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Noori P, Sotoodehnejadnematalahi F, Rahimi P, Siadat SD. Akkermansia muciniphila and Its Extracellular Vesicles Affect Endocannabinoid System in in vitro Model. Digestion 2025:1-11. [PMID: 40081347 DOI: 10.1159/000543446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 01/04/2025] [Indexed: 03/16/2025]
Abstract
INTRODUCTION Recent studies indicate that the gut microbiota controls the host's immune system. Probiotics use different signaling pathways to regulate intestinal permeability, barrier integrity, and energy balance. METHODS This research examined how Akkermansia muciniphila and its extracellular vesicles (EVs) impact inflammation and genes related to the endocannabinoid system in the STC-1 cell line through RT-PCR and ELISA assays. RESULTS The study's results indicated that EVs had a significant impact on GLP-1 expression compared to the multiplicity of infections (MOI) ratio. Notably, there was a substantial increase in the expression of PYY and GLP-1 genes across all treatments (p < 0.05). Conversely, the expression of CB-1, CB-2, and FAAH genes notably decreased in the STC-1 cell line when treated with MOI 50 of A. muciniphila and an EV concentration of 100 μg/mL (p < 0.05). Both MOI 50 of A. muciniphila and an EV concentration of 100 μg/mL significantly enhanced the expression of the TLR-2 gene. In contrast, EVs at a concentration of 100 μg/mL substantially reduced TLR-4 gene expression. A. muciniphila-derived EVs notably decreased the levels of inflammatory cytokines (TNF-α and IL-6), while increasing IL-10 expression at MOI 100 and an EV concentration of 100 μg/mL. These findings suggest that A. muciniphila and its EVs could regulate the expression of specific genes, serving as targets for maintaining host energy balance. CONCLUSIONS In summary, this study illustrates that A. muciniphila-derived EVs exhibit anti-inflammatory properties and have the potential to modulate gene expression in cases of obesity and gastrointestinal tract inflammation.
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Affiliation(s)
- Pegah Noori
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Pooneh Rahimi
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Davar Siadat
- Department of Mycobacteriology and Pulmonary Research, Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
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Aloisio Caruso E, De Nunzio V, Tutino V, Notarnicola M. The Endocannabinoid System: Implications in Gastrointestinal Physiology and Pathology. Int J Mol Sci 2025; 26:1306. [PMID: 39941074 PMCID: PMC11818434 DOI: 10.3390/ijms26031306] [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: 01/10/2025] [Revised: 01/31/2025] [Accepted: 02/02/2025] [Indexed: 02/16/2025] Open
Abstract
The endocannabinoid system (ECS), composed of receptors, endocannabinoids, and enzymes that regulate biosynthesis and degradation, plays a fundamental role in the physiology and pathology of the gastrointestinal tract, particularly in the small and large intestine and liver. Specifically, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), located principally in the nervous system and immune cells, orchestrate processes such as intestinal motility, intestinal and hepatic inflammation, and energy metabolism, respectively. The main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), influence appetite, body weight regulation, and inflammatory states and thus have implications in obesity, non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS). Recent studies have highlighted the therapeutic potential of targeting the ECS to modulate gastrointestinal and metabolic diseases. In particular, peripheral CB1R antagonists and CB2R agonists have shown efficacy in treating intestinal inflammation, reducing hepatic steatosis, and controlling IBS symptoms. Moreover, the ECS is emerging as a potential target for the treatment of colorectal cancer, acting on cell proliferation and apoptosis. This review highlights the opportunity to exploit the endocannabinoid system in the search for innovative therapeutic strategies, emphasizing the importance of a targeted approach to optimize treatment efficacy and minimize side effects.
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Affiliation(s)
- Emanuela Aloisio Caruso
- Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Bari, Italy; (E.A.C.); (V.D.N.)
| | - Valentina De Nunzio
- Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Bari, Italy; (E.A.C.); (V.D.N.)
| | - Valeria Tutino
- Laboratory of Clinical Pathology, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Bari, Italy;
| | - Maria Notarnicola
- Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Bari, Italy; (E.A.C.); (V.D.N.)
