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Nakagawa Y, Yamada S. Novel hypothesis and therapeutic interventions for irritable bowel syndrome: interplay between metal dyshomeostasis, gastrointestinal dysfunction, and neuropsychiatric symptoms. Mol Cell Biochem 2025; 480:2661-2676. [PMID: 39503802 DOI: 10.1007/s11010-024-05153-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/26/2024] [Indexed: 05/03/2025]
Abstract
Irritable bowel syndrome is a gastrointestinal disorder due to multiple pathologies. While patients with this condition experience anxiety and depressed mood more frequently than healthy individuals, it is unclear how gastrointestinal dysfunction interacts with such neuropsychiatric symptoms. Data suggest that irritable bowel syndrome patients predominantly display a lower zinc intake, which presumably impairs enterochromaffin cells producing 5-hydroxytryptamine, gut bacteria fermenting short-chain fatty acids, and barrier system in the intestine, with the accompanying constipation, diarrhea, low-grade mucosal inflammation, and visceral pain. Dyshomeostasis of copper and zinc concentrations as well as elevated pro-inflammatory cytokine levels in the blood can disrupt blood-cerebrospinal fluid barrier function, leading to locus coeruleus neuroinflammation and hyperactivation with resultant amygdalar overactivation and dorsolateral prefrontal cortex hypoactivation as found in neuropsychiatric disorders. The dysregulation between the dorsolateral prefrontal cortex and amygdala is likely responsible for visceral pain-related anxiety, depressed mood caused by anticipatory anxiety, and visceral pain catastrophizing due to catastrophic thinking or cognitive distortion. Collectively, these events can result in a spiral of gastrointestinal symptoms and neuropsychiatric signs, prompting the progression of irritable bowel syndrome. Given that the negative feedback mechanism in regulation of the hypothalamic-pituitary-adrenal axis is preserved in a subset of neuropsychiatric cases, dorsolateral prefrontal cortex abnormality accompanied by neuropsychiatric symptoms may be a more significant contributing factor in brain-gut axis malfunction than activation of the hypothalamic corticotropin-releasing hormone system. The proposed mechanistic model could predict novel therapeutic interventions for comorbid irritable bowel syndrome and neuropsychiatric disorders.
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Affiliation(s)
- Yutaka Nakagawa
- Center for Pharma-Food Research (CPFR), Division of Pharmaceutical Sciences, Graduate School of Integrative Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka, 422-8526, Japan.
| | - Shizuo Yamada
- Center for Pharma-Food Research (CPFR), Division of Pharmaceutical Sciences, Graduate School of Integrative Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka, 422-8526, Japan
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2
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Cheng Y, Zhao C, Bin Y, Liu Y, Cheng L, Xia F, Tian X, Liu X, Liu S, Ying B, Shao Z, Yan W. The pathophysiological functions and therapeutic potential of GPR39: Focus on agonists and antagonists. Int Immunopharmacol 2024; 143:113491. [PMID: 39549543 DOI: 10.1016/j.intimp.2024.113491] [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: 09/03/2024] [Revised: 10/09/2024] [Accepted: 10/21/2024] [Indexed: 11/18/2024]
Abstract
G protein-coupled receptor 39 (GPR39), a member of the growth hormone-releasing peptide family, exhibits widespread expression across various tissues and demonstrates high constitutive activity, primarily activated by zinc ions. It plays critical roles in cell proliferation, differentiation, survival, apoptosis, and ion transport through the recruitment of Gq/11, Gs, G12/13, and β-arrestin proteins. GPR39 is involved in anti-inflammatory and antioxidant responses, highlighting its diverse pathophysiological functions. Recent discoveries of endogenous ligands have enhanced our understanding of GPR39's physiological roles. Aberrant expression and reactivation of GPR39 have been implicated in a range of diseases, particularly central nervous system disorders, endocrine disruptions, cardiovascular diseases, cancers, and liver conditions. These findings position GPR39 as a promising therapeutic target, with the efficacy of synthetic ligands validated in various in vivo models. Nonetheless, their clinical applicability remains uncertain, necessitating further exploration of novel agonists-especially biased agonists-and antagonists. This review examines the unique residues contributing to the high constitutive activity of GPR39, its endogenous and synthetic ligands, and its pathophysiological implications, aiming to elucidate its pharmacological potential for clinical application in disease treatment.
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Affiliation(s)
- Yuhui Cheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Chang Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yan Bin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yuan Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Lin Cheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000 China
| | - Fan Xia
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Xiaowen Tian
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Xinlei Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Sicen Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Binwu Ying
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
| | - Zhenhua Shao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Tianfu Jincheng Laboratory, Frontiers Medical Center, Chengdu 610212, Sichuan, China.
| | - Wei Yan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
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Wang R, Huang Q, Zhu S, Xie C, Zeng Q, Yuan Y. The zinc absorption of the novel peptide-Zn complex in Caco-2 cells: effects of soybean peptides charge and hydrophobicity. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:9220-9227. [PMID: 39011979 DOI: 10.1002/jsfa.13744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/04/2024] [Accepted: 07/01/2024] [Indexed: 07/17/2024]
Abstract
BACKGROUND The supplemental effect of zinc depends not only on adequate intake, but also on how efficiently it is absorbed in the small intestine. In the present study, weak hydrophobic peptides (WHP), strong hydrophobic peptides (SHP), positively charged peptides (PCP) and negatively charged peptides (NCP) were isolated from soybean peptides (SP). The peptide-Zn complexes (PCP-Zn, NCP-Zn, WHP-Zn, SHP-Zn and SP-Zn) were prepared to compare their promotion zinc absorption capacity in the Caco-2 cells monolayers model. RESULTS We found that the carboxyl, carbonyl and amino groups in peptide were the primary binding sites of Zn. Compared with zinc sulfate, the peptide-Zn complexes with different charge and hydrophobic peptides could improve zinc solubility at different pH. NCP-Zn had a lower Zn-binding capacity but a higher zinc absorption capacity compared to that of PCP-Zn in Caco-2 cells. In addition, the capacity of PCP-Zn to promote zinc absorption was lower than the control group (SP-Zn). There were no significant differences in transport rates, retention rates and uptake rates of WHP-Zn, SHP-Zn and SP-Zn. NCP-Zn could improve the activity of Zn-related enzymes, and the expression levels of PepT1 and ZnT1 were higher than other peptide-Zn complexes. CONCLUSION The promotion zinc absorption capacity of peptide-Zn complexes was not completely dependent on the Zn-binding capacity, but also depended on the charge and hydrophobicity of peptides. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Rongxin Wang
- School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, China
| | - Qing Huang
- School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, China
| | - Suyin Zhu
- School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, China
| | - Cuina Xie
- School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, China
| | - Qingzhu Zeng
- School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, China
| | - Yang Yuan
- School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, China
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Shendge AK, Sekler I, Hershfinkel M. ZnR/GPR39 regulates hepatic insulin signaling, tunes liver bioenergetics and ROS production, and mitigates liver fibrosis and injury. Redox Biol 2024; 78:103403. [PMID: 39514940 PMCID: PMC11584770 DOI: 10.1016/j.redox.2024.103403] [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: 09/01/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
Adequate supply of zinc is essential for hepatic function and its deficiency is associated with acute liver injury (ALI) and chronic nonalcoholic fatty liver disease (NAFLD). However, how zinc controls hepatic function is unknown. We found that the zinc sensitive ZnR/GPR39, a mediator of zinc signaling, enhances hepatic phosphorylation of ERK1/2, which is reduced in ZnR/GPR39 deficient livers. Surprisingly, livers from ZnR/GPR39 knockout (KO) mice exhibited elevated insulin receptor expression and downstream AKT activation. Moreover, ZnR/GPR39 KO mice had higher blood fasting glucose level, pronounced hepatic lipid accumulation, increased hepatocyte oxygen consumption rate (OCR) and reactive oxygen species (ROS) levels. These data suggest that ZnR/GPR39 modulates insulin receptor signaling, a major pathway in hepatic metabolism. Associated with the impaired signaling, ZnR/GPR39 KO livers exhibited increased tissue fibrosis, manifested by marked elevation of collagen expression, compared to wildtype (WT). Additionally, we found alteration of hepatocyte junctional proteins that was accompanied by increased macrophage infiltration and higher liver inflammation in ZnR/GPR39 KO mice. To determine the role of ZnR/GPR39 in ALI, we applied a mild LPS challenge that induced profound decrease in hepatic OCR, also leading to higher ROS generation in ZnR/GPR39 KO hepatocytes, but not in WT. We further found increased serum IL-2 and AST/ALT ratio only in ZnR/GPR39 KO mice. Our findings reveal a role of ZnR/GPR39 in controlling hepatic insulin receptor signaling and mitigating liver fibrosis and inflammation, thus underscoring the important role of ZnR/GPR39 in liver signaling and function.
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Affiliation(s)
- Anil Khushalrao Shendge
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
| | - Israel Sekler
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
| | - Michal Hershfinkel
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
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Maywald M, Rink L. Zinc Deficiency and Zinc Supplementation in Allergic Diseases. Biomolecules 2024; 14:863. [PMID: 39062576 PMCID: PMC11274920 DOI: 10.3390/biom14070863] [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: 05/27/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
In recent decades, it has become clear that allergic diseases are on the rise in both Western and developing countries. The exact reason for the increase in prevalence has not been conclusively clarified yet. Multidimensional approaches are suspected in which diet and nutrition seem to play a particularly important role. Allergic diseases are characterized by a hyper-reactive immune system to usually harmless allergens, leading to chronic inflammatory diseases comprising respiratory diseases like asthma and allergic rhinitis (AR), allergic skin diseases like atopic dermatitis (AD), and food allergies. There is evidence that diet can have a positive or negative influence on both the development and severity of allergic diseases. In particular, the intake of the essential trace element zinc plays a very important role in modulating the immune response, which was first demonstrated around 60 years ago. The most prevalent type I allergies are mainly based on altered immunoglobulin (Ig)E and T helper (Th)2 cytokine production, leading to type 2 inflammation. This immune status can also be observed during zinc deficiency and can be positively influenced by zinc supplementation. The underlying immunological mechanisms are very complex and multidimensional. Since zinc supplements vary in dose and bioavailability, and clinical trials often differ in design and structure, different results can be observed. Therefore, different results are not surprising. However, the current literature suggests a link between zinc deficiency and the development of allergies, and shows positive effects of zinc supplementation on modulating the immune system and reducing allergic symptoms, which are discussed in more detail in this review.
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Affiliation(s)
| | - Lothar Rink
- Institute of Immunology, Faculty of Medicine, RWTH Aachen University Hospital, 52074 Aachen, Germany;
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Zhang T, Zhang N, Peng S, Zhang Y, Wang H, Huang S, Zhu M, Ma Y. Effects of Dietary Valine Chelated Zinc Supplementation on Growth Performance, Antioxidant Capacity, Immunity, and Intestine Health in Weaned Piglets. Biol Trace Elem Res 2024; 202:2577-2587. [PMID: 37730969 PMCID: PMC11052861 DOI: 10.1007/s12011-023-03870-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 09/13/2023] [Indexed: 09/22/2023]
Abstract
This study was conducted to investigate the effects of dietary valine chelated zinc (ZnVal) supplementation on growth performance, antioxidant capacity, immunity, and intestine health in weaned piglets. A total of 240 healthy 35-day-old weaned piglets (Duroc × Landrace × Yorkshire, average weight 10.70 ± 0.14 kg) were randomly divided into five groups with six replicate pens and eight piglets per pen. Dietary treatments were a corn-soybean meal basal diet supplemented with 0, 25, 50, 75, and 100 mg/kg ZnVal, respectively. The experiment lasted for 28 days. Results showed that average daily gain (ADG) was increased (P < 0.05) by ZnVal with 75-100 mg/kg supplementation on days 15-28 and with 50-100 mg/kg supplementation on days 1-28. Supplementation of 25-100 mg/kg ZnVal reduced (P < 0.01) the diarrhea rate of weaned piglets on days 1 to 14 and 1 to 28. Dietary supplementation with 25-100 mg/kg ZnVal increased (P < 0.05) copper/zinc-superoxide dismutase (Cu/Zn-SOD) and decreased malonaldehyde (MDA) activities in the serum on day 14 and 28. Supplementation of 25-100 mg/kg ZnVal increased (P < 0.05) glutathione peroxidase (GSH-Px) activity in serum on day 14. Additionally, the supplementation of 75 mg/kg ZnVal significantly increased the activity of superoxide dismutase (SOD) and Cu/Zn-SOD in the liver (P < 0.05). Furthermore, the supplementation of 25-100 mg/kg ZnVal significantly increased the total antioxidant capacity (T-AOC) in the liver (P < 0.05). Higher (P < 0.05) concentrations of IgG in the serum were measured from piglets supplemented with 75-100 mg/kg ZnVal on day 14 and dietary supplementation with 25-100 mg/kg ZnVal increased the level of immunoglobulin G (IgG) in serum on day 28 (P < 0.05). In addition, higher (P < 0.05) concentrations of immunoglobulin A (IgA) in the duodenum and ileum were measured from piglets supplemented with 75 mg/kg ZnVal and the supplementation of 25-100 mg/kg ZnVal also showed a higher (P < 0.05) concentration of immunoglobulin G (IgG) in duodenum. Supplementation of 50-100 mg/kg ZnVal increased the villus height and villus height/crypt depth of jejunum (P < 0.05). Moreover, dietary supplementation with 75-100 mg/kg ZnVal showed a higher (P < 0.05) concentration of zinc in the liver and supplementation of 50-100 mg/kg ZnVal increased (P < 0.05) the concentration of zinc in the heart, spleen, and kidney. In conclusion, the present research showed that supplementation of ZnVal improves growth performance by increasing antioxidant capacity and immunity and regulating intestinal morphology and the optimal inclusion level of ZnVal was 65~80 mg/kg.
