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Vámos E, Vántus VB, Deák P, Kálmán N, Sturm EM, Nayak BB, Makszin L, Loránd T, Gallyas FJ, Radnai B. MIF tautomerase inhibitor TE-11 prevents inflammatory macrophage activation and glycolytic reprogramming while reducing leukocyte migration and improving Crohn's disease-like colitis in male mice. Front Immunol 2025; 16:1558079. [PMID: 40330457 PMCID: PMC12053165 DOI: 10.3389/fimmu.2025.1558079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 03/28/2025] [Indexed: 05/08/2025] Open
Abstract
Background & aims Crohn's disease (CD) is a chronic inflammatory disorder primarily affecting the gastrointestinal tract. Leukocyte recruitment, M1 macrophage polarization and associated metabolic reprogramming are hallmarks of its pathomechanism. Here, we tested TE-11, a potent MIF tautomerase inhibitor (IC50 = 5.63 μmol/dm3) in experimental Crohn's disease in male mice, in leukocyte recruitment and in inflammatory M1 macrophage activation. Methods 2,4,6-trinitrobenzenesulfonic acid-(TNBS)-induced colitis was utilized as a CD-model in male mice. We performed macroscopic scoring and cytokine measurements. We also analyzed MIF-induced leukocyte migration and evaluated apoptosis. LPS+IFN-γ-induced RAW264.7 cells were applied as a M1 macrophage model. We performed qPCR, ROS and nitrite determinations, ELISA measurements, mitochondrial oxygen consumption rate and extracellular acidification rate determinations. Results TE-11 improved mucosal damage, reduced inflammation score and concentration of IL-1β and IL-6 in the colon. It inhibited MIF-induced human blood eosinophil and neutrophil migration and counteracted the anti-apoptotic effect of MIF. In macrophages, MIF inhibition prevented M1 polarization by downregulating HIF-1α gene expression in LPS+IFN-γ-activated cells. Additionally, the molecule reduced mRNA transcription and protein expression of chemokine CCL-2 and cytokine IL-6 while further increasing SOD2 gene transcription and decreased ROS and nitrite production in macrophages. During inflammatory metabolic reprogramming, TE-11 prevented LPS+IFN-γ-induced metabolic shift from OXPHOS to glycolysis. Similarly to anti-inflammatory M2 cells, TE-11 improved mitochondrial energy production by increasing basal respiration, ATP production, coupling efficiency, maximal respiration and spare respiratory capacity. Conclusion Comprehensively, TE-11, a MIF tautomerase inhibitor ameliorates CD-like colitis, reduces MIF-induced eosinophil and neutrophil migration and prevents M1 polarization and associated metabolic reprogramming; therefore, it may prove beneficial as a potential drug candidate regarding CD therapy.
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Affiliation(s)
- Eszter Vámos
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, Hungary
| | - Viola Bagóné Vántus
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Deák
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, Hungary
| | - Nikoletta Kálmán
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, Hungary
| | - Eva Maria Sturm
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Barsha Baisakhi Nayak
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Lilla Makszin
- Institute of Bioanalysis, Medical School, Szentágothai Research Center, University of Pécs, Pécs, Hungary
| | - Tamás Loránd
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, Hungary
| | - Ferenc Jr Gallyas
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, Hungary
| | - Balázs Radnai
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, Hungary
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Jiang W, Yu W, Tan Y. Activation of GPR55 alleviates neuropathic pain and chronic inflammation. Biotechnol Appl Biochem 2025; 72:196-206. [PMID: 39219239 DOI: 10.1002/bab.2656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/03/2024] [Indexed: 09/04/2024]
Abstract
Neuropathic pain (NP) significantly impacts the quality of life due to its prolonged duration and lack of effective treatment. Recent findings suggest that targeting neuroinflammation is a promising approach for treating NP. G protein-coupled receptor 55 (GPR55), a member of the GPCR family, plays an important role in neuroinflammatory regulation. CID16020046, a GPR55 agonist, possesses promising anti-neuroinflammatory effects. Herein, the therapeutic effect of CID16020046 on NP was investigated in an NP rat model. The NP model was established using the unilateral sciatic nerve chronic constriction injury (CCI) assay. Both sham and CCI rats were intraperitoneally administered with 20 mg/kg CID16020046. NP was assessed using paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). First, we showed that GPR55 was downregulated in the spinal dorsal horn of CCI rats. After CCI rats were treated with CID16020046, the values of PWT and PWL were increased, indicating their effect on pain relief. The treated rats had attenuated release of inflammatory cytokines in the spinal cord, decreased spinal malondialdehyde (MDA) levels, and increased spinal glutathione peroxidase (GSH-PX) activity. Additionally, the increased levels of phosphorylated nuclear factor (NF)-κB p65 in CCI rats were significantly alleviated by CID16020046 treatment. Mechanistically, we showed that CID16020046 significantly suppressed the activation of the Janus kinase (JAK2)/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in the spinal cord of CCI-treated rats. However, Colivelin TFA (a STAT3 agonist) abolished the effect of CID16020046 on JAK2/STAT3 activation. In conclusion, our data demonstrate that the activation of GPR55 by CID16020046 alleviates NP and neuroinflammation in CCI rats by mediating the JAK2/STAT3 pathway.
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Affiliation(s)
- Weiqun Jiang
- Department of Anesthesiology, Nanchang First Hospital, Nanchang, Jiangxi, China
| | - Wenbin Yu
- Department of Anesthesiology, Nanchang First Hospital, Nanchang, Jiangxi, China
| | - Yu Tan
- Department of Anesthesiology, Nanchang First Hospital, Nanchang, Jiangxi, China
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Osorio-Perez RM, Cruz SL, Gonzalez-Espinosa C. FcεRI/PLC axis promotes anandamide synthesis and the formation of CB2-GPR55 heteromers, modulating cytokine production in mast cells. Int Immunopharmacol 2025; 146:113891. [PMID: 39732104 DOI: 10.1016/j.intimp.2024.113891] [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: 11/01/2024] [Revised: 12/12/2024] [Accepted: 12/16/2024] [Indexed: 12/30/2024]
Abstract
Mast cells (MC) are crucial effectors in immediate allergic reactions. Monomeric IgE sensitizes MC and triggers various signaling responses. FcεRI/IgE/antigen crosslinking induces the release of several mediators, including bioactive lipids, but little is known about endocannabinoids (eCBs) secretion. Here, we studied the effects of IgE-induced sensitization and FcεRI crosslinking on anandamide (AEA) synthesis and release in bone marrow-derived mast cells (BMMC). Our results showed that mIgE induced AEA secretion through phospholipase C activation. Secreted AEA contributed to p38 phosphorylation induced by mIgE sensitization. Prolonged mIgE sensitization promoted the formation of long-lasting CB2-GPR55 heteromers. FcεRI crosslinking also caused AEA production. Notably, CB2 deficiency increased IL-2 and IL-3 cytokine expression in response to FcɛRI crosslinking. CB2 and GPR55 agonists reduced IL-2 and IL-3 mRNA expression caused by FcεRI activation. Our findings suggest that a) IgE binding to FcɛRI and its antigen-dependent activation leads to an AEA-dependent autocrine regulatory loop that contributes to intracellular signaling in MC and that b) CB2 and GPR55 receptors play a critical role in modulating the effector phase of MC activation by specifically regulating cytokine expression.
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MESH Headings
- Mast Cells/immunology
- Mast Cells/metabolism
- Endocannabinoids/metabolism
- Endocannabinoids/biosynthesis
- Animals
- Receptor, Cannabinoid, CB2/metabolism
- Receptor, Cannabinoid, CB2/genetics
- Arachidonic Acids/metabolism
- Arachidonic Acids/biosynthesis
- Receptors, IgE/metabolism
- Receptors, IgE/immunology
- Polyunsaturated Alkamides/metabolism
- Cytokines/metabolism
- Cytokines/genetics
- Mice, Inbred C57BL
- Mice
- Mice, Knockout
- Type C Phospholipases/metabolism
- Immunoglobulin E/immunology
- Immunoglobulin E/metabolism
- Receptors, Cannabinoid/metabolism
- Cells, Cultured
- Signal Transduction
- Receptors, G-Protein-Coupled/metabolism
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Affiliation(s)
- Rubi M Osorio-Perez
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Sede Sur, Calzada de los Tenorios No. 235, Col. Granjas Coapa, Tlalpan, CP 14330 Mexico City, Mexico
| | - Silvia L Cruz
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Sede Sur, Calzada de los Tenorios No. 235, Col. Granjas Coapa, Tlalpan, CP 14330 Mexico City, Mexico.
| | - Claudia Gonzalez-Espinosa
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Sede Sur, Calzada de los Tenorios No. 235, Col. Granjas Coapa, Tlalpan, CP 14330 Mexico City, Mexico; Centro de Investigación sobre el Envejecimiento, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Sede Sur, Calzada de los Tenorios No. 235, Col. Granjas Coapa, Tlalpan, CP 14330 Mexico City, Mexico.
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Apweiler M, Saliba SW, Sun L, Streyczek J, Normann C, Hellwig S, Bräse S, Fiebich BL. Modulation of neuroinflammation and oxidative stress by targeting GPR55 - new approaches in the treatment of psychiatric disorders. Mol Psychiatry 2024; 29:3779-3788. [PMID: 38796643 PMCID: PMC11609097 DOI: 10.1038/s41380-024-02614-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 05/10/2024] [Accepted: 05/15/2024] [Indexed: 05/28/2024]
Abstract
Pharmacological treatment of psychiatric disorders remains challenging in clinical, pharmacological, and scientific practice. Even if many different substances are established for treating different psychiatric conditions, subgroups of patients show only small or no response to the treatment. The neuroinflammatory hypothesis of the genesis of psychiatric disorders might explain underlying mechanisms in these non-responders. For that reason, recent research focus on neuroinflammatory processes and oxidative stress as possible causes of psychiatric disorders. G-protein coupled receptors (GPCRs) form the biggest superfamily of membrane-bound receptors and are already well known as pharmacological targets in various diseases. The G-protein coupled receptor 55 (GPR55), a receptor considered part of the endocannabinoid system, reveals promising modulation of neuroinflammatory and oxidative processes. Different agonists and antagonists reduce pro-inflammatory cytokine release, enhance the synthesis of anti-inflammatory mediators, and protect cells from oxidative damage. For this reason, GPR55 ligands might be promising compounds in treating subgroups of patients suffering from psychiatric disorders related to neuroinflammation or oxidative stress. New approaches in drug design might lead to new compounds targeting different pathomechanisms of those disorders in just one molecule.
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Affiliation(s)
- Matthias Apweiler
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104, Freiburg, Germany
- Department of Cardiology and Angiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany
| | - Soraya Wilke Saliba
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104, Freiburg, Germany
| | - Lu Sun
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104, Freiburg, Germany
| | - Jana Streyczek
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104, Freiburg, Germany
| | - Claus Normann
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104, Freiburg, Germany
| | - Sabine Hellwig
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104, Freiburg, Germany
| | - Stefan Bräse
- Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, D-76131, Karlsruhe, Germany
- Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, D-76131, Karlsruhe, Germany
| | - Bernd L Fiebich
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104, Freiburg, Germany.
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5
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Son SE, Lee YJ, Shin YJ, Kim DH, Im DS. GPR55 Antagonist CID16020046 Attenuates Obesity-Induced Airway Inflammation by Suppressing Chronic Low-Grade Inflammation in the Lungs. Int J Mol Sci 2024; 25:7358. [PMID: 39000464 PMCID: PMC11242637 DOI: 10.3390/ijms25137358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 06/27/2024] [Accepted: 07/02/2024] [Indexed: 07/16/2024] Open
Abstract
GPR55 is a receptor for lysophosphatidylinositols (LPIs) in digestive metabolites. Overnutrition leads to obesity, insulin resistance, and increased LPI levels in the plasma. The involvement of LPIs and GPR55 in adiposity, hepatic steatosis, and atherosclerosis has been previously elucidated. However, the therapeutic efficacy of GPR55 antagonists against obesity-induced airway inflammation has not been studied. The present study investigated whether CID16020046, a selective antagonist of GPR55, could modulate obesity-induced airway inflammation caused by a high-fat diet (HFD) in C57BL/6 mice. Administration of CID16020046 (1 mg/kg) inhibits HFD-induced adiposity and glucose intolerance. Analysis of immune cells in BALF showed that CID16020046 inhibited HFD-induced increase in immune cell infiltration. Histological analysis revealed the HFD induced hypersecretion of mucus and extensive fibrosis in the lungs. CID16020046 inhibited these HFD-induced pathological features. qRT-PCR revealed the HFD-induced increase in the expression of Ifn-γ, Tnf-α, Il-6, Il-13, Il-17A, Il-1β, Nlrp3, and Mpo mRNAs in the lungs. CID16020046 inhibited the HFD-induced increases in these genes. The expression levels of adipokines were regulated by the HFD and CID16020046. AdipoQ in the lungs and gonadal white adipose tissue was decreased by the HFD and reversed by CID16020046. In contrast, Lep was increased by the HFD and suppressed by CID16020046. The findings suggest the potential application of the GPR55 antagonist CID16020046 in obesity-induced airway inflammation.