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Su C, Lin Z, Ye Z, Liang J, Yu R, Wan Z, Hou J. Development of a prognostic model for early-stage gastric cancer-related DNA methylation-driven genes and analysis of immune landscape. Front Mol Biosci 2024; 11:1455890. [PMID: 39575189 PMCID: PMC11579923 DOI: 10.3389/fmolb.2024.1455890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 09/13/2024] [Indexed: 11/24/2024] Open
Abstract
Background and Aims This study aimed to develop a prognostic model based on DNA methylation-driven genes for patients with early-stage gastric cancer and to examine immune infiltration and function across varying risk levels. Methods We analyzed data from stage I/II gastric cancer patients in The Cancer Genome Atlas which included clinical details, mRNA expression profiles, and level 3 DNA methylation array data. Using the empirical Bayes method of the limma package, we identified differentially expressed genes (DEGs), and the MethylMix package facilitated the identification of DNA methylation-driven genes (DMGs). Univariate Cox regression and LASSO (least absolute shrinkage and selector operation) analyses were utilized to pinpoint critical genes. A risk score prediction model was formulated using two genes that demonstrated the most significant hazard ratios (HRs). Model performance was evaluated within the initial cohort and verified in the GSE84437 cohort; a nomogram was also constructed based on these genes. We further examined 50 methylation sites associated with three CpG islands in C1orf35 and 14 methylation sites linked to one CpG island in FAAH. The CIBERSORT package was employed to identify immune cell clusters in the prediction model. Results A total of 176 DNA methylation-driven genes were refined down to a four-gene signature (ZC3H12A was hypermethylated; GATA3, C1orf35, and FAAH were hypomethylated), which exhibited a significant correlation with overall survival (OS), as evidenced by p-values below 0.05 following univariate Cox regression and LASSO analysis. Specifically, for the risk score prediction model, C1orf35, which had the highest hazard ratio (HR = 2.035, p = 0.028), and FAAH, with the lowest hazard ratio (HR = 0.656, p = 0.012), were selected. The Kaplan-Meier analysis demonstrated distinct survival outcomes between the high-risk and low-risk score groups. The model's predictive accuracy was confirmed with an area under the curve (AUC) of 0.611 for 3-year survival and 0.564 for 5-year survival. Notably, the hypomethylation of the three CpG islands in C1orf35 and the single CpG island in FAAH was significantly different in stage I/II gastric cancer patients compared to normal tissues. Additionally, the high-risk score group showed a notable association with resting CD4 memory T cells. Conclusion Promoter hypomethylation of C1orf35 and FAAH in early-stage gastric cancer underscores their potential as biomarkers for accurate diagnosis and treatment. The developed predictive model employing genes affected by DNA methylation serves as a crucial independent prognostic factor in early-stage gastric cancer.
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Affiliation(s)
- Chen Su
- The School of Clinical Medical, Fujian Medical University, Fuzhou, Fujian, China
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen, China
| | - Zeyang Lin
- Department of Pathology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Zhijian Ye
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen, China
| | - Jing Liang
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Rong Yu
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen, China
| | - Zheng Wan
- Department of Minimally Invasive and Interventional Therapy for Cancer, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen, China
| | - Jingjing Hou
- The School of Clinical Medical, Fujian Medical University, Fuzhou, Fujian, China
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen, China
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Rakotoarivelo V, Mayer TZ, Simard M, Flamand N, Di Marzo V. The Impact of the CB 2 Cannabinoid Receptor in Inflammatory Diseases: An Update. Molecules 2024; 29:3381. [PMID: 39064959 PMCID: PMC11279428 DOI: 10.3390/molecules29143381] [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: 06/18/2024] [Revised: 07/10/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
The emergence of inflammatory diseases is a heavy burden on modern societies. Cannabis has been used for several millennia to treat inflammatory disorders such as rheumatism or gout. Since the characterization of cannabinoid receptors, CB1 and CB2, the potential of cannabinoid pharmacotherapy in inflammatory conditions has received great interest. Several studies have identified the importance of these receptors in immune cell migration and in the production of inflammatory mediators. As the presence of the CB2 receptor was documented to be more predominant in immune cells, several pharmacological agonists and antagonists have been designed to treat inflammation. To better define the potential of the CB2 receptor, three online databases, PubMed, Google Scholar and clinicaltrial.gov, were searched without language restriction. The full texts of articles presenting data on the endocannabinoid system, the CB2 receptor and its role in modulating inflammation in vitro, in animal models and in the context of clinical trials were reviewed. Finally, we discuss the clinical potential of the latest cannabinoid-based therapies in inflammatory diseases.