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Affiliation(s)
- Tuan Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Nan Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Shuyu Peng
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Yawei Zhang
- Changsha Xinjia Bio-Engineeriong Co., Ltd, Changsha, China
| | - Huakai Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Shiyu Huang
- Changsha Xinjia Bio-Engineeriong Co., Ltd, Changsha, China
| | - Min Zhu
- Changsha Xinjia Bio-Engineeriong Co., Ltd, Changsha, China
| | - Yongxi Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
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Shi MH, Yan Y, Niu X, Wang JF, Li S. GPR39-mediated ERK1/2 signaling reduces permethrin-induced proliferation of estrogen receptor α-negative cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 276:116303. [PMID: 38599157 DOI: 10.1016/j.ecoenv.2024.116303] [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: 11/20/2023] [Revised: 03/29/2024] [Accepted: 04/05/2024] [Indexed: 04/12/2024]
Abstract
Certain insecticides are known to have estrogenic effects by activating estrogen receptors through genomic transcription. This has led researchers to associate specific insecticide use with an increased breast cancer risk. However, it is unclear if estrogen receptor-dependent pathways are the only way in which these compounds induce carcinogenic effects. The objective of this study was to determine the impact of the pyrethroid insecticide permethrin on the growth of estrogen receptor negative breast cancer cells MDA-MB-231. Using tandem mass spectrometric techniques, the effect of permethrin on cellular protein expression was investigated, and gene ontology and pathway function enrichment analyses were performed on the deregulated proteins. Finally, molecular docking simulations of permethrin with the candidate target protein was performed and the functionality of the protein was confirmed through gene knockdown experiments. Our findings demonstrate that exposure to 10-40 μM permethrin for 48 h enhanced cell proliferation and cell cycle progression in MDA-MB-231. We observed deregulated expression in 83 upregulated proteins and 34 downregulated proteins due to permethrin exposure. These deregulated proteins are primarily linked to transmembrane signaling and chemical carcinogenesis. Molecular docking simulations revealed that the overexpressed transmembrane signaling protein, G protein-coupled receptor 39 (GPR39), has the potential to bind to permethrin. Knockdown of GPR39 partially impeded permethrin-induced cellular proliferation and altered the expression of proliferation marker protein PCNA and cell cycle-associated protein cyclin D1 via the ERK1/2 signaling pathway. These findings offer novel evidence for permethrin as an environmental breast cancer risk factor, displaying its potential to impact breast cancer cell proliferation via an estrogen receptor-independent pathway.
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Affiliation(s)
- Ming-Hui Shi
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Institute of Agro-bioengineering, Guizhou University, Guiyang, Guizhou Province 550025, China
| | - Yi Yan
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Institute of Agro-bioengineering, Guizhou University, Guiyang, Guizhou Province 550025, China
| | - Xi Niu
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Institute of Agro-bioengineering, Guizhou University, Guiyang, Guizhou Province 550025, China
| | - Jia-Fu Wang
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Institute of Agro-bioengineering, Guizhou University, Guiyang, Guizhou Province 550025, China
| | - Sheng Li
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Institute of Agro-bioengineering, Guizhou University, Guiyang, Guizhou Province 550025, China.
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8
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Hershfinkel M. Cross-talk between zinc and calcium regulates ion transport: A role for the zinc receptor, ZnR/GPR39. J Physiol 2024; 602:1579-1594. [PMID: 37462604 DOI: 10.1113/jp283834] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 06/26/2023] [Indexed: 04/21/2024] Open
Abstract
Zinc is essential for many physiological functions, with a major role in digestive system, skin health, and learning and memory. On the cellular level, zinc is involved in cell proliferation and cell death. A selective zinc sensing receptor, ZnR/GPR39 is a Gq-coupled receptor that acts via the inositol trisphosphate pathway to release intracellular Ca2+. The ZnR/GPR39 serves as a mediator between extracellular changes in Zn2+ concentration and cellular Ca2+ signalling. This signalling pathway regulates ion transporters activity and thereby controls the formation of transepithelial gradients or neuronal membrane potential, which play a fundamental role in the physiological function of these tissues. This review focuses on the role of Ca2+ signalling, and specifically ZnR/GPR39, with respect to the regulation of the Na+/H+ exchanger, NHE1, and of the K+/Cl- cotransporters, KCC1-3, and also describes the physiological implications of this regulation.
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Affiliation(s)
- Michal Hershfinkel
- Department of Physiology and Cell Biology and the School of Brain Sciences and Cognition, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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9
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Zi Z, Rao Y. Discoveries of GPR39 as an evolutionarily conserved receptor for bile acids and of its involvement in biliary acute pancreatitis. SCIENCE ADVANCES 2024; 10:eadj0146. [PMID: 38306436 PMCID: PMC10836733 DOI: 10.1126/sciadv.adj0146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 01/04/2024] [Indexed: 02/04/2024]
Abstract
Acute pancreatitis (AP) is one of the most common gastrointestinal diseases. Bile acids (BAs) were proposed to be a cause of AP nearly 170 years ago, though the underlying mechanisms remain unclear. Here, we report that two G protein-coupled receptors, GPR39 and GHSR, mediated cellular responses to BAs. Our results revealed GPR39 as an evolutionarily conserved receptor for BAs, particularly 3-O-sulfated lithocholic acids. In cultured cell lines, GPR39 is sufficient for BA-induced Ca2+ elevation. In pancreatic acinar cells, GPR39 mediated BA-induced Ca2+ elevation and necrosis. Furthermore, AP induced by BAs was significantly reduced in GPR39 knockout mice. Our findings provide in vitro and in vivo evidence demonstrating that GPR39 is necessary and sufficient to mediate BA signaling, highlighting its involvement in biliary AP pathogenesis, and suggesting it as a promising therapeutic target for biliary AP.
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Affiliation(s)
- Zhentao Zi
- Chinese Institutes for Medical Research, Beijing (CIMR, Beijing) and the State Key Laboratory of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, PKU-IDG/McGovern Institute for Brain Research, School of Life Sciences, School of Pharmaceutical Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
| | - Yi Rao
- Chinese Institutes for Medical Research, Beijing (CIMR, Beijing) and the State Key Laboratory of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, PKU-IDG/McGovern Institute for Brain Research, School of Life Sciences, School of Pharmaceutical Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
- Changping Laboratory, Chinese Institute of Brain Research Beijing and Research Unit of Medical Neurobiology, Chinese Academy of Medical Sciences, Beijing 102206, China
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10
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Cao B, Wang J, Feng J. Signaling pathway mechanisms of neurological diseases induced by G protein-coupled receptor 39. CNS Neurosci Ther 2023; 29:1470-1483. [PMID: 36942516 PMCID: PMC10173710 DOI: 10.1111/cns.14174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/14/2023] [Accepted: 02/28/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND G protein-coupled receptor 39 (GPR39) is a transmembrane zinc receptor with two splice variants, which belongs to the G-protein-coupled receptor growth hormone-releasing peptide family. Its expression is induced by zinc, which activates GPR39, and its activation mediates cell proliferation, ion homeostasis, and anti-inflammatory, antioxidant, and other pathophysiological effects via different signaling pathways. AIMS The article reviews the latest literature in this field. In particular, the role of GPR39 in nervous system is discussed. MATERIALS AND METHODS GPR39 can be a promising target in neurological diseases for targeted therapy, which will help doctors overcome the associated problems. DISCUSSION GPR39 is expressed in vivo at several sites. Increasing evidence suggests that GPR39 plays an important role as a neuroprotective agent in vivo and regulates various neurological functions, including neurodegeneration, neuroelectrophysiology, and neurovascular homeostasis. CONCLUSION This review aims to provide an overview of the functions, signal transduction pathways, and pathophysiological role of GPR39 in neurological diseases and summarize the GPR39 agonists that have been identified in the recent years.
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Affiliation(s)
- Bin Cao
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jue Wang
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Juan Feng
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
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11
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Jimenez-Rondan FR, Ruggiero CH, McKinley KL, Koh J, Roberts JF, Triplett EW, Cousins RJ. Enterocyte-specific deletion of metal transporter Zip14 (Slc39a14) alters intestinal homeostasis through epigenetic mechanisms. Am J Physiol Gastrointest Liver Physiol 2023; 324:G159-G176. [PMID: 36537699 PMCID: PMC9925170 DOI: 10.1152/ajpgi.00244.2022] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/21/2022] [Accepted: 11/30/2022] [Indexed: 01/31/2023]
Abstract
Zinc has anti-inflammatory properties using mechanisms that are unclear. Zip14 (Slc39a14) is a zinc transporter induced by proinflammatory stimuli and is highly expressed at the basolateral membrane of intestinal epithelial cells (IECs). Enterocyte-specific Zip14 ablation (Zip14ΔIEC) in mice was developed to study the functions of this transporter in enterocytes. This gene deletion led to increased intestinal permeability, increased IL-6 and IFNγ expression, mild endotoxemia, and intestinal dysbiosis. RNA sequencing was used for transcriptome profiling. These analyses revealed differential expression of specific intestinal proinflammatory and tight junction (TJ) genes. Binding of transcription factors, including NF-κβ, STAT3, and CDX2, to appropriate promoter sites of these genes supports the differential expression shown with chromatin immunoprecipitation assays. Total histone deacetylase (HDAC), and specifically HDAC3, activities were markedly reduced with Zip14 ablation. Intestinal organoids derived from ΔIEC mice display TJ and cytokine gene dysregulation compared with control mice. Differential expression of specific genes was reversed with zinc supplementation of the organoids. We conclude that zinc-dependent HDAC enzymes acquire zinc ions via Zip14-mediated transport and that intestinal integrity is controlled in part through epigenetic modifications.NEW & NOTEWORTHY We show that enterocyte-specific ablation of zinc transporter Zip14 (Slc39a14) results in selective dysbiosis and differential expression of tight junction proteins, claudin 1 and 2, and specific cytokines associated with intestinal inflammation. HDAC activity and zinc uptake are reduced with Zip14 ablation. Using intestinal organoids, the expression defects of claudin 1 and 2 are resolved through zinc supplementation. These novel results suggest that zinc, an essential micronutrient, influences gene expression through epigenetic mechanisms.