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Affiliation(s)
- So-Eun Son
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.-E.S.); (Y.-J.L.); (Y.-J.S.)
| | - Ye-Ji Lee
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.-E.S.); (Y.-J.L.); (Y.-J.S.)
| | - Yoon-Jung Shin
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.-E.S.); (Y.-J.L.); (Y.-J.S.)
| | - Dong-Hyun Kim
- Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Dong-Soon Im
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.-E.S.); (Y.-J.L.); (Y.-J.S.)
- Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea;
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Sun L, Apweiler M, Normann C, Grathwol CW, Hurrle T, Gräßle S, Jung N, Bräse S, Fiebich BL. Anti-Inflammatory Effects of GPR55 Agonists and Antagonists in LPS-Treated BV2 Microglial Cells. Pharmaceuticals (Basel) 2024; 17:674. [PMID: 38931342 PMCID: PMC11206594 DOI: 10.3390/ph17060674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/19/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Chronic inflammation is driven by proinflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and chemokines, such as c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10. Inflammatory processes of the central nervous system (CNS) play an important role in the pathogenesis of various neurological and psychiatric disorders like Alzheimer's disease, Parkinson's disease, and depression. Therefore, identifying novel anti-inflammatory drugs may be beneficial for treating disorders with a neuroinflammatory background. The G-protein-coupled receptor 55 (GPR55) gained interest due to its role in inflammatory processes and possible involvement in different disorders. This study aims to identify the anti-inflammatory effects of the coumarin-based compound KIT C, acting as an antagonist with inverse agonistic activity at GPR55, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells in comparison to the commercial GPR55 agonist O-1602 and antagonist ML-193. All compounds significantly suppressed IL-6, TNF-α, CCL2, CCL3, CXCL2, and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compounds are partially explained by modulation of the phosphorylation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC) pathways, and the transcription factor nuclear factor (NF)-κB, respectively. Due to its potent anti-inflammatory properties, KIT C is a promising compound for further research and potential use in inflammatory-related disorders.
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Affiliation(s)
- Lu Sun
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104 Freiburg, Germany; (L.S.); (M.A.)
| | - Matthias Apweiler
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104 Freiburg, Germany; (L.S.); (M.A.)
| | - Claus Normann
- Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104 Freiburg, Germany;
| | - Christoph W. Grathwol
- Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, D-76131 Karlsruhe, Germany; (C.W.G.); (T.H.); (S.G.); (N.J.); (S.B.)
| | - Thomas Hurrle
- Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, D-76131 Karlsruhe, Germany; (C.W.G.); (T.H.); (S.G.); (N.J.); (S.B.)
- Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, D-76131 Karlsruhe, Germany
| | - Simone Gräßle
- Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, D-76131 Karlsruhe, Germany; (C.W.G.); (T.H.); (S.G.); (N.J.); (S.B.)
| | - Nicole Jung
- Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, D-76131 Karlsruhe, Germany; (C.W.G.); (T.H.); (S.G.); (N.J.); (S.B.)
- Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, D-76131 Karlsruhe, Germany
| | - Stefan Bräse
- Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, D-76131 Karlsruhe, Germany; (C.W.G.); (T.H.); (S.G.); (N.J.); (S.B.)
- Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, D-76131 Karlsruhe, Germany
| | - Bernd L. Fiebich
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104 Freiburg, Germany; (L.S.); (M.A.)
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Wang X, Zhang H, Liu Y, Xu Y, Yang B, Li H, Chen L. An overview on synthetic and biological activities of cannabidiol (CBD) and its derivatives. Bioorg Chem 2023; 140:106810. [PMID: 37659147 DOI: 10.1016/j.bioorg.2023.106810] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/04/2023]
Abstract
(-)-Cannabidiol is a class of non-psychoactive plant cannabinoids derived from cannabis plants. Currently, Epidiolex (Cannabidiol) has been approved by the FDA for the treatment of two rare and severe forms of epilepsy related diseases, namely Lennox-Gastaut syndrome (LGS) and Dravet (DS). In addition, Cannabidiol and its structural analogues have received increasing attention due to their potential therapeutic effects such as neuroprotection, anti-epilepsy, anti-inflammation, anti-anxiety, and anti-cancer. Based on literature review, no comprehensive reviews on the synthesis of Cannabidiol and its derivatives have been found in recent years. Therefore, this article summarizes the published synthesis methods of Cannabidiol and the synthesis routes of Cannabidiol derivatives, and introduces the biological activities of some Cannabidiol analogues that have been studied extensively and have significant activities.
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Affiliation(s)
- Xiuli Wang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Huanbang Zhang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yan Liu
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Heilongjiang 150006, China
| | - Yang Xu
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Bingyou Yang
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Heilongjiang 150006, China.
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
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Diet-Induced Gut Barrier Dysfunction Is Exacerbated in Mice Lacking Cannabinoid 1 Receptors in the Intestinal Epithelium. Int J Mol Sci 2022; 23:ijms231810549. [PMID: 36142461 PMCID: PMC9504303 DOI: 10.3390/ijms231810549] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/23/2022] [Accepted: 09/09/2022] [Indexed: 11/29/2022] Open
Abstract
The gut barrier provides protection from pathogens and its function is compromised in diet-induced obesity (DIO). The endocannabinoid system in the gut is dysregulated in DIO and participates in gut barrier function; however, whether its activity is protective or detrimental for gut barrier integrity is unclear. We used mice conditionally deficient in cannabinoid receptor subtype-1 (CB1R) in the intestinal epithelium (intCB1−/−) to test the hypothesis that CB1Rs in intestinal epithelial cells provide protection from diet-induced gut barrier dysfunction. Control and intCB1−/− mice were placed for eight weeks on a high-fat/sucrose Western-style diet (WD) or a low-fat/no-sucrose diet. Endocannabinoid levels and activity of their metabolic enzymes were measured in the large-intestinal epithelium (LI). Paracellular permeability was tested in vivo, and expression of genes for gut barrier components and inflammatory markers were analyzed. Mice fed WD had (i) reduced levels of endocannabinoids in the LI due to lower activity of their biosynthetic enzymes, and (ii) increased permeability that was exacerbated in intCB1−/− mice. Moreover, intCB1−/− mice fed WD had decreased expression of genes for tight junction proteins and increased expression of inflammatory markers in LI. These results suggest that CB1Rs in the intestinal epithelium serve a protective role in gut barrier function in DIO.
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Srivastava RK, Lutz B, Ruiz de Azua I. The Microbiome and Gut Endocannabinoid System in the Regulation of Stress Responses and Metabolism. Front Cell Neurosci 2022; 16:867267. [PMID: 35634468 PMCID: PMC9130962 DOI: 10.3389/fncel.2022.867267] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/14/2022] [Indexed: 11/26/2022] Open
Abstract
The endocannabinoid system, with its receptors and ligands, is present in the gut epithelium and enteroendocrine cells, and is able to modulate brain functions, both indirectly through circulating gut-derived factors and directly through the vagus nerve, finally acting on the brain’s mechanisms regarding metabolism and behavior. The gut endocannabinoid system also regulates gut motility, permeability, and inflammatory responses. Furthermore, microbiota composition has been shown to influence the activity of the endocannabinoid system. This review examines the interaction between microbiota, intestinal endocannabinoid system, metabolism, and stress responses. We hypothesize that the crosstalk between microbiota and intestinal endocannabinoid system has a prominent role in stress-induced changes in the gut-brain axis affecting metabolic and mental health. Inter-individual differences are commonly observed in stress responses, but mechanisms underlying resilience and vulnerability to stress are far from understood. Both gut microbiota and the endocannabinoid system have been implicated in stress resilience. We also discuss interventions targeting the microbiota and the endocannabinoid system to mitigate metabolic and stress-related disorders.
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Affiliation(s)
- Raj Kamal Srivastava
- Department of Zoology, Indira Gandhi National Tribal University, Anuppur, India
- *Correspondence: Raj Kamal Srivastava,
| | - Beat Lutz
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- Leibniz Institute for Resilience Research (LIR), Mainz, Germany
| | - Inigo Ruiz de Azua
- Leibniz Institute for Resilience Research (LIR), Mainz, Germany
- Inigo Ruiz de Azua,
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10
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Chen R, Xu H, Guo Z, Zhang P, Chen J, Chen Z. CID16020046, a GPR55 antagonist, attenuates sepsis‑induced acute kidney injury. Mol Med Rep 2022; 25:155. [PMID: 35244189 PMCID: PMC8941374 DOI: 10.3892/mmr.2022.12671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/17/2021] [Indexed: 11/06/2022] Open
Abstract
Acute kidney injury (AKI) is the most common and serious complication of sepsis, and it is also the main cause of mortality in patients with sepsis. The G protein‑coupled receptor 55 (GPR55) inhibitor CID16020046 was found to suppress the inflammatory response in sepsis models in mice. The aim of the present study was to investigate the effect of CID16020046 on AKI in sepsis mouse models and elucidate the possible underlying mechanisms. A sepsis model in mice was established by cecal ligation/perforation (CLP). The expression levels of GPR55 in the serum of patients with sepsis and the renal tissues of septic mice were determined via reverse transcription‑quantitative PCR and western blot analyses, respectively. The pathological injury of renal tissue was evaluated using H&E and periodic acid‑Schiff staining. ELISA was performed to detect the levels of renal injury‑related factors, including blood urea nitrogen (BUN), creatinine (Cre), kidney injury molecule 1 (KIM1) and neutrophil gelatinase‑associated lipocalin (NGAL) in septic mice. Moreover, the levels of pro‑inflammatory cytokines (TNF‑α, IL‑6 and IL‑1β) were detected via ELISA and western blotting. Apoptosis was determined using TUNEL staining and western blotting. The expression levels of Rho‑associated protein kinase (ROCK) pathway‑related proteins (Ras homolog family member A, ROCK1 and ROCK2) was measured via western blotting. Finally, H&E staining was used to evaluate the effect of CID16020046 on various organs in mice. Compared with the control subjects, the expression level of GPR55 in the serum of patients with sepsis was significantly increased. Compared with the sham group, CID16020046 (20 mg/kg) significantly decreased the levels of BUN and Cre in the serum, as well as the contents of KIM1 and NGAL in the urine. Furthermore, CID16020046 significantly decreased the contents of TNF‑α, IL‑6 and IL‑1β in the serum and renal tissue of septic mice, and reduced cell apoptosis. In addition, CID16020046 effectively suppressed the expression levels of ROCK pathway‑related proteins, and H&E staining revealed that CID16020046 (20 mg/kg) had no toxic effect on the heart, liver, spleen or lung in normal mice. In conclusion, CID16020046 may prove useful for the development of drugs for the treatment of sepsis‑induced AKI.
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Affiliation(s)
- Rongxin Chen
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
| | - Hailin Xu
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
| | - Zebin Guo
- Department of Intensive Care Unit, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
| | - Peng Zhang
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
| | - Jianxia Chen
- Department of Intensive Care Unit, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
| | - Zheng Chen
- Organ Transplant Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
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11
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Functional Selectivity of Coumarin Derivates Acting via GPR55 in Neuroinflammation. Int J Mol Sci 2022; 23:ijms23020959. [PMID: 35055142 PMCID: PMC8779649 DOI: 10.3390/ijms23020959] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/09/2022] [Accepted: 01/13/2022] [Indexed: 12/22/2022] Open
Abstract
Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Clinical studies demonstrate a reduction of the mentioned diseases’ symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE2-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE2-levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis.