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Affiliation(s)
- Volatiana Rakotoarivelo
- Centre de Recherche de l’Institut Universitaire De Cardiologie Et De Pneumologie de Québec, Département of Médecine, Université Laval, Québec City, QC G1V 4G5, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, QC G1V 0V6, Canada
| | - Thomas Z. Mayer
- Centre de Recherche de l’Institut Universitaire De Cardiologie Et De Pneumologie de Québec, Département of Médecine, Université Laval, Québec City, QC G1V 4G5, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, QC G1V 0V6, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels, and Centre NUTRISS, École de Nutrition, Université Laval, Québec City, QC G1V 0V6, Canada
| | - Mélissa Simard
- Centre de Recherche de l’Institut Universitaire De Cardiologie Et De Pneumologie de Québec, Département of Médecine, Université Laval, Québec City, QC G1V 4G5, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, QC G1V 0V6, Canada
| | - Nicolas Flamand
- Centre de Recherche de l’Institut Universitaire De Cardiologie Et De Pneumologie de Québec, Département of Médecine, Université Laval, Québec City, QC G1V 4G5, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, QC G1V 0V6, Canada
| | - Vincenzo Di Marzo
- Centre de Recherche de l’Institut Universitaire De Cardiologie Et De Pneumologie de Québec, Département of Médecine, Université Laval, Québec City, QC G1V 4G5, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, QC G1V 0V6, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels, and Centre NUTRISS, École de Nutrition, Université Laval, Québec City, QC G1V 0V6, Canada
- Joint International Unit between the CNR of Italy and Université Laval on Chemical and Biomolecular Research on the Microbiome and Its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Québec City, QC G1V 0V6, Canada
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Swierczynski M, Kasprzak Z, Makaro A, Salaga M. Regulators of G-Protein Signaling (RGS) in Sporadic and Colitis-Associated Colorectal Cancer. Int J Mol Sci 2024; 25:577. [PMID: 38203748 PMCID: PMC10778579 DOI: 10.3390/ijms25010577] [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: 11/13/2023] [Revised: 12/21/2023] [Accepted: 12/29/2023] [Indexed: 01/12/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most common neoplasms worldwide. Among the risk factors of CRC, inflammatory bowel disease (IBD) is one of the most important ones leading to the development of colitis-associated CRC (CAC). G-protein coupled receptors (GPCR) are transmembrane receptors that orchestrate a multitude of signaling cascades in response to external stimuli. Because of their functionality, they are promising targets in research on new strategies for CRC diagnostics and treatment. Recently, regulators of G-proteins (RGS) have been attracting attention in the field of oncology. Typically, they serve as negative regulators of GPCR responses to both physiological stimuli and medications. RGS activity can lead to both beneficial and harmful effects depending on the nature of the stimulus. However, the atypical RGS-AXIN uses its RGS domain to antagonize key signaling pathways in CRC development through the stabilization of the β-catenin destruction complex. Since AXIN does not limit the efficiency of medications, it seems to be an even more promising pharmacological target in CRC treatment. In this review, we discuss the current state of knowledge on RGS significance in sporadic CRC and CAC with particular emphasis on the regulation of GPCR involved in IBD-related inflammation comprising opioid, cannabinoid and serotonin receptors.
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Affiliation(s)
| | | | | | - Maciej Salaga
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland; (M.S.); (Z.K.); (A.M.)
