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Son SE, Im DS. GPR55 antagonist CID16020046 suppresses DNCB-induced atopic dermatitis-like symptoms by suppressing Th1/Th2/Th17 populations in mice. Eur J Pharmacol 2024; 985:177088. [PMID: 39486767 DOI: 10.1016/j.ejphar.2024.177088] [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: 02/14/2024] [Revised: 10/11/2024] [Accepted: 10/30/2024] [Indexed: 11/04/2024]
Abstract
G protein-coupled receptor 55 (GPR55) is a lipid-sensing receptor that plays a role as an immune mediator and is primarily upregulated during immune cell activation. There is a lack of knowledge about the role of GPR55 in allergic inflammatory diseases such as atopic dermatitis. The purpose of this study was to investigate the role of GPR55 through the use of its antagonist, CID16020046, in an atopic dermatitis mouse model. It was found that BALB/c mice develop lesions similar to those associated with atopic dermatitis following sensitization and repeated exposure to 1-chloro-2,4-dinitrobenzene (DNCB). It was found that CID16020046 (1 mg/kg, i. p.) alleviated the atopic dermatitis-like symptoms as well as immune dysregulation caused by DNCB. Based on histopathological analysis, CID16020046 reduced ear thickening and mast cell counts in the dermis. CID16020046 decreased DNCB-induced increases in serum IgE levels, as measured using enzyme-linked immunosorbent assays. A significant reduction in lymph node hypertrophy was also observed with CID16020046 as well as significant reductions in CD4+ T helper 1 (Th1), Th2, and Th17 cells in the lymph nodes. As a result of the administration of CID16020046, cytokines of Th1 (IFN-γ), Th2 (IL-4 and IL-13), and Th17 (IL-17 A) types were also reduced in the skin and lymph nodes. In conclusion, blocking GPR55 alleviates DNCB-induced atopic dermatitis-like symptoms, suggesting that GPR55 is a potential therapeutic target for allergic inflammatory diseases via immunoregulation.
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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
| | - Dong-Soon Im
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea; Department of Basic Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
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2
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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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Hidalgo I, Sorolla MA, Sorolla A, Salud A, Parisi E. Secreted Phospholipases A2: Drivers of Inflammation and Cancer. Int J Mol Sci 2024; 25:12408. [PMID: 39596471 PMCID: PMC11594849 DOI: 10.3390/ijms252212408] [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: 10/02/2024] [Revised: 11/08/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
Secreted phospholipase 2 (sPLA2) is the largest family of phospholipase A2 (PLA2) enzymes with 11 mammalian isoforms. Each sPLA2 exhibits different localizations and specific properties, being involved in a very wide spectrum of biological processes. The enzymatic activity of sPLA2 has been well described; however, recent findings have shown that they could regulate different signaling pathways by acting directly as ligands. Arachidonic acid (AA) and its derivatives are produced by sPLA2 in collaboration with other molecules in the extracellular space, making important impacts on the cellular environment, being especially relevant in the contexts of immunity and cancer. For these reasons, this review focuses on sPLA2 functions in processes such as the promotion of EMT, angiogenesis, and immunomodulation in the context of tumor initiation and progression. Finally, we will also describe how this knowledge has been applied in the search for new sPLA2 inhibitory compounds that can be used for cancer treatment.
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Affiliation(s)
- Ivan Hidalgo
- Research Group of Cancer Biomarkers, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
| | - Maria Alba Sorolla
- Research Group of Cancer Biomarkers, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
| | - Anabel Sorolla
- Research Group of Cancer Biomarkers, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
| | - Antonieta Salud
- Research Group of Cancer Biomarkers, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
- Department of Medical Oncology, Arnau de Vilanova University Hospital (HUAV), 25198 Lleida, Spain
- Department of Medicine, University of Lleida, 25198 Lleida, Spain
| | - Eva Parisi
- Research Group of Cancer Biomarkers, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
- Department of Experimental Medicine, University of Lleida, 25198 Lleida, Spain
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4
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Luo B. Insights into the advances in therapeutic drugs for neuroinflammation-related diseases. Int J Neurosci 2024; 134:1256-1281. [PMID: 37722706 DOI: 10.1080/00207454.2023.2260088] [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: 08/11/2023] [Revised: 09/05/2023] [Accepted: 09/12/2023] [Indexed: 09/20/2023]
Abstract
Studies have shown that neurodegenerative diseases such as AD and PD are related to neuroinflammation. Neuroinflammation is a common inflammatory condition that can lead to a variety of dysfunction in the body. At present, it is no medications specifically approved to prevent or cure neuroinflammation, so even though many drugs can temporarily control the neurological symptoms of neuroinflammation, but no one can reverse the progress of neuroinflammation, let al.one completely cure neuroinflammation. Therefore, it is urgent to develop new drug development for neuroinflammation treatment. In this review, we highlight the therapeutic advancement in the field of neurodegenerative disorders, by focusing on the impact of neuroinflammation treatment has on these conditions, and the effective drugs for the treatment of neuroinflammation and neurodegenerative diseases and their latest research progress are reviewed according to the related signaling pathway, as well as the prospect of their clinical application is also discussed. The purpose of this review is to enable specialists to better understand the mechanisms underlying neuroinflammation and anti-inflammatory drugs, promote the development of therapeutic drugs for neuroinflammation and neurodegenerative diseases, and further provide therapeutic references for clinical neurologists.
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Affiliation(s)
- Bozhi Luo
- School of Basic Medicine, Hengyang Medical College, University of South China, Hengyang, China
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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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Jin C, Chen H, Xie L, Zhou Y, Liu LL, Wu J. GPCRs involved in metabolic diseases: pharmacotherapeutic development updates. Acta Pharmacol Sin 2024; 45:1321-1336. [PMID: 38326623 PMCID: PMC11192902 DOI: 10.1038/s41401-023-01215-2] [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: 09/21/2023] [Accepted: 12/11/2023] [Indexed: 02/09/2024]
Abstract
G protein-coupled receptors (GPCRs) are expressed in a variety of cell types and tissues, and activation of GPCRs is involved in enormous metabolic pathways, including nutrient synthesis, transportation, storage or insulin sensitivity, etc. This review intends to summarize the regulation of metabolic homeostasis and mechanisms by a series of GPCRs, such as GPR91, GPR55, GPR119, GPR109a, GPR142, GPR40, GPR41, GPR43 and GPR120. With deep understanding of GPCR's structure and signaling pathways, it is attempting to uncover the role of GPCRs in major metabolic diseases, including metabolic syndrome, diabetes, dyslipidemia and nonalcoholic steatohepatitis, for which the global prevalence has risen during last two decades. An extensive list of agonists and antagonists with their chemical structures in a nature of small molecular compounds for above-mentioned GPCRs is provided as pharmacologic candidates, and their preliminary data of preclinical studies are discussed. Moreover, their beneficial effects in correcting abnormalities of metabolic syndrome, diabetes and dyslipidemia are summarized when clinical trials have been undertaken. Thus, accumulating data suggest that these agonists or antagonists might become as new pharmacotherapeutic candidates for the treatment of metabolic diseases.
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Affiliation(s)
- Cheng Jin
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
- College of Clinical Medicine, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Hui Chen
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Li Xie
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Yuan Zhou
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Li-Li Liu
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, 200032, China.
| | - Jian Wu
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China.
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, 200032, China.
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7
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Sharon N, Yarmolinsky L, Khalfin B, Fleisher-Berkovich S, Ben-Shabat S. Cannabinoids' Role in Modulating Central and Peripheral Immunity in Neurodegenerative Diseases. Int J Mol Sci 2024; 25:6402. [PMID: 38928109 PMCID: PMC11204381 DOI: 10.3390/ijms25126402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/30/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Cannabinoids (the endocannabinoids, the synthetic cannabinoids, and the phytocannabinoids) are well known for their various pharmacological properties, including neuroprotective and anti-inflammatory features, which are fundamentally important for the treatment of neurodegenerative diseases. The aging of the global population is causing an increase in these diseases that require the development of effective drugs to be even more urgent. Taking into account the unavailability of effective drugs for neurodegenerative diseases, it seems appropriate to consider the role of cannabinoids in the treatment of these diseases. To our knowledge, few reviews are devoted to cannabinoids' impact on modulating central and peripheral immunity in neurodegenerative diseases. The objective of this review is to provide the best possible information about the cannabinoid receptors and immuno-modulation features, peripheral immune modulation by cannabinoids, cannabinoid-based therapies for the treatment of neurological disorders, and the future development prospects of making cannabinoids versatile tools in the pursuit of effective drugs.
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Affiliation(s)
| | | | | | | | - Shimon Ben-Shabat
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel; (N.S.); (L.Y.); (B.K.); (S.F.-B.)
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8
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Gajghate S, Li H, Rom S. GPR55 Inactivation Diminishes Splenic Responses and Improves Neurological Outcomes in the Mouse Ischemia/Reperfusion Stroke Model. Cells 2024; 13:280. [PMID: 38334672 PMCID: PMC10855118 DOI: 10.3390/cells13030280] [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: 12/06/2023] [Revised: 01/30/2024] [Accepted: 01/31/2024] [Indexed: 02/10/2024] Open
Abstract
Although strokes are frequent and severe, treatment options are scarce. Plasminogen activators, the only FDA-approved agents for clot treatment (tissue plasminogen activators (tPAs)), are used in a limited patient group. Moreover, there are few approaches for handling the brain's inflammatory reactions to a stroke. The orphan G protein-coupled receptor 55 (GPR55)'s connection to inflammatory processes has been recently reported; however, its role in stroke remains to be discovered. Post-stroke neuroinflammation involves the central nervous system (CNS)'s resident microglia activation and the infiltration of leukocytes from circulation into the brain. Additionally, splenic responses have been shown to be detrimental to stroke recovery. While lymphocytes enter the brain in small numbers, they regularly emerge as a very influential leukocyte subset that causes secondary inflammatory cerebral damage. However, an understanding of how this limited lymphocyte presence profoundly impacts stroke outcomes remains largely unclear. In this study, a mouse model for transient middle cerebral artery occlusion (tMCAO) was used to mimic ischemia followed by a reperfusion (IS/R) stroke. GPR55 inactivation, with a potent GPR55-specific antagonist, ML-193, starting 6 h after tMCAO or the absence of the GPR55 in mice (GPR55 knock out (GPR55ko)) resulted in a reduced infarction volume, improved neurological outcomes, and decreased splenic responses. The inhibition of GPR55 with ML-193 diminished CD4+T-cell spleen egress and attenuated CD4+T-cell brain infiltration. Additionally, ML-193 treatment resulted in an augmented number of regulatory T cells (Tregs) in the brain post-tMCAO. Our report offers documentation and the functional evaluation of GPR55 in the brain-spleen axis and lays the foundation for refining therapeutics for patients after ischemic attacks.