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12
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Hryhorowicz S, Kaczmarek-Ryś M, Zielińska A, Scott RJ, Słomski R, Pławski A. Endocannabinoid System as a Promising Therapeutic Target in Inflammatory Bowel Disease - A Systematic Review. Front Immunol 2021; 12:790803. [PMID: 35003109 PMCID: PMC8727741 DOI: 10.3389/fimmu.2021.790803] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/29/2021] [Indexed: 12/20/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a general term used to describe a group of chronic inflammatory conditions of the gastrointestinal tract of unknown etiology, including two primary forms: Crohn's disease (CD) and ulcerative colitis (UC). The endocannabinoid system (ECS) plays an important role in modulating many physiological processes including intestinal homeostasis, modulation of gastrointestinal motility, visceral sensation, or immunomodulation of inflammation in IBD. It consists of cannabinoid receptors (CB1 and CB2), transporters for cellular uptake of endocannabinoid ligands, endogenous bioactive lipids (Anandamide and 2-arachidonoylglycerol), and the enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), the manipulation of which through agonists and antagonists of the system, shows a potential therapeutic role for ECS in inflammatory bowel disease. This review summarizes the role of ECS components on intestinal inflammation, suggesting the advantages of cannabinoid-based therapies in inflammatory bowel disease.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/pharmacology
- Anti-Inflammatory Agents/therapeutic use
- Cannabinoid Receptor Agonists/pharmacology
- Cannabinoid Receptor Agonists/therapeutic use
- Cannabinoid Receptor Antagonists/pharmacology
- Cannabinoid Receptor Antagonists/therapeutic use
- Colitis, Ulcerative/drug therapy
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/pathology
- Crohn Disease/drug therapy
- Crohn Disease/immunology
- Crohn Disease/pathology
- Disease Models, Animal
- Drug Evaluation, Preclinical
- Endocannabinoids/agonists
- Endocannabinoids/antagonists & inhibitors
- Endocannabinoids/metabolism
- Gastrointestinal Motility/drug effects
- Humans
- Intestinal Mucosa/drug effects
- Intestinal Mucosa/immunology
- Intestinal Mucosa/pathology
- Randomized Controlled Trials as Topic
- Receptor, Cannabinoid, CB1/agonists
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Cannabinoid, CB2/agonists
- Receptor, Cannabinoid, CB2/antagonists & inhibitors
- Receptor, Cannabinoid, CB2/metabolism
- Signal Transduction/drug effects
- Signal Transduction/immunology
- Treatment Outcome
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Affiliation(s)
| | | | | | - Rodney J. Scott
- Discipline of Medical Genetics and Centre for Information-Based Medicine, The University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW, Australia
- Division of Molecular Medicine, New South Wales Health Pathology North, Newcastle, NSW, Australia
| | - Ryszard Słomski
- Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland
| | - Andrzej Pławski
- Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland
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13
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Wnorowski A, Wójcik J, Maj M. Gene Expression Data Mining Reveals the Involvement of GPR55 and Its Endogenous Ligands in Immune Response, Cancer, and Differentiation. Int J Mol Sci 2021; 22:ijms222413328. [PMID: 34948125 PMCID: PMC8707311 DOI: 10.3390/ijms222413328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/05/2021] [Accepted: 12/08/2021] [Indexed: 12/04/2022] Open
Abstract
G protein-coupled receptor 55 (GPR55) is a recently deorphanized lipid- and peptide-sensing receptor. Its lipidic endogenous agonists belong to lysoglycerophospholipids, with lysophosphatidylinositol (LPI) being the most studied. Peptide agonists derive from fragmentation of pituitary adenylate cyclase-activating polypeptide (PACAP). Although GPR55 and its ligands were implicated in several physiological and pathological conditions, their biological function remains unclear. Thus, the aim of the study was to conduct a large-scale re-analysis of publicly available gene expression datasets to identify physiological and pathological conditions affecting the expression of GPR55 and the production of its ligands. The study revealed that regulation of GPR55 occurs predominantly in the context of immune activation pointing towards the role of the receptor in response to pathogens and in immune cell lineage determination. Additionally, it was revealed that there is almost no overlap between the experimental conditions affecting the expression of GPR55 and those modulating agonist production. The capacity to synthesize LPI was enhanced in various types of tumors, indicating that cancer cells can hijack the motility-related activity of GPR55 to increase aggressiveness. Conditions favoring accumulation of PACAP-derived peptides were different than those for LPI and were mainly related to differentiation. This indicates a different function of the two agonist classes and possibly the existence of a signaling bias.
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14
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Lian J, Casari I, Falasca M. Modulatory role of the endocannabinoidome in the pathophysiology of the gastrointestinal tract. Pharmacol Res 2021; 175:106025. [PMID: 34883211 DOI: 10.1016/j.phrs.2021.106025] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/29/2021] [Accepted: 12/05/2021] [Indexed: 12/13/2022]
Abstract
Originating from Eastern Asia, the plant Cannabis sativa has been used for centuries as a medicinal treatment. The unwanted psychotropic effects of one of its major components, Δ9-tetrahydrocannabinol, discouraged its therapeutic employment until, recently, the discovery of cannabinoids receptors and their endogenous ligands endocannabinoids reignited the interest. The endocannabinoid system has lately been found to play an important role in the maintenance of human health, both centrally and peripherally. However, the initial idea of the endocannabinoid system structure has been quickly understood to be too simplistic and, as new receptors, mediators, and enzymes have been discovered to participate in a complex relationship, the new, more comprehensive term "expanded endocannabinoid system" or "endocannabinoidome", has taken over. The discovery of other endocannabinoid-like receptors, such as the G protein-coupled receptor 119 and G protein-coupled receptor 55, has opened the way to the development of potential therapeutic targets for the treatment of various metabolic disorders. In addition, recent findings have also provided evidence suggesting the potential therapeutic link between the endocannabinoidome and various inflammatory-based gut diseases, such as inflammatory bowel disease and cancer. This review will provide an introduction to the endocannabinoidome, focusing on its modulatory role in the gastrointestinal tract and on the interest generated by the link between gut microbiota, the endocannabinoid system and metabolic diseases such as inflammatory bowel disease, type-2 diabetes and obesity. In addition, we will look at the potential novel aspects and benefits of drugs targeting the endocannabinoid system.
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Affiliation(s)
- Jerome Lian
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Ilaria Casari
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia.
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15
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Zaiachuk M, Pryimak N, Kovalchuk O, Kovalchuk I. Cannabinoids, Medical Cannabis, and Colorectal Cancer Immunotherapy. Front Med (Lausanne) 2021; 8:713153. [PMID: 34631734 PMCID: PMC8497796 DOI: 10.3389/fmed.2021.713153] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 08/24/2021] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer is a major public health problem. Unfortunately, currently, no effective curative option exists for this type of malignancy. The most promising cancer treatment nowadays is immunotherapy which is also called biological or targeted therapy. This type of therapy boosts the patient's immune system ability to fight the malignant tumor. However, cancer cells may become resistant to immunotherapy and escape immune surveillance by obtaining genetic alterations. Therefore, new treatment strategies are required. In the recent decade, several reports suggest the effectiveness of cannabinoids and Cannabis sativa extracts for inhibiting cancer proliferation in vitro and in vivo, including intestinal malignancies. Cannabinoids were shown to modulate the pathways involved in cell proliferation, angiogenesis, programmed cell death and metastasis. Because of that, they are proposed as adjunct therapy for many malignancies. By far less information exists on the potential of the use of cannabis in combination with immunotherapy. Here, we explore the possibility of the use of cannabinoids for modulation of immunotherapy of colon cancer and discuss possible advantages and limitations.
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Affiliation(s)
| | | | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada
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16
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Kovács D, Vántus VB, Vámos E, Kálmán N, Schicho R, Gallyas F, Radnai B. Olaparib: A Clinically Applied PARP Inhibitor Protects from Experimental Crohn's Disease and Maintains Barrier Integrity by Improving Bioenergetics through Rescuing Glycolysis in Colonic Epithelial Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:7308897. [PMID: 34567413 PMCID: PMC8457969 DOI: 10.1155/2021/7308897] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 08/24/2021] [Indexed: 01/03/2023]
Abstract
Crohn's disease (CD) is an inflammatory disorder of the intestines characterized by epithelial barrier dysfunction and mucosal damage. The activity of poly(ADP-ribose) polymerase-1 (PARP-1) is deeply involved in the pathomechanism of inflammation since it leads to energy depletion and mitochondrial failure in cells. Focusing on the epithelial barrier integrity and bioenergetics of epithelial cells, we investigated whether the clinically applied PARP inhibitor olaparib might improve experimental CD. We used the oral PARP inhibitor olaparib in the 2,4,6-trinitrobenzene sulfonic acid- (TNBS-) induced mouse colitis model. Inflammatory scoring, cytokine levels, colon histology, hematological analysis, and intestinal permeability were studied. Caco-2 monolayer culture was utilized as an epithelial barrier model, on which we used qPCR and light microscopy imaging, and measured impedance-based barrier integrity, FITC-dextran permeability, apoptosis, mitochondrial oxygen consumption rate, and extracellular acidification rate. Olaparib reduced the inflammation score, the concentration of IL-1β and IL-6, enhanced the level of IL-10, and decreased the intestinal permeability in TNBS-colitis. Blood cell ratios, such as lymphocyte to monocyte ratio, platelet to lymphocyte ratio, and neutrophil to lymphocyte ratio were improved. In H2O2-treated Caco-2 monolayer, olaparib decreased morphological changes, barrier permeability, and preserved barrier integrity. In oxidative stress, olaparib enhanced glycolysis (extracellular acidification rate), and it improved mitochondrial function (mitochondrial coupling efficiency, maximal respiration, and spare respiratory capacity) in epithelial cells. Olaparib, a PARP inhibitor used in human cancer therapy, improved experimental CD and protected intestinal barrier integrity by preventing its energetic collapse; therefore, it could be repurposed for the therapy of Crohn's disease.
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Affiliation(s)
- Dominika Kovács
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Viola Bagóné Vántus
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Eszter Vámos
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Nikoletta Kálmán
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Rudolf Schicho
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria
- BioTechMed, 8010 Graz, Austria
| | - Ferenc Gallyas
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary
- Szentagothai Research Centre, University of Pecs, 7624 Pecs, Hungary
- HAS-UP Nuclear-Mitochondrial Interactions Research Group, 1245 Budapest, Hungary
| | - Balázs Radnai
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 7624 Pécs, Hungary
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17
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Melatonin Attenuates Dextran Sodium Sulfate Induced Colitis in Obese Mice. Pharmaceuticals (Basel) 2021; 14:ph14080822. [PMID: 34451919 PMCID: PMC8399719 DOI: 10.3390/ph14080822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 01/03/2023] Open
Abstract
Epidemiological studies have indicated that obesity is an independent risk factor for colitis and that a high-fat diet (HFD) increases the deterioration of colitis-related indicators in mice. Melatonin has multiple anti-inflammatory effects, including inhibiting tumor growth and regulating immune defense. However, the mechanism of its activity in ameliorating obesity-promoted colitis is still unclear. This study explored the possibility that melatonin has beneficial functions in HFD-induced dextran sodium sulfate (DSS)-induced colitis in mice. Here, we revealed that HFD-promoted obesity accelerated DSS-induced colitis, while melatonin intervention improved colitis. Melatonin significantly alleviated inflammation by increasing anti-inflammatory cytokine release and reducing the levels of proinflammatory cytokines in HFD- and DSS-treated mice. Furthermore, melatonin expressed antioxidant activities and reversed intestinal barrier integrity, resulting in improved colitis in DSS-treated obese mice. We also found that melatonin could reduce the ability of inflammatory cells to utilize fatty acids and decrease the growth-promoting effect of lipids by inhibiting autophagy. Taken together, our study indicates that the inhibitory effect of melatonin on autophagy weakens the lipid-mediated prosurvival advantage, which suggests that melatonin-targeted autophagy may provide an opportunity to prevent colitis in obese individuals.
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18
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Kurano M, Kobayashi T, Sakai E, Tsukamoto K, Yatomi Y. Lysophosphatidylinositol, especially albumin-bound form, induces inflammatory cytokines in macrophages. FASEB J 2021; 35:e21673. [PMID: 34042213 DOI: 10.1096/fj.202100245r] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/23/2021] [Accepted: 05/03/2021] [Indexed: 12/12/2022]
Abstract
Lysophosphatidylinositol (LPI) is a glycero-lysophospholipid and a natural agonist against GPR55. The roles of the LPI/GPR55 axis in the pathogenesis of inflammation have been controversial. In the present study, we attempted to elucidate the roles of the LPI/GPR55 axis in inflammation, especially the secretion of inflammatory cytokines, IL-6 and TNF-α from macrophages. We treated RAW264.7 cells and mouse peritoneal macrophages (MPMs) with LPI and observed that LPI induced the secretion of IL-6 and TNF-α from these cells, as well as the phosphorylation of p38. These responses were inhibited by treatment with CID16020046 (CID), an antagonist against GPR55, or SB202190, an inhibitor of p38 cascade or knockdown of GPR55 with siRNA. Treatment with CID or ML-193, another antagonist against GPR55, attenuated the elevation of inflammatory cytokines in the plasma or tissue of db/db mice and in a septic mouse model induced using lipopolysaccharide, suggesting contributions to the improvement of insulin resistance and protection against organ injuries by treatment with CID or ML-193, respectively. In human subjects, although the serum LPI levels were not different, the levels of LPI in the lipoprotein fractions were lower and the levels in the lipoprotein-depleted fractions were higher in subjects with diabetes. LPI bound to albumin induced the secretion of IL-6 and TNF-α from RAW264.7 cells to a greater degree than LPI bound to LDL or HDL. These results suggest that LPI, especially the albumin-bound form, induced inflammatory cytokines depending on the GPR55/p38 pathway, which might contribute to the pathogenesis of obesity-induced inflammation and acute inflammation.
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Affiliation(s)
- Makoto Kurano
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
| | - Tamaki Kobayashi
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
| | - Eri Sakai
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
| | - Kazuhisa Tsukamoto
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
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19
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Osafo N, Yeboah OK, Antwi AO. Endocannabinoid system and its modulation of brain, gut, joint and skin inflammation. Mol Biol Rep 2021; 48:3665-3680. [PMID: 33909195 DOI: 10.1007/s11033-021-06366-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023]
Abstract
The discovery of endogenous cannabinoid receptors CB1 and CB2 and their endogenous ligands has generated interest in the endocannabinoid system and has contributed to the understanding of the role of the endocannabinoid system. Its role in the normal physiology of the body and its implication in pathological states such as cardiovascular diseases, neoplasm, depression and pain have been subjects of scientific interest. In this review the authors focus on the endogenous cannabinoids, and the critical role of cannabinoid receptor signaling in neurodegeneration and other inflammatory responses such as gut, joint and skin inflammation. This review also discusses the potential of endocannabinoid pathways as drug targets in the amelioration of some inflammatory conditions. Though the exact role of the endocannabinoid system is not fully understood, the evidence found much clearly points to a great potential in exploiting both its central and peripheral pathways in disease management. Cannabinoid therapy has proven promising in several preclinical and clinical trials.
