry via TRPA1 channels inhibited the activity of TRPV4 channels in HCoEpiC, but not vice versa. ZPT significantly promoted migration of IECs by activating TRPA1 and TRPV4 channels. ZPT reversed lipopolysaccharides (LPS)-induced changes in mRNA expression of TRPA1 and TRPV4. Moreover, ZPT decreased mRNA levels of pro-inflammatory factors promoted by LPS in HCoEpiC, which were restored by selective TRPA1 blocker. In whole animal studies in vivo, ZPT significantly ameliorated DSS-induced body weight loss, colon shortening and increases in stool score, serum calprotectin and lactic acid (LD) in mouse model of colitis. SIGNIFICANCE ZPT exerts anti-colitic action likely by anti-inflammation and pro-mucosal healing through TRP channels in IECs. The present study not only expands pharmacology spectrum of ZPT in GI tract, but also repurposes it to a potential drug for colitis therapy.
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Affiliation(s)
- Mengting Zhang
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China
| | - Xiongying Chen
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China; Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Luyun Zhang
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China; Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Junhui Li
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China; Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Chensijin Sun
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China
| | - Guolong Zhou
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China
| | - Hanxing Wan
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Wei Lu
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China.
| | - Hui Dong
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China.
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Liu D, Mao M, Liu W, Xie L, Zhong X, Cao W, Chen L. The Role of the TRPV4 Channel in Intestinal Physiology and Pathology. J Inflamm Res 2024; 17:9307-9317. [PMID: 39588136 PMCID: PMC11587805 DOI: 10.2147/jir.s483350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/06/2024] [Indexed: 11/27/2024] Open
Abstract
The transient receptor potential vanilloid 4 channel (TRPV4) is an important member of the TRP superfamily of cation channels. The channel can be activated by different physical and chemical stimuli, such as heat, osmotic, and mechanical stress. It regulates the release of nociceptive peptides (substance P and calcitonin gene-related peptide), and mediates neurogenic inflammation, which indicates the involvement of TRPV4 as a nociceptor. Previous studies show that TRPV4 regulates the contraction of intestinal smooth muscle, mucosal barrier permeability, intestinal ion transport, activation of submucosal enteric neurons, and generation of immune cells. TRPV4 is involved in various pathophysiological activities, and altered TRPV4 expression has been detected in some intestinal diseases (IBD, IBS, intestinal tumors, etc). Evidence indicates that TRPV4 plays a noxious role in intestinal barrier function when the intestine is damaged. This review focuses on the role of the TRPV4 channel in the physiological and pathological functions of the intestine, and evaluates the potential clinical significance to target TRPV4 channel in the treatment of intestinal diseases.
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Affiliation(s)
- Dandan Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Mingli Mao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Wenjia Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Lihua Xie
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Xiaolin Zhong
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Wenyu Cao
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Ling Chen
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
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Murayama Y, Tabuchi M, Utsumi D, Naruse K, Tokuyama K, Ikedo A, Morimasa E, Kato S, Matsumoto K. Role of transient receptor potential vanilloid 4 channels in an ovalbumin-induced murine food allergic model. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:6061-6074. [PMID: 38396155 DOI: 10.1007/s00210-024-02969-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 01/17/2024] [Indexed: 02/25/2024]
Abstract
The prevalence of food allergy (FA) has increased worldwide but an effective therapeutic strategy has not been established. Transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive nonselective cation channel, is mainly expressed in the epithelium of various organs. The present study investigated the role of TRPV4 in the pathogenesis of an ovalbumin (OVA)-induced FA model in mice. Wild-type (WT) and TRPV4-deficient (TRPV4KO) mice were sensitized and challenged by OVA to establish FA model. Intestinal tissue samples were processed for biochemical, molecular, and image analyses. Intestinal permeability and antigen uptake assay were conducted using FITC-dextran and OVA-FITC, respectively. TRPV4 was expressed in the colonic epithelium in normal and OVA-treated WT mice. Repeated oral administration of OVA to mice induced systemic allergic symptoms, diarrhea, upregulation of T helper 2 cytokines, OVA-specific immunoglobulin, and FA-related inflammatory cells. These responses were significantly augmented in TRPV4KO mice compared with WT mice. After the induction of FA, the intestinal permeability was significantly increased in TRPV4KO mice compared with WT mice. The expressions of the tight junction protein occludin and adherence junction protein E-cadherin in the colon were significantly lower in TRPV4KO mice compared with WT mice under normal and FA conditions. In addition, the uptake of OVA by CD11c-positive cells was significantly increased in TRPV4KO mice compared with WT mice under FA conditions. These results suggest that epithelial TRPV4 protects against OVA-induced FA symptoms by suppressing the penetration of allergens by maintaining epithelial barrier functions.
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Affiliation(s)
- Yuki Murayama
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Mayumi Tabuchi
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Daichi Utsumi
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Kei Naruse
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Kouga Tokuyama
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Ayana Ikedo
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Emina Morimasa
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Shinichi Kato
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Kenjiro Matsumoto
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
- Laboratory of Pathophysiology, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo Kyotanabe, Kyoto, 610-0395, Japan.
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Naganuma T, Fujinami N, Arita M. Polyunsaturated Fatty Acid-Derived Lipid Mediators That Regulate Epithelial Homeostasis. Biol Pharm Bull 2022; 45:998-1007. [DOI: 10.1248/bpb.b22-00252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Tatsuro Naganuma
- Division of Physiological Chemistry and Metabolism, Keio University Faculty of Pharmacy
| | - Nodoka Fujinami
- Division of Physiological Chemistry and Metabolism, Keio University Faculty of Pharmacy
| | - Makoto Arita
- Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama-City University
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Stetska VО, ESC “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Ukraine, Dovbynchuk TV, Dziubenko NV, Zholos AV, Tolstanova GM, ESC “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Ukraine;, Institute of High Technologies, Taras Shevchenko National University of Kyiv, Ukraine;, ESC “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Ukraine;, Institute of High Technologies, Taras Shevchenko National University of Kyiv, Ukraine;. Changes in the expression of TRPV4 and TRPM8 channels in the colon of rats with 6-OHDA-induced Parkinson’s disease. UKRAINIAN BIOCHEMICAL JOURNAL 2022. [DOI: 10.15407/ubj94.02.057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Parkinson’s disease (PD) is neurodegenerative disease, which is accompanied by degeneration of dopaminergic neurons in subtantia nigra. Non-motor symptoms, in particular, disorders of the gastrointestinal (GI) tract are observed in 20-80% of patients some 15-20 years before clinically diagnosed PD and are not a least important feature of PD pathogenesis. The transient receptor potential (TRP) channels are expressed throughout the GI tract, where they play an important role in taste, thermoregulation, pain, mucosal function and homeostasis, control of interstitial motility etc. The aim of this study was to investigate the contribution of TRPV4 and TRPM8 channels in the GI motor function in the colon of rats with PD, incduced by injection of the 12 μg 6-hydroxydopamine (6-OHDA). The studies were performed on the 4th week and the 7th month after PD induction The rats were randomly divided into: I group – the sham-lesioned rats, 4 μl 0.9% NaCl, autopsy 4 weeks after injection (n = 5); II group – the 6-OHDA-PD rats, 4 μl 12 μg of 6-OHDA, autopsy 4 weeks after injection (n = 5); III group – the sham-lesioned rats, 4 μl 0.9% NaCl, autopsy 7 months after injection (n = 4); IV group – the 6-OHDA-PD rats, 4 μl 12 μg of 6-OHDA, autopsy 7 months after injection (n = 5). We evaluated the body weight of rats, GI transit time, the cecum weight index and immunohistochemical identification of tyrosine hydroxylase (TH) -positive cells, and TRPV4, TRPM8 expression in rat’s colon. We showed that on the 7th month of the experiment, the GI transit time doubles over time; the cecum weight index of 6-OHDA rats increased by 57%; the number of TH-positive cells in colon rats decreased 2-fold, while TRPM8 ion channels were downregulated in PD rats and TRPV4 ion channels were upregulated in the colon of rats with 6-OHDA-PD. It was concluded that TRPV4 and TRPM8 ion channels may be considered pharmacological targets in the progression of PD pathology.