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Affiliation(s)
- Sachin Gajghate
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Hongbo Li
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA;
| | - Slava Rom
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA;
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9
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Thapa D, Warne LN, Falasca M. Pharmacohistory of Cannabis Use-A New Possibility in Future Drug Development for Gastrointestinal Diseases. Int J Mol Sci 2023; 24:14677. [PMID: 37834122 PMCID: PMC10572150 DOI: 10.3390/ijms241914677] [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: 08/19/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
Humans have employed cannabis for multiple uses including medicine, recreation, food, and fibre. The various components such as roots, flowers, seeds, and leaves have been utilized to alleviate pain, inflammation, anxiety, and gastrointestinal disorders like nausea, vomiting, diarrhoea, and inflammatory bowel diseases (IBDs). It has occupied a significant space in ethnomedicines across cultures and religions. Despite multi-dimensional uses, the global prohibition of cannabis by the USA through the introduction of the Marijuana Tax Act in 1937 led to prejudice about the perceived risks of cannabis, overshadowing its medicinal potential. Nevertheless, the discovery of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, and the endocannabinoid system renewed scientific interest in understanding the role of cannabis in modulating different conditions, including gastrointestinal disorders. Preparations combining cannabidiol and THC have shown promise in mitigating gut symptoms through anti-inflammatory and motility-enhancing effects. This review revisits the ethnomedicinal use of cannabis in gastrointestinal diseases and emphasizes the need for further research to determine optimal dosages, formulations, and safety profiles of cannabis-based medicines. It also underscores the future potential of cannabinoid-based therapies by leveraging the role of the expanded endocannabinoid system, an endocannabinoidome, in the modulation of gastrointestinal ailments.
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Affiliation(s)
- Dinesh Thapa
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (D.T.); (L.N.W.)
| | - Leon N. Warne
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (D.T.); (L.N.W.)
- Little Green Pharma, West Perth, WA 6872, Australia
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (D.T.); (L.N.W.)
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10
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Wang T, Xia K, Qiu T, Han S, Chen Z, Ma X, Zhang L, Zou J, Zhang Y, Yu B, Kong C, Guo J, Liu Y, Zhou J, Zheng S. A comprehensive survival and prognosis analysis of GPR55 expression in hepatocellular carcinoma. Aging (Albany NY) 2023; 15:8930-8947. [PMID: 37688769 PMCID: PMC10522392 DOI: 10.18632/aging.205008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 08/20/2023] [Indexed: 09/11/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common subtype, accounting for about 90% of all primary liver cancers. The liver is rich in a large number of immune cells, thus forming a special immune microenvironment, which plays a key role in the occurrence and development of hepatocellular carcinoma. Nowadays, tumor immunotherapy has become one of the most promising cancer treatment methods. Immune checkpoint inhibitors (ICIs) combined with VEGF inhibitors are listed as first-line treatment options for advanced HCC. Therefore, the search for a potential biomarker to predict the response to immunotherapy in HCC patients is urgently needed. The G protein-coupled receptor 55 (GPR55), a lysophosphatidylinositol (LPI) receptor, has recently emerged as a potential new target for anti-tumor therapy. Previous studies have found that GPR55 is highly expressed in breast cancer, pancreatic cancer, skin cancer and cholangiocarcinoma, and is involved in tumor proliferation and migration. However, the role and mechanism of GPR55 in HCC has not been elucidated. Therefore, this article discusses the clinical significance of GPR55 in HCC and its correlation with the immune response of HCC patients, so as to provide theoretical basis for improving the prognosis of HCC.
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Affiliation(s)
- Tianyu Wang
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Kang Xia
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Tao Qiu
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shangting Han
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhongbao Chen
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoxiong Ma
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Long Zhang
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jilin Zou
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yalong Zhang
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Bo Yu
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chenyang Kong
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jiayu Guo
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yiting Liu
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jiangqiao Zhou
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shusen Zheng
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, Zhejiang, China
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Shimai R, Hanafusa K, Nakayama H, Oshima E, Kato M, Kano K, Matsuo I, Miyazaki T, Tokano T, Hirabayashi Y, Iwabuchi K, Minamino T. Lysophosphatidylglucoside/GPR55 signaling promotes foam cell formation in human M2c macrophages. Sci Rep 2023; 13:12740. [PMID: 37544935 PMCID: PMC10404585 DOI: 10.1038/s41598-023-39904-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 08/01/2023] [Indexed: 08/08/2023] Open
Abstract
Atherosclerosis is a major cause of cerebral and cardiovascular diseases. Intravascular plaques, a well-known pathological finding of atherosclerosis, have a necrotic core composed of macrophages and dead cells. Intraplaque macrophages, which are classified into various subtypes, play key roles in maintenance of normal cellular microenvironment. Excessive uptake of oxidized low-density lipoprotein causes conversion of macrophages to foam cells, and consequent progression/exacerbation of atherosclerosis. G-protein-coupled receptor 55 (GPR55) signaling has been reported to associate with atherosclerosis progression. We demonstrated recently that lysophosphatidylglucoside (lysoPtdGlc) is a specific ligand of GPR55, although in general physiological ligands of GPR55 are poorly understood. Phosphatidylglucoside is expressed on human monocytes and can be converted to lysoPtdGlc. In the present study, we examined possible involvement of lysoPtdGlc/GPR55 signaling in foam cell formation. In monocyte-derived M2c macrophages, lysoPtdGlc/GPR55 signaling inhibited translocation of ATP binding cassette subfamily A member 1 to plasma membrane, and cholesterol efflux. Such inhibitory effect was reversed by GPR55 antagonist ML193. LysoPtdGlc/GPR55 signaling in M2c macrophages was involved in excessive lipid accumulation, thereby promoting foam cell formation. Our findings suggest that lysoPtdGlc/GPR55 signaling is a potential therapeutic target for inhibition of atherosclerosis progression.
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Affiliation(s)
- Ryosuke Shimai
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Tomioka, Urayasu, Chiba, 279-0021, Japan
| | - Kei Hanafusa
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Tomioka, Urayasu, Chiba, 279-0021, Japan
| | - Hitoshi Nakayama
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Tomioka, Urayasu, Chiba, 279-0021, Japan
- Infection Control Nursing, Juntendo University Graduate School of Health Care and Nursing, 2-5-1 Takasu, Urayasu, Chiba, 279-0021, Japan
| | - Eriko Oshima
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Tomioka, Urayasu, Chiba, 279-0021, Japan
| | - Masaki Kato
- Laboratory for Transcriptome Technology, RIKEN Center for Integrative Medical Sciences, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
| | - Koki Kano
- Division of Molecular Science, Gunma University, Kiryu, Gunma, 376-8515, Japan
| | - Ichiro Matsuo
- Division of Molecular Science, Gunma University, Kiryu, Gunma, 376-8515, Japan
| | - Tetsuro Miyazaki
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Takashi Tokano
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Yoshio Hirabayashi
- RIKEN Cluster for Pioneering Research, RIKEN, 2-1, Hirosawa, Wako, Saitama, 351-0198, Japan
| | - Kazuhisa Iwabuchi
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Tomioka, Urayasu, Chiba, 279-0021, Japan.
- Infection Control Nursing, Juntendo University Graduate School of Health Care and Nursing, 2-5-1 Takasu, Urayasu, Chiba, 279-0021, Japan.
- Preparation Office for Establishment of the Faculty of Pharmaceutical Science, Juntendo University, 6-8-1 Hinode , Urayasu, Chiba, 279-0013, Japan.
| | - Tohru Minamino
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
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12
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Wang B, Li D, Fiselier A, Kovalchuk I, Kovalchuk O. High-CBD cannabis extracts inhibit the expression of proinflammatory factors via miRNA-mediated silencing in human small intestinal epithelial cells. Heliyon 2023; 9:e18817. [PMID: 37664748 PMCID: PMC10468390 DOI: 10.1016/j.heliyon.2023.e18817] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 09/05/2023] Open
Abstract
The incidence of chronic inflammatory disorders and autoimmune diseases is rapidly growing. To date, the COVID-19 pandemic caused by SARS-CoV-2 has killed over 6,209,000 people globally, while no drug has been proven effective for the disease. Screening natural anti-inflammatory compounds for clinical application has drawn much attention. In this study, we showed that high-CBD cannabis extracts #1, #5, #7, #169, and #317 suppressed the levels of expression of proinflammatory cyclooxygenase 2 (COX2) and increased the expression of the anti-inflammatory suppressor of cytokine signaling 3 (SOCS3) in human small intestinal epithelial cells (HSIEC) in TNFα/IFNγ-triggered inflammation. We revealed that these extracts, with the exception of extract #169, also profoundly attenuated induction of proinflammatory cytokines interleukin-6 (IL-6) and/or IL-8 proteins through miR-760- and miR-302c-3p-mediated silencing. The prevalent components in extracts #1 and #7 influenced the levels of IL-8 both individually as well as in combination with each other. However, the high-dose cannabis extracts displayed an inhibitory effect in the growth of HSIEC cells. These results show that our high-CBD cannabis extracts decrease the levels of proinflammatory molecules COX2, IL-6, and IL-8 via transcriptional suppression or miRNA-mediated silencing, highlighting their potential against COVID-19-associated cytokine storm syndrome.
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Affiliation(s)
- Bo Wang
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, T1K 3M4, Canada
- Pathway Rx Inc., Calgary, Alberta, T3H 4Z2, Canada
| | - Dongping Li
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, T1K 3M4, Canada
- Pathway Rx Inc., Calgary, Alberta, T3H 4Z2, Canada
| | - Anna Fiselier
- Pathway Rx Inc., Calgary, Alberta, T3H 4Z2, Canada
- Swysh Inc., Calgary, Alberta, T3H 4Z2, Canada
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, T1K 3M4, Canada
- Pathway Rx Inc., Calgary, Alberta, T3H 4Z2, Canada
- Swysh Inc., Calgary, Alberta, T3H 4Z2, Canada
| | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, T1K 3M4, Canada
- Pathway Rx Inc., Calgary, Alberta, T3H 4Z2, Canada
- Swysh Inc., Calgary, Alberta, T3H 4Z2, Canada
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13
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Venneri T, Giorgini G, Leblanc N, Flamand N, Borrelli F, Silvestri C, Di Marzo V. Altered endocannabinoidome bioactive lipid levels accompany reduced DNBS-induced colonic inflammation in germ-free mice. Lipids Health Dis 2023; 22:63. [PMID: 37189092 DOI: 10.1186/s12944-023-01823-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 04/24/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND Gut microbiota are involved in the onset and development of chronic intestinal inflammation. The recently described endocannabinoidome (eCBome), a diverse and complex system of bioactive lipid mediators, has been reported to play a role in various physio-pathological processes such as inflammation, immune responses and energy metabolism. The eCBome and the gut microbiome (miBIome) are closely linked and form the eCBome - miBIome axis, which may be of special relevance to colitis. METHODS Colitis was induced in conventionally raised (CR), antibiotic-treated (ABX) and germ-free (GF) mice with dinitrobenzene sulfonic acid (DNBS). Inflammation was assessed by Disease Activity Index (DAI) score, body weight change, colon weight-length ratio, myeloperoxidase (MPO) activity and cytokine gene expression. Colonic eCBome lipid mediator concentrations were measured by HPLC-MS /MS. RESULTS GF mice showed increased levels of anti-inflammatory eCBome lipids (LEA, OEA, DHEA and 13- HODE-EA) in the healthy state and higher MPO activity. DNBS elicited reduced inflammation in GF mice, having lower colon weight/length ratios and lower expression levels of Il1b, Il6, Tnfa and neutrophil markers compared to one or both of the other DNBS-treated groups. Il10 expression was also lower and the levels of several N-acyl ethanolamines and 13-HODE-EA levels were higher in DNBS-treated GF mice than in CR and ABX mice. The levels of these eCBome lipids negatively correlated with measures of colitis and inflammation. CONCLUSIONS These results suggest that the depletion of the gut microbiota and subsequent differential development of the gut immune system in GF mice is followed by a compensatory effect on eCBome lipid mediators, which may explain, in part, the observed lower susceptibility of GF mice to develop DNBS-induced colitis.