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Affiliation(s)
- Newman Osafo
- Department of Pharmacology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
| | - Oduro K Yeboah
- Department of Pharmacology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Aaron O Antwi
- Department of Pharmacology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
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20
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Chalhoub G, Kolleritsch S, Maresch LK, Taschler U, Pajed L, Tilp A, Eisner H, Rosina P, Kien B, Radner FPW, Schicho R, Oberer M, Schoiswohl G, Haemmerle G. Carboxylesterase 2 proteins are efficient diglyceride and monoglyceride lipases possibly implicated in metabolic disease. J Lipid Res 2021; 62:100075. [PMID: 33872605 PMCID: PMC8131317 DOI: 10.1016/j.jlr.2021.100075] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 04/12/2021] [Accepted: 04/12/2021] [Indexed: 12/31/2022] Open
Abstract
Carboxylesterase 2 (CES2/Ces2) proteins exert established roles in (pro)drug metabolism. Recently, human and murine CES2/Ces2c have been discovered as triglyceride (TG) hydrolases implicated in the development of obesity and fatty liver disease. The murine Ces2 family consists of seven homologous genes as opposed to a single CES2 gene in humans. However, the mechanistic role of Ces2 protein family members is not completely understood. In this study, we examined activities of all Ces2 members toward TGs, diglycerides (DGs), and monoglycerides (MGs) as the substrate. Besides CES2/Ces2c, we measured significant TG hydrolytic activities for Ces2a, Ces2b, and Ces2e. Notably, these Ces2 members and CES2 efficiently hydrolyzed DGs and MGs, and their activities even surpassed those measured for TG hydrolysis. The localization of CES2/Ces2c proteins at the ER may implicate a role of these lipases in lipid signaling pathways. We found divergent expression of Ces2 genes in the liver and intestine of mice on a high-fat diet, which could relate to changes in lipid signaling. Finally, we demonstrate reduced CES2 expression in the colon of patients with inflammatory bowel disease and a similar decline in Ces2 expression in the colon of a murine colitis model. Together, these results demonstrate that CES2/Ces2 members are highly efficient DG and MG hydrolases that may play an important role in liver and gut lipid signaling.
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Affiliation(s)
- Gabriel Chalhoub
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | | | - Lisa K Maresch
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Ulrike Taschler
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Laura Pajed
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Anna Tilp
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Helgit Eisner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Philipp Rosina
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Benedikt Kien
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Franz P W Radner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Rudolf Schicho
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Monika Oberer
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | | | - Guenter Haemmerle
- Institute of Molecular Biosciences, University of Graz, Graz, Austria.
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21
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Mpofu R, Otwombe K, Mlisana K, Nchabeleng M, Allen M, Kublin J, McElrath MJ, Bekker LG, Churchyard G, Gray G, Laher F. Benign ethnic neutropenia in a South African population, and its association with HIV acquisition and adverse event reporting in an HIV vaccine clinical trial. PLoS One 2021; 16:e0241708. [PMID: 33481787 PMCID: PMC7822320 DOI: 10.1371/journal.pone.0241708] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 10/18/2020] [Indexed: 11/18/2022] Open
Abstract
Benign ethnic neutropenia (BEN) is defined as a neutrophil count of <1.5×109 cells/L in healthy individuals and is more common in populations of certain ethnicities, e.g. African or Middle Eastern ethnicity. Neutrophil values are commonly included in eligibility criteria for research participation, but little is known about the relationship between BEN, HIV acquisition, and the occurrence of adverse events during clinical trials. We investigated these relationships using data from an HIV vaccine efficacy trial of healthy adults from 5 South African sites. We analysed data from the double-blind, placebo-controlled, randomized trial HVTN 503, and its follow-on study HVTN 503-S to assess the prevalence of BEN, its association with HIV infection, and adverse event reporting. These data were then compared with a time- and age-matched, non-pregnant cohort from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007-2008 in the United States (US). The 739 South African participants had a median age of 22.0 years (interquartile range = 20-26) and 56% (n = 412) were male. Amongst the US cohort of 845 participants, the median age was 26 (IQR: 21-30) and the majority (54%, 457/745) were also male. BEN was present at enrolment in 7.0% (n = 52) of South African participants (6% in the placebo group versus 8% in the vaccine group); 81% (n = 42) of those with BEN were male. Pretoria North had the highest prevalence of BEN (11.6%, 5/43), while Cape Town had the lowest (0.7%, 1/152). Participants with BEN had a lower median neutrophil count (1.3 vs. 3.2x109 cells/L; p<0.001) and BMI (20.8 vs. 22.3 kg/m2; p<0.001) when compared to those without BEN. A greater proportion of Black South Africans had neutrophil counts <1.5×109 cells/L compared to US non-Hispanic Whites from the NHANES cohort (7% [52/739] vs. 0.6% [3/540]; p<0.001). BEN did not increase the odds for HIV infection (adjusted odds ratio [aOR]: 1.364, 95% confidence interval [95% CI]: 0.625-2.976; p = 0.4351). However, female gender (aOR: 1.947, 95% CI: 1.265-2.996; p = 0.0025) and cannabis use (aOR: 2.192, 95% CI: 1.126-4.266; p = 0.0209) increased the odds of HIV acquisition. The incidence rates of adverse events were similar between participants in the placebo group with BEN, and those without: 12.1 (95% CI: 7.3-20.1) vs. 16.5 (95% CI: 14.6-18.7; p = 0.06) events per 100 person-years (py) were noted in the infections and infestations system organ class, respectively. The vaccine group had an event incidence rate of 19.7 (95% CI: 13.3-29.2) vs. 14.8 (95% CI: 13.0-16.8; p = 0.07) events per 100py in the group with, and without BEN, respectively. BEN is more prevalent in Black South Africans compared to US Non-Hispanic Whites. Our data do not support excluding populations from HIV vaccine trials because of BEN. BEN was not associated with increased risk for HIV infection or Adverse events on a vaccine trial. Predictors of HIV infection risk were females and cannabis use, underlying the continued importance of prevention programmes in focusing on these populations.
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Affiliation(s)
- Rephaim Mpofu
- Faculty of Health Sciences, Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa
- Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Kennedy Otwombe
- Faculty of Health Sciences, Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa
- Faculty of Health Sciences, School of Public Health, University of the Witwatersrand, Johannesburg, South Africa
| | - Koleka Mlisana
- National Health Laboratory Service (NHLS), Cape Town, South Africa
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Johannesburg, South Africa
| | - Maphoshane Nchabeleng
- Mecru Clinical Research Unit, Sefako Makgatho Health Sciences University, Pretoria, South Africa
| | - Mary Allen
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - James Kublin
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - M. Juliana McElrath
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Linda-Gail Bekker
- Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa
| | | | - Glenda Gray
- Faculty of Health Sciences, Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa
- South African Medical Research Council, Cape Town, South Africa
| | - Fatima Laher
- Faculty of Health Sciences, Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa
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22
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Im DS. GPR119 and GPR55 as Receptors for Fatty Acid Ethanolamides, Oleoylethanolamide and Palmitoylethanolamide. Int J Mol Sci 2021; 22:ijms22031034. [PMID: 33494185 PMCID: PMC7864322 DOI: 10.3390/ijms22031034] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/15/2021] [Accepted: 01/15/2021] [Indexed: 02/06/2023] Open
Abstract
Oleoylethanolamide and palmitoylethanolamide are members of the fatty acid ethanolamide family, also known as acylethanolamides. Their physiological effects, including glucose homeostasis, anti-inflammation, anti-anaphylactic, analgesia, and hypophagia, have been reported. They have affinity for different receptor proteins, including nuclear receptors such as PPARα, channels such as TRPV1, and membrane receptors such as GPR119 and GPR55. In the present review, the pathophysiological functions of fatty acid ethanolamides have been discussed from the perspective of receptor pharmacology and drug discovery.
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Affiliation(s)
- Dong-Soon Im
- Laboratory of Pharmacology, College of Pharmacy, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea; ; Tel.: +82-2-961-9377; Fax: +82-2-961-9580
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
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23
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The Role of Atypical Cannabinoid Ligands O-1602 and O-1918 on Skeletal Muscle Homeostasis with a Focus on Obesity. Int J Mol Sci 2020; 21:ijms21165922. [PMID: 32824681 PMCID: PMC7460607 DOI: 10.3390/ijms21165922] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/28/2020] [Accepted: 08/13/2020] [Indexed: 11/17/2022] Open
Abstract
O-1602 and O-1918 are atypical cannabinoid ligands for GPR55 and GPR18, which may be novel pharmaceuticals for the treatment of obesity by targeting energy homeostasis regulation in skeletal muscle. This study aimed to determine the effect of O-1602 or O-1918 on markers of oxidative capacity and fatty acid metabolism in the skeletal muscle. Diet-induced obese (DIO) male Sprague Dawley rats were administered a daily intraperitoneal injection of O-1602, O-1918 or vehicle for 6 weeks. C2C12 myotubes were treated with O-1602 or O-1918 and human primary myotubes were treated with O-1918. GPR18 mRNA was expressed in the skeletal muscle of DIO rats and was up-regulated in red gastrocnemius when compared with white gastrocnemius. O-1602 had no effect on mRNA expression on selected markers for oxidative capacity, fatty acid metabolism or adiponectin signalling in gastrocnemius from DIO rats or in C2C12 myotubes, while APPL2 mRNA was up-regulated in white gastrocnemius in DIO rats treated with O-1918. In C2C12 myotubes treated with O-1918, PGC1α, NFATc1 and PDK4 mRNA were up-regulated. There were no effects of O-1918 on mRNA expression in human primary myotubes derived from obese and obese T2DM individuals. In conclusion, O-1602 does not alter mRNA expression of key pathways important for skeletal muscle energy homeostasis in obesity. In contrast, O-1918 appears to alter markers of oxidative capacity and fatty acid metabolism in C2C12 myotubes only. GPR18 is expressed in DIO rat skeletal muscle and future work could focus on selectively modulating GPR18 in a tissue-specific manner, which may be beneficial for obesity-targeted therapies.
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24
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Wróbel A, Serefko A, Szopa A, Ulrich D, Poleszak E, Rechberger T. O-1602, an Agonist of Atypical Cannabinoid Receptors GPR55, Reverses the Symptoms of Depression and Detrusor Overactivity in Rats Subjected to Corticosterone Treatment. Front Pharmacol 2020; 11:1002. [PMID: 32733244 PMCID: PMC7360849 DOI: 10.3389/fphar.2020.01002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 06/22/2020] [Indexed: 11/21/2022] Open
Abstract
In view of the fact that GPR55 receptors are localized in brain areas implicated in the pathophysiology of depression, GPR55 gene expression is reduced in the dorsolateral prefrontal cortex of suicide victims, and GPR55 receptor agonism exerts an anxiolytic-like effect, GPR55 receptors have drawn our attention as a potential target in the treatment of mood disorders. Therefore, in the present study, we wanted to check whether a 7-day intravenous administration of O-1602 (0.25 mg/kg/day) – a phytocannabinoid-like analogue of cannabidiol that belongs to the agonists of GPR55 receptors, was able to reverse the corticosterone-induced depressive-like behavior accompanied by detrusor overactivity in female Wistar rats. Additionally, we tried to determine the influence of GPR55 stimulation on the bladder, hippocampal and urine levels of several biomarkers that play a role in the functioning of the urinary bladder and/or the pathophysiology of depression. Our experiments showed that O-1602 therapy improved signs of depression (measured by the forced swim test) and detrusor contractility (measured by conscious cystometry) in animals exposed to the corticosterone treatment. Moreover, the treatment reduced the oxidative damage in the urinary bladder and neuroinflammation (observed as the reduction of elevated levels of 3-NIT, MAL, and IL-1β, TNF-α, CRF, respectively). The O-1602 treatment also reversed the abnormal changes in the bladder, hippocampal or urine values of CGRP, OCT3, VAChT, BDNF, and NGF. The above-mentioned findings allow to suggest that in the future the modulation of atypical cannabinoid receptors GPR55 could have a potential role in the treatment of depression and overactive bladder.