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Wan H, Chen XY, Zhang F, Chen J, Chu F, Sellers ZM, Xu F, Dong H. Capsaicin inhibits intestinal Cl - secretion and promotes Na + absorption by blocking TRPV4 channels in healthy and colitic mice. J Biol Chem 2022; 298:101847. [PMID: 35314195 PMCID: PMC9035713 DOI: 10.1016/j.jbc.2022.101847] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 01/06/2023] Open
Abstract
Although capsaicin has been studied extensively as an activator of the transient receptor potential vanilloid cation channel subtype 1 (TRPV1) channels in sensory neurons, little is known about its TRPV1-independent actions in gastrointestinal health and disease. Here, we aimed to investigate the pharmacological actions of capsaicin as a food additive and medication on intestinal ion transporters in mouse models of ulcerative colitis (UC). The short-circuit current (Isc) of the intestine from WT, TRPV1-, and TRPV4-KO mice were measured in Ussing chambers, and Ca2+ imaging was performed on small intestinal epithelial cells. We also performed Western blots, immunohistochemistry, and immunofluorescence on intestinal epithelial cells and on intestinal tissues following UC induction with dextran sodium sulfate. We found that capsaicin did not affect basal intestinal Isc but significantly inhibited carbachol- and caffeine-induced intestinal Isc in WT mice. Capsaicin similarly inhibited the intestinal Isc in TRPV1 KO mice, but this inhibition was absent in TRPV4 KO mice. We also determined that Ca2+ influx via TRPV4 was required for cholinergic signaling-mediated intestinal anion secretion, which was inhibited by capsaicin. Moreover, the glucose-induced jejunal Iscvia Na+/glucose cotransporter was suppressed by TRPV4 activation, which could be relieved by capsaicin. Capsaicin also stimulated ouabain- and amiloride-sensitive colonic Isc. Finally, we found that dietary capsaicin ameliorated the UC phenotype, suppressed hyperaction of TRPV4 channels, and rescued the reduced ouabain- and amiloride-sensitive Isc. We therefore conclude that capsaicin inhibits intestinal Cl- secretion and promotes Na+ absorption predominantly by blocking TRPV4 channels to exert its beneficial anti-colitic action.
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Affiliation(s)
- Hanxing Wan
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Xiong Ying Chen
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Fenglian Zhang
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jun Chen
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Fenglan Chu
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Zachary M Sellers
- Pediatric Gastroenterology Hepatology & Nutrition, Stanford University School of Medicine, Palo Alto, California, USA
| | - Feng Xu
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China.
| | - Hui Dong
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China; Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China; Department of Medicine, School of Medicine, University of California, San Diego, California, USA.
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Tobita N, Tsuneto K, Ito S, Yamamoto T. Human TRPV1 and TRPA1 are receptors for bacterial quorum sensing molecules. J Biochem 2021; 170:775-785. [PMID: 34557892 DOI: 10.1093/jb/mvab099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 09/17/2021] [Indexed: 11/13/2022] Open
Abstract
In this study, we investigated the activation of TRPV1 and TRPA1 by N-acyl homoserine lactones, quorum sensing molecules produced by Gram-negative bacteria, and the inhibitory effect of TRPV1 and TRPA1 by autoinducing peptides, quorum sensing molecules produced by Gram-positive bacteria, using human embryonic kidney 293T cell lines stably expressing human TRPV1 and TRPA1, respectively. As a result, we found that some N-acyl homoserine lactones, such as N-octanoyl-L-homoserine lactone (C8-HSL), N-nonanoyl-L-homoserine lactone (C9-HSL) and N-decanoyl-L-homoserine lactone (C10-HSL) activated both TRPV1 and TRPA1. In addition, we clarified that some N-acyl homoserine lactones, for example, N-3-oxo-dodecanoyl-L-homoserine lactone (3-oxo-C12-HSL) only activated TRPV1, and N-acyl homoserine lactones having saturated short acyl chain, such as N-acetyl-L-homoserine lactone (C2-HSL) and N-butyryl-L-homoserine lactone (C4-HSL) only activated TRPA1, respectively. Furthermore, we found that an autoinducing peptide, simple linear peptide CHWPR, inhibited both TRPV1 and TRPA1, and peptide having thiolactone ring DICNAYF, thiolactone ring were formed between C3 to F7, strongly inhibited only the TRPV1. Although the specificity of TRPV1 and TRPA1 for quorum sensing molecules were different, these data suggest that both TRPV1 and TRPA1 would function as receptors for quorum sensing molecule produced by bacteria.