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Affiliation(s)
- Tommaso Venneri
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Giada Giorgini
- Joint International Research Unit (JIRU) for Chemical and Biomolecular Research on the Microbiome and its impact on Metabolic Health and Nutrition (MicroMeNu) between Université Laval and the Consiglio Nazionale delle Ricerche (CNR), Institute of Biomolecular Chemistry, Pozzuoli, NA, Italy
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada
| | - Nadine Leblanc
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada
| | - Nicolas Flamand
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada
| | - Francesca Borrelli
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Cristoforo Silvestri
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada.
- Centre NUTRISS, École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, Canada.
| | - Vincenzo Di Marzo
- Joint International Research Unit (JIRU) for Chemical and Biomolecular Research on the Microbiome and its impact on Metabolic Health and Nutrition (MicroMeNu) between Université Laval and the Consiglio Nazionale delle Ricerche (CNR), Institute of Biomolecular Chemistry, Pozzuoli, NA, Italy.
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada.
- Centre NUTRISS, École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, Canada.
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, Canada.
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14
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McCloskey AG, Miskelly MG, Lafferty RA, Flatt PR, McKillop AM. Antidiabetic actions of GPR55 agonist Abn-CBD and sitagliptin in obese-diabetic high fat fed mice. Biochem Pharmacol 2023; 208:115398. [PMID: 36581052 DOI: 10.1016/j.bcp.2022.115398] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 12/27/2022]
Abstract
GPR55 has been recognized as a novel anti-diabetic target exerting positive effects on beta cell function and mass. This study evaluated the metabolic actions and therapeutic efficacy of GPR55 agonist abnormal cannabidiol (Abn-CBD) administered alone and in combination with sitagliptin in diet-induced obese-diabetic mice. Chronic effects of 21-day oral administration of Abn-CBD (0.1 µmol/kg BW) monotherapy and in combination with sitagliptin (50 mg/kg BW) were assessed in obese-diabetic HFF mice (n = 8). Assessments of plasma glucose, circulating insulin, DPP-IV activity, CRP, amylase, lipids, body weight and food intake were undertaken. Glucose tolerance, insulin sensitivity, DEXA scanning and islet morphology analysis were performed at 21-days. Sitagliptin, Abn-CBD alone and in combination with sitagliptin attenuated plasma glucose by 37-53 % (p < 0.01 - p < 0.001) and enhanced circulating insulin concentrations by 23-31 % (p < 0.001). Abn-CBD alone and with sitagliptin reduced bodyweight by 9-10 % (p < 0.05). After 21-days, Abn-CBD in combination with sitagliptin (44 %; p < 0.01) improved glucose tolerance, whilst enhancing insulin sensitivity by 79 % (p < 0.01). Abn-CBD increased islet area (86 %; p < 0.05), beta cell mass (p < 0.05) and beta cell proliferation (164 %; p < 0.001), whilst in combination with sitagliptin islet area was decreased (50 %; p < 0.01). Abn-CBD alone, in combination with sitagliptin or sitagliptin alone decreased triglycerides by 34-65 % (p < 0.001) and total cholesterol concentrations by 15-25 % (p < 0.001). In addition, Abn-CBD in combination with sitagliptin reduced fat mass by 19 % (p < 0.05) and reduced CRP concentrations (39 %; p < 0.05). These findings advocate Abn-CBD monotherapy and in combination with sitagliptin as a novel and effective approach for bodyweight control and the treatment of glucose intolerance and dyslipidaemia in type-2-diabetes.
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Affiliation(s)
- Andrew G McCloskey
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, U.K; Health and Biomedical Research Centre (HEAL), Atlantic Technological University, ATU Sligo, Ash Lane, Sligo, F91 YW50, Ireland
| | - Michael G Miskelly
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, U.K
| | - Ryan A Lafferty
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, U.K
| | - Peter R Flatt
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, U.K
| | - Aine M McKillop
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, U.K.
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15
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Coccurello R, Marrone MC, Maccarrone M. The Endocannabinoids-Microbiota Partnership in Gut-Brain Axis Homeostasis: Implications for Autism Spectrum Disorders. Front Pharmacol 2022; 13:869606. [PMID: 35721203 PMCID: PMC9204215 DOI: 10.3389/fphar.2022.869606] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 04/20/2022] [Indexed: 11/13/2022] Open
Abstract
The latest years have witnessed a growing interest towards the relationship between neuropsychiatric disease in children with autism spectrum disorders (ASD) and severe alterations in gut microbiota composition. In parallel, an increasing literature has focused the attention towards the association between derangement of the endocannabinoids machinery and some mechanisms and symptoms identified in ASD pathophysiology, such as alteration of neural development, immune system dysfunction, defective social interaction and stereotypic behavior. In this narrative review, we put together the vast ground of endocannabinoids and their partnership with gut microbiota, pursuing the hypothesis that the crosstalk between these two complex homeostatic systems (bioactive lipid mediators, receptors, biosynthetic and hydrolytic enzymes and the entire bacterial gut ecosystem, signaling molecules, metabolites and short chain fatty acids) may disclose new ideas and functional connections for the development of synergic treatments combining “gut-therapy,” nutritional intervention and pharmacological approaches. The two separate domains of the literature have been examined looking for all the plausible (and so far known) overlapping points, describing the mutual changes induced by acting either on the endocannabinoid system or on gut bacteria population and their relevance for the understanding of ASD pathophysiology. Both human pathology and symptoms relief in ASD subjects, as well as multiple ASD-like animal models, have been taken into consideration in order to provide evidence of the relevance of the endocannabinoids-microbiota crosstalk in this major neurodevelopmental disorder.
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Affiliation(s)
- Roberto Coccurello
- Institute for Complex Systems (ISC), National Council of Research (CNR), Rome, Italy
- European Center for Brain Research/Santa Lucia Foundation IRCCS, Rome, Italy
- *Correspondence: Roberto Coccurello, ; Mauro Maccarrone,
| | - Maria Cristina Marrone
- Ministry of University and Research, Mission Unity for Recovery and Resilience Plan, Rome, Italy
| | - Mauro Maccarrone
- European Center for Brain Research/Santa Lucia Foundation IRCCS, Rome, Italy
- Department of Biotechnological and Applied Clinical and Sciences, University of L’Aquila, L’Aquila, Italy
- *Correspondence: Roberto Coccurello, ; Mauro Maccarrone,
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16
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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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17
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Feng Z, Sun R, Cong Y, Liu Z. Critical roles of G protein-coupled receptors in regulating intestinal homeostasis and inflammatory bowel disease. Mucosal Immunol 2022; 15:819-828. [PMID: 35732818 DOI: 10.1038/s41385-022-00538-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/29/2022] [Accepted: 06/05/2022] [Indexed: 02/04/2023]
Abstract
G protein-coupled receptors (GPCRs) are a group of membrane proteins that mediate most of the physiological responses to various signaling molecules such as hormones, neurotransmitters, and environmental stimulants. Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract and presents a spectrum of heterogeneous disorders falling under two main clinical subtypes including Crohn's disease (CD) and ulcerative colitis (UC). The pathogenesis of IBD is multifactorial and is related to a genetically dysregulated mucosal immune response to environmental drivers, mainly microbiotas. Although many drugs, such as 5-aminosalicylic acid, glucocorticoids, immunosuppressants, and biological agents, have been approved for IBD treatment, none can cure IBD permanently. Emerging evidence indicates significant associations between GPCRs and the pathogenesis of IBD. Here, we provide an overview of the essential physiological functions and signaling pathways of GPCRs and their roles in mucosal immunity and IBD regulation.
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Affiliation(s)
- Zhongsheng Feng
- Center for Inflammatory Bowel Disease Research, Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Ruicong Sun
- Center for Inflammatory Bowel Disease Research, Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Zhanju Liu
- Center for Inflammatory Bowel Disease Research, Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, China.
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18
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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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19
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Li WJ, Shen J. Antagonism of G protein-coupled receptor 55 prevents lipopolysaccharide-induced damages in human dental pulp cells. Hum Exp Toxicol 2022; 41:9603271221099598. [PMID: 35608548 DOI: 10.1177/09603271221099598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Pulpitis is a common oral inflammatory disease in dental pulp commonly associated with bacterial infection. G protein-coupled receptor 55 (GPR55) is a member of the G protein-coupled receptors family that has been found to regulate inflammatory response. However, its roles in dental pulp inflammation have not been investigated. In this study, we used lipopolysaccharide (LPS) to induce inflammation in human dental pulp cells (hDPCs) to simulate an in vitro model of pulpitis. We found that LPS markedly induced the GPR55 expression in hDPCs. Treatment with the GPR55 antagonist ML-193 ameliorated the LPS-caused decrease in cell viability and increase in lactate dehydrogenase release. The upregulated inflammatory cytokines, interleukin-6 (IL-6) and tumour necrosis factor α, in LPS-challenged hDPCs were also attenuated by ML-193. Treatment with ML-193 ameliorated LPS-induced production of the inflammatory mediators cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2), and inducible nitric oxide synthase/nitric oxide (iNOS/NO) in hDPCs. ML-193 also inhibited the activation of Toll-like receptor 4-myeloid differentiation primary response 88-nuclear factor-κB (TLR4-Myd88-NF-κB) signaling in LPS-induced hDPCs via decreased expressions of TLR4, Myd88, and p-NF-κB 65. Our study provides evidence that the GPR55 antagonist ML-193 exhibited anti-inflammatory activity in LPS-stimulated hDPCs through inhibiting TLR4-Myd88-NF-κB signaling. The results imply that ML-193 might be a novel agent for pulpitis.