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Affiliation(s)
- Andrzej Wróbel
- Second Department of Gynecology, Medical University of Lublin, Lublin, Poland
| | - Anna Serefko
- Laboratory of Preclinical Testing, Chair and Department of Applied and Social Pharmacy, Medical University of Lublin, Lublin, Poland
| | - Aleksandra Szopa
- Laboratory of Preclinical Testing, Chair and Department of Applied and Social Pharmacy, Medical University of Lublin, Lublin, Poland
| | - Daniela Ulrich
- Department of Obstetrics and Gynaecology, Medical University Graz, Graz, Germany
| | - Ewa Poleszak
- Laboratory of Preclinical Testing, Chair and Department of Applied and Social Pharmacy, Medical University of Lublin, Lublin, Poland
| | - Tomasz Rechberger
- Second Department of Gynecology, Medical University of Lublin, Lublin, Poland
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25
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Maeda A. Recruitment of Mesenchymal Stem Cells to Damaged Sites by Plant-Derived Components. Front Cell Dev Biol 2020; 8:437. [PMID: 32582713 PMCID: PMC7295908 DOI: 10.3389/fcell.2020.00437] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 05/11/2020] [Indexed: 12/22/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are capable of differentiating into a limited number of diverse cells and secrete regenerative factors that contribute to the repair of damaged tissue. In response to signals emitted by tissue damage, MSCs migrate from the bone marrow and area surrounding blood vessels within tissues into the circulating blood, and accumulate at the site of damage. Hence, MSC transplantation therapy is beginning to be applied to the treatment of various intractable human diseases. Recent medicinal plants studies have shown that plant-derived components can activate cell functions. For example, several plant-derived components activate cell signaling pathways, such as phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK), enhance expression of the CXCL12/CXCR4 axis, stimulate extracellular matrix remodeling, and consequently, promote cell migration of MSCs. Moreover, plant-derived components have been shown to promote recruitment of MSCs to damaged tissues and enhance healing in disease models, potentially advancing their therapeutic use. This article provides a comprehensive review of several plant-derived components that activate MSC migration and homing to damaged sites to promote tissue repair.
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Affiliation(s)
- Akito Maeda
- Skin Regeneration, PIAS Collaborative Research, Graduate School of Pharmaceutical Science, Osaka University, Suita, Japan
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26
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Wróbel A, Serefko A, Szopa A, Poleszak E. Stimulation of atypical cannabinoid receptor GPR55 abolishes the symptoms of detrusor overactivity in spontaneously hypertensive rats. Eur J Pharm Sci 2020; 150:105329. [PMID: 32360768 DOI: 10.1016/j.ejps.2020.105329] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 03/26/2020] [Accepted: 03/28/2020] [Indexed: 12/29/2022]
Abstract
Overactive bladder is a troublesome disease that affects 15% of the population in developed countries. Since pharmacotherapy of this condition is frequently associated with side effects, the better tolerated drugs are being searched for. The main objective of our study was to check whether activation of the atypical cannabinoid receptor GPR55 would normalize the changes in cystometric, cardiovascular and biochemical parameters in the hypertensive female Wistar-Kyoto rats presenting the symptoms of overactive bladder accompanied by inflammation and oxidative damage in the urinary tracts. A 14-day intra-arterial administration of O-1602 (0.25 mg/kg/day), a potent agonist of GRP55 receptors, was able to abolish the signs of detrusor overactivity, inflammation and oxidative damage in the urinary bladder of the spontaneously hypertensive animals. Moreover, it increased their heart rate, reduced the mean blood pressure, and normalized the levels of several proteins that play a significant role in the proper functioning of the urinary bladder (i.e., calcitonin gene related peptide, organic cation transporter 3, extracellular signal-regulated kinase 1/2, vesicular acetylcholine transporter, RhoA). Based on the outcomes of our experiments, the atypical cannabinoid receptor GPR55 has emerged as a potential drug target for the treatment of overactive bladder in female subjects. It could be particularly attractive in the cases in which this condition is accompanied with elevated blood pressure, though further studies on this subject are needed.
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Affiliation(s)
- Andrzej Wróbel
- Second Department of Gynecology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland.
| | - Anna Serefko
- Chair and Department of Applied and Social Pharmacy, Laboratory of Preclinical Testing, Medical University of Lublin, Chodźki 1, 20-093, Lublin, Poland.
| | - Aleksandra Szopa
- Chair and Department of Applied and Social Pharmacy, Laboratory of Preclinical Testing, Medical University of Lublin, Chodźki 1, 20-093, Lublin, Poland
| | - Ewa Poleszak
- Chair and Department of Applied and Social Pharmacy, Laboratory of Preclinical Testing, Medical University of Lublin, Chodźki 1, 20-093, Lublin, Poland
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27
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Zeng Z, Mukherjee A, Varghese AP, Yang XL, Chen S, Zhang H. Roles of G protein-coupled receptors in inflammatory bowel disease. World J Gastroenterol 2020; 26:1242-1261. [PMID: 32256014 PMCID: PMC7109274 DOI: 10.3748/wjg.v26.i12.1242] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/18/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a complex disease with multiple pathogenic factors. Although the pathogenesis of IBD is still unclear, a current hypothesis suggests that genetic susceptibility, environmental factors, a dysfunctional immune system, the microbiome, and the interactions of these factors substantially contribute to the occurrence and development of IBD. Although existing and emerging drugs have been proven to be effective in treating IBD, none can cure IBD permanently. G protein-coupled receptors (GPCRs) are critical signaling molecules implicated in the immune response, cell proliferation, inflammation regulation and intestinal barrier maintenance. Breakthroughs in the understanding of the structures and functions of GPCRs have provided a driving force for exploring the roles of GPCRs in the pathogenesis of diseases, thereby leading to the development of GPCR-targeted medication. To date, a number of GPCRs have been shown to be associated with IBD, significantly advancing the drug discovery process for IBD. The associations between GPCRs and disease activity, disease severity, and disease phenotypes have also paved new avenues for the precise management of patients with IBD. In this review, we mainly focus on the roles of the most studied proton-sensing GPCRs, cannabinoid receptors, and estrogen-related GPCRs in the pathogenesis of IBD and their potential clinical values in IBD and some other diseases.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Arjudeb Mukherjee
- West China School of Medicine, Sichuan University, Chengdu 410061, Sichuan Province, China
| | | | - Xiao-Li Yang
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Sha Chen
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Hu Zhang
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
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28
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McCloskey AG, Miskelly MG, Moore CBT, Nesbit MA, Christie KA, Owolabi AI, Flatt PR, McKillop AM. CRISPR/Cas9 gene editing demonstrates metabolic importance of GPR55 in the modulation of GIP release and pancreatic beta cell function. Peptides 2020; 125:170251. [PMID: 31923454 DOI: 10.1016/j.peptides.2019.170251] [Citation(s) in RCA: 14] [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: 10/11/2019] [Revised: 12/18/2019] [Accepted: 12/28/2019] [Indexed: 12/28/2022]
Abstract
G-protein coupled receptor-55 (GPR55), an endocannabinoid receptor, is a novel anti-diabetic target. This study aimed to assess the metabolic functionality of GPR55 ligands using CRISPR/Cas9 gene editing to determine their regulatory role in beta cell function and incretin-secreting enteroendocrine cells. A clonal Gpr55 knockout beta cell line was generated by CRISPR/Cas9 gene editing to investigate insulin secretion and Gpr55 signalling. Acute effects of GPR55 agonists were investigated in high fat fed (HFD) diabetic HsdOla:TO (Swiss TO) mice. Atypical and endogenous endocannabinoid ligands (10-7-10-4M) stimulated insulin secretion (p < 0.05-0.001) in rodent (BRIN-BD11) and human (1.1B4) beta cells, with 2-2.7-fold (p < 0.001) increase demonstrated in BRIN-BD11 cells (10-4M). The insulinotropic effect of Abn-CBD (42 %), AM251 (30 %) and PEA (53 %) were impaired (p < 0.05) in Gpr55 knockout BRIN-BD11 cells, with the secretory effect of O-1602 completely abolished (p < 0.001). Gpr55 ablation abolished the release of intracellular Ca2+ upon treatment with O-1602, Abn-CBD and PEA. Upregulation of insulin mRNA by Abn-CBD and AM251 (1.7-3-fold; p < 0.01) was greatly diminished (p < 0.001) in Gpr55 null cells. Orally administered Abn-CBD and AM251 (0.1 μmol/kgBW) improved GIP (p < 0.05-p < 0.01), GLP-1 (p < 0.05-p < 0.001), glucose tolerance (p < 0.001) and circulating insulin (p < 0.05-p < 0.001) in HFD diabetic mice. Abn-CBD in combination therapy with DPP-IV inhibitor (Sitagliptin) resulted in greater improvement in glucose tolerance (p < 0.05) and insulin release (p < 0.05). Antagonism of Gpr55 in-vivo attenuated the glucoregulatory effects of Abn-CBD (p < 0.05). Conclusively, GPR55 agonists enhance insulin, GIP and GLP-1 release, thereby promoting GPR55 agonist monotherapy and combinational therapy as a novel approach for the treatment of type-2-diabetes.
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Affiliation(s)
- A G McCloskey
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland
| | - M G Miskelly
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland
| | - C B T Moore
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland
| | - M A Nesbit
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland
| | - K A Christie
- Center for Genomic Medicine, Massachusetts General Hospital & Harvard Medical School, 185 Cambridge St. Boston, MA 02115, USA
| | - A I Owolabi
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland
| | - P R Flatt
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland
| | - A M McKillop
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland.
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29
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Wei D, Wang H, Yang J, Dai Z, Yang R, Meng S, Li Y, Lin X. Effects of O-1602 and CBD on TNBS-induced colonic disturbances. Neurogastroenterol Motil 2020; 32:e13756. [PMID: 31802588 DOI: 10.1111/nmo.13756] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 09/22/2019] [Accepted: 10/14/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND This study attempted to provide the effects and mechanisms of two cannabinoids, O-1602 and cannabidiol (CBD), on colonic motility of 2,4,6-trinitro-benzene sulfonic acid (TNBS) colitis. METHODS TNBS was used to induce the model of motility disorder. G protein-coupled receptor 55 (GPR55) expression was detected using real-time PCR and immunohistochemistry in colon. Pro-inflammatory cytokines and myeloperoxidase were also measured. The colonic motility was measured by upper GI transit in vivo and recorded using electrical stimulation organ bath technique in vitro. Freshly isolated smooth muscle from the rat colon were applied to determine the membrane potential and Ca2+ -ATPase activity, respectively. KEY RESULTS CBD or O-1602 separately improved inflammatory conditions significantly in TNBS-induced colitis rats. However, sole CBD pretreatment reduced GPR55 expression, which was up-regulated in TNBS colitis. O-1602 and CBD each lowered MPO and IL-6 levels remarkably in TNBS colitis, while TNF-α levels experienced no change. CBD rescued the downward colonic motility in TNBS colitis in vivo; however, it decreased the upward contraction of the smooth muscle strip under electrical stimulation in vitro. Pretreatment with CBD prevented against TNBS-induced changes of Ca2+ -ATPase activity of smooth muscle cells. However, membrane potential of the smooth muscle cells decreased by TNBS experienced no change after O-1602 or CBD import. CONCLUSIONS & INFERENCES The present study suggested that CBD participated in the regulation of colonic motility in rats, and the mechanisms may be involved in the regulation of inlammatory factors and Ca2+ -ATPase activity through GPR55.
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Affiliation(s)
- DanDan Wei
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan University, Kaifeng, China
| | - HuiChao Wang
- Department of Nephrology, First Affiliated Hospital of Henan University, Kaifeng, China
| | - JingNan Yang
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan University, Kaifeng, China
| | - ZhiFeng Dai
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan University, Kaifeng, China
| | - RuiLin Yang
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan University, Kaifeng, China
| | - ShuangShuang Meng
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan University, Kaifeng, China
| | - YongYu Li
- Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Shanghai, China
| | - XuHong Lin
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan University, Kaifeng, China
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30
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Yanagida K, Valentine WJ. Druggable Lysophospholipid Signaling Pathways. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1274:137-176. [DOI: 10.1007/978-3-030-50621-6_7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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31
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Zhou J, Yang H, Lehmann C. Inhibition of GPR 55 improves dysregulated immune response in experimental sepsis. Clin Hemorheol Microcirc 2019; 70:553-561. [PMID: 30347614 DOI: 10.3233/ch-189320] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Sepsis is a medical condition caused by dysregulated systemic inflammatory response against infection, resulting in high mortality. Despite intensive research over the last few decades, the results from multiple clinical trials targeting specific inflammatory mediators have been disappointing. In the present study, we investigated the role of G protein-coupled receptor GPR55 modulation on immune response in an experimental sepsis model (endotoxemia). Immune response was evaluated by analyzing leukocyte-endothelial interactions and capillary perfusion in the intestinal microcirculation using intravital microscopy. In addition, the levels of plasma inflammatory cytokines were measured. The results demonstrated that GPR55 inhibition using antagonists, CID16020046 or O-1918, significantly reduced leukocyte adherence in intestinal submucosal venules and decreased proinflammatory cytokine TNF-α and IL-6 production. These data suggest that GPR55 inhibition may be a novel therapeutic target for attenuating hyperinflammation during sepsis.