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Affiliation(s)
- Naoya Tobita
- Tobacco Science Research Center, Japan Tobacco Inc., 6-2 Umegaoka, Aoba, Yokohama, Kanagawa, 227-8512, Japan
| | - Kana Tsuneto
- Tobacco Science Research Center, Japan Tobacco Inc., 6-2 Umegaoka, Aoba, Yokohama, Kanagawa, 227-8512, Japan
| | - Shigeaki Ito
- Scientific Product Assessment Center, Japan Tobacco Inc., 6-2 Umegaoka, Aoba, Yokohama, Kanagawa, 227-8512, Japan
| | - Takeshi Yamamoto
- Tobacco Science Research Center, Japan Tobacco Inc., 6-2 Umegaoka, Aoba, Yokohama, Kanagawa, 227-8512, Japan
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Cui Y, Chu F, Yin K, Chen X, Wan H, Luo G, Dong H, Xu F. Role of Serosal TRPV4-Constituted SOCE Mechanism in Secretagogues-Stimulated Intestinal Epithelial Anion Secretion. Front Pharmacol 2021; 12:684538. [PMID: 34335254 PMCID: PMC8317263 DOI: 10.3389/fphar.2021.684538] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/24/2021] [Indexed: 12/05/2022] Open
Abstract
As little is known about the role of calcium (Ca2+) signaling mediating the small intestinal epithelial anion secretion, we aimed to study its regulatory role in secretagogue-stimulated duodenal anion secretion and the underlying molecular mechanisms. Therefore, intestinal anion secretion from native mouse duodenal epithelia was examined with Ussing chambers to monitor PGE2-, 5-HT-, and CCh-induced short-circuit currents (Isc). PGE2 (10 μM) and 5-HT (10 μM) induced mouse duodenal Isc, markedly attenuated by serosal Ca2+-free solution and selective blockers of store-operated Ca2+ channels on the serosal side of the duodenum. Furthermore, PGE2- and 5-HT-induced duodenal Isc was also inhibited by ER Ca2+ chelator TPEN. However, dantrolene, a selective blocker of ryanodine receptors, inhibited PGE2-induced duodenal Isc, while LiCl, an inhibitor of IP3 production, inhibited 5-HT-induced Isc. Moreover, duodenal Isc response to the serosal applications of both PGE2 and 5-HT was significantly attenuated in transient receptor potential vanilloid 4 (TRPV4) knockout mice. Finally, mucosal application of carbachol (100 μM) also induced duodenal Isc via selective activation of muscarinic receptors, which was significantly inhibited in serosal Ca2+-free solution but neither in mucosal Ca2+-free solution nor by nifedipine. Therefore, the serosal TRPV4-constituted SOCE mechanism is likely universal for the most common and important secretagogues-induced and Ca2+-dependent intestinal anion secretion. These findings will enhance our knowledge about gastrointestinal (G.I.) epithelial physiology and the associated G.I. diseases, such as diarrhea and constipation.
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Affiliation(s)
- Yinghui Cui
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Fenglan Chu
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Kai Yin
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Xiongying Chen
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Hanxing Wan
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Gang Luo
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hui Dong
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China.,Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Feng Xu
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
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Pacheco G, Oliveira AP, Noleto IRSG, Araújo AK, Lopes ALF, Sousa FBM, Chaves LS, Alves EHP, Vasconcelos DFP, Araujo AR, Nicolau LD, Magierowski M, Medeiros JVR. Activation of transient receptor potential vanilloid channel 4 contributes to the development of ethanol-induced gastric injury in mice. Eur J Pharmacol 2021; 902:174113. [PMID: 33901460 DOI: 10.1016/j.ejphar.2021.174113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/09/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
The transient receptor potential vanilloid channel 4 (TRPV4) is associated with the development of several pathologies, particularly gastric disorders. However, there are no studies associating this receptor with the pathophysiology of gastric erosions. The aim of this study was to investigate the role of TRPV4 in the development of ethanol-induced gastric damage in vivo. Gastric lesions were induced by ethanol in Swiss mice pretreated with TRPV4 antagonists, GSK2193874 (0.1; 0.3 and 0.9 mg/kg) or Ruthenium red (0.03; 0.1 or 0.3 mg/kg) or its agonist, GSK1016790A (0.9 mg/kg). Gastric mucosal samples were taken for histopathology, immunohistochemistry, atomic force microscopy and evaluation of antioxidant parameters. The gastric mucus content and TRPV4 mRNA expression were analyzed. Ethanol exposure induced upregulation of gastric mRNA and protein expression of TRPV4. TRPV4 blockade promoted gastroprotection against ethanol-induced injury on macro- and microscopic levels, leading to reduced hemorrhage, cell loss and edema and enhanced gastric mucosal integrity. Moreover, an increase in superoxide dismutase (SOD) and glutathione (GSH) activity was observed, followed by a decrease in malondialdehyde (MDA) levels. TRPV4 blockade during alcohol challenge reestablished gastric mucus content. The combination of TRPV4 agonist and ethanol revealed macroscopic exacerbation of gastric damage area. Our results confirmed the association of TRPV4 with the development of gastric injury, showing the importance of this receptor for further investigations in the field of gastrointestinal pathophysiology and pharmacology.
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Affiliation(s)
- Gabriella Pacheco
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - Ana P Oliveira
- The Northeastern Biotechnology Network (RENORBIO), Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Isabela R S G Noleto
- The Northeastern Biotechnology Network (RENORBIO), Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Andreza K Araújo
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - André L F Lopes
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - Francisca B M Sousa
- The Northeastern Biotechnology Network (RENORBIO), Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Letícia S Chaves
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - Even H P Alves
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - Daniel F P Vasconcelos
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil; The Northeastern Biotechnology Network (RENORBIO), Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Alyne R Araujo
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - LucasA D Nicolau
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - Marcin Magierowski
- Gaseous Mediators and Experimental Gastroenterology Laboratory, Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Jand Venes R Medeiros
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil; The Northeastern Biotechnology Network (RENORBIO), Federal University of Piauí (UFPI), Teresina, PI, Brazil.
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10
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Matsumoto K, Kato S. [Physiological and pathophysiological roles of TRPV4 channel in gastrointestinal tract]. Nihon Yakurigaku Zasshi 2019; 154:92-96. [PMID: 31527366 DOI: 10.1254/fpj.154.92] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel that responds to mechanical, thermal, and chemical stimuli in addition to various endogenous ligands, such as arachidonic acid metabolites. The present study aimed to elucidate the expression of TRPV4 in the gastrointestinal tract and the pathogenic roles of TRPV4 in dextran sulphate sodium (DSS)-induced colitis. TRPV4-immunoreactivity was detected in epithelial-like cells of the mouse tongue, esophagus, stomach, ileum, and colon; TRPV4 expression in the tongue was higher than other gastrointestinal tracts. TRPV4 colocalized with a type IV cell marker sonic hedgehog in circumvallate papillae. These findings suggest that TRPV4 contributes to sour taste sensing by regulating type III taste cell differentiation in mice. DSS-induced colitis was significantly attenuated in TRPV4-knockout (TRPV4KO) mice when compared to wild-type mice. DSS treatment upregulated TRPV4 expression in vascular endothelia of colonic mucosa and submucosa. DSS treatment increased vascular permeability, which was abolished in TRPV4KO mice. The activation of TRPV4 decreased VE-cadherin expression in mouse aortic endothelial cells exposed to TNF-α. These findings indicate that the upregulation of TRPV4 in vascular endothelial cells contributes to the progression of colonic inflammation via the activation of vascular permeability. Thus, TRPV4 is an attractive target for the treatment of inflammatory bowel diseases.