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Affiliation(s)
- Felix R Jimenez-Rondan
- Center for Nutritional Sciences and Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida
| | - Courtney H Ruggiero
- Center for Nutritional Sciences and Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida
| | - Kelley Lobean McKinley
- Department of Microbiology and Cell Science, College of Agricultural and Life Sciences, University of Florida, Gainesville, Florida
| | - Jin Koh
- Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, Florida
| | - John F Roberts
- Department of Comparative, Diagnostic and Population Medicine, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Eric W Triplett
- Department of Microbiology and Cell Science, College of Agricultural and Life Sciences, University of Florida, Gainesville, Florida
| | - Robert J Cousins
- Center for Nutritional Sciences and Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida
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12
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Zinc Laurate Protects against Intestinal Barrier Dysfunction and Inflammation Induced by ETEC in a Mice Model. Nutrients 2022; 15:nu15010054. [PMID: 36615713 PMCID: PMC9824434 DOI: 10.3390/nu15010054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/15/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Enterotoxigenic Escherichia coli (ETEC) infection is one of the most common bacterial causes of diarrhea in children and young farm animals. Medium-chain fatty acids (MCFAs) have been widely used for their antibacterial and immune functions. However, there is limited information regarding the role of MCFAs chelated with Zn in diarrhea induced by ETEC infection. Here, zinc laurate (ZnLa) was used to evaluate its protective effect in a mice diarrhea model induced by ETEC. A total of 45 ICR-weaned female mice were randomly assigned to marginal zinc deficiency (dZn), dZn, and ETEC infection groups (dZn+ETEC); ETEC infection was co-treated with a low, middle, or high dose of ZnLa (ZnLa LOW+ETEC, ZnLa MID+ETEC, and ZnLa HIGH+ETEC), respectively, to explore the effect and its mechanism of ZnLa on diarrhea and intestinal health of mice challenged with ETEC. To further compare the antibacterial efficiency of ZnLa and ZnSO4 in mice with ETEC infection, a total of 36 ICR-weaned female mice were randomly divided into ZnLa, ZnLa+ETEC, ZnSO4, and ZnSO4 and ETEC infection groups (ZnSO4+ETEC); moreover, the growth curve of ETEC also compared ZnLa and ZnSO4 in vitro. Mice pretreated with ZnLa were effectively guarded against body weight losses and increases in diarrhea scores induced by ETEC. ZnLa pretreatment also prevented intestinal barrier damage and ion transport in mice challenged with ETEC, as evidenced by the fact that the intestinal villus height and the ratio of villus height and crypt depth, tight junction protein, and Na+ absorption were higher, whereas intestinal permeability and anion secretion were lower in mice pretreated with ZnLa. In addition, ZnLa conferred effective protection against ETEC-induced intestinal inflammatory responses, as the increases in protein and mRNAs of proinflammatory cytokines were prevented in serum and jejunum, which was likely associated with the TLR4/MYD88/NF-κB signaling pathway. The increase in ETEC shedding and virulence-related gene expression was prevented in mice with ZnLa pretreatment. Finally, the growth of ETEC and virulence-related gene expression were lower in the ZnLa group than in ZnSO4 with an equal concentration of zinc. These findings suggest that ZnLa is a promising prevention strategy to remedy ETEC infection.
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13
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Nathani S, Mishra R, Katiyar P, Sircar D, Roy P. Zinc Acts Synergistically with Berberine for Enhancing Its Efficacy as an Anti-cancer Agent by Inducing Clusterin-Dependent Apoptosis in HT-29 Colorectal Cancer Cells. Biol Trace Elem Res 2022:10.1007/s12011-022-03460-8. [PMID: 36394793 DOI: 10.1007/s12011-022-03460-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 10/22/2022] [Indexed: 11/18/2022]
Abstract
It is now widely accepted that anti-cancer medications are most effective when administered in combination. Zinc is an essential micronutrient whilst berberine is a well-known natural phytochemical, both having multiple molecular mechanisms of action. The present study aimed to determine the combinatorial effect of zinc and berberine on the human adenocarcinoma HT-29 cancer cell line. The anti-proliferative activity of berberine and zinc was determined by cell viability and colony-forming assays. The combination index and drug reduction index values of zinc and berberine co-treatments were estimated by suitable software. Flow cytometry was used to analyse cell cycle distribution and Annexin V/PI staining. The expression of apoptosis and zinc signalling markers were analysed by RT-qPCR and immunoblot analysis. Berberine decreased the viability of colon cancer cells in a dose-dependent manner whilst zinc alone had no significant influence on it. However, zinc and berberine co-treatment resulted in a synergistic anti-cancer action which was demonstrated by G2/M phase arrest of cell growth at a lower dose of berberine. Annexin V assay demonstrated that the synergistic impact of zinc and berberine boosted the number of apoptotic cells. Gene expression analysis at both transcriptional and translational levels showed the upregulation of apoptotic (caspase-3 and caspase-8) and a zinc-sensing receptor (GPR39) gene with concomitant downregulation of anti-apoptotic genes like proliferating cell nuclear antigen (PCNA) and clusterin. Our findings showed that the combination of zinc and berberine has synergistic anti-cancer efficacy and thus could be used as a potential chemopreventive option for colon cancer.
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Affiliation(s)
- Sandip Nathani
- Molecular Endocrinology Laboratory, Department of Biosciences & Bioengineering, Indian Institute of Technology Roorkee, Roorkee, 247 667, Uttarakhand, India
| | - Rutusmita Mishra
- Molecular Endocrinology Laboratory, Department of Biosciences & Bioengineering, Indian Institute of Technology Roorkee, Roorkee, 247 667, Uttarakhand, India
| | - Parul Katiyar
- Molecular Endocrinology Laboratory, Department of Biosciences & Bioengineering, Indian Institute of Technology Roorkee, Roorkee, 247 667, Uttarakhand, India
| | - Debabrata Sircar
- Plant Molecular Biology Laboratory, Department of Biosciences & Bioengineering, Indian Institute of Technology Roorkee, Roorkee, 247 667, Uttarakhand, India
| | - Partha Roy
- Molecular Endocrinology Laboratory, Department of Biosciences & Bioengineering, Indian Institute of Technology Roorkee, Roorkee, 247 667, Uttarakhand, India.
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14
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Gutiérrez-Rojas RA, Aguayo-Cerón KA, Vargas-De-León C, Cabrera-Becerra SE, Almanza-Pérez JC, Huang F, Villafaña S, Romero-Nava R. Glycine Effect on the Expression Profile of Orphan Receptors GPR21, GPR26, GPR39, GPR82 and GPR6 in a Model of Inflammation in 3T3-L1 Cells. Life (Basel) 2022; 12:1687. [PMID: 36362842 PMCID: PMC9696036 DOI: 10.3390/life12111687] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/19/2022] [Accepted: 10/21/2022] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Chronic or low-grade inflammation is a process where various immune cells are recruited from the periphery into adipose tissue. This event gives rise to localised inflammation, in addition to having a close interaction with cardiometabolic pathologies where the mediation of orphan receptors is observed. The aim of this study was to analyse the participation of the orphan receptors GPR21, GPR39, GPR82 and GPR6 in a chronic inflammatory process in 3T3-L1 cells. The 3T3-L1 cells were stimulated with TNF-α (5 ng/mL) for 60 min as an inflammatory model. Gene expression was measured by RT-qPCR. RESULTS We showed that the inflammatory stimulus of TNF-α in adipocytes decreased the expression of the orphan receptors GPR21, GPR26, GPR39, GPR82 and GPR6, which are related to low-grade inflammation. CONCLUSIONS Our results suggest that GPR21 and GPR82 are modulated by glycine, it shows a possible protective role in the presence of an inflammatory environment in adipocytes, and they could be a therapeutic target to decrease the inflammation in some diseases related to low-grade inflammation such as diabetes, obesity and metabolic syndrome.
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Affiliation(s)
| | - Karla Aidee Aguayo-Cerón
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado, Escuela Superior de Medicina del Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | - Cruz Vargas-De-León
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado, Escuela Superior de Medicina del Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
- División de Investigación, Hospital Juárez de México, Ciudad de México 07760, Mexico
| | - Sandra Edith Cabrera-Becerra
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado, Escuela Superior de Medicina del Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | - Julio Cesar Almanza-Pérez
- Laboratorio de Farmacología, Departamento de Ciencias de la Salud, DCBS, Universidad Autónoma Metropolitana-Iztapalapa (UAM-I), Ciudad de México 09340, Mexico
| | - Fengyang Huang
- Laboratorio de Investigación en Farmacología, Hospital Infantil de México Federico Gómez (HIMFG), Ciudad de México 06720, Mexico
| | - Santiago Villafaña
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado, Escuela Superior de Medicina del Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | - Rodrigo Romero-Nava
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado, Escuela Superior de Medicina del Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
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15
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Functions of the Zinc-Sensing Receptor GPR39 in Regulating Intestinal Health in Animals. Int J Mol Sci 2022; 23:ijms232012133. [PMID: 36292986 PMCID: PMC9602648 DOI: 10.3390/ijms232012133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 10/08/2022] [Accepted: 10/10/2022] [Indexed: 11/17/2022] Open
Abstract
G protein-coupled receptor 39 (GPR39) is a zinc-sensing receptor (ZnR) that can sense changes in extracellular Zn2+, mediate Zn2+ signal transmission, and participate in the regulation of numerous physiological activities in living organisms. For example, GPR39 activates the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and phosphatidylinositol3-kinase/protein kinase B (PI3K/AKT) signaling pathways upon Zn2+ stimulation, enhances the proliferation and differentiation of colonic cells, and regulates ion transport, as well as exerting other functions. In recent years, with the increased attention to animal gut health issues and the intensive research on GPR39, GPR39 has become a potential target for regulating animal intestinal health. On the one hand, GPR39 is involved in regulating ion transport in the animal intestine, mediating the Cl− efflux by activating the K+/Cl− synergistic protein transporter, and relieving diarrhea symptoms. On the other hand, GPR39 can maintain the homeostasis of the animal intestine, promoting pH restoration in colonic cells, regulating gastric acid secretion, and facilitating nutrient absorption. In addition, GPR39 can affect the expression of tight junction proteins in intestinal epithelial cells, improving the barrier function of the animal intestinal mucosa, and maintaining the integrity of the intestine. This review summarizes the structure and signaling transduction processes involving GPR39 and the effect of GPR39 on the regulation of intestinal health in animals, with the aim of further highlighting the role of GPR39 in regulating animal intestinal health and providing new directions and ideas for studying the prevention and treatment of animal intestinal diseases.
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16
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Marginal Zinc Deficiency Aggravated Intestinal Barrier Dysfunction and Inflammation through ETEC Virulence Factors in a Mouse Model of Diarrhea. Vet Sci 2022; 9:vetsci9090507. [PMID: 36136723 PMCID: PMC9503546 DOI: 10.3390/vetsci9090507] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 11/21/2022] Open
Abstract
Simple Summary Enterotoxigenic Escherichia coli (ETEC) is one of the most common bacterial causes of diarrhea in children and farm animals. Zinc has received widespread attention for its roles in the prevention and treatment of diarrhea. However, zinc is also essential for the pathogenesis of ETEC. This study aimed to explore the accurate effect and mechanisms of marginal zinc deficiency on ETEC k88 infection and host intestinal health. Using the newly developed marginal zinc deficiency and ETEC k88 infection mouse model, we found that marginal zinc deficiency aggravated growth impairment, diarrhea, intestinal morphology, intestinal permeability, and inflammation induced by ETEC k88 infection. Consistently, intestinal ETEC k88 shedding was also higher in mice with marginal zinc deficiency. However, marginal zinc deficiency failed to affect host zinc levels and correspondingly the zinc-receptor GPR39 expression in the jejunum. In addition, marginal zinc deficiency upregulated the relative expression of virulence genes involved in heat-labile and heat-stable enterotoxins, motility, cellular adhesion, and biofilm formation in the cecum content of mice with ETEC infection. These findings provide a new explanation for zinc treatment of ETEC infection. Abstract Zinc is both essential and inhibitory for the pathogenesis of enterotoxigenic Escherichia coli (ETEC). However, the accurate effects and underlying mechanism of marginal zinc deficiency on ETEC infection are not fully understood. Here, a marginal zinc-deficient mouse model was established by feeding mice with a marginal zinc-deficient diet, and ETEC k88 was further administrated to mice after antibiotic disruption of the normal microbiota. Marginal zinc deficiency aggravated growth impairment, diarrhea, intestinal morphology, intestinal permeability, and inflammation induced by ETEC k88 infection. In line with the above observations, marginal zinc deficiency also increased the intestinal ETEC shedding, though the concentration of ETEC in the intestinal content was not different or even decreased in the stool. Moreover, marginal zinc deficiency failed to change the host’s zinc levels, as evidenced by the fact that the serum zinc levels and zinc-receptor GPR39 expression in jejunum were not significantly different in mice with ETEC challenge. Finally, marginal zinc deficiency upregulated the relative expression of virulence genes involved in heat-labile and heat-stable enterotoxins, motility, cellular adhesion, and biofilm formation in the cecum content of mice with ETEC infection. These findings demonstrated that marginal zinc deficiency likely regulates ETEC infection through the virulence factors, whereas it is not correlated with host zinc levels.