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Affiliation(s)
- Wei-Jie Li
- Department of Stomatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jie Shen
- Department of Stomatology, 74753Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
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20
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Wu W, Li WX, Huang CH. Phospholipase A 2, a nonnegligible enzyme superfamily in gastrointestinal diseases. Biochimie 2021; 194:79-95. [PMID: 34974145 DOI: 10.1016/j.biochi.2021.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 12/25/2021] [Accepted: 12/28/2021] [Indexed: 11/16/2022]
Abstract
Gastrointestinal tract is important for digestion, absorption, detoxification and immunity. Gastrointestinal diseases are mainly caused by the imbalance of protective and attacking factors in gastrointestinal mucosa, which can seriously harm human health. Phospholipase A2 (PLA2) is a large family closely involved in lipid metabolism and is found in almost all human cells. A growing number of studies have revealed that its metabolites are deeply implicated in various inflammatory pathways and also regulates the maintenance of numerous biological events such as dietary digestion, membrane remodeling, barrier action, and host immunity. In addition to their phospholipase activity, some members of the superfamily also have other catalytic activities. Based on the in-depth effects of phospholipase A2 on bioactive lipid metabolism and inflammatory cytokines, PLA2 and its metabolites are likely to be involved in the pathogenesis, development or prevention of gastrointestinal diseases. Therefore, this review will focus on the physiological and pathogenic roles of several important PLA2 enzymes in the gastrointestinal tract, and reveals the potential of PLA2 as a therapeutic target for gastrointestinal diseases.
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Affiliation(s)
- Wei Wu
- Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi, China
| | - Wen-Xuan Li
- Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi, China
| | - Chun-Hong Huang
- School of Basic Medical Sciences, 330006, Nanchang University, Nanchang, Jiangxi, China.
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21
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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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22
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Xu K, Shao Y, Saaoud F, Gillespie A, Drummer C, Liu L, Lu Y, Sun Y, Xi H, Tükel Ç, Pratico D, Qin X, Sun J, Choi ET, Jiang X, Wang H, Yang X. Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation. Front Cardiovasc Med 2021; 8:773473. [PMID: 34912867 PMCID: PMC8668339 DOI: 10.3389/fcvm.2021.773473] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 10/04/2021] [Indexed: 12/14/2022] Open
Abstract
To determine whether pro-inflammatory lipid lysophosphatidylinositols (LPIs) upregulate the expressions of membrane proteins for adhesion/signaling and secretory proteins in human aortic endothelial cell (HAEC) activation, we developed an EC biology knowledge-based transcriptomic formula to profile RNA-Seq data panoramically. We made the following primary findings: first, G protein-coupled receptor 55 (GPR55), the LPI receptor, is expressed in the endothelium of both human and mouse aortas, and is significantly upregulated in hyperlipidemia; second, LPIs upregulate 43 clusters of differentiation (CD) in HAECs, promoting EC activation, innate immune trans-differentiation, and immune/inflammatory responses; 72.1% of LPI-upregulated CDs are not induced in influenza virus-, MERS-CoV virus- and herpes virus-infected human endothelial cells, which hinted the specificity of LPIs in HAEC activation; third, LPIs upregulate six types of 640 secretomic genes (SGs), namely, 216 canonical SGs, 60 caspase-1-gasdermin D (GSDMD) SGs, 117 caspase-4/11-GSDMD SGs, 40 exosome SGs, 179 Human Protein Atlas (HPA)-cytokines, and 28 HPA-chemokines, which make HAECs a large secretory organ for inflammation/immune responses and other functions; fourth, LPIs activate transcriptomic remodeling by upregulating 172 transcription factors (TFs), namely, pro-inflammatory factors NR4A3, FOS, KLF3, and HIF1A; fifth, LPIs upregulate 152 nuclear DNA-encoded mitochondrial (mitoCarta) genes, which alter mitochondrial mechanisms and functions, such as mitochondrial organization, respiration, translation, and transport; sixth, LPIs activate reactive oxygen species (ROS) mechanism by upregulating 18 ROS regulators; finally, utilizing the Cytoscape software, we found that three mechanisms, namely, LPI-upregulated TFs, mitoCarta genes, and ROS regulators, are integrated to promote HAEC activation. Our results provide novel insights into aortic EC activation, formulate an EC biology knowledge-based transcriptomic profile strategy, and identify new targets for the development of therapeutics for cardiovascular diseases, inflammatory conditions, immune diseases, organ transplantation, aging, and cancers.
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Affiliation(s)
- Keman Xu
- Centers of Cardiovascular Research, Inflammation and Lung Research, Philadelphia, PA, United States
| | - Ying Shao
- Centers of Cardiovascular Research, Inflammation and Lung Research, Philadelphia, PA, United States
| | - Fatma Saaoud
- Centers of Cardiovascular Research, Inflammation and Lung Research, Philadelphia, PA, United States
| | - Aria Gillespie
- Neural Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Charles Drummer
- Centers of Cardiovascular Research, Inflammation and Lung Research, Philadelphia, PA, United States
| | - Lu Liu
- Departments of Cardiovascular Sciences, Metabolic Disease Research, Thrombosis Research, Philadelphia, PA, United States
| | - Yifan Lu
- Centers of Cardiovascular Research, Inflammation and Lung Research, Philadelphia, PA, United States
| | - Yu Sun
- Centers of Cardiovascular Research, Inflammation and Lung Research, Philadelphia, PA, United States
| | - Hang Xi
- Departments of Cardiovascular Sciences, Metabolic Disease Research, Thrombosis Research, Philadelphia, PA, United States
| | - Çagla Tükel
- Center for Microbiology & Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Domenico Pratico
- Alzheimer's Center, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Xuebin Qin
- National Primate Research Center, Tulane University, Covington, LA, United States
| | - Jianxin Sun
- Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, United States
| | - Eric T. Choi
- Surgery (Division of Vascular and Endovascular Surgery), Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Xiaohua Jiang
- Centers of Cardiovascular Research, Inflammation and Lung Research, Philadelphia, PA, United States
- Departments of Cardiovascular Sciences, Metabolic Disease Research, Thrombosis Research, Philadelphia, PA, United States
| | - Hong Wang
- Departments of Cardiovascular Sciences, Metabolic Disease Research, Thrombosis Research, Philadelphia, PA, United States
| | - Xiaofeng Yang
- Centers of Cardiovascular Research, Inflammation and Lung Research, Philadelphia, PA, United States
- Departments of Cardiovascular Sciences, Metabolic Disease Research, Thrombosis Research, Philadelphia, PA, United States
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23
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Cherkasova V, Kovalchuk O, Kovalchuk I. Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer. Cancers (Basel) 2021; 13:4353. [PMID: 34503163 PMCID: PMC8430689 DOI: 10.3390/cancers13174353] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 08/25/2021] [Indexed: 01/02/2023] Open
Abstract
Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world's disease and mortality rates. The development of novel therapy is in critical need, and based on recent experimental data, cannabinoids could become excellent candidates. This review covered known experimental studies regarding the effects of cannabinoids on intestinal inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and treatment depends on the type of the disease, its etiology, driver mutations, and the expression levels of cannabinoid receptors. In this review, we describe the molecular changes of the endocannabinoid system in the pathologies of the large intestine, focusing on inflammation and cancer.
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Affiliation(s)
| | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 7X8, Canada;
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 7X8, Canada;
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24
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Polidoro G, Galiazzo G, Giancola F, Papadimitriou S, Kouki M, Sabattini S, Rigillo A, Chiocchetti R. Expression of cannabinoid and cannabinoid-related receptors in the oral mucosa of healthy cats and cats with chronic gingivostomatitis. J Feline Med Surg 2021; 23:679-691. [PMID: 33174485 PMCID: PMC10812186 DOI: 10.1177/1098612x20970510] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Feline chronic gingivostomatitis (FCGS) is an oral disease. Cats with FCGS experience intense oral pain. Some cats remain refractory to current therapies based on dental extraction and adjuvant medical treatment; it is therefore necessary to investigate alternative therapeutic targets involved in inflammatory mechanisms and pain, namely the endocannabinoid system (ECS). The present study investigated the expression of cannabinoid receptors type 1 (CB1R) and 2 (CB2R), and cannabinoid-related receptors G protein-coupled receptor 55 (GPR55), transient receptor potential ankyrin 1 (TRPA1) and serotonin 1a receptor (5-HT1aR), in the oral mucosa of healthy cats to determine whether there was altered expression and distribution in cats with FCGS. METHODS Samples of caudal oral mucosa were collected from eight control cats (CTRL cats) and from eight cats with FCGS (FCGS cats). Tissue samples were processed using an immunofluorescence assay with cat-specific antibodies, and the immunolabelling of the receptors studied was semiquantitatively evaluated. RESULTS The mucosal epithelium of the CTRL cats showed CB1R, TRPA1 and 5-HT1aR immunoreactivity (IR), while CB2R and GPR55 IR were generally not expressed. In the CTRL cats, the subepithelial inflammatory cells expressed CB2R, GPR55 and 5-HT1aR IR. In the FCGS cats, all the receptors studied were markedly upregulated in the epithelium and inflammatory infiltrate. CONCLUSIONS AND RELEVANCE Cannabinoid and cannabinoid-related receptors are widely expressed in the oral mucosa of healthy cats and are upregulated during the course of FCGS. The presence of cannabinoid and cannabinoid-related receptors in healthy tissues suggests the possible role of the ECS in the homeostasis of the feline oral mucosa, while their overexpression in the inflamed tissues of FCGS cats suggests the involvement of the ECS in the pathogenesis of this disease, with a possible role in the related inflammation and pain. Based on the present findings, ECS could be considered a potential therapeutic target for patients with FCGS.
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Affiliation(s)
- Giulia Polidoro
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), Alma Mater Studiorum University of Bologna, Bologna, Italy
- Companion Animal Clinic, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Giorgia Galiazzo
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Fiorella Giancola
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Serafeim Papadimitriou
- Companion Animal Clinic, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria Kouki
- Companion Animal Clinic, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Silvia Sabattini
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Antonella Rigillo
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Roberto Chiocchetti
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), Alma Mater Studiorum University of Bologna, Bologna, Italy
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25
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Graczyk M, Lewandowska AA, Dzierżanowski T. The Therapeutic Potential of Cannabis in Counteracting Oxidative Stress and Inflammation. Molecules 2021; 26:molecules26154551. [PMID: 34361704 PMCID: PMC8347461 DOI: 10.3390/molecules26154551] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/25/2021] [Accepted: 07/26/2021] [Indexed: 12/26/2022] Open
Abstract
Significant growth of interest in cannabis (Cannabis sativa L.), especially its natural anti-inflammatory and antioxidative properties, has been observed recently. This narrative review aimed to present the state of the art of research concerning the anti-inflammatory activity of all classes of cannabinoids published in the last five years. Multimodal properties of cannabinoids include their involvement in immunological processes, anti-inflammatory, and antioxidative effects. Cannabinoids and non-cannabinoid compounds of cannabis proved their anti-inflammatory effects in numerous animal models. The research in humans is missing, and the results are unconvincing. Although preclinical evidence suggests cannabinoids are of value in treating chronic inflammatory diseases, the clinical evidence is scarce, and further well-designed clinical trials are essential to determine the prospects for using cannabinoids in inflammatory conditions.