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Affiliation(s)
- Kenjiro Matsumoto
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University
| | - Shinichi Kato
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University
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11
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Mukaiyama M, Yamasaki Y, Usui T, Nagumo Y. Transient receptor potential V4 channel stimulation induces reversible epithelial cell permeability in
MDCK
cell monolayers. FEBS Lett 2019; 593:2250-2260. [PMID: 31206656 DOI: 10.1002/1873-3468.13490] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 06/03/2019] [Accepted: 06/03/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Minagi Mukaiyama
- Graduate School of Life and Environmental Sciences University of Tsukuba Japan
| | - Yohei Yamasaki
- Graduate School of Life and Environmental Sciences University of Tsukuba Japan
| | - Takeo Usui
- Faculty of Life and Environmental Sciences University of Tsukuba Japan
- Microbiology Research Center for Sustainability (MiCS) University of Tsukuba Japan
| | - Yoko Nagumo
- Faculty of Life and Environmental Sciences University of Tsukuba Japan
- Alliance for Research on the Mediterranean and North Africa (ARENA) University of Tsukuba Japan
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12
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Transient receptor potential vanilloid 4 mediates sour taste sensing via type III taste cell differentiation. Sci Rep 2019; 9:6686. [PMID: 31040368 PMCID: PMC6491610 DOI: 10.1038/s41598-019-43254-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Accepted: 04/16/2019] [Indexed: 12/31/2022] Open
Abstract
Taste buds are comprised of taste cells, which are classified into types I to IV. Transient receptor potential (TRP) channels play a significant role in taste perception. TRP vanilloid 4 (TRPV4) is a non-selective cation channel that responds to mechanical, thermal, and chemical stimuli. The present study aimed to define the function and expression of TRPV4 in taste buds using Trpv4-deficient mice. In circumvallate papillae, TRPV4 colocalized with a type IV cell and epithelial cell marker but not type I, II, or III markers. Behavioural studies showed that Trpv4 deficiency reduced sensitivity to sourness but not to sweet, umami, salty, and bitter tastes. Trpv4 deficiency significantly reduced the expression of type III cells compared with that in wild type (WT) mice in vivo and in taste bud organoid experiments. Trpv4 deficiency also significantly reduced Ki67-positive cells and β-catenin expression compared with those in WT circumvallate papillae. Together, the present results suggest that TRPV4 contributes to sour taste sensing by regulating type III taste cell differentiation in mice.
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13
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Mihara H, Uchida K, Koizumi S, Moriyama Y. Involvement of VNUT-exocytosis in transient receptor potential vanilloid 4-dependent ATP release from gastrointestinal epithelium. PLoS One 2018; 13:e0206276. [PMID: 30365528 PMCID: PMC6203352 DOI: 10.1371/journal.pone.0206276] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Accepted: 10/10/2018] [Indexed: 01/25/2023] Open
Abstract
Adenosine triphosphate (ATP) modulates mechanosensitive vagal afferent nerves in the gastrointestinal tract. ATP is stored in secretory vesicles via the ATP transporter VNUT. Recently, the bisphosphate clodronate was reported to inhibit VNUT and was suggested to be a safe potent therapeutic option for chronic pain. Transient receptor potential vanilloid 4 (TRPV4) is activated by mechanical stimuli and some epoxyeicosatrienoic acids and becomes sensitized under inflammatory conditions. We have previously reported that TRPV4 and VNUT are expressed in mouse esophageal keratinocytes and that TRPV4 activation induces ATP release in gastric epithelial cells. Here we show the expression of TRPV4 and VNUT in normal human gastrointestinal cell derived cell lines (GES-1 and CCD 841) and in tissues from normal and VNUT-KO mice. TRPV4 agonists (GSK101 or 8,9-EET) induced an increase in cytosolic Ca2+ and/or current responses in mouse primary colonic epithelial cells and CCD 841 cells, but not in cells isolated from TRPV4-KO mice. TRPV4 agonists (GSK101 or 5.6-EET) also induced ATP release in GES-1 and CCD 841 cells, which could be blocked by the VNUT inhibitor, clodronate. Thus, VNUT inhibition with clodronate could represent a novel therapeutic option for visceral pain.
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Affiliation(s)
- Hiroshi Mihara
- Center for Medical Education and Career Development, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
- Department of Gastroenterology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
- * E-mail:
| | - Kunitoshi Uchida
- Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan
| | - Schuichi Koizumi
- Department of Neuropharmacology, University of Yamanashi, Yamanashi, Japan
| | - Yoshinori Moriyama
- Department of Membrane Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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14
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Liang Q, Lv X, Cai Q, Cai Y, Zhao B, Li G. Novobiocin, a Newly Found TRPV1 Inhibitor, Attenuates the Expression of TRPV1 in Rat Intestine and Intestinal Epithelial Cell Line IEC-6. Front Pharmacol 2018; 9:1171. [PMID: 30374305 PMCID: PMC6196238 DOI: 10.3389/fphar.2018.01171] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 09/26/2018] [Indexed: 01/26/2023] Open
Abstract
Background and Purpose: Novobiocin (NOVO), an ABC transporter inhibitor, decreases intestinal wall permeability of capsaicin (CAP), an ABC transporter substrate. However, the mechanism of this effect is not consistent with the action of NOVO as an ABC transporter inhibitor. We previously found that CAP can also be transported via TRPV1, which was site-specific in the permeability of CAP across the intestine. We explored the regulation by NOVO of TRPV1 in the present study. Methods: Rats and transfected IEC-6 cells were used as the models to assess intestinal permeability and expression of TRPV1. Ussing chamber and intracellular accumulation were used to evaluate the influence of NOVO on the transport of CAP in vitro. The expression of TRPV1 was detected after administration of NOVO by qRT-PCR, western blot and immunofluorescent imaging. In addition, MTT and lactate dehydrogenase (LDH) were used to evaluate the cytotoxicity of NOVO in both rat and cell models. Finally, the effect of NOVO on the absorption of CAP in vivo was studied by LC-MS/MS. Results: In vitro data showed that there existed a dose-dependent relationship in the range of concentration between 5 and 50 μM, and even 5 μM NOVO could decrease intestinal permeability of CAP across the intestine. Meanwhile, cytosolic accumulation of CAP decreased when NOVO was used simultaneously or 24 h in advance. NOVO exhibited an inhibition level similar to that of ruthenium red (RR) or SB-705498, a TRPV1-specific inhibitor. NOVO down-regulated TRPV1 expression in the intestine and in transfected cells in a concentration-dependent fashion, hinting that its inhibition of the permeability of CAP is due to its inhibition of TRPV1 expression. Immunofluorescent imaging data showed that the fluorescence intensity of TRPV1 was reduced after pre-treatment with NOVO and SB-705498. In vivo data further demonstrated that oral co-administration of NOVO decreased Cmax and AUC of CAP in dosage-dependent ways, consistent with its role as a TRPV1 inhibitor. Conclusion: NOVO could be a potential TRPV1 inhibitor by attenuating the expression of TRPV1 and may be used to attenuate permeability of TRPV1 substrates.