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17
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Wan Y, Zhang B. The Impact of Zinc and Zinc Homeostasis on the Intestinal Mucosal Barrier and Intestinal Diseases. Biomolecules 2022; 12:biom12070900. [PMID: 35883455 PMCID: PMC9313088 DOI: 10.3390/biom12070900] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/06/2022] [Accepted: 06/11/2022] [Indexed: 02/04/2023] Open
Abstract
Zinc is an essential trace element for living organisms, and zinc homeostasis is essential for the maintenance of the normal physiological functions of cells and organisms. The intestine is the main location for zinc absorption and excretion, while zinc and zinc homeostasis is also of great significance to the structure and function of the intestinal mucosal barrier. Zinc excess or deficiency and zinc homeostatic imbalance are all associated with many intestinal diseases, such as IBD (inflammatory bowel disease), IBS (irritable bowel syndrome), and CRC (colorectal cancer). In this review, we describe the role of zinc and zinc homeostasis in the intestinal mucosal barrier and the relevance of zinc homeostasis to gastrointestinal diseases.
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18
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Moonwiriyakit A, Pathomthongtaweechai N, Steinhagen PR, Chantawichitwong P, Satianrapapong W, Pongkorpsakol P. Tight junctions: from molecules to gastrointestinal diseases. Tissue Barriers 2022; 11:2077620. [PMID: 35621376 PMCID: PMC10161963 DOI: 10.1080/21688370.2022.2077620] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Intestinal epithelium functions as a tissue barrier to prevent interaction between the internal compartment and the external milieu. Intestinal barrier function also determines epithelial polarity for the absorption of nutrients and the secretion of waste products. These vital functions require strong integrity of tight junction proteins. In fact, intestinal tight junctions that seal the paracellular space can restrict mucosal-to-serosal transport of hostile luminal contents. Tight junctions can form both an absolute barrier and a paracellular ion channel. Although defective tight junctions potentially lead to compromised intestinal barrier and the development and progression of gastrointestinal (GI) diseases, no FDA-approved therapies that recover the epithelial tight junction barrier are currently available in clinical practice. Here, we discuss the impacts and regulatory mechanisms of tight junction disruption in the gut and related diseases. We also provide an overview of potential therapeutic targets to restore the epithelial tight junction barrier in the GI tract.
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Affiliation(s)
- Aekkacha Moonwiriyakit
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand
| | - Nutthapoom Pathomthongtaweechai
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand
| | - Peter R Steinhagen
- Department of Hepatology and Gastroenterology, Charité Medical School, Berlin, Germany
| | | | | | - Pawin Pongkorpsakol
- Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Bangkok, Thailand
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19
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Zhang L, Guo Q, Duan Y, Lin X, Ni H, Zhou C, Li F. Comparison of the Effects of Inorganic or Amino Acid-Chelated Zinc on Mouse Myoblast Growth in vitro and Growth Performance and Carcass Traits in Growing-Finishing Pigs. Front Nutr 2022; 9:857393. [PMID: 35464034 PMCID: PMC9021508 DOI: 10.3389/fnut.2022.857393] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 02/28/2022] [Indexed: 11/16/2022] Open
Abstract
This study aimed to investigate the effects of the supplementation of different sources of zinc on mouse myoblast growth in vitro and the growth performance and carcass traits in growing-finishing pigs. In the in vitro trial, 25 or 75 mM zinc sulfate (ZnSO4), methionine-chelated zinc (ZnMet), and glycine-chelated zinc (ZnGly) were co-cultured with the myoblast during proliferation and differentiation. The results showed that the amino acid-chelated zinc supplementation, especially ZnMet, enhances cell proliferation and differentiation in mouse myoblast, and regulates the distribution in S and G2/M phases (P < 0.05). Meanwhile, the protein expression levels of the mammalian target of rapamycin pathways were up-regulated after treatment with 25 μM ZnMet (P < 0.05), which is consistent with the results of the enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway in the transcriptome analysis. In the in vivo trial, 27 Duroc × (Landrace × Large White) pigs with an initial average weight of 31.62 ± 0.36 kg were divided into three groups with nine replicates per treatment. The dietary treatment groups were as follows: (1) ZnSO4 group, basal diet +75 mg/kg ZnSO4; (2) ZnMet group, basal diet +75 mg/kg ZnMet; and (3) ZnGly group, basal diet +75 mg/kg ZnGly. The whole trial lasted for 75 days. Increased final body weight, average daily gain, and decreased F/G were noted in the ZnMet group (P < 0.05). Moreover, the ZnMet group had higher carcass weight and loin eye area (P = 0.05). The ZnMet and ZnGly group both had lower serum total protein (P < 0.05), while the ZnMet group had higher serum alkaline phosphatase (P < 0.05). Also, the addition of ZnMet showed higher concentrations of zinc and iron in muscle, kidney, and serum (P < 0.05), improving the deposition and availability of micronutrients. In conclusion, amino acid-chelated zinc, particularly ZnMet, had the best effect, which could improve growth in vitro and increase growth performance while boosting bioavailability in growing-finishing pigs, ultimately, enhancing muscle mass, providing a theoretical basis and guidance for the future use of amino acid-chelated zinc to effectively replenish energy in animal nutrition and production.
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Affiliation(s)
- Lingyu Zhang
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Beijing, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
- National Engineering Laboratory for Rice and By-product Deep Processing, Central South University of Forestry and Technology, Changsha, China
| | - Qiuping Guo
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Beijing, China
- *Correspondence: Qiuping Guo
| | - Yehui Duan
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Beijing, China
| | - Xue Lin
- Guangzhou Tanke Bio-tech Co., Ltd., Guangzhou, China
| | - Hengjia Ni
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Beijing, China
| | - Chuanshe Zhou
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Beijing, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Fengna Li
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Beijing, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
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20
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Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy. Int J Mol Sci 2022; 23:ijms23062995. [PMID: 35328419 PMCID: PMC8951934 DOI: 10.3390/ijms23062995] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/01/2022] [Indexed: 02/04/2023] Open
Abstract
The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care—but also medical prophylactic and therapeutic care in general—to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.
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21
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Sauer AK, Malijauskaite S, Meleady P, Boeckers TM, McGourty K, Grabrucker AM. Zinc is a key regulator of gastrointestinal development, microbiota composition and inflammation with relevance for autism spectrum disorders. Cell Mol Life Sci 2021; 79:46. [PMID: 34936034 PMCID: PMC11072240 DOI: 10.1007/s00018-021-04052-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/31/2021] [Accepted: 11/18/2021] [Indexed: 12/15/2022]
Abstract
Gastrointestinal (GI) problems and microbiota alterations have been frequently reported in autism spectrum disorders (ASD). In addition, abnormal perinatal trace metal levels have been found in ASD. Accordingly, mice exposed to prenatal zinc deficiency display features of ASD-like behavior. Here, we model GI development using 3D intestinal organoids grown under zinc-restricted conditions. We found significant morphological alterations. Using proteomic approaches, we identified biological processes affected by zinc deficiency that regulate barrier permeability and pro-inflammatory pathways. We confirmed our results in vivo through proteomics studies and investigating GI development in zinc-deficient mice. These show altered GI physiology and pro-inflammatory signaling, resulting in chronic systemic and neuroinflammation, and gut microbiota composition similar to that reported in human ASD cases. Thus, low zinc status during development is sufficient to compromise intestinal barrier integrity and activate pro-inflammatory signaling, resulting in changes in microbiota composition that may aggravate inflammation, altogether mimicking the co-morbidities frequently observed in ASD.
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Affiliation(s)
- Ann Katrin Sauer
- Cellular Neurobiology and Neuro-Nanotechnology Lab, Department of Biological Sciences, University of Limerick, Bernal Institute, Analog Devices Building AD3-018, Castletroy, Limerick, V94PH61, Ireland
- Bernal Institute, University of Limerick, Limerick, Ireland
- Health Research Institute (HRI), University of Limerick, Limerick, Ireland
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany
| | - Sigita Malijauskaite
- Bernal Institute, University of Limerick, Limerick, Ireland
- Department of Chemical Sciences, University of Limerick, Limerick, Ireland
| | - Paula Meleady
- School of Biotechnology and National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
| | - Tobias M Boeckers
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany
- DZNE, Ulm Unit, Ulm, Germany
| | - Kieran McGourty
- Bernal Institute, University of Limerick, Limerick, Ireland
- Health Research Institute (HRI), University of Limerick, Limerick, Ireland
- Department of Chemical Sciences, University of Limerick, Limerick, Ireland
| | - Andreas M Grabrucker
- Cellular Neurobiology and Neuro-Nanotechnology Lab, Department of Biological Sciences, University of Limerick, Bernal Institute, Analog Devices Building AD3-018, Castletroy, Limerick, V94PH61, Ireland.
- Bernal Institute, University of Limerick, Limerick, Ireland.
- Health Research Institute (HRI), University of Limerick, Limerick, Ireland.
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22
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Fortea M, Albert-Bayo M, Abril-Gil M, Ganda Mall JP, Serra-Ruiz X, Henao-Paez A, Expósito E, González-Castro AM, Guagnozzi D, Lobo B, Alonso-Cotoner C, Santos J. Present and Future Therapeutic Approaches to Barrier Dysfunction. Front Nutr 2021; 8:718093. [PMID: 34778332 PMCID: PMC8582318 DOI: 10.3389/fnut.2021.718093] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
There is converging and increasing evidence, but also uncertainty, for the role of abnormal intestinal epithelial barrier function in the origin and development of a growing number of human gastrointestinal and extraintestinal inflammatory disorders, and their related complaints. Despite a vast literature addressing factors and mechanisms underlying changes in intestinal permeability in humans, and its connection to the appearance and severity of clinical symptoms, the ultimate link remains to be established in many cases. Accordingly, there are no directives or clinical guidelines related to the therapeutic management of intestinal permeability disorders that allow health professionals involved in the management of these patients to carry out a consensus treatment based on clinical evidence. Instead, there are multiple pseudoscientific approaches and commercial propaganda scattered on the internet that confuse those affected and health professionals and that often lack scientific rigor. Therefore, in this review we aim to shed light on the different therapeutic options, which include, among others, dietary management, nutraceuticals and medical devices, microbiota and drugs, and epigenetic and exosomes-manipulation, through an objective evaluation of the scientific publications in this field. Advances in the knowledge and management of intestinal permeability will sure enable better options of dealing with this group of common disorders to enhance quality of life of those affected.
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Affiliation(s)
- Marina Fortea
- Laboratory for Enteric NeuroScience, Translational Research Center for GastroIntestinal Disorders, University of Leuven, Leuven, Belgium
| | - Mercé Albert-Bayo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Mar Abril-Gil
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - John-Peter Ganda Mall
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Xavier Serra-Ruiz
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Alejandro Henao-Paez
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Elba Expósito
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Ana María González-Castro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Danila Guagnozzi
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| | - Beatriz Lobo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Carmen Alonso-Cotoner
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Santos
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
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Zinc Signaling in the Mammary Gland: For Better and for Worse. Biomedicines 2021; 9:biomedicines9091204. [PMID: 34572390 PMCID: PMC8469023 DOI: 10.3390/biomedicines9091204] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/06/2021] [Accepted: 09/06/2021] [Indexed: 02/07/2023] Open
Abstract
Zinc (Zn2+) plays an essential role in epithelial physiology. Among its many effects, most prominent is its action to accelerate cell proliferation, thereby modulating wound healing. It also mediates affects in the gastrointestinal system, in the testes, and in secretory organs, including the pancreas, salivary, and prostate glands. On the cellular level, Zn2+ is involved in protein folding, DNA, and RNA synthesis, and in the function of numerous enzymes. In the mammary gland, Zn2+ accumulation in maternal milk is essential for supporting infant growth during the neonatal period. Importantly, Zn2+ signaling also has direct roles in controlling mammary gland development or, alternatively, involution. During breast cancer progression, accumulation or redistribution of Zn2+ occurs in the mammary gland, with aberrant Zn2+ signaling observed in the malignant cells. Here, we review the current understanding of the role of in Zn2+ the mammary gland, and the proteins controlling cellular Zn2+ homeostasis and signaling, including Zn2+ transporters and the Gq-coupled Zn2+ sensing receptor, ZnR/GPR39. Significant advances in our understanding of Zn2+ signaling in the normal mammary gland as well as in the context of breast cancer provides new avenues for identification of specific targets for breast cancer therapy.