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Camilleri M, Zheng T. Cannabinoids and the Gastrointestinal Tract. Clin Gastroenterol Hepatol 2023; 21:3217-3229. [PMID: 37678488 PMCID: PMC10872845 DOI: 10.1016/j.cgh.2023.07.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/18/2023] [Accepted: 07/25/2023] [Indexed: 09/09/2023]
Abstract
The synthesis and degradation of endocannabinoids, location of cannabinoid (CB) receptors, and cannabinoid mechanisms of action on immune/inflammatory, neuromuscular, and sensory functions in digestive organs are well documented. CB2 mechanisms are particularly relevant in immune and sensory functions. Increasing use of cannabinoids in the United States is impacted by social determinants of health including racial discrimination, which is associated with tobacco and cannabis co-use, and combined use disorders. Several conditions associated with emesis are related to cannabinoid use, including cannabinoid hyperemesis or withdrawal, cyclic vomiting syndrome, and nausea and vomiting of pregnancy. Cannabinoids generally inhibit gastrointestinal motor function; yet they relieve symptoms in patients with gastroparesis and diverse nausea syndromes. Cannabinoid effects on inflammatory mechanisms have shown promise in relatively small placebo-controlled studies in reducing disease activity and abdominal pain in patients with inflammatory bowel disease. Cannabinoids have been studied in disorders of motility, pain, and disorders of gut-brain interaction. The CB2-receptor agonist, cannabidiol, reduced the total Gastroparesis Cardinal Symptom Index and increases the ability to tolerate a meal in patients with gastroparesis appraised over 4 weeks of treatment. In contrast, predominant-pain end points in functional dyspepsia with normal gastric emptying were not improved significantly with cannabidiol. The CB2 agonist, olorinab, reduced abdominal pain in inflammatory bowel disease in an open-label trial and in constipation-predominant irritable bowel syndrome in a placebo-controlled trial. Cannabinoid mechanisms alter inflammation in pancreatic and liver diseases. In conclusion, cannabinoids, particularly agents affecting CB2 mechanisms, have potential for inflammatory, gastroparesis, and pain disorders; however, the trials require replication and further understanding of risk-benefit to enhance use of cannabinoids in gastrointestinal diseases.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Ting Zheng
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Berg BB, Linhares AFS, Martins DM, Rachid MA, Cau SBDA, Souza GGD, Carvalho JCSD, Sorgi CA, Romero TRL, Pinho V, Teixeira MM, Castor MGME. Anandamide reduces the migration of lymphocytes to the intestine by CB2 activation and reduces TNF-α in the target organs, protecting mice from graft-versus-host disease. Eur J Pharmacol 2023; 956:175932. [PMID: 37536622 DOI: 10.1016/j.ejphar.2023.175932] [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: 05/16/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 08/05/2023]
Abstract
Graft-versus-host disease (GVHD) is a serious inflammatory illness that often occurs as a secondary complication of bone marrow transplantation. Current therapies have limited effectiveness and fail to achieve a balance between inflammation and the graft-versus-tumor effect. In this study, we investigate the effects of the endocannabinoid anandamide on the complex pathology of GVHD. We assess the effects of an irreversible inhibitor of fatty acid amine hydrolase or exogenous anandamide and find that they increase survival and reduce clinical signs in GVHD mice. In the intestine of GVHD mice, treatment with exogenous anandamide also leads to a reduction in the number of CD3+, CD3+CD4+, and CD3+CD8+ cells, which reduces the activation of CD3+CD4+ and CD3+CD8+ cells, as assessed by enhanced CD28 expression, a T cell co-stimulatory molecule. Exogenous AEA was also able to reduce TNF-α and increase IL-10 in the intestine of GVHD mice. In the liver, exogenous AEA reduces injury, TNF-α levels, and the number of CD3+CD8+ cells. Interestingly, anandamide reduces Mac-1α, which lowers the adhesion of transplanted cells in mesenteric veins. These effects are mimicked by JWH133-a CB2 selective agonist-and abolished by treatment with a CB2 antagonist. Furthermore, the effects caused by anandamide treatment on survival were related to the CB2 receptor, as the CB2 antagonist abolished it. This study shows the critical role of the CB2 receptor in the modulation of the inflammatory response of GVHD by treatment with anandamide, the most prominent endocannabinoid.
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Affiliation(s)
- Bárbara Betônico Berg
- Graduate Program in Biological Sciences: Physiology and Pharmacology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Ana Flávia Santos Linhares
- Graduate Program in Biological Sciences: Physiology and Pharmacology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | | | | | | | | | - Carlos Arterio Sorgi
- Chemistry Department, Faculty of Philosophy Sciences and Letters of Ribeirão Preto, São Paulo, Brazil
| | | | - Vanessa Pinho
- Morphology Department, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Mauro Martins Teixeira
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil
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Ben-Mustapha Y, Ben-Fradj MK, Hadj-Taieb S, Serghini M, Ben Ahmed M, Boubaker J, Feki M. Altered mucosal and plasma polyunsaturated fatty acids, oxylipins, and endocannabinoids profiles in Crohn's disease. Prostaglandins Other Lipid Mediat 2023; 168:106741. [PMID: 37149256 DOI: 10.1016/j.prostaglandins.2023.106741] [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: 02/16/2023] [Revised: 04/13/2023] [Accepted: 05/02/2023] [Indexed: 05/08/2023]
Abstract
Selected mucosal and plasma polyunsaturated fatty acids (PUFAs) and related oxylipins and endocannabinoids were determined in 28 Crohn's disease (CD) patients and 39 controls. Fasting blood and colonic biopsies were collected in all participants, during a disease flare for the patients. Thirty-two lipid mediators including PUFAs, oxylipins, and endocannabinoids were assessed by LC-MS/MS. The pattern of lipid mediators in CD patients is characterized by an increase in arachidonic acid-derived oxylipins and endocannabinoids and a decrease in n-3 PUFAs and related endocannabinoids. A model combining increased 6-epi-lipoxin A4 and 2-arachidonyl glycerol with decreased docoasapentaenoic acid in plasma fairly discriminates patients from controls and may represent a lipidomic signature for CD flare. The study findings suggest that lipid mediators are involved in CD pathophysiology and may serve as biomarkers for disease flare. Further research is required to confirm the role of these bioactive lipids and test their therapeutic potential in CD.