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Affiliation(s)
- Qianying Liang
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Rational Medication Evaluation and Drug Delivery Technology Lab, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xueli Lv
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Rational Medication Evaluation and Drug Delivery Technology Lab, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qing Cai
- General Hospital of Guangzhou Military Command of PLA, Guangzhou, China
| | - Yun Cai
- Department of Pharmacy, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Boxin Zhao
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Rational Medication Evaluation and Drug Delivery Technology Lab, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guofeng Li
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Rational Medication Evaluation and Drug Delivery Technology Lab, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, China
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15
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Matsumoto K, Kato S. [TRPV4 regulates vascular endothelial permeability during colonic inflammation in dextran sulphate sodium-induced murine colitis]. Nihon Yakurigaku Zasshi 2018; 152:170-174. [PMID: 30298837 DOI: 10.1254/fpj.152.170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
The transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel involved in physical sensing in various tissue types. The present study aimed to elucidate the function and expression of TRPV4 in colonic vascular endothelial cells during dextran sulphate sodium (DSS)-induced colitis. The role of TRPV4 in the progression of colonic inflammation was examined in the 2% DSS-induced murine colitis model using immunohistochemical analysis, Western blotting, and Evans blue dye extrusion assay. DSS-induced colitis was significantly attenuated in TRPV4-deficient (TRPV4 KO) mice when compared to wild-type mice. Repeated intrarectal administration of GSK1016790A, a TRPV4 agonist, exacerbated the severity of DSS-induced colitis. Bone marrow transfer experiments demonstrated a dominant role of TRPV4 in non-haematopoietic cells for DSS-induced colitis. DSS treatment upregulated TRPV4 expression in the vascular endothelia of colonic mucosa and submucosa. DSS treatment increased vascular permeability, which was abolished in TRPV4 KO mice. The DSS-induced increase in vascular permeability was further enhanced by intravenous administration of GSK1016790A, which was abrogated by a TRPV4 antagonist RN1734. TRPV4 was co-localized with vascular endothelial (VE)-cadherin, and VE-cadherin expression was decreased by repeated intravenous administration of GSK1016790A during colitis. Furthermore, TRPV4 activation by GSK106790A decreased VE-cadherin expression in mouse aortic endothelial cells exposed to TNF-α. These findings indicate that TRPV4 upregulation in vascular endothelial cells contributes to the progression of colonic inflammation via the activation of vascular permeability. Thus, TRPV4 is an attractive target for the treatment of inflammatory bowel diseases.
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Affiliation(s)
- Kenjiro Matsumoto
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University
| | - Shinichi Kato
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University
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16
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Matsumoto K, Yamaba R, Inoue K, Utsumi D, Tsukahara T, Amagase K, Tominaga M, Kato S. Transient receptor potential vanilloid 4 channel regulates vascular endothelial permeability during colonic inflammation in dextran sulphate sodium-induced murine colitis. Br J Pharmacol 2017; 175:84-99. [PMID: 29053877 DOI: 10.1111/bph.14072] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 09/14/2017] [Accepted: 10/08/2017] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND AND PURPOSE The transient receptor potential vanilloid 4 (TRPV4) channel is a non-selective cation channel involved in physical sensing in various tissue types. The present study aimed to elucidate the function and expression of TRPV4 channels in colonic vascular endothelial cells during dextran sulphate sodium (DSS)-induced colitis. EXPERIMENTAL APPROACH The role of TRPV4 channels in the progression of colonic inflammation was examined in a murine DSS-induced colitis model using immunohistochemical analysis, Western blotting and Evans blue dye extrusion assay. KEY RESULTS DSS-induced colitis was significantly attenuated in TRPV4-deficient (TRPV4 KO) as compared to wild-type mice. Repeated intrarectal administration of GSK1016790A, a TRPV4 agonist, exacerbated the severity of DSS-induced colitis. Bone marrow transfer experiments demonstrated the important role of TRPV4 in non-haematopoietic cells for DSS-induced colitis. DSS treatment up-regulated TRPV4 expression in the vascular endothelia of colonic mucosa and submucosa. DSS treatment increased vascular permeability, which was abolished in TRPV4 KO mice. This DSS-induced increase in vascular permeability was further enhanced by i.v. administration of GSK1016790A, and this effect was abolished by the TRPV4 antagonist RN1734. TRPV4 was co-localized with vascular endothelial (VE)-cadherin, and VE-cadherin expression was decreased by repeated i.v. administration of GSK1016790A during colitis. Furthermore, GSK106790A decreased VE-cadherin expression in mouse aortic endothelial cells exposed to TNF-α. CONCLUSION AND IMPLICATIONS These findings indicate that an up-regulation of TRPV4 channels in vascular endothelial cells contributes to the progression of colonic inflammation by increasing vascular permeability. Thus, TRPV4 is an attractive target for the treatment of inflammatory bowel diseases.
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Affiliation(s)
- Kenjiro Matsumoto
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Riho Yamaba
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Ken Inoue
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Daichi Utsumi
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Takuya Tsukahara
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Kikuko Amagase
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Makoto Tominaga
- Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), Okazaki, Japan
| | - Shinichi Kato
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
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17
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Beckers AB, Weerts ZZRM, Helyes Z, Masclee AAM, Keszthelyi D. Review article: transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome. Aliment Pharmacol Ther 2017; 46:938-952. [PMID: 28884838 DOI: 10.1111/apt.14294] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 06/06/2017] [Accepted: 08/17/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Abdominal pain in irritable bowel syndrome (IBS) remains challenging to treat effectively. Researchers have attempted to elucidate visceral nociceptive processes in order to guide treatment development. Transient receptor potential (TRP) channels have been implied in the generation (TRPV1, TRPV4, TRPA1) and inhibition (TRPM8) of visceral pain signals. Pathological changes in their functioning have been demonstrated in inflammatory conditions, and appear to be present in IBS as well. AIM To provide a comprehensive review of the current literature on TRP channels involved in visceral nociception. In particular, we emphasise the clinical implications of these nociceptors in the treatment of IBS. METHODS Evidence to support this review was obtained from an electronic database search via PubMed using the search terms "visceral nociception," "visceral hypersensitivity," "irritable bowel syndrome" and "transient receptor potential channels." After screening the abstracts the articles deemed relevant were cross-referenced for additional manuscripts. RESULTS Recent studies have resulted in significant advances in our understanding of TRP channel mediated visceral nociception. The diversity of TRP channel sensitization pathways is increasingly recognised. Endogenous TRP agonists, including poly-unsaturated fatty acid metabolites and hydrogen sulphide, have been implied in augmented visceral pain generation in IBS. New potential targets for treatment development have been identified (TRPA1 and TRPV4,) and alternative means of affecting TRP channel signalling (partial antagonists, downstream targeting and RNA-based therapy) are currently being explored. CONCLUSIONS The improved understanding of mechanisms involved in visceral nociception provides a solid basis for the development of new treatment strategies for abdominal pain in IBS.