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Affiliation(s)
- Michał Graczyk
- Department of Palliative Care, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 87-100 Toruń, Poland;
| | | | - Tomasz Dzierżanowski
- Laboratory of Palliative Medicine, Department of Social Medicine and Public Health, Medical University of Warsaw, 02-007 Warsaw, Poland
- Correspondence:
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26
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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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27
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Pandelides Z, Aluru N, Thornton C, Watts HE, Willett KL. Transcriptomic Changes and the Roles of Cannabinoid Receptors and PPARγ in Developmental Toxicities Following Exposure to Δ9-Tetrahydrocannabinol and Cannabidiol. Toxicol Sci 2021; 182:44-59. [PMID: 33892503 PMCID: PMC8285010 DOI: 10.1093/toxsci/kfab046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Human consumption of cannabinoid-containing products during early life or pregnancy is rising. However, information about the molecular mechanisms involved in early life stage Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) toxicities is critically lacking. Here, larval zebrafish (Danio rerio) were used to measure THC- and CBD-mediated changes on transcriptome and the roles of cannabinoid receptors (Cnr) 1 and 2 and peroxisome proliferator activator receptor γ (PPARγ) in developmental toxicities. Transcriptomic profiling of 96-h postfertilization (hpf) cnr+/+ embryos exposed (6 - 96 hpf) to 4 μM THC or 0.5 μM CBD showed differential expression of 904 and 1095 genes for THC and CBD, respectively, with 360 in common. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched in the THC and CBD datasets included those related to drug, retinol, and steroid metabolism and PPAR signaling. The THC exposure caused increased mortality and deformities (pericardial and yolk sac edemas, reduction in length) in cnr1-/- and cnr2-/- fish compared with cnr+/+ suggesting Cnr receptors are involved in protective pathways. Conversely, the cnr1-/- larvae were more resistant to CBD-induced malformations, mortality, and behavioral alteration implicating Cnr1 in CBD-mediated toxicity. Behavior (decreased distance travelled) was the most sensitive endpoint to THC and CBD exposure. Coexposure to the PPARγ inhibitor GW9662 and CBD in cnr+/+ and cnr2-/- strains caused more adverse outcomes compared with CBD alone, but not in the cnr1-/- fish, suggesting that PPARγ plays a role in CBD metabolism downstream of Cnr1. Collectively, PPARγ, Cnr1, and Cnr2 play important roles in the developmental toxicity of cannabinoids with Cnr1 being the most critical.
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Affiliation(s)
- Zacharias Pandelides
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA
| | - Neelakanteswar Aluru
- Biology Department, Woods Hole Oceanographic Institution and Woods Hole Center for Oceans and Human Health, Woods Hole, Massachusetts 02543, USA
| | - Cammi Thornton
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA
| | - Haley E Watts
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA
| | - Kristine L Willett
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA
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28
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Minamihata T, Takano K, Moriyama M, Nakamura Y. Lysophosphatidylinositol, an Endogenous Ligand for G Protein-Coupled Receptor 55, Has Anti-inflammatory Effects in Cultured Microglia. Inflammation 2021; 43:1971-1987. [PMID: 32519268 DOI: 10.1007/s10753-020-01271-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Lysophosphatidylinositol (LysoPI), an endogenous ligand for G protein-coupled receptor (GPR) 55, has been known to show various functions in several tissues and cells; however, its roles in the central nervous system (CNS) are not well known. In particular, the detailed effects of LysoPI on microglial inflammatory responses remain unknown. Microglia is the immune cell that has important functions in maintaining immune homeostasis of the CNS. In this study, we explored the effects of LysoPI on inflammatory responses using the mouse microglial cell line BV-2, which was stimulated with lipopolysaccharide (LPS), and some results were confirmed also in rat primary microglia. LysoPI was found to reduce LPS-induced nitric oxide (NO) production and inducible NO synthase protein expression without affecting cell viability in BV-2 cells. LysoPI also suppressed intracellular generation of reactive oxygen species both in BV-2 cells and primary microglia and cytokine release in BV-2 cells. In addition, LysoPI treatment decreased phagocytic activity of LPS-stimulated BV-2 cells and primary microglia. The GPR55 antagonist CID16020046 completely inhibited LysoPI-induced downregulation of phagocytosis in BV-2 microglia, but did not affect the LysoPI-induced decrease in NO production. Our results suggest that LysoPI suppresses microglial phagocytosis via a GPR55-dependent pathway and NO production via a GPR55-independent pathway. LysoPI may contribute to neuroprotection in pathological conditions such as brain injury or neurodegenerative diseases, through its suppressive role in the microglial inflammatory response.
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Affiliation(s)
- Tomoki Minamihata
- Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, 1-58 Rinku Ourai Kita, Izumisano, Osaka, 598-8531, Japan
| | - Katsura Takano
- Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, 1-58 Rinku Ourai Kita, Izumisano, Osaka, 598-8531, Japan
| | - Mitsuaki Moriyama
- Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, 1-58 Rinku Ourai Kita, Izumisano, Osaka, 598-8531, Japan.
| | - Yoichi Nakamura
- Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, 1-58 Rinku Ourai Kita, Izumisano, Osaka, 598-8531, Japan
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29
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Mosca MG, Mangini M, Cioffi S, Barba P, Mariggiò S. Peptide targeting of lysophosphatidylinositol-sensing GPR55 for osteoclastogenesis tuning. Cell Commun Signal 2021; 19:48. [PMID: 33902596 PMCID: PMC8073907 DOI: 10.1186/s12964-021-00727-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 02/20/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The G-protein-coupled receptor GPR55 has been implicated in multiple biological activities, which has fuelled interest in its functional targeting. Its controversial pharmacology and often species-dependent regulation have impacted upon the potential translation of preclinical data involving GPR55. RESULTS With the aim to identify novel GPR55 regulators, we have investigated lysophosphatidylinositol (LPI)-induced GPR55-mediated signal transduction. The expression system for wild-type and mutated GPR55 was HeLa cells silenced for their endogenous receptor by stable expression of a short-hairpin RNA specific for GPR55 5'-UTR, which allowed definition of the requirement of GPR55 Lys80 for LPI-induced MAPK activation and receptor internalisation. In RAW264.7 macrophages, GPR55 pathways were investigated by Gpr55 silencing using small-interfering RNAs, which demonstrated that LPI increased intracellular Ca2+ levels and induced actin filopodium formation through GPR55 activation. Furthermore, the LPI/GPR55 axis was shown to have an active role in osteoclastogenesis of precursor RAW264.7 cells induced by 'receptor-activator of nuclear factor kappa-β ligand' (RANKL). Indeed, this differentiation into mature osteoclasts was associated with a 14-fold increase in Gpr55 mRNA levels. Moreover, GPR55 silencing and antagonism impaired RANKL-induced transcription of the osteoclastogenesis markers: 'nuclear factor of activated T-cells, cytoplasmic 1', matrix metalloproteinase-9, cathepsin-K, tartrate-resistant acid phosphatase, and the calcitonin receptor, as evaluated by real-time PCR. Phage display was previously used to identify peptides that bind to GPR55. Here, the GPR55-specific peptide-P1 strongly inhibited osteoclast maturation of RAW264.7 macrophages, confirming its activity as a blocker of GPR55-mediated functions. Although osteoclast syncytium formation was not affected by pharmacological regulation of GPR55, osteoclast activity was dependent on GPR55 signalling, as shown with resorption assays on bone slices, where LPI stimulated and GPR55 antagonists inhibited bone erosion. CONCLUSIONS Our data indicate that GPR55 represents a target for development of novel therapeutic approaches for treatment of pathological conditions caused by osteoclast-exacerbated bone degradation, such as in osteoporosis or during establishment of bone metastases. Video abstract.
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Affiliation(s)
| | - Maria Mangini
- Institute of Protein Biochemistry, National Research Council, Naples, Italy.,Institute of Biochemistry and Cell Biology, National Research Council, Naples, Italy
| | - Stefania Cioffi
- Institute of Protein Biochemistry, National Research Council, Naples, Italy.,Institute of Biochemistry and Cell Biology, National Research Council, Naples, Italy
| | - Pasquale Barba
- Institute of Genetics and Biophysics, National Research Council, Naples, Italy
| | - Stefania Mariggiò
- Institute of Protein Biochemistry, National Research Council, Naples, Italy. .,Institute of Biochemistry and Cell Biology, National Research Council, Naples, Italy.
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30
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Zhao M, Wang Z, Yang M, Ding Y, Zhao M, Wu H, Zhang Y, Lu Q. The Roles of Orphan G Protein-Coupled Receptors in Autoimmune Diseases. Clin Rev Allergy Immunol 2021; 60:220-243. [PMID: 33411320 DOI: 10.1007/s12016-020-08829-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2020] [Indexed: 12/26/2022]
Abstract
G protein-coupled receptors (GPCRs) constitute the largest family of plasma membrane receptors in nature and mediate the effects of a variety of extracellular signals, such as hormone, neurotransmitter, odor, and light signals. Due to their involvement in a broad range of physiological and pathological processes and their accessibility, GPCRs are widely used as pharmacological targets of treatment. Orphan G protein-coupled receptors (oGPCRs) are GPCRs for which no natural ligands have been found, and they not only play important roles in various physiological functions, such as sensory perception, reproduction, development, growth, metabolism, and responsiveness, but are also closely related to many major diseases, such as central nervous system (CNS) diseases, metabolic diseases, and cancer. Recently, many studies have reported that oGPCRs play increasingly important roles as key factors in the occurrence and progression of autoimmune diseases. Therefore, oGPCRs are likely to become potential therapeutic targets and may provide a breakthrough in the study of autoimmune diseases. In this article, we focus on reviewing the recent research progress and clinical treatment effects of oGPCRs in three common autoimmune diseases: multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE), shedding light on novel strategies for treatments.