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Xu Y, Barnes AP, Alkayed NJ. Role of GPR39 in Neurovascular Homeostasis and Disease. Int J Mol Sci 2021; 22:8200. [PMID: 34360964 PMCID: PMC8346997 DOI: 10.3390/ijms22158200] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/24/2021] [Accepted: 07/26/2021] [Indexed: 12/26/2022] Open
Abstract
GPR39, a member of the ghrelin family of G protein-coupled receptors, is zinc-responsive and contributes to the regulation of diverse neurovascular and neurologic functions. Accumulating evidence suggests a role as a homeostatic regulator of neuronal excitability, vascular tone, and the immune response. We review GPR39 structure, function, and signaling, including constitutive activity and biased signaling, and summarize its expression pattern in the central nervous system. We further discuss its recognized role in neurovascular, neurological, and neuropsychiatric disorders.
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Affiliation(s)
- Yifan Xu
- Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239, USA;
| | - Anthony P. Barnes
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR 97239, USA;
| | - Nabil J. Alkayed
- Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239, USA;
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR 97239, USA;
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25
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Laitakari A, Liu L, Frimurer TM, Holst B. The Zinc-Sensing Receptor GPR39 in Physiology and as a Pharmacological Target. Int J Mol Sci 2021; 22:ijms22083872. [PMID: 33918078 PMCID: PMC8070507 DOI: 10.3390/ijms22083872] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/31/2021] [Accepted: 04/06/2021] [Indexed: 12/16/2022] Open
Abstract
The G-protein coupled receptor GPR39 is abundantly expressed in various tissues and can be activated by changes in extracellular Zn2+ in physiological concentrations. Previously, genetically modified rodent models have been able to shed some light on the physiological functions of GPR39, and more recently the utilization of novel synthetic agonists has led to the unraveling of several new functions in the variety of tissues GPR39 is expressed. Indeed, GPR39 seems to be involved in many important metabolic and endocrine functions, but also to play a part in inflammation, cardiovascular diseases, saliva secretion, bone formation, male fertility, addictive and depression disorders and cancer. These new discoveries offer opportunities for the development of novel therapeutic approaches against many diseases where efficient therapeutics are still lacking. This review focuses on Zn2+ as an endogenous ligand as well as on the novel synthetic agonists of GPR39, placing special emphasis on the recently discovered physiological functions and discusses their pharmacological potential.
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Affiliation(s)
- Anna Laitakari
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; (A.L.); (L.L.); (T.M.F.)
| | - Lingzhi Liu
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; (A.L.); (L.L.); (T.M.F.)
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Thomas M. Frimurer
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; (A.L.); (L.L.); (T.M.F.)
| | - Birgitte Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; (A.L.); (L.L.); (T.M.F.)
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
- Correspondence:
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26
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Xia P, Lian S, Wu Y, Yan L, Quan G, Zhu G. Zinc is an important inter-kingdom signal between the host and microbe. Vet Res 2021; 52:39. [PMID: 33663613 PMCID: PMC7931793 DOI: 10.1186/s13567-021-00913-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 02/08/2021] [Indexed: 12/15/2022] Open
Abstract
Zinc (Zn) is an essential trace element in living organisms and plays a vital role in the regulation of both microbial virulence and host immune responses. A growing number of studies have shown that zinc deficiency or the internal Zn concentration does not meet the needs of animals and microbes, leading to an imbalance in zinc homeostasis and intracellular signalling pathway dysregulation. Competition for zinc ions (Zn2+) between microbes and the host exists in the use of Zn2+ to maintain cell structure and physiological functions. It also affects the interplay between microbial virulence factors and their specific receptors in the host. This review will focus on the role of Zn in the crosstalk between the host and microbe, especially for changes in microbial pathogenesis and nociceptive neuron-immune interactions, as it may lead to new ways to prevent or treat microbial infections.
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Affiliation(s)
- Pengpeng Xia
- College of Veterinary Medicine (Institute of Comparative Medicine), Yangzhou University, Yangzhou, 225009, China. .,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China. .,Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China.
| | - Siqi Lian
- College of Veterinary Medicine (Institute of Comparative Medicine), Yangzhou University, Yangzhou, 225009, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China
| | - Yunping Wu
- College of Veterinary Medicine (Institute of Comparative Medicine), Yangzhou University, Yangzhou, 225009, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China
| | - Li Yan
- College of Veterinary Medicine (Institute of Comparative Medicine), Yangzhou University, Yangzhou, 225009, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China
| | - Guomei Quan
- College of Veterinary Medicine (Institute of Comparative Medicine), Yangzhou University, Yangzhou, 225009, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China
| | - Guoqiang Zhu
- College of Veterinary Medicine (Institute of Comparative Medicine), Yangzhou University, Yangzhou, 225009, China. .,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China. .,Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China.
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27
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Buddington RK, Wong T, Howard SC. Paracellular Filtration Secretion Driven by Mechanical Force Contributes to Small Intestinal Fluid Dynamics. Med Sci (Basel) 2021; 9:medsci9010009. [PMID: 33572202 PMCID: PMC7931054 DOI: 10.3390/medsci9010009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/26/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
Studies of fluid secretion by the small intestine are dominated by the coupling with ATP-dependent generation of ion gradients, whereas the contribution of filtration secretion has been overlooked, possibly by the lack of a known mechanistic basis. We measured apical fluid flow and generation of hydrostatic pressure gradients by epithelia of cultured mouse enterocytes, Caco-2 and T-84 cells, and fibroblasts exposed to mechanical force provided by vigorous aeration and in response to ion gradients, inhibitors of ion channels and transporters and in vitro using intact mouse and rat small intestine. We describe herein a paracellular pathway for unidirectional filtration secretion that is driven by mechanical force, requires tight junctions, is independent of ionic and osmotic gradients, generates persistent hydrostatic pressure gradients, and would contribute to the fluid shifts that occur during digestion and diarrhea. Zinc inhibits the flow of fluid and the paracellular marker fluorescein isothyocyanate conjugated dextran (MW = 4 kD) across epithelia of cultured enterocytes (>95%; p < 0.001) and intact small intestine (>40%; p = 0.03). We propose that mechanical force drives fluid secretion through the tight junction complex via a “one-way check valve” that can be regulated. This pathway of filtration secretion complements chloride-coupled fluid secretion during high-volume fluid flow. The role of filtration secretion in the genesis of diarrhea in intact animals needs further study. Our findings may explain a potential linkage between intestinal motility and intestinal fluid dynamics.
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Affiliation(s)
- Randal K. Buddington
- School of Health Studies, University of Memphis, Memphis, TN 38152, USA;
- Babies Taking Flight, Memphis, TN 38117, USA
- Correspondence: ; Tel.: +1-662-418-2666
| | - Thomas Wong
- School of Health Studies, University of Memphis, Memphis, TN 38152, USA;
| | - Scott C. Howard
- Department of Acute and Tertiary Care, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA;
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28
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Time- and Zinc-Related Changes in Biomechanical Properties of Human Colorectal Cancer Cells Examined by Atomic Force Microscopy. BIOLOGY 2020; 9:biology9120468. [PMID: 33327597 PMCID: PMC7765036 DOI: 10.3390/biology9120468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/10/2020] [Accepted: 12/11/2020] [Indexed: 12/24/2022]
Abstract
Simple Summary We aimed to study how cellular zinc status (adequate vs. deficiency), closely related to colorectal cancer, does affect the nanomechanical properties of cell lines HT-29 and HT-29-MTX during their early proliferation (24–96 h). These properties and their variations can be characterized by means of Atomic Force Microscopy (AFM), a technique that allows perpendicular indentation of cells with a sharp nanometric tip, under controlled speed and load, while recording the real time variation of tip-to-cell interacting forces on approach, contact, and retraction segments. From each of these sections, complete information about the respective elastic modulus, relaxation behavior, and adhesion is extracted, thus identifying cell line- and zinc-related nanomechanical fingerprints. Our results show how the impact of zinc deficiency on the mechanical response of the cells underlines the relevance of monitoring the nutritional zinc status of tumor samples when analyzing cancerous tissues or single cells with AFM, particularly regarding the development and validation of biomechanical fingerprints as diagnostic markers for cancer. Abstract Monitoring biomechanics of cells or tissue biopsies employing atomic force microscopy (AFM) offers great potential to identify diagnostic biomarkers for diseases, such as colorectal cancer (CRC). Data on the mechanical properties of CRC cells, however, are still scarce. There is strong evidence that the individual zinc status is related to CRC risk. Thus, this study investigates the impact of differing zinc supply on the mechanical response of the in vitro CRC cell lines HT-29 and HT-29-MTX during their early proliferation (24–96 h) by measuring elastic modulus, relaxation behavior, and adhesion factors using AFM. The differing zinc supply severely altered the proliferation of these cells and markedly affected their mechanical properties. Accordingly, zinc deficiency led to softer cells, quantitatively described by 20–30% lower Young’s modulus, which was also reflected by relevant changes in adhesion and rupture event distribution compared to those measured for the respective zinc-adequate cultured cells. These results demonstrate that the nutritional zinc supply severely affects the nanomechanical response of CRC cell lines and highlights the relevance of monitoring the zinc content of cancerous cells or biopsies when studying their biomechanics with AFM in the future.
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29
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Loviscach L, Backes TM, Langfermann DS, Ulrich M, Thiel G. Zn 2+ ions inhibit gene transcription following stimulation of the Ca 2+ channels Ca v1.2 and TRPM3. Metallomics 2020; 12:1735-1747. [PMID: 33030499 DOI: 10.1039/d0mt00180e] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Zinc, a trace element, is necessary for the correct structure and function of many proteins. Therefore, Zn2+ has to be taken up by the cells, using specific Zn2+ transporters or Ca2+ channels. In this study, we have focused on two Ca2+ channels, the L-type voltage-gated Cav1.2 channel and the transient receptor potential channel TRPM3. Stimulation of either channel induces an intracellular signaling cascade leading to the activation of the transcription factor AP-1. The influx of Ca2+ ions into the cytoplasm is essential for this activity. We asked whether extracellular Zn2+ ions affect Cav1.2 or TRPM3-induced gene transcription following stimulation of the channels. The results show that extracellular Zn2+ ions reduced the activation of AP-1 by more than 80% following stimulation of either voltage-gated Cav1.2 channels or TRPM3 channels. Experiments performed with cells maintained in Ca2+-free medium revealed that Zn2+ ions cannot replace Ca2+ ions in inducing gene transcription via stimulation of Cav1.2 and TRPM3 channels. Re-addition of Ca2+ ions to the cell culture medium, however, restored the ability of these Ca2+ channels to induce a signaling cascade leading to the activation of AP-1. Secretory cells, including neurons and pancreatic β-cells, release Zn2+ ions during exocytosis. We propose that the released Zn2+ ions function as a negative feedback loop for stimulus-induced exocytosis by inhibiting Ca2+ channel signaling.
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Affiliation(s)
- Louisa Loviscach
- Department of Medical Biochemistry and Molecular Biology, Saarland University Medical Faculty, D-66421 Homburg, Germany.
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30
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Suzuki T. Regulation of the intestinal barrier by nutrients: The role of tight junctions. Anim Sci J 2020; 91:e13357. [PMID: 32219956 PMCID: PMC7187240 DOI: 10.1111/asj.13357] [Citation(s) in RCA: 395] [Impact Index Per Article: 79.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 01/29/2020] [Accepted: 02/05/2020] [Indexed: 12/13/2022]
Abstract
Tight junctions (TJs) play an important role in intestinal barrier function. TJs in intestinal epithelial cells are composed of different junctional molecules, such as claudin and occludin, and regulate the paracellular permeability of water, ions, and macromolecules in adjacent cells. One of the most important roles of the TJ structure is to provide a physical barrier to luminal inflammatory molecules. Impaired integrity and structure of the TJ barrier result in a forcible activation of immune cells and chronic inflammation in different tissues. According to recent studies, the intestinal TJ barrier could be regulated, as a potential target, by dietary factors to prevent and reduce different inflammatory disorders, although the precise mechanisms underlying the dietary regulation remain unclear. This review summarizes currently available information on the regulation of the intestinal TJ barrier by food components.