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Affiliation(s)
- A B Beckers
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
| | - Z Z R M Weerts
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
| | - Z Helyes
- Department of Pharmacology and Pharmacotherapy, Molecular Pharmacology Research Team, University of Pécs Medical School, János Szentágothai Research Centre, University of Pécs, Pécs, Baranya, Hungary
| | - A A M Masclee
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
| | - D Keszthelyi
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
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18
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Xie R, Xu J, Xiao Y, Wu J, Wan H, Tang B, Liu J, Fan Y, Wang S, Wu Y, Dong TX, Zhu MX, Carethers JM, Dong H, Yang S. Calcium Promotes Human Gastric Cancer via a Novel Coupling of Calcium-Sensing Receptor and TRPV4 Channel. Cancer Res 2017; 77:6499-6512. [PMID: 28951460 DOI: 10.1158/0008-5472.can-17-0360] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 06/19/2017] [Accepted: 09/21/2017] [Indexed: 12/18/2022]
Abstract
Although dietary calcium intake has long been recommended for disease prevention, the influence of calcium in development of cancer in the upper gastrointestinal tract has not been explored. Here, we assess the roles of calcium and calcium-sensing receptor (CaSR) in gastric cancer development. CaSR expression was enhanced in gastric cancer specimens, which positively correlated with serum calcium concentrations, tumor progression, poor survival, and male gender in gastric cancer patients. CaSR and transient receptor potential cation channel subfamily V member 4 (TRPV4) were colocalized in gastric cancer cells, and CaSR activation evoked TRPV4-mediated Ca2+ entry. Both CaSR and TRPV4 were involved in Ca2+-induced proliferation, migration, and invasion of gastric cancer cells through a Ca2+/AKT/β-catenin relay, which occurred only in gastric cancer cells or normal cells overexpressing CaSR. Tumor growth and metastasis of gastric cancer depended on CaSR in nude mice. Overall, our findings indicate that calcium may enhance expression and function of CaSR to potentially promote gastric cancer, and that targeting the novel CaSR/TRPV4/Ca2+ pathway might serve as preventive or therapeutic strategies for gastric cancer. Cancer Res; 77(23); 6499-512. ©2017 AACR.
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Affiliation(s)
- Rui Xie
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.,Department of Gastroenterology, Affiliated Hospital to Zunyi Medical College, Zunyi, China
| | - Jingyu Xu
- Department of Gastroenterology, Affiliated Hospital to Zunyi Medical College, Zunyi, China
| | - Yufeng Xiao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Jilin Wu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Hanxing Wan
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Bo Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Jingjing Liu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yahan Fan
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Suming Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yuyun Wu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Tobias Xiao Dong
- Department of Medicine, University of California, San Diego, California
| | - Michael X Zhu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas
| | - John M Carethers
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Hui Dong
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China. .,Department of Medicine, University of California, San Diego, California
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
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Extraoral Taste Receptor Discovery: New Light on Ayurvedic Pharmacology. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017. [PMID: 28642799 PMCID: PMC5469997 DOI: 10.1155/2017/5435831] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
More and more research studies are revealing unexpectedly important roles of taste for health and pathogenesis of various diseases. Only recently it has been shown that taste receptors have many extraoral locations (e.g., stomach, intestines, liver, pancreas, respiratory system, heart, brain, kidney, urinary bladder, pancreas, adipose tissue, testis, and ovary), being part of a large diffuse chemosensory system. The functional implications of these taste receptors widely dispersed in various organs or tissues shed a new light on several concepts used in ayurvedic pharmacology (dravyaguna vijnana), such as taste (rasa), postdigestive effect (vipaka), qualities (guna), and energetic nature (virya). This review summarizes the significance of extraoral taste receptors and transient receptor potential (TRP) channels for ayurvedic pharmacology, as well as the biological activities of various types of phytochemical tastants from an ayurvedic perspective. The relative importance of taste (rasa), postdigestive effect (vipaka), and energetic nature (virya) as ethnopharmacological descriptors within Ayurveda boundaries will also be discussed.
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20
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White JPM, Cibelli M, Urban L, Nilius B, McGeown JG, Nagy I. TRPV4: Molecular Conductor of a Diverse Orchestra. Physiol Rev 2017; 96:911-73. [PMID: 27252279 DOI: 10.1152/physrev.00016.2015] [Citation(s) in RCA: 287] [Impact Index Per Article: 35.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Transient receptor potential vanilloid type 4 (TRPV4) is a calcium-permeable nonselective cation channel, originally described in 2000 by research teams led by Schultz (Nat Cell Biol 2: 695-702, 2000) and Liedtke (Cell 103: 525-535, 2000). TRPV4 is now recognized as being a polymodal ionotropic receptor that is activated by a disparate array of stimuli, ranging from hypotonicity to heat and acidic pH. Importantly, this ion channel is constitutively expressed and capable of spontaneous activity in the absence of agonist stimulation, which suggests that it serves important physiological functions, as does its widespread dissemination throughout the body and its capacity to interact with other proteins. Not surprisingly, therefore, it has emerged more recently that TRPV4 fulfills a great number of important physiological roles and that various disease states are attributable to the absence, or abnormal functioning, of this ion channel. Here, we review the known characteristics of this ion channel's structure, localization and function, including its activators, and examine its functional importance in health and disease.
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Affiliation(s)
- John P M White
- Anaesthetics, Pain Medicine and Intensive Care Section, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Department of Anaesthetics, The Queen Elizabeth Hospital, Birmingham, United Kingdom; Academic Department of Anaesthesia and Intensive Care Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom; Preclinical Secondary Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, Cambridge, Massachusetts; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg, Leuven, Belgium; and School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Mario Cibelli
- Anaesthetics, Pain Medicine and Intensive Care Section, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Department of Anaesthetics, The Queen Elizabeth Hospital, Birmingham, United Kingdom; Academic Department of Anaesthesia and Intensive Care Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom; Preclinical Secondary Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, Cambridge, Massachusetts; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg, Leuven, Belgium; and School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Laszlo Urban
- Anaesthetics, Pain Medicine and Intensive Care Section, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Department of Anaesthetics, The Queen Elizabeth Hospital, Birmingham, United Kingdom; Academic Department of Anaesthesia and Intensive Care Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom; Preclinical Secondary Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, Cambridge, Massachusetts; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg, Leuven, Belgium; and School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Bernd Nilius
- Anaesthetics, Pain Medicine and Intensive Care Section, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Department of Anaesthetics, The Queen Elizabeth Hospital, Birmingham, United Kingdom; Academic Department of Anaesthesia and Intensive Care Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom; Preclinical Secondary Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, Cambridge, Massachusetts; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg, Leuven, Belgium; and School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - J Graham McGeown
- Anaesthetics, Pain Medicine and Intensive Care Section, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Department of Anaesthetics, The Queen Elizabeth Hospital, Birmingham, United Kingdom; Academic Department of Anaesthesia and Intensive Care Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom; Preclinical Secondary Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, Cambridge, Massachusetts; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg, Leuven, Belgium; and School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Istvan Nagy
- Anaesthetics, Pain Medicine and Intensive Care Section, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Department of Anaesthetics, The Queen Elizabeth Hospital, Birmingham, United Kingdom; Academic Department of Anaesthesia and Intensive Care Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom; Preclinical Secondary Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, Cambridge, Massachusetts; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg, Leuven, Belgium; and School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
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Role of Nonneuronal TRPV4 Signaling in Inflammatory Processes. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2017; 79:117-139. [PMID: 28528666 DOI: 10.1016/bs.apha.2017.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Transient receptor potential (TRP) ion channels are important signaling components in nociceptive and inflammatory pathways. This is attributed to their ability to function as polymodal sensors of environmental stimuli (chemical and mechanical) and as effector molecules in receptor signaling pathways. TRP vanilloid 4 (TRPV4) is a nonselective cation channel that is activated by multiple endogenous stimuli including shear stress, membrane stretch, and arachidonic acid metabolites. TRPV4 contributes to many important physiological processes and dysregulation of its activity is associated with chronic conditions of metabolism, inflammation, peripheral neuropathies, musculoskeletal development, and cardiovascular regulation. Mechanosensory and receptor- or lipid-mediated signaling functions of TRPV4 have historically been attributed to central and peripheral neurons. However, with the development of potent and selective pharmacological tools, transgenic mice and improved molecular and imaging techniques, many new roles for TRPV4 have been revealed in nonneuronal cells. In this chapter, we discuss these recent findings and highlight the need for greater characterization of TRPV4-mediated signaling in nonneuronal cell types that are either directly associated with neurons or indirectly control their excitability through release of sensitizing cellular factors. We address the integral role of these cells in sensory and inflammatory processes as well as their importance when considering undesirable on-target effects that may be caused by systemic delivery of TRPV4-selective pharmaceutical agents for treatment of chronic diseases. In future, this will drive a need for targeted drug delivery strategies to regulate such a diverse and promiscuous protein.