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Affiliation(s)
- Mingming Zhao
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zheyu Wang
- University of South China, Hengyang, Hunan, China.,Maternal & Child Health Care Hospital Hainan Province, Haikou, Hainan, China
| | - Ming Yang
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yan Ding
- Maternal & Child Health Care Hospital Hainan Province, Haikou, Hainan, China.,Hainan Province Dermatol Disease Hospital, Haikou, Hainan, China
| | - Ming Zhao
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Haijing Wu
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Yan Zhang
- Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. .,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, 311121, China. .,Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou, 310058, China. .,MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Qianjin Lu
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
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31
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Effects of a Novel GPR55 Antagonist on the Arachidonic Acid Cascade in LPS-Activated Primary Microglial Cells. Int J Mol Sci 2021; 22:ijms22052503. [PMID: 33801492 PMCID: PMC7958845 DOI: 10.3390/ijms22052503] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/24/2021] [Accepted: 02/25/2021] [Indexed: 11/16/2022] Open
Abstract
Neuroinflammation is a crucial process to maintain homeostasis in the central nervous system (CNS). However, chronic neuroinflammation is detrimental, and it is described in the pathogenesis of CNS disorders, including Alzheimer’s disease (AD) and depression. This process is characterized by the activation of immune cells, mainly microglia. The role of the orphan G-protein-coupled receptor 55 (GPR55) in inflammation has been reported in different models. However, its role in neuroinflammation in respect to the arachidonic acid (AA) cascade in activated microglia is still lacking of comprehension. Therefore, we synthesized a novel GPR55 antagonist (KIT 10, 0.1–25 µM) and tested its effects on the AA cascade in lipopolysaccharide (LPS, 10 ng / mL)-treated primary rat microglia using Western blot and EIAs. We show here that KIT 10 potently prevented the release of prostaglandin E2 (PGE2), reduced microsomal PGE2 synthase (mPGES-1) and cyclooxygenase-2 (COX-2) synthesis, and inhibited the phosphorylation of Ikappa B-alpha (IκB-α), a crucial upstream step of the inflammation-related nuclear factor-kappaB (NF-κB) signaling pathway. However, no effects were observed on COX-1 and -2 activities and mitogen-activated kinases (MAPK). In summary, the novel GPR55 receptor antagonist KIT 10 reduces neuroinflammatory parameters in microglia by inhibiting the COX-2/PGE2 pathway. Further experiments are necessary to better elucidate its effects and mechanisms. Nevertheless, the modulation of inflammation by GPR55 might be a new therapeutic option to treat CNS disorders with a neuroinflammatory background such as AD or depression.
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32
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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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33
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Alhouayek M, Ameraoui H, Muccioli GG. Bioactive lipids in inflammatory bowel diseases - From pathophysiological alterations to therapeutic opportunities. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1866:158854. [PMID: 33157277 DOI: 10.1016/j.bbalip.2020.158854] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/16/2020] [Accepted: 10/27/2020] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, are lifelong diseases that remain challenging to treat. IBDs are characterized by alterations in intestinal barrier function and dysregulation of the innate and adaptive immunity. An increasing number of lipids are found to be important regulators of inflammation and immunity as well as gut physiology. Therefore, the study of lipid mediators in IBDs is expected to improve our understanding of disease pathogenesis and lead to novel therapeutic opportunities. Here, through selected examples - such as fatty acids, specialized proresolving mediators, lysophospholipids, endocannabinoids, and oxysterols - we discuss how lipid signaling is involved in IBD physiopathology and how modulating lipid signaling pathways could affect IBDs.
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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.
| | - Hafsa Ameraoui
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Bruxelles, Belgium
| | - 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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34
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Biological Activity of Cannabis sativa L. Extracts Critically Depends on Solvent Polarity and Decarboxylation. SEPARATIONS 2020. [DOI: 10.3390/separations7040056] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Minor cannabinoid and non-cannabinoid molecules have been proposed to significantly contribute to the pharmacological profile of cannabis extracts. Phytoplant Research has developed highly productive cannabis cultivars with defined chemotypes, as well as proprietary methods for the extraction and purification of cannabinoids. Here, we investigate the effect of solvent selection and decarboxylation on the composition and pharmacological activity of cannabis extracts. A library of forty cannabis extracts was generated from ten different cannabis cultivars registered by Phytoplant Research at the EU Community Plant Variety Office. Plant material was extracted using two different solvents, ethanol and hexane, and crude extracts were subsequently decarboxylated or not. Cannabinoid content in the resulting extracts was quantified, and biological activity was screened in vitro at three molecular targets involved in hypoxia and inflammation (NF-κB, HIF-1α and STAT3). Changes in transcriptional activation were strongly associated to solvent selection and decarboxylation. Two decarboxylated extracts prepared with hexane were the most potent at inhibiting NF-κB transcription, while HIF-1α activation was preferentially inhibited by ethanolic extracts, and decarboxylated extracts were generally more potent at inhibiting STAT3 induction. Our results indicate that solvent selection and proper decarboxylation represent key aspects of the standardized production of cannabis extracts with reproducible pharmacological activity.
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Murakami M, Sato H, Taketomi Y. Updating Phospholipase A 2 Biology. Biomolecules 2020; 10:E1457. [PMID: 33086624 PMCID: PMC7603386 DOI: 10.3390/biom10101457] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/09/2020] [Accepted: 10/15/2020] [Indexed: 12/30/2022] Open
Abstract
The phospholipase A2 (PLA2) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA2 has the capacity to hydrolyze the sn-2 position of glycerophospholipids to release fatty acids and lysophospholipids, yet several enzymes in this superfamily catalyze other reactions rather than or in addition to the PLA2 reaction. PLA2 enzymes play crucial roles in not only the production of lipid mediators, but also membrane remodeling, bioenergetics, and body surface barrier, thereby participating in a number of biological events. Accordingly, disturbance of PLA2-regulated lipid metabolism is often associated with various diseases. This review updates the current state of understanding of the classification, enzymatic properties, and biological functions of various enzymes belonging to the PLA2 superfamily, focusing particularly on the novel roles of PLA2s in vivo.
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Affiliation(s)
- Makoto Murakami
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; (H.S.); (Y.T.)
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36
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Motwani K, Peters LD, Vliegen WH, El-sayed AG, Seay HR, Lopez MC, Baker HV, Posgai AL, Brusko MA, Perry DJ, Bacher R, Larkin J, Haller MJ, Brusko TM. Human Regulatory T Cells From Umbilical Cord Blood Display Increased Repertoire Diversity and Lineage Stability Relative to Adult Peripheral Blood. Front Immunol 2020; 11:611. [PMID: 32351504 PMCID: PMC7174770 DOI: 10.3389/fimmu.2020.00611] [Citation(s) in RCA: 34] [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: 09/14/2019] [Accepted: 03/17/2020] [Indexed: 12/22/2022] Open
Abstract
The human T lymphocyte compartment is highly dynamic over the course of a lifetime. Of the many changes, perhaps most notable is the transition from a predominantly naïve T cell state at birth to the acquisition of antigen-experienced memory and effector subsets following environmental exposures. These phenotypic changes, including the induction of T cell exhaustion and senescence, have the potential to negatively impact efficacy of adoptive T cell therapies (ACT). When considering ACT with CD4+CD25+CD127-/lo regulatory T cells (Tregs) for the induction of immune tolerance, we previously reported ex vivo expanded umbilical cord blood (CB) Tregs remained more naïve, suppressed responder T cells equivalently, and exhibited a more diverse T cell receptor (TCR) repertoire compared to expanded adult peripheral blood (APB) Tregs. Herein, we hypothesized that upon further characterization, we would observe increased lineage heterogeneity and phenotypic diversity in APB Tregs that might negatively impact lineage stability, engraftment capacity, and the potential for Tregs to home to sites of tissue inflammation following ACT. We compared the phenotypic profiles of human Tregs isolated from CB versus the more traditional source, APB. We conducted analysis of fresh and ex vivo expanded Treg subsets at both the single cell (scRNA-seq and flow cytometry) and bulk (microarray and cytokine profiling) levels. Single cell transcriptional profiles of pre-expansion APB Tregs highlighted a cluster of cells that showed increased expression of genes associated with effector and pro-inflammatory phenotypes (CCL5, GZMK, CXCR3, LYAR, and NKG7) with low expression of Treg markers (FOXP3 and IKZF2). CB Tregs were more diverse in TCR repertoire and homogenous in phenotype, and contained fewer effector-like cells in contrast with APB Tregs. Interestingly, expression of canonical Treg markers, such as FOXP3, TIGIT, and IKZF2, were increased in CB CD4+CD127+ conventional T cells (Tconv) compared to APB Tconv, post-expansion, implying perinatal T cells may adopt a default regulatory program. Collectively, these data identify surface markers (namely CXCR3) that could be depleted to improve purity and stability of APB Tregs, and support the use of expanded CB Tregs as a potentially optimal ACT modality for the treatment of autoimmune and inflammatory diseases.
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Affiliation(s)
- Keshav Motwani
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Leeana D. Peters
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Willem H. Vliegen
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Ahmed Gomaa El-sayed
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Howard R. Seay
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - M. Cecilia Lopez
- Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Henry V. Baker
- Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Amanda L. Posgai
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Maigan A. Brusko
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Daniel J. Perry
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Rhonda Bacher
- Department of Biostatistics, University of Florida, Gainesville, FL, United States
| | - Joseph Larkin
- Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, United States
| | - Michael J. Haller
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Todd M. Brusko
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, United States
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37
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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: 34] [Impact Index Per Article: 6.8] [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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Pandelides Z, Thornton C, Faruque AS, Whitehead AP, Willett KL, Ashpole NM. Developmental exposure to cannabidiol (CBD) alters longevity and health span of zebrafish (Danio rerio). GeroScience 2020; 42:785-800. [PMID: 32221778 DOI: 10.1007/s11357-020-00182-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 03/09/2020] [Indexed: 12/20/2022] Open
Abstract
Consumption of cannabinoid-containing products is on the rise, even during pregnancy. Unfortunately, the long-term, age-related consequences of developmental cannabidiol (CBD) exposure remain largely unknown. This is a critical gap given the established Developmental Origins of Health and Disease (DOHaD) paradigm which emphasizes that stressors, like drug exposure, early in life can instigate molecular and cellular changes that ultimately lead to adverse outcomes later in life. Thus, we exposed zebrafish (Danio rerio) to varying concentrations of CBD (0.02, 0.1, 0.5 μM) during larval development and assessed aging in both the F0 (exposed generation) and their F1 offspring 30 months later. F0 exposure to CBD significantly increased survival (~ 20%) and reduced size (wet weight and length) of female fish. While survival was increased, the age-related loss of locomotor function was unaffected and the effects on fecundity varied by sex and dose. Treatment with 0.5 μM CBD significantly reduced sperm concentration in males, but 0.1 μM increased egg production in females. Similar to other model systems, control aged zebrafish exhibited increased kyphosis as well as increased expression markers of senescence, and inflammation (p16ink4ab, tnfα, il1b, il6, and pparγ) in the liver. Exposure to CBD significantly reduced the expression of several of these genes in a dose-dependent manner relative to the age-matched controls. The effects of CBD on size, gene expression, and reproduction were not reproduced in the F1 generation, suggesting the influence on aging was not cross-generational. Together, our results demonstrate that developmental exposure to CBD causes significant effects on the health and longevity of zebrafish.