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Affiliation(s)
- Takuya Suzuki
- Department of Biofunctional Science and Technology, Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima, Japan.,Program of Food and AgriLife Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
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31
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Kim Y, Hwang SW, Kim S, Lee YS, Kim TY, Lee SH, Kim SJ, Yoo HJ, Kim EN, Kweon MN. Dietary cellulose prevents gut inflammation by modulating lipid metabolism and gut microbiota. Gut Microbes 2020; 11:944-961. [PMID: 32138587 PMCID: PMC7524403 DOI: 10.1080/19490976.2020.1730149] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
A Western diet comprising high fat, high carbohydrate, and low fiber content has been suggested to contribute to an increased prevalence of colitis. To clarify the effect of dietary cellulose (an insoluble fiber) on gut homeostasis, for 3 months mice were fed a high-cellulose diet (HCD) or a low-cellulose diet (LCD) based on the AIN-93G formulation. Histologic evaluation showed crypt atrophy and goblet cell depletion in the colons of LCD-fed mice. RNA-sequencing analysis showed a higher expression of genes associated with immune system processes, especially those of chemokines and their receptors, in the colon tissues of LCD-fed mice than in those of HCD-fed mice. The HCD was protective against dextran sodium sulfate-induced colitis in mice, while LCD exacerbated gut inflammation; however, the depletion of gut microbiota by antibiotic treatment diminished both beneficial and non-beneficial effects of the HCD and LCD on colitis, respectively. A comparative analysis of the cecal contents of mice fed the HCD or the LCD showed that the LCD did not influence the diversity of gut microbiota, but it resulted in a higher and lower abundance of Oscillibacter and Akkermansia organisms, respectively. Additionally, linoleic acid, nicotinate, and nicotinamide pathways were most affected by cellulose intake, while the levels of short-chain fatty acids were comparable in HCD- and LCD-fed mice. Finally, oral administration of Akkermansia muciniphila to LCD-fed mice elevated crypt length, increased goblet cells, and ameliorated colitis. These results suggest that dietary cellulose plays a beneficial role in maintaining gut homeostasis through the alteration of gut microbiota and metabolites.
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Affiliation(s)
- Yeji Kim
- Mucosal Immunology Laboratory, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea
| | - Sung Wook Hwang
- Mucosal Immunology Laboratory, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea,Department of Gastroenterology, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea
| | - Seungil Kim
- Mucosal Immunology Laboratory, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea
| | - Yong-Soo Lee
- Mucosal Immunology Laboratory, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea
| | - Tae-Young Kim
- Mucosal Immunology Laboratory, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea
| | - Su-Hyun Lee
- Mucosal Immunology Laboratory, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea
| | - Su Jung Kim
- Department of Convergence Medicine, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea
| | - Hyun Ju Yoo
- Department of Convergence Medicine, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea
| | - Eun Na Kim
- Department of Pathology, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea
| | - Mi-Na Kweon
- Mucosal Immunology Laboratory, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea,CONTACT Mi-Na Kweon Mucosal Immunology Laboratory, Department of Convergence Medicine, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea
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32
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A G-protein coupled receptor 39 agonist stimulates proliferation of keratinocytes via an ERK-dependent pathway. Biomed Pharmacother 2020; 127:110160. [PMID: 32371316 DOI: 10.1016/j.biopha.2020.110160] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/08/2020] [Accepted: 04/13/2020] [Indexed: 12/27/2022] Open
Abstract
Keratinocyte proliferation serves as a crucial process in skin wound healing. The zinc-sensing G-protein coupled receptor 39 (GPR39), which is highly expressed in keratinocytes, has been shown to promote skin wound healing. The aim of this study was to investigate the effect of GPR39 activation on proliferation of keratinocytes and its underlying mechanism using immortalized human keratinocytes (HaCaT) as an in vitro model. GPR39 was functionally expressed in HaCaT cells. BrdU proliferation assays showed that treatment with GPR39 agonist TC-G 1008 (100 nM and 1 μM) increased cell proliferation. TC-G 1008 also enhanced ERK phosphorylation in time- and concentration-dependent manners. This effect was suppressed by co-treatment with wortmannin (PI3K inhibitor) and U0126 (MKK inhibitor). Of note, neither inhibition of Gαq-phospholipase C (PLC)-[Ca2+]i nor Gαs-PKA pathway affected GPR39 stimulation-induced ERK phosphorylation. Similarly, barbadin, an inhibitor of G-protein-independent β-arrestin pathway, did not suppress ERK phosphorylation induced by GPR39 activation. Of particular importance, wortmannin, U0126, and FR180204 (ERK inhibitor) abrogated the effect of TC-G 1008-induced cell proliferation. Taken together, this study reveals novel insights into the role of GPR39 in regulating keratinocyte proliferation via a PI3K-MKK-ERK-dependent mechanism. GPR39 agonists may be used in enhancing keratinocyte proliferation, which may be beneficial for the cutaneous wound treatment.
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33
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Chen Z, Gordillo-Martinez F, Jiang L, He P, Hong W, Wei X, Staines KA, Macrae VE, Zhang C, Yu D, Fu X, Zhu D. Zinc ameliorates human aortic valve calcification through GPR39 mediated ERK1/2 signalling pathway. Cardiovasc Res 2020; 117:820-835. [PMID: 32259211 DOI: 10.1093/cvr/cvaa090] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/11/2020] [Accepted: 04/01/2020] [Indexed: 12/12/2022] Open
Abstract
AIMS Calcific aortic valve disease (CAVD) is the most common heart valve disease in the Western world. It has been reported that zinc is accumulated in calcified human aortic valves. However, whether zinc directly regulates CAVD is yet to be elucidated. The present study sought to determine the potential role of zinc in the pathogenesis of CAVD. METHODS AND RESULTS Using a combination of a human valve interstitial cell (hVIC) calcification model, human aortic valve tissues, and blood samples, we report that 20 μM zinc supplementation attenuates hVIC in vitro calcification, and that this is mediated through inhibition of apoptosis and osteogenic differentiation via the zinc-sensing receptor GPR39-dependent ERK1/2 signalling pathway. Furthermore, we report that GPR39 protein expression is dramatically reduced in calcified human aortic valves, and there is a significant reduction in zinc serum levels in patients with CAVD. Moreover, we reveal that 20 μM zinc treatment prevents the reduction of GPR39 observed in calcified hVICs. We also show that the zinc transporter ZIP13 and ZIP14 are significantly increased in hVICs in response to zinc treatment. Knockdown of ZIP13 or ZIP14 significantly inhibited hVIC in vitro calcification and osteogenic differentiation. CONCLUSIONS Together, these findings suggest that zinc is a novel inhibitor of CAVD, and report that zinc transporter ZIP13 and ZIP14 are important regulators of hVIC in vitro calcification and osteogenic differentiation. Zinc supplementation may offer a potential therapeutic strategy for CAVD.
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Affiliation(s)
- Ziying Chen
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
| | - Flora Gordillo-Martinez
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
| | - Lei Jiang
- Guangdong Geriatric Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Pengcheng He
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China
| | - Wanzi Hong
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China
| | - Xuebiao Wei
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China
| | - Katherine A Staines
- School of Applied Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK
| | - Vicky E Macrae
- The Roslin Institute, RDSVS, Easter Bush Campus, University of Edinburgh, Midlothian EH25 9RG, UK
| | - Chunxiang Zhang
- Department of Biomedical Engineering, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Danqing Yu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China
| | - Xiaodong Fu
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
| | - Dongxing Zhu
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
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Deguchi M, Jose H, Nishida K, Ooi K. Transepidermal Water Loss (TEWL)-decreasing Effect by Administration of Zinc in the Elderly People. YAKUGAKU ZASSHI 2020; 140:313-318. [DOI: 10.1248/yakushi.19-00198] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Masataka Deguchi
- Laboratory of Clinical Pharmacology, Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science
- Life Pharmacy
| | | | - Keigo Nishida
- Laboratory of Immune Regulation, Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science
| | - Kazuya Ooi
- Laboratory of Clinical Pharmacology, Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science
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35
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Sun L, Wang L, Chen T, Yao B, Wang Y, Li Q, Yang W, Liu Z. microRNA-1914, which is regulated by lncRNA DUXAP10, inhibits cell proliferation by targeting the GPR39-mediated PI3K/AKT/mTOR pathway in HCC. J Cell Mol Med 2019; 23:8292-8304. [PMID: 31576658 PMCID: PMC6850956 DOI: 10.1111/jcmm.14705] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 08/21/2019] [Accepted: 09/15/2019] [Indexed: 12/18/2022] Open
Abstract
Increasing studies have confirmed that abnormally expressed microRNAs (miRNAs) take part in the carcinogenesis as well as the aggravation of hepatocellular carcinoma (HCC). However, little information is currently available about miR-1914 in HCC. Here, we first confirmed that miR-1914 inhibition in HCC cell lines and tumour specimens correlates with tumour size and histological grade. In a series of functional experiments, miR-1914 inhibited tumour proliferation and colony formation, resulting in cell cycle arrest and increased apoptosis. Moreover, miR-1914 mediated its functional effects by directly targeting GPR39 in HCC cells, leading to PI3K/AKT/mTOR repression. Restoring GPR39 expression incompletely counteracted the physiological roles of miR-1914 in HCC cells. In addition, down-regulation of AKT phosphorylation inhibited the effects of miR-1914 in HCC. Furthermore, the overexpression of lncRNA DUXAP10 negatively correlated with the expression of miR-1914 in HCC; thus, lncRNA DUXAP10 regulated miR-1914 expression and modulated the GPR39/PI3K/AKT-mediated cellular behaviours. In summary, the present study demonstrated for the first time that lncRNA DUXAP10-regulated miR-1914 plays a functional role in inhibiting HCC progression by targeting GPR39-mediated PI3K/AKT/mTOR pathway, and this miRNA represents a novel therapeutic target for patients with HCC.
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MESH Headings
- Aged
- Animals
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/therapy
- Cell Line, Tumor
- Cell Proliferation/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Hep G2 Cells
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/therapy
- Male
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/genetics
- Middle Aged
- Phosphatidylinositol 3-Kinases/metabolism
- Phosphotransferases/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- RNA, Long Noncoding/genetics
- RNAi Therapeutics/methods
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Signal Transduction
- TOR Serine-Threonine Kinases/metabolism
- Xenograft Model Antitumor Assays/methods
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Affiliation(s)
- Liankang Sun
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Liang Wang
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Tianxiang Chen
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Bowen Yao
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Yufeng Wang
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Qing Li
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Wei Yang
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Zhikui Liu
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
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36
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Dabravolski SA, Kavalionak YK. Effect of corn lectins on the intestinal transport of trace elements. J Verbrauch Lebensm 2019. [DOI: 10.1007/s00003-019-01261-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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37
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Anderson KJ, Cormier RT, Scott PM. Role of ion channels in gastrointestinal cancer. World J Gastroenterol 2019; 25:5732-5772. [PMID: 31636470 PMCID: PMC6801186 DOI: 10.3748/wjg.v25.i38.5732] [Citation(s) in RCA: 134] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 07/26/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca2+), sodium (Na+), potassium (K+), chloride (Cl-) and zinc (Zn2+) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K+ channel and CFTR Cl- channel in colorectal cancer (CRC). Ca2+ is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn2+ transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K+ channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K+ channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl- channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity can contribute to malignant transformation and tumor progression. Further, because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation, they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs.