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Mihara H, Suzuki N, Muhammad JS, Nanjo S, Ando T, Fujinami H, Kajiura S, Hosokawa A, Sugiyama T. Transient receptor potential vanilloid 4 (TRPV4) silencing in Helicobacter pylori-infected human gastric epithelium. Helicobacter 2017; 22:e12361. [PMID: 27687509 PMCID: PMC5363345 DOI: 10.1111/hel.12361] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 08/22/2016] [Accepted: 09/04/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Helicobacter pylori (HP) infection induces methylation silencing of specific genes in gastric epithelium. Various stimuli activate the nonselective cation channel TRPV4, which is expressed in gastric epithelium where it detects mechanical stimuli and promotes ATP release. As CpG islands in TRPV4 are methylated in HP-infected gastric epithelium, we evaluated HP infection-dependent changes in TRPV4 expression in gastric epithelium. MATERIALS AND METHODS Human gastric biopsy samples, a human gastric cancer cell line (AGS), and a normal gastric epithelial cell line (GES-1) were used to detect TRPV4 mRNA and protein expression by RT-PCR and Western blotting, respectively. Ca2+ imaging was used to evaluate TRPV4 ion channel activity. TRPV4 methylation status was assessed by methylation-specific PCR (MSP). ATP release was measured by a luciferin-luciferase assay. RESULTS TRPV4 mRNA and protein were detected in human gastric biopsy samples and in GES-1 cells. MSP and demethylation assays showed TRPV4 methylation silencing in AGS cells. HP coculture directly induced methylation silencing of TRPV4 in GES-1 cells. In human samples, HP infection was associated with TRPV4 methylation silencing that recovered after HP eradication in a time-dependent manner. CONCLUSION HP infection-dependent DNA methylation suppressed TRPV4 expression in human gastric epithelia, suggesting that TRPV4 methylation may be involved in HP-associated dyspepsia.
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Affiliation(s)
- Hiroshi Mihara
- Department of GastroenterologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan,Center for Medical Education and Career DevelopmentUniversity of ToyamaToyamaJapan
| | - Nobuhiro Suzuki
- Department of GastroenterologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Jibran Sualeh Muhammad
- Department of GastroenterologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan,Department of Biological and Biomedical SciencesFaculty of Health SciencesThe Aga Khan UniversityKarachiPakistan
| | - Sohachi Nanjo
- Department of GastroenterologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Takayuki Ando
- Department of GastroenterologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Haruka Fujinami
- Department of GastroenterologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Shinya Kajiura
- Department of GastroenterologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Ayumu Hosokawa
- Department of GastroenterologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Toshiro Sugiyama
- Department of GastroenterologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
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Suppression of calpain expression by NSAIDs is associated with inhibition of cell migration in rat duodenum. Toxicology 2017; 383:1-12. [PMID: 28342779 DOI: 10.1016/j.tox.2017.03.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 02/20/2017] [Accepted: 03/20/2017] [Indexed: 12/27/2022]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the alleviation of pain and inflammation, but these drugs are also associated with a suite of negative side effects. Gastrointestinal (GI) toxicity is particularly concerning since it affects an estimated 70% of individuals taking NSAIDs routinely, and evidence suggests the majority of toxicity is occurring in the small intestine. Traditionally, NSAID-induced GI toxicity has been associated with indiscriminate inhibition of cyclooxygenase isoforms, but other mechanisms, including inhibition of cell migration, intestinal restitution, and wound healing, are likely to contribute to toxicity. Previous efforts demonstrated that treatment of cultured intestinal epithelial cells (IEC) with NSAIDs inhibits expression and activity of calpain proteases, but the effects of specific inhibition of calpain expression in vitro or the effects of NSAIDs on intestinal cell migration in vivo remain to be determined. Accordingly, we examined the effect of suppression of calpain protease expression with siRNA on cell migration in cultured IECs and evaluated the effects of NSAID treatment on epithelial cell migration and calpain protease expression in rat duodenum. Our results show that calpain siRNA inhibits protease expression and slows migration in cultured IECs. Additionally, NSAID treatment of rats slowed migration up the villus axis and suppressed calpain expression in duodenal epithelial cells. Our results are supportive of the hypothesis that suppression of calpain expression leading to slowing of cell migration is a potential mechanism through which NSAIDs cause GI toxicity.
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Blockage of transient receptor potential vanilloid 4 alleviates myocardial ischemia/reperfusion injury in mice. Sci Rep 2017; 7:42678. [PMID: 28205608 PMCID: PMC5311718 DOI: 10.1038/srep42678] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 01/13/2017] [Indexed: 12/15/2022] Open
Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable nonselective cation channel and can be activated during ischemia/reperfusion (I/R). This study tested whether blockade of TRPV4 can alleviate myocardial I/R injury in mice. TRPV4 expression began to increase at 1 h, reached statistically at 4 h, and peaked at 24–72 h. Treatment with the selective TRPV4 antagonist HC-067047 or TRPV4 knockout markedly ameliorated myocardial I/R injury as demonstrated by reduced infarct size, decreased troponin T levels and improved cardiac function at 24 h after reperfusion. Importantly, the therapeutic window for HC-067047 lasts for at least 12 h following reperfusion. Furthermore, treatment with HC-067047 reduced apoptosis, as evidenced by the decrease in TUNEL-positive myocytes, Bax/Bcl-2 ratio, and caspase-3 activation. Meanwhile, treatment with HC-067047 attenuated the decrease in the activation of reperfusion injury salvage kinase (RISK) pathway (phosphorylation of Akt, ERK1/2, and GSK-3β), while the activation of survival activating factor enhancement (SAFE) pathway (phosphorylation of STAT3) remained unchanged. In addition, the anti-apoptotic effects of HC-067047 were abolished by the RISK pathway inhibitors. We conclude that blockade of TRPV4 reduces apoptosis via the activation of RISK pathway, and therefore might be a promising strategy to prevent myocardial I/R injury.