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Affiliation(s)
- Zacharias Pandelides
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, 38677, USA
| | - Cammi Thornton
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, 38677, USA
| | - Anika S Faruque
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, 38677, USA
| | - Alyssa P Whitehead
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, 38677, USA
| | - Kristine L Willett
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, 38677, USA
- Research Institute of Pharmaceutical Sciences, University of Mississippi School of Pharmacy, Oxford, MS, 38677, USA
| | - Nicole M Ashpole
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, 38677, USA.
- Research Institute of Pharmaceutical Sciences, University of Mississippi School of Pharmacy, Oxford, MS, 38677, USA.
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39
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Wang Y, Pan W, Wang Y, Yin Y. The GPR55 antagonist CID16020046 protects against ox-LDL-induced inflammation in human aortic endothelial cells (HAECs). Arch Biochem Biophys 2020; 681:108254. [PMID: 31904362 DOI: 10.1016/j.abb.2020.108254] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 12/13/2019] [Accepted: 01/02/2020] [Indexed: 11/28/2022]
Abstract
Atherosclerosis is a commonplace cardiovascular disease which affects most people in old age. While its causes are currently poorly understood, continuous study is being performed in order to elucidate both the pathogenesis and treatment of this insidious disease. Atherosclerosis is presently thought to be linked to several factors such as endothelial dysfunction, monocyte adhesion to the intima of the artery, and increased oxidative stress. Oxidized low-density lipoprotein (ox-LDL), colloquially known as the "bad cholesterol", is known to play a critical role in the previously mentioned atherosclerotic processes. In this study, our goal was to elucidate the role of the lysophospholipid receptor G protein-coupled receptor 55 (GPR55) and its antagonist, the cannabinoid CID16020046, in endothelial dysfunction. While their existence and especially their role in atherosclerosis has only semi-recently been elucidated, a growing body of research has begun to link their interaction to antiatherosclerosis. In our research, we found CID16020046 to have distinct atheroprotective properties such as anti-inflammation, antioxidant, and inhibition of monocyte attachment to endothelial cells. While there was previously a small body of research regarding the potential of cannabinoids to treat or prevent atherosclerosis, studies on the treatment potential of CID16020046 were even fewer. Thus, this study is one of the first to explore the effects of cannabinoids in atherosclerosis. Our findings in the present study provide a strong argument for the use of CID16020046 in the treatment of atherosclerosis as well as a basis for further experimentation using cannabinoids as therapy against atherosclerosis.
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Affiliation(s)
- Yaowen Wang
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmias Therapeutic Service Center, Chongqing, 400010, China
| | - Wei Pan
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmias Therapeutic Service Center, Chongqing, 400010, China; Department of Endocrinology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Yan Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563006, China.
| | - Yuehui Yin
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmias Therapeutic Service Center, Chongqing, 400010, China.
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40
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Localization of cannabinoid and cannabinoid related receptors in the cat gastrointestinal tract. Histochem Cell Biol 2020; 153:339-356. [PMID: 32095931 DOI: 10.1007/s00418-020-01854-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2020] [Indexed: 02/07/2023]
Abstract
A growing body of literature indicates that activation of cannabinoid receptors may exert beneficial effects on gastrointestinal inflammation and visceral hypersensitivity. The present study aimed to immunohistochemically investigate the distribution of the canonical cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) and the putative cannabinoid receptors G protein-coupled receptor 55 (GPR55), nuclear peroxisome proliferator-activated receptor alpha (PPARα), transient receptor potential ankyrin 1 (TRPA1), and serotonin receptor 5-HT1a 5-HT1aR) in tissue samples of the gastrointestinal tract of the cat. CB1R-immunoreactivity (CB1R-IR) was observed in gastric epithelial cells, intestinal enteroendocrine cells (EECs) and goblet cells, lamina propria mast cells (MCs), and enteric neurons. CB2R-IR was expressed by EECs, enterocytes, and macrophages. GPR55-IR was expressed by EECs, macrophages, immunocytes, and MP neurons. PPARα-IR was expressed by immunocytes, smooth muscle cells, and enteroglial cells. TRPA1-IR was expressed by enteric neurons and intestinal goblet cells. 5-HT1a receptor-IR was expressed by gastrointestinal epithelial cells and gastric smooth muscle cells. Cannabinoid receptors showed a wide distribution in the feline gastrointestinal tract layers. Although not yet confirmed/supported by functional evidences, the present research might represent an anatomical substrate potentially useful to support, in feline species, the therapeutic use of cannabinoids during gastrointestinal inflammatory diseases.
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41
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Manca C, Boubertakh B, Leblanc N, Deschênes T, Lacroix S, Martin C, Houde A, Veilleux A, Flamand N, Muccioli GG, Raymond F, Cani PD, Di Marzo V, Silvestri C. Germ-free mice exhibit profound gut microbiota-dependent alterations of intestinal endocannabinoidome signaling. J Lipid Res 2020; 61:70-85. [PMID: 31690638 PMCID: PMC6939599 DOI: 10.1194/jlr.ra119000424] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 10/26/2019] [Indexed: 01/10/2023] Open
Abstract
The gut microbiota is a unique ecosystem of microorganisms interacting with the host through several biochemical mechanisms. The endocannabinoidome (eCBome), a complex signaling system including the endocannabinoid system, approximately 50 receptors and metabolic enzymes, and more than 20 lipid mediators with important physiopathologic functions, modulates gastrointestinal tract function and may mediate host cell-microbe communications there. Germ-free (GF) mice, which lack an intestinal microbiome and so differ drastically from conventionally raised (CR) mice, offer a unique opportunity to explore the eCBome in a microbe-free model and in the presence of a reintroduced functional gut microbiome through fecal microbiota transplant (FMT). We aimed to gain direct evidence for a link between the microbiome and eCBome systems by investigating eCBome alterations in the gut in GF mice before and after FMT. Basal eCBome gene expression and lipid profiles were measured in various segments of the intestine of GF and CR mice at juvenile and adult ages using targeted quantitative PCR transcriptomics and LC-MS/MS lipidomics. GF mice exhibited age-dependent modifications in intestinal eCBome gene expression and lipid mediator levels. FMT from CR donor mice to age-matched GF male mice reversed several of these alterations, particularly in the ileum and jejunum, after only 1 week, demonstrating that the gut microbiome directly impacts the host eCBome and providing a cause-effect relationship between the presence or absence of intestinal microbes and eCBome signaling. These results open the way to new studies investigating the mechanisms through which intestinal microorganisms exploit eCBome signaling to exert some of their physiopathologic functions.
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Affiliation(s)
- Claudia Manca
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, Canada; Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada
| | - Besma Boubertakh
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, Canada; Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada
| | - Nadine Leblanc
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, Canada; Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada; Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, Canada
| | - Thomas Deschênes
- Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada; Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, Canada; École de Nutrition, Faculté des Sciences de l'Agriculture et de l'Alimentation (FSAA), Université Laval, Québec, Canada
| | - Sebastien Lacroix
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, Canada; Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada; Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, Canada
| | - Cyril Martin
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, Canada; Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada
| | - Alain Houde
- Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada; Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, Canada
| | - Alain Veilleux
- Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada; Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, Canada; École de Nutrition, Faculté des Sciences de l'Agriculture et de l'Alimentation (FSAA), Université Laval, Québec, Canada
| | - Nicolas Flamand
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, Canada; Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada
| | - Giulio G Muccioli
- Louvain Drug Research Institute (LDRI), Bioanalysis and Pharmacology of Bioactive Lipids Research Group, UCLouvain (Université Catholique de Louvain), Brussels, Belgium
| | - Frédéric Raymond
- Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada; Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, Canada; École de Nutrition, Faculté des Sciences de l'Agriculture et de l'Alimentation (FSAA), Université Laval, Québec, Canada
| | - Patrice D Cani
- Louvain Drug Research Institute (LDRI), Bioanalysis and Pharmacology of Bioactive Lipids Research Group, UCLouvain (Université Catholique de Louvain), Brussels, Belgium; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Metabolism and Nutrition Research Group, UCLouvain (Université Catholique de Louvain), Brussels, Belgium
| | - Vincenzo Di Marzo
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, Canada; Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada; Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, Canada; École de Nutrition, Faculté des Sciences de l'Agriculture et de l'Alimentation (FSAA), Université Laval, Québec, Canada
| | - Cristoforo Silvestri
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, Canada; Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, Canada.
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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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Beggiato S, Tomasini MC, Ferraro L. Palmitoylethanolamide (PEA) as a Potential Therapeutic Agent in Alzheimer's Disease. Front Pharmacol 2019; 10:821. [PMID: 31396087 PMCID: PMC6667638 DOI: 10.3389/fphar.2019.00821] [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: 04/29/2019] [Accepted: 06/25/2019] [Indexed: 12/20/2022] Open
Abstract
N-Palmitoylethanolamide (PEA) is a non-endocannabinoid lipid mediator belonging to the class of the N-acylethanolamine phospolipids and was firstly isolated from soy lecithin, egg yolk, and peanut meal. Either preclinical or clinical studies indicate that PEA is potentially useful in a wide range of therapeutic areas, including eczema, pain, and neurodegeneration. PEA-containing products are already licensed for use in humans as a nutraceutical, a food supplement, or a food for medical purposes, depending on the country. PEA is especially used in humans for its analgesic and anti-inflammatory properties and has demonstrated high safety and tolerability. Several preclinical in vitro and in vivo studies have proven that PEA can induce its biological effects by acting on several molecular targets in both central and peripheral nervous systems. These multiple mechanisms of action clearly differentiate PEA from classic anti-inflammatory drugs and are attributed to the compound that has quite unique anti(neuro)inflammatory properties. According to this view, preclinical studies indicate that PEA, especially in micronized or ultramicronized forms (i.e., formulations that maximize PEA bioavailability and efficacy), could be a potential therapeutic agent for the effective treatment of different pathologies characterized by neurodegeneration, (neuro)inflammation, and pain. In particular, the potential neuroprotective effects of PEA have been demonstrated in several experimental models of Alzheimer's disease. Interestingly, a single-photon emission computed tomography (SPECT) case study reported that a mild cognitive impairment (MCI) patient, treated for 9 months with ultramicronized-PEA/luteolin, presented an improvement of cognitive performances. In the present review, we summarized the current preclinical and clinical evidence of PEA as a possible therapeutic agent in Alzheimer's disease. The possible PEA neuroprotective mechanism(s) of action is also described.