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Affiliation(s)
- Kyle J Anderson
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
| | - Robert T Cormier
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
| | - Patricia M Scott
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
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38
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Mnatsakanyan H, Sabater I Serra R, Salmeron-Sanchez M, Rico P. Zinc Maintains Embryonic Stem Cell Pluripotency and Multilineage Differentiation Potential via AKT Activation. Front Cell Dev Biol 2019; 7:180. [PMID: 31544103 PMCID: PMC6728745 DOI: 10.3389/fcell.2019.00180] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 08/19/2019] [Indexed: 12/18/2022] Open
Abstract
Embryonic stem cells (ESCs) possess remarkable abilities, as they can differentiate into all cell types (pluripotency) and be self-renewing, giving rise to two identical cells. These characteristics make ESCs a powerful research tool in fundamental embryogenesis as well as candidates for use in regenerative medicine. Significant efforts have been devoted to developing protocols to control ESC fate, including soluble and complex cocktails of growth factors and small molecules seeking to activate/inhibit key signaling pathways for the maintenance of pluripotency states or activate differentiation. Here we describe a novel method for the effective maintenance of mouse ESCs, avoiding the supplementation of complex inhibitory cocktails or cytokines, e.g., LIF. We show that the addition of zinc to ESC cultures leads to a stable pluripotent state that shares biochemical, transcriptional and karyotypic features with the classical LIF treatment. We demonstrate for the first time that ESCs maintained in long-term cultures with added zinc, are capable of sustaining a stable ESCs pluripotent phenotype, as well as differentiating efficiently upon external stimulation. We show that zinc promotes long-term ESC self-renewal (>30 days) via activation of ZIP7 and AKT signaling pathways. Furthermore, the combination of zinc with LIF results in a synergistic effect that enhances LIF effects, increases AKT and STAT3 activity, promotes the expression of pluripotency regulators and avoids the expression of differentiation markers.
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Affiliation(s)
- Hayk Mnatsakanyan
- Centre for Biomaterials and Tissue Engineering (CBIT), Universitat Politècnica de València, Valencia, Spain
| | - Roser Sabater I Serra
- Centre for Biomaterials and Tissue Engineering (CBIT), Universitat Politècnica de València, Valencia, Spain.,Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
| | - Manuel Salmeron-Sanchez
- Centre for Biomaterials and Tissue Engineering (CBIT), Universitat Politècnica de València, Valencia, Spain.,Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.,Division of Biomedical Engineering, Centre for the Cellular Microenvironment, School of Engineering, University of Glasgow, Glasgow, United Kingdom
| | - Patricia Rico
- Centre for Biomaterials and Tissue Engineering (CBIT), Universitat Politècnica de València, Valencia, Spain.,Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
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39
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Ohashi W, Hara T, Takagishi T, Hase K, Fukada T. Maintenance of Intestinal Epithelial Homeostasis by Zinc Transporters. Dig Dis Sci 2019; 64:2404-2415. [PMID: 30830525 DOI: 10.1007/s10620-019-05561-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 02/22/2019] [Indexed: 12/12/2022]
Abstract
Zinc is an essential micronutrient for normal organ function, and dysregulation of zinc metabolism has been implicated in a wide range of diseases. Emerging evidence has revealed that zinc transporters play diverse roles in cellular homeostasis and function by regulating zinc trafficking via organelles or the plasma membrane. In the gastrointestinal tract, zinc deficiency leads to diarrhea and dysfunction of intestinal epithelial cells. Studies also showed that zinc transporters are very important in intestinal epithelial homeostasis. In this review, we describe the physiological roles of zinc transporters in intestinal epithelial functions and relevance of zinc transporters in gastrointestinal diseases.
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Affiliation(s)
- Wakana Ohashi
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Takafumi Hara
- Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro, Tokushima, 770-8055, Japan
| | - Teruhisa Takagishi
- Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro, Tokushima, 770-8055, Japan
| | - Koji Hase
- Division of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Toshiyuki Fukada
- Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro, Tokushima, 770-8055, Japan.
- Division of Pathology, Department of Oral Diagnostic Sciences, School of dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
- RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0042, Japan.
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40
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He G, Zhu H, Yao Y, Chai H, Wang Y, Zhao W, Fu S, Wang Y. Cysteine-rich intestinal protein 1 silencing alleviates the migration and invasive capability enhancement induced by excessive zinc supplementation in colorectal cancer cells. Am J Transl Res 2019; 11:3578-3588. [PMID: 31312368 PMCID: PMC6614615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 05/05/2019] [Indexed: 06/10/2023]
Abstract
Cysteine-rich intestinal protein 1 (CRIP1) is overexpressed in colorectal cancer (CRC) tissues and functions as an oncogene in regulating the migration and invasion of CRC cells. However, the underlying mechanism is unclear. CRIP1 has a role in zinc absorption and functions as an intracellular zinc transport protein. Here, we aimed to focus on the function of zinc and its underlying mechanism in CRC and determine whether CRIP1 promotes invasion and CRC metastasis through excessive zinc-induced epithelial-mesenchymal transition (EMT) by affecting the phosphorylated glycogen synthase kinase (GSK)-3beta. The results showed that ZnSO4 (Zn2+) supplementation in medium increased the labile intracellular zinc content. Furthermore, excessive Zn2+ supplementation activated the GSK3/mTOR signaling pathway in both SW620 and LoVo cells, and excessive Zn2+ supplementation promoted migration, invasion, and EMT of SW620 and LoVo cells. This migration promotion was alleviated by the specific mTOR inhibitor rapamycin, indicating that the GSK3/mTOR signaling pathway was involved in this process. CRIP1 silencing increased the labile intracellular zinc content and inhibited EMT and GSK3/mTOR signaling pathway. CRIP1 silencing alleviated the zinc supplementation effects on migration, invasion, EMT, and GSK3/mTOR signaling pathway. In conclusion, excessive Zn2+ promotes migration and invasion capabilities of SW620 and LoVo cells through GSK3/mTOR signaling pathway-induced EMT.
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Affiliation(s)
- Guoyang He
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
- Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Southern Medical UniversityGuangzhou 510000, Guangdong Province, China
| | - Huifang Zhu
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Yakun Yao
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Huanran Chai
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Yongqiang Wang
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Wenli Zhao
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Suzhen Fu
- The First Affiliated Hospital of Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Yongxia Wang
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
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41
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Mero M, Asraf H, Sekler I, Taylor KM, Hershfinkel M. ZnR/GPR39 upregulation of K +/Cl --cotransporter 3 in tamoxifen resistant breast cancer cells. Cell Calcium 2019; 81:12-20. [PMID: 31146164 DOI: 10.1016/j.ceca.2019.05.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/20/2019] [Accepted: 05/20/2019] [Indexed: 01/01/2023]
Abstract
Expression of the zinc receptor, ZnR/GPR39, is increased in higher grade breast cancer tumors and cells. Zinc, its ligand, is accumulated at larger concentrations in the tumor tissue and can therefore activate ZnR/GPR39-dependent Ca2+ signaling leading to tumor progression. The K+/Cl- co-transporters (KCC), activated by intracellular signaling, enhance breast cancer cell migration and invasion. We asked if ZnR/GPR39 enhances breast cancer cell malignancy by activating KCC. Activation of ZnR/GPR39 by Zn2+ upregulated K+/Cl- co-transport activity, measured using NH4+ as a surrogate to K+ while monitoring intracellular pH. Upregulation of NH4+ transport was monitored in tamoxifen resistant cells with functional ZnR/GPR39-dependent Ca2+ signaling but not in MCF-7 cells lacking this response. The NH4+ transport was Na+-independent, and we therefore focused on KCC family members. Silencing of KCC3, but not KCC4, expression abolished Zn2+-dependent K+/Cl- co-transport, suggesting that KCC3 is mediating upregulated NH4+ transport. The ZnR/GPR39-dependent KCC3 activation accelerated scratch closure rate, which was abolished by inhibiting KCC transport with [(DihydroIndenyl) Oxy] Alkanoic acid (DIOA). Importantly, silencing of either ZnR/GPR39 or KCC3 attenuated Zn2+-dependent scratch closure. Thus, a novel link between KCC3 and Zn2+, via ZnR/GPR39, promotes breast cancer cell migration and proliferation.
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Affiliation(s)
- Maayan Mero
- Department of Physiology and Cell Biology and The Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Hila Asraf
- Department of Physiology and Cell Biology and The Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Israel Sekler
- Department of Physiology and Cell Biology and The Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Kathryn M Taylor
- Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Redwood Building, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK
| | - Michal Hershfinkel
- Department of Physiology and Cell Biology and The Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
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42
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Cuzon Carlson VC, Ford MM, Carlson TL, Lomniczi A, Grant KA, Ferguson B, Cervera-Juanes RP. Modulation of Gpr39, a G-protein coupled receptor associated with alcohol use in non-human primates, curbs ethanol intake in mice. Neuropsychopharmacology 2019; 44:1103-1113. [PMID: 30610192 PMCID: PMC6461847 DOI: 10.1038/s41386-018-0308-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 12/13/2018] [Accepted: 12/26/2018] [Indexed: 12/17/2022]
Abstract
Alcohol use disorder (AUD) is a chronic condition with devastating health and socioeconomic effects. Still, pharmacotherapies to treat AUD are scarce. In a prior study aimed at identifying novel AUD therapeutic targets, we investigated the DNA methylome of the nucleus accumbens core (NAcc) of rhesus macaques after chronic alcohol use. The G-protein coupled receptor 39 (GPR39) gene was hypermethylated and its expression downregulated in heavy alcohol drinking macaques. GPR39 encodes a Zn2+-binding metabotropic receptor known to modulate excitatory and inhibitory neurotransmission, the balance of which is altered in AUD. These prior findings suggest that a GPR39 agonist would reduce alcohol intake. Using a drinking-in-the-dark two bottle choice (DID-2BC) model, we showed that an acute 7.5 mg/kg dose of the GPR39 agonist, TC-G 1008, reduced ethanol intake in mice without affecting total fluid intake, locomotor activity or saccharin preference. Furthermore, repeated doses of the agonist prevented ethanol escalation in an intermittent access 2BC paradigm (IA-2BC). This effect was reversible, as ethanol escalation followed agonist "wash out". As observed during the DID-2BC study, a subsequent acute agonist challenge during the IA-2BC procedure reduced ethanol intake by ~47%. Finally, Gpr39 activation was associated with changes in Gpr39 and Bdnf expression, and in glutamate release in the NAcc. Together, our findings suggest that GPR39 is a promising target for the development of prevention and treatment therapies for AUD.
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Affiliation(s)
- Verginia C Cuzon Carlson
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, USA
- Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon, USA
| | - Matthew M Ford
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, USA
- Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon, USA
| | - Timothy L Carlson
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, USA
| | - Alejandro Lomniczi
- Division of Genetics, Oregon National Primate Research, Oregon Health and Sciences University, Beaverton, Oregon, USA
| | - Kathleen A Grant
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, USA
- Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon, USA
| | - Betsy Ferguson
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, USA
- Division of Genetics, Oregon National Primate Research, Oregon Health and Sciences University, Beaverton, Oregon, USA
- Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland, Oregon, USA
| | - Rita P Cervera-Juanes
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, USA.
- Division of Genetics, Oregon National Primate Research, Oregon Health and Sciences University, Beaverton, Oregon, USA.
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43
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Contribution of Zinc and Zinc Transporters in the Pathogenesis of Inflammatory Bowel Diseases. J Immunol Res 2019; 2019:8396878. [PMID: 30984791 PMCID: PMC6431494 DOI: 10.1155/2019/8396878] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 01/29/2019] [Indexed: 02/06/2023] Open
Abstract
Intestinal epithelial cells cover the surface of the intestinal tract. The cells are important for preserving the integrity of the mucosal barriers to protect the host from luminal antigens and pathogens. The mucosal barriers are maintained by the continuous and rapid self-renewal of intestinal epithelial cells. Defects in the self-renewal of these cells are associated with gastrointestinal diseases, including inflammatory bowel diseases and diarrhea. Zinc is an essential trace element for living organisms, and zinc deficiency is closely linked to the impaired mucosal integrity. Recent evidence has shown that zinc transporters contribute to the barrier function of intestinal epithelial cells. In this review, we describe the recent advances in understanding the role of zinc and zinc transporters in the barrier function and homeostasis of intestinal epithelial cells.