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32
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Ambrose T, Simmons A. Cannabis, Cannabinoids, and the Endocannabinoid System-Is there Therapeutic Potential for Inflammatory Bowel Disease? J Crohns Colitis 2019; 13:525-535. [PMID: 30418525 PMCID: PMC6441301 DOI: 10.1093/ecco-jcc/jjy185] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cannabis sativa and its extracts have been used for centuries, both medicinally and recreationally. There is accumulating evidence that exogenous cannabis and related cannabinoids improve symptoms associated with inflammatory bowel disease [IBD], such as pain, loss of appetite, and diarrhoea. In vivo, exocannabinoids have been demonstrated to improve colitis, mainly in chemical models. Exocannabinoids signal through the endocannabinoid system, an increasingly understood network of endogenous lipid ligands and their receptors, together with a number of synthetic and degradative enzymes and the resulting products. Modulating the endocannabinoid system using pharmacological receptor agonists, genetic knockout models, or inhibition of degradative enzymes have largely shown improvements in colitis in vivo. Despite these promising experimental results, this has not translated into meaningful benefits for human IBD in the few clinical trials which have been conducted to date, the largest study being limited by poor medication tolerance due to the Δ9-tetrahydrocannabinol component. This review article synthesises the current literature surrounding the modulation of the endocannabinoid system and administration of exocannabinoids in experimental and human IBD. Findings of clinical surveys and studies of cannabis use in IBD are summarised. Discrepancies in the literature are highlighted together with identifying novel areas of interest.
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Affiliation(s)
- Tim Ambrose
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK,MRC Human Immunology Unit, John Radcliffe Hospital, Oxford, UK,Corresponding author: Dr Tim Ambrose, BSc (Hons), MBChB, MRCP (UK) (Gastroenterology), c/o Prof. Alison Simmons, MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK. Tel.: 01865 222628;
| | - Alison Simmons
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK,MRC Human Immunology Unit, John Radcliffe Hospital, Oxford, UK
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Simcocks AC, Jenkin KA, O’Keefe L, Samuel CS, Mathai ML, McAinch AJ, Hryciw DH. Atypical cannabinoid ligands O-1602 and O-1918 administered chronically in diet-induced obesity. Endocr Connect 2019; 8:203-216. [PMID: 30707678 PMCID: PMC6391900 DOI: 10.1530/ec-18-0535] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/01/2019] [Indexed: 01/01/2023]
Abstract
Atypical cannabinoid compounds O-1602 and O-1918 are ligands for the putative cannabinoid receptors G protein-coupled receptor 55 and G protein-coupled receptor 18. The role of O-1602 and O-1918 in attenuating obesity and obesity-related pathologies is unknown. Therefore, we aimed to determine the role that either compound had on body weight and body composition, renal and hepatic function in diet-induced obesity. Male Sprague-Dawley rats were fed a high-fat diet (40% digestible energy from lipids) or a standard chow diet for 10 weeks. In a separate cohort, male Sprague-Dawley rats were fed a high-fat diet for 9 weeks and then injected daily with 5 mg/kg O-1602, 1 mg/kg O-1918 or vehicle (0.9% saline/0.75% Tween 80) for a further 6 weeks. Our data demonstrated that high-fat feeding upregulates whole kidney G protein receptor 55 expression. In diet-induced obesity, we also demonstrated O-1602 reduces body weight, body fat and improves albuminuria. Despite this, treatment with O-1602 resulted in gross morphological changes in the liver and kidney. Treatment with O-1918 improved albuminuria, but did not alter body weight or fat composition. In addition, treatment with O-1918 also upregulated circulation of pro-inflammatory cytokines including IL-1α, IL-2, IL-17α, IL-18 and RANTES as well as plasma AST. Thus O-1602 and O-1918 appear not to be suitable treatments for obesity and related comorbidities, due to their effects on organ morphology and pro-inflammatory signaling in obesity.
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Affiliation(s)
- Anna C Simcocks
- Institute for Health and Sport, Victoria University, St Albans campus, Melbourne, Victoria, Australia
| | - Kayte A Jenkin
- Institute for Health and Sport, Victoria University, St Albans campus, Melbourne, Victoria, Australia
- School of Science and Health, Western Sydney University, Campbelltown, New South Wales, Australia
| | - Lannie O’Keefe
- Institute for Health and Sport, Victoria University, St Albans campus, Melbourne, Victoria, Australia
| | - Chrishan S Samuel
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Michael L Mathai
- Institute for Health and Sport, Victoria University, St Albans campus, Melbourne, Victoria, Australia
- The Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Victoria, Australia
| | - Andrew J McAinch
- Institute for Health and Sport, Victoria University, St Albans campus, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia
| | - Deanne H Hryciw
- Institute for Health and Sport, Victoria University, St Albans campus, Melbourne, Victoria, Australia
- School of Environment and Sciences, Griffith University, Nathan, Queensland, Australia
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Guerrero-Alba R, Barragán-Iglesias P, González-Hernández A, Valdez-Moráles EE, Granados-Soto V, Condés-Lara M, Rodríguez MG, Marichal-Cancino BA. Some Prospective Alternatives for Treating Pain: The Endocannabinoid System and Its Putative Receptors GPR18 and GPR55. Front Pharmacol 2019; 9:1496. [PMID: 30670965 PMCID: PMC6331465 DOI: 10.3389/fphar.2018.01496] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 12/07/2018] [Indexed: 12/12/2022] Open
Abstract
Background: Marijuana extracts (cannabinoids) have been used for several millennia for pain treatment. Regarding the site of action, cannabinoids are highly promiscuous molecules, but only two cannabinoid receptors (CB1 and CB2) have been deeply studied and classified. Thus, therapeutic actions, side effects and pharmacological targets for cannabinoids have been explained based on the pharmacology of cannabinoid CB1/CB2 receptors. However, the accumulation of confusing and sometimes contradictory results suggests the existence of other cannabinoid receptors. Different orphan proteins (e.g., GPR18, GPR55, GPR119, etc.) have been proposed as putative cannabinoid receptors. According to their expression, GPR18 and GPR55 could be involved in sensory transmission and pain integration. Methods: This article reviews select relevant information about the potential role of GPR18 and GPR55 in the pathophysiology of pain. Results: This work summarized novel data supporting that, besides cannabinoid CB1 and CB2 receptors, GPR18 and GPR55 may be useful for pain treatment. Conclusion: There is evidence to support an antinociceptive role for GPR18 and GPR55.
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Affiliation(s)
- Raquel Guerrero-Alba
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Paulino Barragán-Iglesias
- School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, United States
| | - Abimael González-Hernández
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Santiago de Querétaro, Mexico
| | - Eduardo E Valdez-Moráles
- Cátedras CONACYT, Departamento de Cirugía, Centro de Ciencias Biomédicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Vinicio Granados-Soto
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, Mexico City, Mexico
| | - Miguel Condés-Lara
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Santiago de Querétaro, Mexico
| | - Martín G Rodríguez
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Bruno A Marichal-Cancino
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
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Uranga JA, Vera G, Abalo R. Cannabinoid pharmacology and therapy in gut disorders. Biochem Pharmacol 2018; 157:134-147. [PMID: 30076849 DOI: 10.1016/j.bcp.2018.07.048] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 07/31/2018] [Indexed: 12/14/2022]
Abstract
Cannabis sp. and their products (marijuana, hashish…), in addition to their recreational, industrial and other uses, have a long history for their use as a remedy for symptoms related with gastrointestinal diseases. After many reports suggesting these beneficial effects, it was not surprising to discover that the gastrointestinal tract expresses endogenous cannabinoids, their receptors, and enzymes for their synthesis and degradation, comprising the so-called endocannabinoid system. This system participates in the control of tissue homeostasis and important intestinal functions like motor and sensory activity, nausea, emesis, the maintenance of the epithelial barrier integrity, and the correct cellular microenvironment. Thus, different cannabinoid-related pharmacological agents may be useful to treat the main digestive pathologies. To name a few examples, in irritable bowel syndrome they may normalize dysmotility and reduce pain, in inflammatory bowel disease they may decrease inflammation, and in colorectal cancer, apart from alleviating some symptoms, they may play a role in the regulation of the cell niche. This review summarizes the main recent findings on the role of cannabinoid receptors, their synthetic or natural ligands and their metabolizing enzymes in normal gastrointestinal function and in disorders including irritable bowel syndrome, inflammatory bowel disease, colon cancer and gastrointestinal chemotherapy-induced adverse effects (nausea/vomiting, constipation, diarrhea).
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Affiliation(s)
- J A Uranga
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain; Unidad Asociada I+D+i al Instituto de Investigación en Ciencias de la Alimentación, CIAL (CSIC), Spain; Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Spain
| | - G Vera
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain; Unidad Asociada I+D+i al Instituto de Investigación en Ciencias de la Alimentación, CIAL (CSIC), Spain; Unidad Asociada I+D+i al Instituto de Química Médica, IQM (CSIC), Spain; Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Spain
| | - R Abalo
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain; Unidad Asociada I+D+i al Instituto de Investigación en Ciencias de la Alimentación, CIAL (CSIC), Spain; Unidad Asociada I+D+i al Instituto de Química Médica, IQM (CSIC), Spain; Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Spain.
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McAleer JP, Fan J, Roar B, Primerano DA, Denvir J. Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon Receptor and Gq-Coupled Receptors. Sci Rep 2018; 8:10954. [PMID: 30026493 PMCID: PMC6053392 DOI: 10.1038/s41598-018-29262-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 07/09/2018] [Indexed: 12/11/2022] Open
Abstract
Th17 cells contribute to host defense on mucosal surfaces but also provoke autoimmune diseases when directed against self-antigens. Identifying therapeutic targets that regulate Th17 cell differentiation and/or cytokine production has considerable value. Here, we study the aryl hydrocarbon receptor (AhR)-dependent transcriptome in human CD4 T cells treated with Th17-inducing cytokines. We show that the AhR reciprocally regulates IL-17 and IL-22 production in human CD4 T cells. Global gene expression analysis revealed that AhR ligation decreased IL21 expression, correlating with delayed upregulation of RORC during culture with Th17-inducing cytokines. Several of the AhR-dependent genes have known roles in cellular assembly, organization, development, growth and proliferation. We further show that expression of GPR15, GPR55 and GPR68 positively correlates with IL-22 production in the presence of the AhR agonist FICZ. Activation of GPR68 with the lorazepam derivative ogerin resulted in suppression of IL-22 and IL-10 secretion by T cells, with no effect on IL-17. Under neutral Th0 conditions, ogerin and the Gq/11 receptor inhibitor YM254890 blunted IL-22 induction by FICZ. These data reveal the AhR-dependent transcriptome in human CD4 T cells and suggest the mechanism through which the AhR regulates T cell function may be partially dependent on Gq-coupled receptors including GPR68.
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Affiliation(s)
- Jeremy P McAleer
- Department of Pharmaceutical Science and Research, Marshall University School of Pharmacy, Huntington, WV, 25755, USA.
| | - Jun Fan
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, 25755, USA
| | - Bryanna Roar
- Department of Pharmaceutical Science and Research, Marshall University School of Pharmacy, Huntington, WV, 25755, USA
| | - Donald A Primerano
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, 25755, USA
| | - James Denvir
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, 25755, USA
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Hill JD, Zuluaga-Ramirez V, Gajghate S, Winfield M, Persidsky Y. Activation of GPR55 increases neural stem cell proliferation and promotes early adult hippocampal neurogenesis. Br J Pharmacol 2018; 175:3407-3421. [PMID: 29888782 DOI: 10.1111/bph.14387] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 04/30/2018] [Accepted: 05/28/2018] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND AND PURPOSE The cannabinoid system exerts functional regulation of neural stem cell (NSC) proliferation and adult neurogenesis, yet not all effects of cannabinoid-like compounds seen can be attributed to the cannabinoid 1 (CB1 ) or CB2 receptor. The recently de-orphaned GPR55 has been shown to be activated by numerous cannabinoid ligands suggesting that GPR55 is a third cannabinoid receptor. Here, we examined the role of GPR55 activation in NSC proliferation and early adult neurogenesis. EXPERIMENTAL APPROACH The effects of GPR55 agonists (LPI, O-1602, ML184) on human (h) NSC proliferation in vitro were assessed by flow cytometry. Human NSC differentiation was determined by flow cytometry, qPCR and immunohistochemistry. Immature neuron formation in the hippocampus of C57BL/6 and GPR55-/- mice was evaluated by immunohistochemistry. KEY RESULTS Activation of GPR55 significantly increased proliferation rates of hNSCs in vitro. These effects were attenuated by ML193, a selective GPR55 antagonist. ML184 significantly promoted neuronal differentiation in vitro while ML193 reduced differentiation rates as compared to vehicle treatment. Continuous administration of O-1602 into the hippocampus via a cannula connected to an osmotic pump resulted in increased Ki67+ cells within the dentate gyrus. O-1602 increased immature neuron generation, as assessed by DCX+ and BrdU+ cells, as compared to vehicle-treated animals. GPR55-/- animals displayed reduced rates of proliferation and neurogenesis within the hippocampus while O-1602 had no effect as compared to vehicle controls. CONCLUSIONS AND IMPLICATIONS Together, these findings suggest GPR55 activation as a novel target and strategy to regulate NSC proliferation and adult neurogenesis.