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Affiliation(s)
- Sarah Beggiato
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.,Technopole of Ferrara, LTTA Laboratory for the Technologies for Advanced Therapies, Ferrara, Italy.,IRET Foundation, Bologna, Italy
| | - Maria Cristina Tomasini
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.,Technopole of Ferrara, LTTA Laboratory for the Technologies for Advanced Therapies, Ferrara, Italy
| | - Luca Ferraro
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.,Technopole of Ferrara, LTTA Laboratory for the Technologies for Advanced Therapies, Ferrara, Italy.,IRET Foundation, Bologna, Italy
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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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45
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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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46
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Members of the endocannabinoid system are distinctly regulated in inflammatory bowel disease and colorectal cancer. Sci Rep 2019; 9:2358. [PMID: 30787385 PMCID: PMC6382821 DOI: 10.1038/s41598-019-38865-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 01/11/2019] [Indexed: 12/21/2022] Open
Abstract
Preclinical studies have demonstrated that the endocannabinoid system (ECS) plays an important role in the protection against intestinal inflammation and colorectal cancer (CRC); however, human data are scarce. We determined members of the ECS and related components of the ‘endocannabinoidome’ in patients with inflammatory bowel disease (IBD) and CRC, and compared them to control subjects. Anandamide (AEA) and oleoylethanolamide (OEA) were increased in plasma of ulcerative colitis (UC) and Crohn’s disease (CD) patients while 2-arachidonoylglycerol (2-AG) was elevated in patients with CD, but not UC. 2-AG, but not AEA, PEA and OEA, was elevated in CRC patients. Lysophosphatidylinositol (LPI) 18:0 showed higher levels in patients with IBD than in control subjects whereas LPI 20:4 was elevated in both CRC and IBD. Gene expression in intestinal mucosal biopsies revealed different profiles in CD and UC. CD, but not UC patients, showed increased gene expression for the 2-AG synthesizing enzyme diacylglycerol lipase alpha. Transcripts of CNR1 and GPR119 were predominantly decreased in CD. Our data show altered plasma levels of endocannabinoids and endocannabinoid-like lipids in IBD and CRC and distinct transcript profiles in UC and CD. We also report alterations for less known components in intestinal inflammation, such as GPR119, OEA and LPI.
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Saliba SW, Jauch H, Gargouri B, Keil A, Hurrle T, Volz N, Mohr F, van der Stelt M, Bräse S, Fiebich BL. Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells. J Neuroinflammation 2018; 15:322. [PMID: 30453998 PMCID: PMC6240959 DOI: 10.1186/s12974-018-1362-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 11/07/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Neuroinflammation plays a vital role in Alzheimer's disease and other neurodegenerative conditions. Microglia are the resident mononuclear immune cells of the central nervous system, and they play essential roles in the maintenance of homeostasis and responses to neuroinflammation. The orphan G-protein-coupled receptor 55 (GPR55) has been reported to modulate inflammation and is expressed in immune cells such as monocytes and microglia. However, its effects on neuroinflammation, mainly on the production of members of the arachidonic acid pathway in activated microglia, have not been elucidated in detail. METHODS In this present study, a series of coumarin derivatives, that exhibit GPR55 antagonism properties, were designed. The effects of these compounds on members of the arachidonic acid cascade were studied in lipopolysaccharide (LPS)-treated primary rat microglia using Western blot, qPCR, and ELISA. RESULTS We demonstrate here that the various compounds with GPR55 antagonistic activities significantly inhibited the release of PGE2 in primary microglia. The inhibition of LPS-induced PGE2 release by the most potent candidate KIT 17 was partially dependent on reduced protein synthesis of mPGES-1 and COX-2. KIT 17 did not affect any key enzyme involved on the endocannabinoid system. We furthermore show that microglia expressed GPR55 and that a synthetic antagonist of the GPR receptor (ML193) demonstrated the same effect of the KIT 17 on the inhibition of PGE2. CONCLUSIONS Our results suggest that KIT 17 is acting as an inverse agonist on GPR55 independent of the endocannabinoid system. Targeting GPR55 might be a new therapeutic option to treat neurodegenerative diseases with a neuroinflammatory background such as Alzheimer's disease, Parkinson, and multiple sclerosis (MS).
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Affiliation(s)
- Soraya Wilke Saliba
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Hannah Jauch
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Brahim Gargouri
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Albrecht Keil
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Thomas Hurrle
- Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.,Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | - Nicole Volz
- Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Florian Mohr
- Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.,Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands
| | - Mario van der Stelt
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands
| | - Stefan Bräse
- Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.,Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, 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, Freiburg, Germany. .,Department of Psychiatry and Psychotherapy, Laboratory of Translational Psychiatry, University Hospital Freiburg, Hauptstr. 5, 79104, Freiburg, Germany.
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Lysophosphatidylinositols in inflammation and macrophage activation: Altered levels and anti-inflammatory effects. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:1458-1468. [PMID: 30251703 DOI: 10.1016/j.bbalip.2018.09.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 08/26/2018] [Accepted: 09/09/2018] [Indexed: 02/08/2023]
Abstract
Lysophosphatidylinositols (LPI) are bioactive lipids that are implicated in several pathophysiological processes such as cell proliferation, migration and tumorigenesis and were shown to play a role in obesity and metabolic disorders. Often, these effects of LPI were due to activation of the G protein-coupled receptor GPR55. However, the role of LPI and GPR55 in inflammation and macrophage activation remains unclear. Therefore, we thought to study the effect of macrophage activation and inflammation on LPI levels and metabolism. To do so, we used J774 and BV2 cells in culture activated with lipopolysaccharides (LPS, 100 ng/mL) as well as primary mouse alveolar and peritoneal macrophages. We also quantified LPI levels in the cerebellum, lung, liver, spleen and colon of mice with a systemic inflammation induced by LPS (300 μg/kg) and in the colon of mice with acute colitis induced by dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) and chronic DSS-induced colitis. Our data show that LPS-induced macrophage activation leads to altered LPI levels in both the cells and culture medium. We also show that cytosolic phospholipase A2α (cPLA2α) and α/β‑hydrolase domain 6 (ABHD6) are among the enzymes implicated in LPI metabolism in J774 macrophages. Indeed, ABHD6 and cPLA2α inhibition increased 20:4-LPI levels in LPS-activated macrophages. Furthermore, incubation of LPS-activated cells with LPI decreased J774 activation in a GPR55-dependent manner. In vivo, LPI levels were altered by inflammation in the liver, spleen and colon. These alterations are tissue dependent and could highlight a potential role for LPI in inflammatory processes.
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Cellular localization and regulation of receptors and enzymes of the endocannabinoid system in intestinal and systemic inflammation. Histochem Cell Biol 2018; 151:5-20. [PMID: 30196316 PMCID: PMC6328631 DOI: 10.1007/s00418-018-1719-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2018] [Indexed: 12/26/2022]
Abstract
Surveys suggest that Cannabis provides benefit for people with inflammatory bowel disease. However, mechanisms underlying beneficial effects are not clear. We performed in situ hybridization RNAscope® combined with immunohistochemistry to show cell-specific distribution and regulation of cannabinoid receptor 1 and 2 (CB1, CB2), G protein-coupled receptor 55 (GPR55), and monoacylglycerol lipase (MGL) mRNA in immune cells using murine models of intestinal and systemic inflammation. In healthy animals, the presence in enteric ganglia is high for CB1 mRNA, but low for CB2 and GPR55 mRNAs. MGL mRNA is predominant throughout the intestinal wall including myenteric neurons, epithelium, circular and longitudinal muscular layers, and the lamina propria. Within the immune system, B220+ cells exhibit high gene expression for CB2 while the expression of CB2 in F4/80+ and CD3+ cells is less prominent. In contrast, GPR55 mRNA is highly present in F4/80+ and CD3+ cells. qRT-PCR of total colonic segments shows that the expression of GPR55 and MGL genes drops during intestinal inflammation. Also at cellular levels, GPR55 and MGL gene expression is reduced in F4/80+, but not CD3+ cells. As to systemic inflammation, reduced gene expression of MGL is observed in ileum by qRT-PCR, while at cellular levels, altered gene expression is also seen for CB1 and GPR55 in CD3+ but not F4/80+ cells. In summary, our study reveals changes in gene expression of members of the endocannabinoid system in situ attesting particularly GPR55 and MGL a distinct cellular role in the regulation of the immune response to intestinal and systemic inflammation.
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50
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Castillo-Chabeco B, Figueroa G, Parira T, Napuri J, Agudelo M. Ethanol-induced modulation of GPR55 expression in human monocyte-derived dendritic cells is accompanied by H4K12 acetylation. Alcohol 2018; 71:25-31. [PMID: 29957399 DOI: 10.1016/j.alcohol.2018.05.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 05/17/2018] [Accepted: 05/17/2018] [Indexed: 01/13/2023]
Abstract
Inflammation supports the progression of alcohol-related organ injury. Recent research findings have linked ethanol exposure to changes in histone acetylation and deacetylation in the brain and in peripheral tissues, leading to ethanol-dependence related damage. One of the mechanisms that has been shown to play a major role during inflammation is the cannabinoid system. Previous research has demonstrated that ethanol can modulate cannabinoid receptors' functions. Our lab has shown that the G protein-coupled receptor (GPR55), a novel cannabinoid receptor, is upregulated in binge drinkers and in cells treated acutely with ethanol. Additionally, our group has also uncovered that chronic ethanol exposure leads to an increase in histone modifications, such as acetylation. However, the regulatory mechanism of GPR55 within the immune system under the influence of ethanol is poorly understood. Since changes in histone modifications might lead to changes in gene expression, we hypothesize that the mechanism of ethanol-induced upregulation of GPR55 is linked to epigenetic changes on histone proteins. Taking into account previous findings from our lab, the goal of the present study was to determine whether there is any relevant association between histone hyperacetylation and the regulation of the novel cannabinoid receptor GPR55 in monocyte-derived dendritic cells (MDDCs) of human origin treated acutely with ethanol. Therefore, monocytes were isolated from buffy coats and allowed to differentiate into MDDCs. The cells were treated with ethanol for 24 h, harvested, fixed, and stained with antibodies against GPR55. As expected, based on previous findings, confocal microscopy showed that ethanol exposure increases GPR55 expression. In order to demonstrate the correlation between histone acetylation and GPR55 expression regulation, the cells were treated with ethanol, harvested, and then the chromatin was extracted and fractionated for chromatin immunoprecipitation (ChIP) assay, followed by real-time qPCR for the analysis of DNA fragments. The results showed an enrichment of the histone modification H4K12ac in the GPR55 gene of MDDCs treated with ethanol. Furthermore, siRNA against the histone acetyltransferase Tip60 (responsible for the acetylation of H4K12) resulted in a downregulation of GPR55. In conjunction, these results indicate that in the presence of ethanol, the upregulation of GPR55 expression is accompanied by H4K12 acetylation, which might have a significant effect in the ability of this innate immune system's cells to cope with cellular stress induced by ethanol. However, the causality of ethanol regulation of H4K12ac in GPR55 expression changes still lacks further elucidation; therefore, additional experimental approaches to confirm a significant causality between H4K12 acetylation and ethanol regulation of GPR55 are currently undergoing in our lab.
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