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Martínez-Rendón J, Sánchez-Guzmán E, Rueda A, González J, Gulias-Cañizo R, Aquino-Jarquín G, Castro-Muñozledo F, García-Villegas R. TRPV4 Regulates Tight Junctions and Affects Differentiation in a Cell Culture Model of the Corneal Epithelium. J Cell Physiol 2016; 232:1794-1807. [PMID: 27869310 DOI: 10.1002/jcp.25698] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 11/17/2016] [Indexed: 11/09/2022]
Abstract
TRPV4 (transient receptor potential vanilloid 4) is a cation channel activated by hypotonicity, moderate heat, or shear stress. We describe the expression of TRPV4 during the differentiation of a corneal epithelial cell model, RCE1(5T5) cells. TRPV4 is a late differentiation feature that is concentrated in the apical membrane of the outmost cell layer of the stratified epithelia. Ca2+ imaging experiments showed that TRPV4 activation with GSK1016790A produced an influx of calcium that was blunted by the specific TRPV4 blocker RN-1734. We analyzed the involvement of TRPV4 in RCE1(5T5) epithelial differentiation by measuring the development of transepithelial electrical resistance (TER) as an indicator of the tight junction (TJ) assembly. We showed that TRPV4 activity was necessary to establish the TJ. In differentiated epithelia, activation of TRPV4 increases the TER and the accumulation of claudin-4 in cell-cell contacts. Epidermal Growth Factor (EGF) up-regulates the TER of corneal epithelial cultures, and we show here that TRPV4 activation mimicked this EGF effect. Conversely, TRPV4 inhibition or knock down by specific shRNA prevented the increase in TER. Moreover, TRPP2, an EGF-activated channel that forms heteromeric complexes with TRPV4, is also concentrated in the outmost cell layer of differentiated RCE1(5T5) sheets. This suggests that the EGF regulation of the TJ may involve a heterotetrameric TRPV4-TRPP2 channel. These results demonstrated TRPV4 activity was necessary for the correct establishment of TJ in corneal epithelia and as well as the regulation of both the barrier function of TJ and its ability to respond to EGF. J. Cell. Physiol. 232: 1794-1807, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Jacqueline Martínez-Rendón
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
| | - Erika Sánchez-Guzmán
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
| | - Angélica Rueda
- Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
| | - James González
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
| | - Rosario Gulias-Cañizo
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
| | - Guillermo Aquino-Jarquín
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
| | - Federico Castro-Muñozledo
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
| | - Refugio García-Villegas
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
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Mihara H, Suzuki N, Boudaka AA, Muhammad JS, Tominaga M, Tabuchi Y, Sugiyama T. Transient receptor potential vanilloid 4-dependent calcium influx and ATP release in mouse and rat gastric epithelia. World J Gastroenterol 2016; 22:5512-5519. [PMID: 27350729 PMCID: PMC4917611 DOI: 10.3748/wjg.v22.i24.5512] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 04/11/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the expression of transient receptor potential vanilloid 4 (TRPV4) and its physiological meaning in mouse and rat gastric epithelia.
METHODS: RT-PCR and immunochemistry were used to detect TRPV4 mRNA and protein expression in mouse stomach and a rat normal gastric epithelial cell line (RGE1-01), while Ca2+-imaging and electrophysiology were used to evaluate TRPV4 channel activity. ATP release was measured by a luciferin-luciferase assay. Gastric emptying was also compared between WT and TRPV4 knockout mice.
RESULTS: TRPV4 mRNA and protein were detected in mouse tissues and RGE1-01 cells. A TRPV4-specific agonist (GSK1016790A) increased intracellular Ca2+ concentrations and/or evoked TRPV4-like current activities in WT mouse gastric epithelial cells and RGE1-01 cells, but not TRPV4KO cells. GSK1016790A or mechanical stimuli induced ATP release from RGE1-01 cells while TRPV4 knockout mice displayed delayed gastric emptying in vivo.
CONCLUSION: TRPV4 is expressed in mouse and rat gastric epithelium and contributes to ATP release and gastric emptying.
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27
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Fichna J, Poole DP, Veldhuis N, MacEachern SJ, Saur D, Zakrzewski PK, Cygankiewicz AI, Mokrowiecka A, Małecka-Panas E, Krajewska WM, Liedtke W, Steinhoff MS, Timmermans JP, Bunnett NW, Sharkey KA, Storr MA. Transient receptor potential vanilloid 4 inhibits mouse colonic motility by activating NO-dependent enteric neurotransmission. J Mol Med (Berl) 2015; 93:1297-309. [PMID: 26330151 DOI: 10.1007/s00109-015-1336-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 07/12/2015] [Accepted: 08/17/2015] [Indexed: 01/15/2023]
Abstract
UNLABELLED Recent studies implicate TRPV4 receptors in visceral pain signaling and intestinal inflammation. Our aim was to evaluate the role of TRPV4 in the control of gastrointestinal (GI) motility and to establish the underlying mechanisms. We used immunohistochemistry and PCR to study TRPV4 expression in the GI tract. The effect of TRPV4 activation on GI motility was characterized using in vitro and in vivo motility assays. Calcium and nitric oxide (NO) imaging were performed to study the intracellular signaling pathways. Finally, TRPV4 expression was examined in the colon of healthy human subjects. We demonstrated that TRPV4 can be found on myenteric neurons of the colon and is co-localized with NO synthase (NOS-1). In vitro, the TRPV4 agonist GSK1016790A reduced colonic contractility and increased inhibitory neurotransmission. In vivo, TRPV4 activation slowed GI motility and reduced stool production in mouse models mimicking pathophysiological conditions. We also showed that TRPV4 activation inhibited GI motility by reducing NO-dependent Ca(2+) release from enteric neurons. In conclusion, TRPV4 is involved in the regulation of GI motility in health and disease. KEY MESSAGES • Recent studies implicate TRPV4 in pain signaling and intestinal inflammation. • Our aim was to characterize the role of TRPV4 in the control of GI motility. • We found that TRPV4 activation reduced colonic contractility. • Our studies also showed altered TRPV4 mRNA expression in IBS-C patients. • TRPV4 may be a novel pharmacological target in functional GI diseases.
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Affiliation(s)
- J Fichna
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.,Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, AB, Canada.,Department of Biochemistry, Medical University of Lodz, Lodz, Poland
| | - D P Poole
- Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.,Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia
| | - N Veldhuis
- Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - S J MacEachern
- Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada.,Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - D Saur
- II Medizinische Klinik, Technische Universität München, Munich, Germany
| | - P K Zakrzewski
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - A I Cygankiewicz
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - A Mokrowiecka
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - E Małecka-Panas
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - W M Krajewska
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - W Liedtke
- Center for Translational Neuroscience, Duke University, Durham, NC, USA
| | - M S Steinhoff
- Department of Dermatology and Surgery, University of California San Francisco, San Francisco, CA, USA
| | - J-P Timmermans
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - N W Bunnett
- Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.,Department of Pharmacology, The University of Melbourne, Parkville, VIC, Australia
| | - K A Sharkey
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.,Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada.,Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - M A Storr
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada. .,Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, AB, Canada. .,Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
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