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Affiliation(s)
- Jeremy D Hill
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.,Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Viviana Zuluaga-Ramirez
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Sachin Gajghate
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Malika Winfield
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Yuri Persidsky
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.,Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
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Grill M, Hasenoehrl C, Storr M, Schicho R. Medical Cannabis and Cannabinoids: An Option for the Treatment of Inflammatory Bowel Disease and Cancer of the Colon? Med Cannabis Cannabinoids 2018; 1:28-35. [PMID: 34676319 DOI: 10.1159/000489036] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 04/09/2018] [Indexed: 12/11/2022] Open
Abstract
In the past few years, we have witnessed a surge of new reports dealing with the role of cannabinoids, synthetic as well as herbal, in the mechanisms of inflammation and carcinogenesis. However, despite the wealth of in vitro data and anecdotal reports, evidence that cannabinoids could act as beneficial drugs in inflammatory bowel disease (IBD) or in neoplastic development of the human gastrointestinal tract is lacking. Some insight into the effects of medical Cannabis (usually meaning dried flowers) and cannabinoids in IBD has been gained through questionnaires and small pilot studies. As to colorectal cancer, only preclinical data are available. Currently, Δ9-tetrahydrocannabinol (THC) and its synthetic forms, dronabinol and nabilone, are used as an add-on treatment to alleviate chronic pain and spasticity in multiple sclerosis patients as well as chemotherapy-induced nausea. The use of medical Cannabis is authorized only in a limited number of countries. None of the mentioned substances are currently indicated for IBD. This review is an update of our knowledge on the role of cannabinoids in intestinal inflammation and carcinogenesis and a discussion on their potential therapeutic use.
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Affiliation(s)
- Magdalena Grill
- Otto Loewi Research Center, Pharmacology Section, Medical University of Graz, Graz, Austria
| | - Carina Hasenoehrl
- Otto Loewi Research Center, Pharmacology Section, Medical University of Graz, Graz, Austria
| | - Martin Storr
- Department of Medicine 2, Ludwig-Maximilians University, Munich, Germany.,Zentrum für Endoskopie, Starnberg, Germany
| | - Rudolf Schicho
- Otto Loewi Research Center, Pharmacology Section, Medical University of Graz, Graz, Austria.,BioTechMed, Graz, Austria
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40
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Alhouayek M, Masquelier J, Muccioli GG. Lysophosphatidylinositols, from Cell Membrane Constituents to GPR55 Ligands. Trends Pharmacol Sci 2018; 39:586-604. [PMID: 29588059 DOI: 10.1016/j.tips.2018.02.011] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/20/2018] [Accepted: 02/28/2018] [Indexed: 12/25/2022]
Abstract
Lysophosphatidylinositols (LPIs) are membrane constituents that alter the properties of said membranes. However, recent data showing that the once orphan receptor, GPR55, can act as a receptor for LPIs has sparked a renewed interest in LPIs as bioactive lipids. As evidence supporting the importance of LPIs and/or GPR55 is continuously accumulating and because LPI levels are altered in a number of pathologies such as obesity and cancer, the coming years should bring new, exciting discoveries to this field. In this review, we discuss the recent work on LPIs and on their molecular target, the GPR55 receptor. First, we summarize the metabolism of LPIs before outlining the cellular pathways activated by GPR55. Then, we review the actions of LPIs and GPR55 that could have potential pharmacological or therapeutic applications in several pathophysiological settings, such as cancer, obesity, pain, and inflammation.
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Affiliation(s)
- Mireille Alhouayek
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Bruxelles, Belgium; These authors contributed equally to this work
| | - Julien Masquelier
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Bruxelles, Belgium; These authors contributed equally to this work
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Bruxelles, Belgium.
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Couch DG, Maudslay H, Doleman B, Lund JN, O'Sullivan SE. The Use of Cannabinoids in Colitis: A Systematic Review and Meta-Analysis. Inflamm Bowel Dis 2018; 24:680-697. [PMID: 29562280 DOI: 10.1093/ibd/izy014] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Clinical trials investigating the use of cannabinoid drugs for the treatment of intestinal inflammation are anticipated secondary to preclinical literature demonstrating efficacy in reducing inflammation. METHODS We systematically reviewed publications on the benefit of drugs targeting the endo-cannabinoid system in intestinal inflammation. We collated studies examining outcomes for meta-analysis from EMBASE, MEDLINE and Pubmed until March 2017. Quality was assessed according to mSTAIR and SRYCLE score. RESULTS From 2008 papers, 51 publications examining the effect of cannabinoid compounds on murine colitis and 2 clinical studies were identified. Twenty-four compounds were assessed across 71 endpoints. Cannabidiol, a phytocannabinoid, was the most investigated drug. Macroscopic colitis severity (disease activity index [DAI]) and myeloperoxidase activity (MPO) were assessed throughout publications and were meta-analyzed using random effects models. Cannabinoids reduced DAI in comparison with the vehicle (standard mean difference [SMD] -1.36; 95% CI, -1.62 to-1.09; I2 = 61%). FAAH inhibitor URB597 had the largest effect size (SMD -4.43; 95% CI, -6.32 to -2.55), followed by the synthetic drug AM1241 (SMD -3.11; 95% CI, -5.01 to -1.22) and the endocannabinoid anandamide (SMD -3.03; 95% CI, -4.89 to -1.17; I2 not assessed). Cannabinoids reduced MPO in rodents compared to the vehicle; SMD -1.26; 95% CI, -1.54 to -0.97; I2 = 48.1%. Cannabigerol had the largest effect size (SMD -6.20; 95% CI, -9.90 to -2.50), followed by the synthetic CB1 agonist ACEA (SMD -3.15; 95% CI, -4.75 to -1.55) and synthetic CB1/2 agonist WIN55,212-2 (SMD -1.74; 95% CI, -2.81 to -0.67; I2 = 57%). We found no evidence of reporting bias. No significant difference was found between the prophylactic and therapeutic use of cannabinoid drugs. CONCLUSIONS There is abundant preclinical literature demonstrating the anti-inflammatory effects of cannabinoid drugs in inflammation of the gut. Larger randomised controlled-trials are warranted.
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Affiliation(s)
- Daniel G Couch
- School of Medicine, Royal Derby Hospital, University of Nottingham, Derby, United Kingdom
| | - Henry Maudslay
- School of Medicine, Royal Derby Hospital, University of Nottingham, Derby, United Kingdom
| | - Brett Doleman
- School of Medicine, Royal Derby Hospital, University of Nottingham, Derby, United Kingdom
| | - Jonathan N Lund
- School of Medicine, Royal Derby Hospital, University of Nottingham, Derby, United Kingdom
| | - Saoirse E O'Sullivan
- School of Medicine, Royal Derby Hospital, University of Nottingham, Derby, United Kingdom
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Lin X, Wang H, Li Y, Yang J, Yang R, Wei D, Zhang J, Yang D, Wang B, Ren X, Cheng G. Functional characterization of CXCR4 in mediating the expression of protein C system in experimental ulcerative colitis. Am J Transl Res 2017; 9:4821-4835. [PMID: 29218082 PMCID: PMC5714768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/18/2017] [Indexed: 06/07/2023]
Abstract
The present study aimed to explore the role of CXCR4 and protein C system (PCS) in the experimental ulcerative colitis (UC). The expression of CXCR3, CCR10, and CXCR4 in dextran sulfate sodium (DSS)-induced colitis mouse model was measured by immunohistochemistry and western blot analysis. In vitro studies with microvascular endothelial cells (MVECs) were performed. The expression of endothelial protein C receptor (EPCR) and thrombomodulin (TM) were detected by RT-PCR and western blot analysis. Activities of protein C (PC), protein S (PS), activated PC (APC) were evaluated in cells pre-treated with JNK inhibitor SP600125 and c-Jun silencing. DSS mice showed up-regulated expression of CXCR4, higher macroscopic score and histological score (P<0.05), as well as elevated levels of SDF-1α (P<0.05) compared with wild type, CXCR4-/-, or CXCR4-/- +DSS mice. In DSS mice, EPCR expression was down-regulated (P<0.05), accompanied by decreased activity of PC and PS (P<0.05 or P<0.01) with an up-regulated expression of pJNK MAPK and pc-Jun (P<0.05). Moreover, the macroscopic score and histological score index, SDF-1α levels, EPCR expression, PC activity, pJNK, and pc-Jun were reversed in CXCR4-/- +DSS mice (P<0.05). In vitro, SDF-1α-induced inhibition of the PCS was blunted by SP600125 (P<0.05). Meanwhile, down-regulation of c-Jun rescued the inhibition of PCS (P<0.05). MVECs with retrovirus-mediated transfection of c-Jun demonstrated a strong trans-inactivation effect on the EPCR promoter (P<0.05). These findings suggest that CXCR4 is involved in UC pathogenesis and could be a promising therapeutic target for UC treatment.
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Affiliation(s)
- Xuhong Lin
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan UniversityKaifeng 475000, Henan, China
| | - Huichao Wang
- Department of Nephrology, First Affiliated Hospital of Henan UniversityKaifeng 475000, Henan, China
| | - Yuxia Li
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan UniversityKaifeng 475000, Henan, China
| | - Jingnan Yang
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan UniversityKaifeng 475000, Henan, China
| | - Ruilin Yang
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan UniversityKaifeng 475000, Henan, China
| | - Dandan Wei
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan UniversityKaifeng 475000, Henan, China
| | - Junjie Zhang
- Department of General Surgery, Huaihe Hospital Affiliated to Henan UniversityKaifeng 475000, Henan, China
| | - Desheng Yang
- Department of Gastroenterology, Huaihe Hospital Affiliated to Henan UniversityKaifeng 475000, Henan, China
| | - Bin Wang
- Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan UniversityKaifeng 475000, Henan, China
| | - Xuequn Ren
- Department of General Surgery, Huaihe Hospital Affiliated to Henan UniversityKaifeng 475000, Henan, China
| | - Guanchang Cheng
- Department of Cardiovascular Medicine, Huaihe Hospital Affiliated to Henan UniversityKaifeng 475000, Henan, China
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Włodarczyk M, Sobolewska-Włodarczyk A, Cygankiewicz AI, Jacenik D, Krajewska WM, Stec-Michalska K, Piechota-Polańczyk A, Wiśniewska-Jarosińska M, Fichna J. G protein-coupled receptor 55 (GPR55) expresses differently in patients with Crohn's disease and ulcerative colitis. Scand J Gastroenterol 2017; 52:711-715. [PMID: 28272905 DOI: 10.1080/00365521.2017.1298834] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIM To investigate the levels of G protein-coupled receptor 55 (GPR55) expression in colonic tissue of inflammatory bowel disease (IBD) patients and healthy controls, and its potential implication in IBD treatment. METHODS Fifty patients were enrolled in our prospective study: n = 21 with Crohn's disease (CD) and n = 16 with ulcerative colitis (UC); 19 women and 18 men. Control consisted of 13 non-IBD patients. In each subject, two biopsies were taken from different colonic locations. In IBD patients, biopsies both from endoscopically inflamed and non-inflamed areas were drawn and the development of inflammation confirmed in histopathological examination. GPR55 mRNA and protein expression were measured using real-time PCR and Western blot, respectively. RESULTS GPR55 expression at mRNA and protein level was detected in all samples tested. The level of GPR55 mRNA expression in non-inflamed colonic areas was comparable in all analyzed groups (p = .2438). However, in the inflamed tissues GPR55 mRNA expression was statistically significantly (p < .0001) higher (6.9 fold) in CD patients compared to UC. Moreover, CD patients manifested higher (12.5 fold) GPR55 mRNA expression in inflamed compared with non-inflamed colonic tissues (p < .0001). Although no significant differences were stated, GPR55 protein level tends to decrease in IBD as compared to control. CONCLUSIONS Different patterns of GPR55 expression at mRNA level were observed in IBD patients. We speculate that GPR55 is crucial for the mucosal inflammatory processes in IBD, particularly in CD and its expression may affect disease severity, and response to treatment. The GPR55 receptors may become an attractive target for novel therapeutic strategies in IBD.
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Affiliation(s)
- Marcin Włodarczyk
- a Department of Biochemistry , Medical University of Lodz , Lodz , Poland.,b Department of General and Colorectal Surgery , Medical University of Lodz , Lodz , Poland
| | - Aleksandra Sobolewska-Włodarczyk
- a Department of Biochemistry , Medical University of Lodz , Lodz , Poland.,c Department of Gastroenterology , Medical University of Lodz , Lodz , Poland
| | - Adam I Cygankiewicz
- d Department of Cytobiochemistry, Faculty of Biology and Environmental Protection , University of Lodz , Lodz , Poland
| | - Damian Jacenik
- d Department of Cytobiochemistry, Faculty of Biology and Environmental Protection , University of Lodz , Lodz , Poland
| | - Wanda M Krajewska
- d Department of Cytobiochemistry, Faculty of Biology and Environmental Protection , University of Lodz , Lodz , Poland
| | | | | | | | - Jakub Fichna
- a Department of Biochemistry , Medical University of Lodz , Lodz , Poland
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Blennerhassett MG, Lourenssen SR, Parlow LRG, Ghasemlou N, Winterborn AN. Analgesia and mouse strain influence neuromuscular plasticity in inflamed intestine. Neurogastroenterol Motil 2017; 29:1-12. [PMID: 28466581 DOI: 10.1111/nmo.13097] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 04/03/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Mouse models of inflammatory bowel disease (IBD) identify an impact on the enteric nervous system (ENS) but do not distinguish between Crohn's disease and ulcerative colitis phenotypes. In these models, analgesia is required, but its influence on different strains and disease outcomes is unknown. Therefore, changes to the ENS and intestinal smooth muscle were studied in trinitrobenzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS) induced colitis to identify the effects of analgesia, and compared between two mouse strains. METHODS Colitis was induced in CD1 or BALB/c mice receiving analgesia with either buprenorphine or tramadol. Euthanasia was on Day 8 (DSS) or Day 4 (TNBS). Outcomes were Disease Activity Index and cytokine assay, and quantitative histology and immunocytochemistry were used to evaluate effects of inflammation on neurons and smooth muscle. KEY RESULTS In BALB/c mice, both models of colitis caused >2-fold increase in smooth muscle cell number. DSS caused axon proliferation without neuron loss while TNBS caused significant neuron loss and axonal damage. Buprenorphine (but not tramadol) was generally anti-inflammatory in both strains, but correlated with lethal outcomes to TNBS in BALB/c mice. CONCLUSIONS AND INFERENCES Smooth muscle growth is common to both models of colitis. In contrast, ENS damage in TNBS is correlated with the severe response of a Crohn's disease-like phenotype, while DSS correlates with a milder, ulcerative colitis-like outcome in the deeper tissues. Analgesia with tramadol over buprenorphine is supported for mouse studies of IBD.