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44
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Turan B. A Brief Overview from the Physiological and Detrimental Roles of Zinc Homeostasis via Zinc Transporters in the Heart. Biol Trace Elem Res 2019; 188:160-176. [PMID: 30091070 DOI: 10.1007/s12011-018-1464-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 07/26/2018] [Indexed: 12/15/2022]
Abstract
Zinc (mostly as free/labile Zn2+) is an essential structural constituent of many proteins, including enzymes in cellular signaling pathways via functioning as an important signaling molecule in mammalian cells. In cardiomyocytes at resting condition, intracellular labile Zn2+ concentration ([Zn2+]i) is in the nanomolar range, whereas it can increase dramatically under pathological conditions, including hyperglycemia, but the mechanisms that affect its subcellular redistribution is not clear. Therefore, overall, very little is known about the precise mechanisms controlling the intracellular distribution of labile Zn2+, particularly via Zn2+ transporters during cardiac function under both physiological and pathophysiological conditions. Literature data demonstrated that [Zn2+]i homeostasis in mammalian cells is primarily coordinated by Zn2+ transporters classified as ZnTs (SLC30A) and ZIPs (SLC39A). To identify the molecular mechanisms of diverse functions of labile Zn2+ in the heart, the recent studies focused on the discovery of subcellular localization of these Zn2+ transporters in parallel to the discovery of novel physiological functions of [Zn2+]i in cardiomyocytes. The present review summarizes the current understanding of the role of [Zn2+]i changes in cardiomyocytes under pathological conditions, and under high [Zn2+]i and how Zn2+ transporters are important for its subcellular redistribution. The emerging importance and the promise of some Zn2+ transporters for targeted cardiac therapy against pathological stimuli are also provided. Taken together, the review clearly outlines cellular control of cytosolic Zn2+ signaling by Zn2+ transporters, the role of Zn2+ transporters in heart function under hyperglycemia, the role of Zn2+ under increased oxidative stress and ER stress, and their roles in cancer are discussed.
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Affiliation(s)
- Belma Turan
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey.
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45
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Starowicz G, Jarosz M, Frąckiewicz E, Grzechnik N, Ostachowicz B, Nowak G, Mlyniec K. Long-lasting antidepressant-like activity of the GPR39 zinc receptor agonist TC-G 1008. J Affect Disord 2019; 245:325-334. [PMID: 30419533 DOI: 10.1016/j.jad.2018.11.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 10/04/2018] [Accepted: 11/01/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND The discovery of the zinc-sensing receptor, has provided new possibilities for explaining the neurobiology of zinc. Recent studies indicate that the GPR39 zinc receptor may play an important role in the pathogenesis of depression as well as in the antidepressant mechanism of action. METHODS In this study we evaluated the time-course of the antidepressant response of the GPR39 agonist (TC-G 1008), imipramine, ZnCl2 and MK-801 in the forced swim test in mice 30 min, 3 h, 6 h and 24 h after acute drug administration as well as after 14-day treatment. Zinc level was measured in serum of mice. BDNF protein level was evaluated in hippocampus following both acute and chronic TC-G 1008 treatment. RESULTS A single administration of the GPR39 agonist caused an antidepressant-like effect lasting up to 24 h following the injection, which is longer than the effect of imipramine, ZnCl2 and MK-801. Chronic treatment with these compounds caused a decrease in immobility time in the FST. Serum zinc concentrations showed an increased level following chronic ZnCl2 administration, but not following administration of TC-G 1008, imipramine or MK-801. We also observed some tendencies for increased BDNF following acute TC-G 1008 treatment. LIMITATIONS TC-G 1008 is new drug designed to study GPR39 therefore additional pharmacodynamic and pharmacokinetic properties in preclinical studies are required. CONCLUSION This study shows for the first time the long-lasting antidepressant effect of the GPR39 agonist in comparison with imipramine, ZnCl2 and MK-801. Our findings suggest that GPR39 should be considered as a target in efforts to develop new antidepressant drugs.
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Affiliation(s)
- Gabriela Starowicz
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Krakow, Poland
| | - Magdalena Jarosz
- Department of Radioligands, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Krakow, Poland
| | - Ewelina Frąckiewicz
- Department of Radioligands, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Krakow, Poland
| | - Natalia Grzechnik
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Krakow, Poland
| | - Beata Ostachowicz
- Faculty of Physics and Applied Computer Sciences, AGH University of Science and Technology, Mickiewicza 30, 30-059 Krakow, Poland
| | - Gabriel Nowak
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Krakow, Poland; Institute of Pharmacology, Polish Academy of Sciences, Laboratory of Trace Elements Neurobiology, Department of Neurobiology, Smetna Street 12, 31-343 Krakow, Poland
| | - Katarzyna Mlyniec
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Krakow, Poland.
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Pongkorpsakol P, Buasakdi C, Chantivas T, Chatsudthipong V, Muanprasat C. An agonist of a zinc-sensing receptor GPR39 enhances tight junction assembly in intestinal epithelial cells via an AMPK-dependent mechanism. Eur J Pharmacol 2018; 842:306-313. [PMID: 30459126 DOI: 10.1016/j.ejphar.2018.10.038] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Revised: 10/17/2018] [Accepted: 10/25/2018] [Indexed: 02/08/2023]
Abstract
Intestinal barrier function depends on integrity of tight junctions, which serve as barriers to transepithelial influx of noxious substances/microorganisms from gut lumen. The G-protein coupled receptor 39 (GPR39) is a zinc-sensing receptor, which is expressed in several cell types including intestinal epithelial cells (IECs). The main objective of this study was to investigate the effect of GPR39 activation on tight junction assembly in IECs. Treatment with TC-G 1008 (1 μM -10 μM), a GPR39 agonist, and zinc (10 μM -100 μM) increased tight junction assembly in T84 cells. This effect was suppressed by pretreatment with compound C, an inhibitor of AMP-activated protein kinase (AMPK). In addition, western blot analysis revealed that treatment with TC-G 1008 induced AMPK activation in time- and concentration-dependent manners. Interestingly, inhibitors of phospholipase C (PLC) and calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ) abrogated the effect of TC-G 1008 on inducing AMPK activation, tight junction assembly and zonula occludens-1 re-organization. Collectively, this study reveals a novel role of GPR39 in enhancing tight junction assembly in IECs via PLC-CaMKKβ-AMPK pathways. GPR39 agonists may be beneficial in the treatment of diseases associated impaired intestinal barrier function.
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Affiliation(s)
- Pawin Pongkorpsakol
- Translational Medicine Graduate Program, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand
| | - Chavin Buasakdi
- College of Agricultural and Life Science, University of Wisconsin-Madison, 1450 Linden Dr, Madison, WI 53706, USA
| | - Thanyatorn Chantivas
- Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand
| | - Varanuj Chatsudthipong
- Department of Physiology, Faculty of Science, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand
| | - Chatchai Muanprasat
- Translational Medicine Graduate Program, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand; Excellent Center for Drug Discovery, Faculty of Science, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand; Research Center of Transport Protein for Medical Innovation, Faculty of Science, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand.
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How cellular Zn 2+ signaling drives physiological functions. Cell Calcium 2018; 75:53-63. [PMID: 30145429 DOI: 10.1016/j.ceca.2018.08.004] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 08/16/2018] [Accepted: 08/17/2018] [Indexed: 01/10/2023]
Abstract
Zinc is an essential micronutrient affecting many aspects of human health. Cellular Zn2+ homeostasis is critical for cell function and survival. Zn2+, acting as a first or second messenger, triggers signaling pathways that mediate the physiological roles of Zn2+. Transient changes in Zn2+ concentrations within the cell or in the extracellular region occur following its release from Zn2+ binding metallothioneins, its transport across membranes by the ZnT or ZIP transporters, or release of vesicular Zn2+. These transients activate a distinct Zn2+ sensing receptor, ZnR/GPR39, or modulate numerous proteins and signaling pathways. Importantly, Zn2+ signaling regulates cellular physiological functions such as: proliferation, differentiation, ion transport and secretion. Indeed, novel therapeutic approaches aimed to maintain Zn2+ homeostasis and signaling are evolving. This review focuses on recent findings describing roles of Zn2+ and its transporters in regulating physiological or pathological processes.
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Ventura-Bixenshpaner H, Asraf H, Chakraborty M, Elkabets M, Sekler I, Taylor KM, Hershfinkel M. Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth. Sci Rep 2018; 8:8119. [PMID: 29802348 PMCID: PMC5970167 DOI: 10.1038/s41598-018-26459-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 04/20/2018] [Indexed: 12/14/2022] Open
Abstract
Acquired resistance to the estrogen receptor (ER) antagonist tamoxifen, is a major obstacle in treatment of breast cancer. Changes in Zn2+ accumulation and distribution are associated with tamoxifen-resistance and breast cancer progression. The Zn2+-sensing G-protein coupled receptor, ZnR/GPR39, triggers signaling leading to cell growth, but a role for this receptor in breast cancer in unknown. Using fluorescence imaging, we found Zn2+-dependent Ca2+ release, mediated by ZnR/GPR39 activity, in TAMR tamoxifen-resistant cells derived from MCF-7 cells, but not in ER-expressing MCF-7 or T47D cells. Furthermore, ZnR/GPR39 signaling was monitored in ER negative BT20, MDA-MB-453 and JIMT-1 cells. Expression of ZnR/GPR39 was increased in grade 3 human breast cancer biopsies compared to grade 2. Consistently, analysis of two breast cancer patient cohorts, GDS4057 and TCGA, indicated that in ER-negative tumors higher ZnR/GPR39 mRNA levels are associated with more aggressive tumors. Activation of ZnR/GPR39 in TAMR cells triggered MAPK, mTOR and PI3K signaling. Importantly, enhanced cell growth and invasiveness was observed in the ER negative breast cancer cells, TAMR, MDA-MB-453 and BT20 cells but not in the ER expressing MCF-7 cells. Thus, we suggest ZnR/GPR39 as a potential therapeutic target for combination treatment in breast cancer, particularly relevant in ER negative tumors.
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Affiliation(s)
- Hila Ventura-Bixenshpaner
- Department of Physiology and Cell Biology and The Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Hila Asraf
- Department of Physiology and Cell Biology and The Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Moumita Chakraborty
- Department of Physiology and Cell Biology and The Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Moshe Elkabets
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Israel Sekler
- Department of Physiology and Cell Biology and The Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Kathryn M Taylor
- Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Redwood Building, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK
| | - Michal Hershfinkel
- Department of Physiology and Cell Biology and The Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
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Zhu D, Su Y, Zheng Y, Fu B, Tang L, Qin YX. Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39. Am J Physiol Cell Physiol 2018; 314:C404-C414. [PMID: 29351417 PMCID: PMC5966790 DOI: 10.1152/ajpcell.00279.2017] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 11/28/2017] [Accepted: 12/11/2017] [Indexed: 01/20/2023]
Abstract
Zn2+ is an essential element for cell survival/growth, and its deficiency is linked to many disorders. Extracellular Zn2+ concentration changes participate in modulating fundamental cellular processes such as proliferation, secretion, ion transport, and cell signal transduction in a mechanism that is not well understood. Here, we hypothesize that the Zn2+-sensing receptor ZnR/G protein-coupled receptor 39 (GPR39), found in tissues where dynamic Zn2+ homeostasis takes place, enables extracellular Zn2+ to trigger intracellular signaling pathways regulating key cell functions in vascular cells. Thus, we investigated how extracellular Zn2+ regulates cell viability, proliferation, motility, angiogenesis, vascular tone, and inflammation through ZnR/GPR39 in endothelial cells. Knockdown of GPR39 through siRNA largely abolished Zn2+-triggered cellular activity changes, Ca2+ responses, as well as the downstream activation of Gαq-PLC pathways. Extracellular Zn2+ promoted vascular cell survival/growth through activation of cAMP and Akt as well as overexpressing of platelet-derived growth factor-α receptor and vascular endothelial growth factor A. It also enhanced cell adhesion and mobility, endothelial tubule formation, and cytoskeletal reorganization. Such effects from extracellular Zn2+ were not observed in GPR39-/- endothelial cells. Zn2+ also regulated inflammation-related key molecules such as heme oxygenase-1, selectin L, IL-10, and platelet endothelial cell adhesion molecule 1, as well as vascular tone-related prostaglandin I2 synthase and nitric oxide synthase-3. In sum, extracellular Zn2+ regulates endothelial cell activity in a ZnR/GPR39-dependent manner and through the downstream Gαq-PLC pathways. Thus, ZnR/GPR39 may be a therapeutic target for regulating endothelial activity.
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Affiliation(s)
- Donghui Zhu
- Department of Biomedical Engineering, University of North Texas , Denton, Texas
| | - Yingchao Su
- Department of Biomedical Engineering, University of North Texas , Denton, Texas
| | - Yufeng Zheng
- Department of Materials Science and Engineering, College of Engineering, Peking University , Beijing , China
| | - Bingmei Fu
- Department of Biomedical Engineering, The City College of the City University of New York , New York, New York
| | - Liping Tang
- Department of Bioengineering, University of Texas at Arlington , Arlington, Texas
| | - Yi-Xian Qin
- Department of Biomedical Engineering, State University of New York at Stony Brook , Stony Brook, New York
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