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Affiliation(s)
- M G Blennerhassett
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Kingston, ON, Canada.,Queen's University, Kingston, ON, Canada
| | - S R Lourenssen
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Kingston, ON, Canada.,Queen's University, Kingston, ON, Canada
| | - L R G Parlow
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Kingston, ON, Canada.,Queen's University, Kingston, ON, Canada
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Group III phospholipase A 2 promotes colitis and colorectal cancer. Sci Rep 2017; 7:12261. [PMID: 28947740 PMCID: PMC5612992 DOI: 10.1038/s41598-017-12434-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 09/11/2017] [Indexed: 12/21/2022] Open
Abstract
Lipid mediators play pivotal roles in colorectal cancer and colitis, but only a limited member of the phospholipase A2 (PLA2) subtypes, which lie upstream of various lipid mediators, have been implicated in the positive or negative regulation of these diseases. Clinical and biochemical evidence suggests that secreted PLA2 group III (sPLA2-III) is associated with colorectal cancer, although its precise role remains obscure. Here we have found that sPLA2-III-null (Pla2g3 -/-) mice are highly resistant to colon carcinogenesis. Furthermore, Pla2g3 -/- mice are less susceptible to dextran sulfate-induced colitis, implying that the amelioration of colonic inflammation by sPLA2-III ablation may underlie the protective effect against colon cancer. Lipidomics analysis of the colon revealed significant reduction of pro-inflammatory/pro-tumorigenic lysophosholipids as well as unusual steady-state elevation of colon-protective fatty acids and their oxygenated metabolites in Pla2g3 -/- mice. Overall, our results establish a role of sPLA2-III in the promotion of colorectal inflammation and cancer, expand our understanding of the divergent roles of multiple PLA2 enzymes in the gastrointestinal tract, and point to sPLA2-III as a novel druggable target for colorectal diseases.
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Celorrio M, Rojo-Bustamante E, Fernández-Suárez D, Sáez E, Estella-Hermoso de Mendoza A, Müller CE, Ramírez MJ, Oyarzábal J, Franco R, Aymerich MS. GPR55: A therapeutic target for Parkinson's disease? Neuropharmacology 2017; 125:319-332. [PMID: 28807673 DOI: 10.1016/j.neuropharm.2017.08.017] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 08/04/2017] [Accepted: 08/10/2017] [Indexed: 12/21/2022]
Abstract
The GPR55 receptor is expressed abundantly in the brain, especially in the striatum, suggesting it might fulfill a role in motor function. Indeed, motor behavior is impaired in mice lacking GPR55, which also display dampened inflammatory responses. Abnormal-cannabidiol (Abn-CBD), a synthetic cannabidiol (CBD) isomer, is a GPR55 agonist that may serve as a therapeutic agent in the treatment of inflammatory diseases. In this study, we explored whether modulating GPR55 could also represent a therapeutic approach for the treatment of Parkinson's disease (PD). The distribution of GPR55 mRNA was first analyzed by in situ hybridization, localizing GPR55 transcripts to neurons in brain nuclei related to movement control, striatum, globus pallidus, subthalamic nucleus, substantia nigra and cortex. Striatal expression of GPR55 was downregulated in parkinsonian conditions. When Abn-CBD and CBD (5 mg/kg) were chronically administered to mice treated over 5 weeks with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp), Abn-CBD but not CBD prevented MPTPp induced motor impairment. Although Abn-CBD protected dopaminergic cell bodies, it failed to prevent degeneration of the terminals or preserve dopamine levels in the striatum. Both compounds induced morphological changes in microglia that were compatible with an anti-inflammatory phenotype that did not correlate with a neuroprotective activity. The symptomatic relief of Abn-CBD was further studied in the haloperidol-induced catalepsy mouse model. Abn-CBD had an anti-cataleptic effect that was reversed by CBD and PSB1216, a newly synthesized GPR55 antagonist, and indeed, two other GPR55 agonists also displayed anti-cataleptic effects (CID1792197 and CID2440433). These results demonstrate for the first time that activation of GPR55 might be beneficial in combating PD.
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Affiliation(s)
- Marta Celorrio
- Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona 31008, Spain
| | - Estefanía Rojo-Bustamante
- Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona 31008, Spain
| | - Diana Fernández-Suárez
- Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain
| | - Elena Sáez
- Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain
| | - Ander Estella-Hermoso de Mendoza
- Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain
| | - Christa E Müller
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, An der Immenburg 4, D-53121 Bonn, Germany
| | - María J Ramírez
- Department of Pharmacology, School of Pharmacy, University of Navarra, Pamplona 31008, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain
| | - Julen Oyarzábal
- Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain
| | - Rafael Franco
- Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain; Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona 08028, Spain
| | - María S Aymerich
- Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona 31008, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.
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Carey LM, Gutierrez T, Deng L, Lee WH, Mackie K, Hohmann AG. Inflammatory and Neuropathic Nociception is Preserved in GPR55 Knockout Mice. Sci Rep 2017; 7:944. [PMID: 28428628 PMCID: PMC5430528 DOI: 10.1038/s41598-017-01062-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 03/22/2017] [Indexed: 01/22/2023] Open
Abstract
The G-protein coupled receptor GPR55 has been postulated to serve as a novel cannabinoid receptor. A previous report indicated that GPR55 knockout mice fail to develop mechanical hyperalgesia, suggesting a pro-nociceptive role for GPR55 in the control of nociceptive responding. However, GPR55 knockout mice remain incompletely characterized in models of pathological pain. Here we provide a comprehensive assessment of responses of GPR55 knockout and wild-type mice to mechanical and thermal (heat, cold) stimulation in multiple, mechanistically distinct models of inflammatory and neuropathic pain. Inflammatory sensitization was produced by intraplantar administration of capsaicin, formalin or complete Freund’s adjuvant. No differences in responding were detected between GPR55 knockout and wild-type mice in any model of inflammatory nociception assessed. Neuropathic pain was induced by partial sciatic nerve ligation (which induces hypersensitivity to mechanical, cold and heat stimulation) or by treatment with the chemotherapeutic agent paclitaxel (which induces hypersensitivity to mechanical and cold stimulation only). No differences were observed between GPR55 knockout and wild type mice in either development or maintenance of neuropathic nociception in either neuropathic pain model. In conclusion, genetic deletion of GPR55 did not alter the development of pathological pain in adult mice in any chronic pain model evaluated.
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Affiliation(s)
- Lawrence M Carey
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.,Program in Neuroscience, Indiana University, Bloomington, IN, USA
| | - Tannia Gutierrez
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
| | - Liting Deng
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.,Program in Neuroscience, Indiana University, Bloomington, IN, USA
| | - Wan-Hung Lee
- Interdisciplinary Biochemistry Program, Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, IN, USA.,Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA
| | - Ken Mackie
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.,Program in Neuroscience, Indiana University, Bloomington, IN, USA.,Interdisciplinary Biochemistry Program, Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, IN, USA.,Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA
| | - Andrea G Hohmann
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA. .,Program in Neuroscience, Indiana University, Bloomington, IN, USA. .,Interdisciplinary Biochemistry Program, Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, IN, USA. .,Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA.
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Tudurí E, Imbernon M, Hernández-Bautista RJ, Tojo M, Fernø J, Diéguez C, Nogueiras R. GPR55: a new promising target for metabolism? J Mol Endocrinol 2017; 58:R191-R202. [PMID: 28196832 DOI: 10.1530/jme-16-0253] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 02/14/2017] [Indexed: 01/05/2023]
Abstract
GPR55 is a G-protein-coupled receptor (GPCR) that has been identified as a new cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral tissues, this receptor has emerged as a regulator of multiple biological actions. Lysophosphatidylinositol (LPI) is generally accepted as the endogenous ligand of GPR55. In this review, we will focus on the role of GPR55 in energy balance and glucose metabolism. We will summarize its actions on feeding, nutrient partitioning, gastrointestinal motility and insulin secretion in preclinical models and the scarce data available in humans. The potential of GPR55 to become a new pharmaceutical target to treat obesity and type 2 diabetes, as well as the foreseeing difficulties are also discussed.
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Affiliation(s)
- Eva Tudurí
- Instituto de Investigaciones Sanitarias (IDIS)CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
| | - Monica Imbernon
- Instituto de Investigaciones Sanitarias (IDIS)CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
- Department of PhysiologyCIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Rene Javier Hernández-Bautista
- Instituto de Investigaciones Sanitarias (IDIS)CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
- Department of PhysiologyCIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Marta Tojo
- Instituto de Investigaciones Sanitarias (IDIS)CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
- Department of PhysiologyCIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Johan Fernø
- Department of Clinical ScienceKG Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway
| | - Carlos Diéguez
- Instituto de Investigaciones Sanitarias (IDIS)CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
- Department of PhysiologyCIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Rubén Nogueiras
- Instituto de Investigaciones Sanitarias (IDIS)CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
- Department of PhysiologyCIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
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Hasenoehrl C, Storr M, Schicho R. Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go? Expert Rev Gastroenterol Hepatol 2017; 11:329-337. [PMID: 28276820 PMCID: PMC5388177 DOI: 10.1080/17474124.2017.1292851] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 02/06/2017] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Fifty years after the discovery of Δ9-tetrahydrocannabinol (THC) as the psychoactive component of Cannabis, we are assessing the possibility of translating this herb into clinical treatment of inflammatory bowel diseases (IBDs). Here, a discussion on the problems associated with a potential treatment is given. From first surveys and small clinical studies in patients with IBD we have learned that Cannabis is frequently used to alleviate diarrhea, abdominal pain, and loss of appetite. Single ingredients from Cannabis, such as THC and cannabidiol, commonly described as cannabinoids, are responsible for these effects. Synthetic cannabinoid receptor agonists are also termed cannabinoids, some of which, like dronabinol and nabilone, are already available with a narcotic prescription. Areas covered: Recent data on the effects of Cannabis/cannabinoids in experimental models of IBD and in clinical trials with IBD patients have been reviewed using a PubMed database search. A short background on the endocannabinoid system is also provided. Expert commentary: Cannabinoids could be helpful for certain symptoms of IBD, but there is still a lack of clinical studies to prove efficacy, tolerability and safety of cannabinoid-based medication for IBD patients, leaving medical professionals without evidence and guidelines.
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Affiliation(s)
- Carina Hasenoehrl
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Martin Storr
- Department of Medicine, Ludwig-Maximilians University, Munich, Germany
- Zentrum für Endoskopie, Starnberg, Germany
| | - Rudolf Schicho
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
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Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a lifelong disease of the gastrointestinal tract whose annual incidence and prevalence is on the rise. Current immunosuppressive therapies available for treatment of IBD offer limited benefits and lose effectiveness, exposing a significant need for the development of novel therapies. In the clinical setting, cannabis has been shown to provide patients with IBD symptomatic relief, although the underlying mechanisms of their anti-inflammatory effects remain unclear. METHODS This review reflects our current understanding of how targeting the endocannabinoid system, including cannabinoid receptors 1 and 2, endogenous cannabinoids anandamide and 2-arachidonoylglycerol, atypical cannabinoids, and degrading enzymes including fatty acid amide hydrolase and monoacylglycerol lipase, impacts murine colitis. In addition, the impact of cannabinoids on the human immune system is summarized. RESULTS Cannabinoid receptors 1 and 2, endogenous cannabinoids, and atypical cannabinoids are upregulated in inflammation, and their presence and stimulation attenuate murine colitis, whereas cannabinoid receptor antagonism and cannabinoid receptor deficient models reverse these anti-inflammatory effects. In addition, inhibition of endocannabinoid degradation through monoacylglycerol lipase and fatty acid amide hydrolase blockade can also attenuate colitis development, and is closely linked to cannabinoid receptor expression. CONCLUSIONS Although manipulation of the endocannabinoid system in murine colitis has proven to be largely beneficial in attenuating inflammation, there is a paucity of human study data. Further research is essential to clearly elucidate the specific mechanisms driving this anti-inflammatory effect for the development of therapeutics to target inflammatory disease such as IBD.
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