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Affiliation(s)
- Yamina Ben-Mustapha
- University of Tunis El Manar, Faculty of Medicine of Tunis, 1007 Tunis, Tunisia; University of Tunis El Manar, Faculty of Sciences of Tunis, 2092 Tunis, Tunisia; Rabta Hospital, Laboratory of Biochemistry & LR99ES11, 1007 Tunis, Tunisia
| | - Mohamed Kacem Ben-Fradj
- University of Tunis El Manar, Faculty of Medicine of Tunis, 1007 Tunis, Tunisia; Rabta Hospital, Laboratory of Biochemistry & LR99ES11, 1007 Tunis, Tunisia
| | - Sameh Hadj-Taieb
- University of Tunis El Manar, Faculty of Medicine of Tunis, 1007 Tunis, Tunisia; Rabta Hospital, Laboratory of Biochemistry & LR99ES11, 1007 Tunis, Tunisia
| | - Meriem Serghini
- University of Tunis El Manar, Faculty of Medicine of Tunis, 1007 Tunis, Tunisia; Rabta Hospital, Service of Gastroenterology A, 1007 Tunis, Tunisia
| | - Melika Ben Ahmed
- University of Tunis El Manar, Faculty of Medicine of Tunis, 1007 Tunis, Tunisia; Institute Pasteur of Tunis, Laboratory of Clinical Immunology, 1002, Tunis, Tunisia
| | - Jalel Boubaker
- University of Tunis El Manar, Faculty of Medicine of Tunis, 1007 Tunis, Tunisia; Rabta Hospital, Service of Gastroenterology A, 1007 Tunis, Tunisia
| | - Moncef Feki
- University of Tunis El Manar, Faculty of Medicine of Tunis, 1007 Tunis, Tunisia; Rabta Hospital, Laboratory of Biochemistry & LR99ES11, 1007 Tunis, Tunisia.
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Mock ED, Gagestein B, van der Stelt M. Anandamide and other N-acylethanolamines: A class of signaling lipids with therapeutic opportunities. Prog Lipid Res 2023; 89:101194. [PMID: 36150527 DOI: 10.1016/j.plipres.2022.101194] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 01/18/2023]
Abstract
N-acylethanolamines (NAEs), including N-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), N-arachidonoylethanolamine (AEA, anandamide), N-docosahexaenoylethanolamine (DHEA, synaptamide) and their oxygenated metabolites are a lipid messenger family with numerous functions in health and disease, including inflammation, anxiety and energy metabolism. The NAEs exert their signaling role through activation of various G protein-coupled receptors (cannabinoid CB1 and CB2 receptors, GPR55, GPR110, GPR119), ion channels (TRPV1) and nuclear receptors (PPAR-α and PPAR-γ) in the brain and periphery. The biological role of the oxygenated NAEs, such as prostamides, hydroxylated anandamide and DHEA derivatives, are less studied. Evidence is accumulating that NAEs and their oxidative metabolites may be aberrantly regulated or are associated with disease severity in obesity, metabolic syndrome, cancer, neuroinflammation and liver cirrhosis. Here, we comprehensively review NAE biosynthesis and degradation, their metabolism by lipoxygenases, cyclooxygenases and cytochrome P450s and the biological functions of these signaling lipids. We discuss the latest findings and therapeutic potential of modulating endogenous NAE levels by inhibition of their degradation, which is currently under clinical evaluation for neuropsychiatric disorders. We also highlight NAE biosynthesis inhibition as an emerging topic with therapeutic opportunities in endocannabinoid and NAE signaling.
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Affiliation(s)
- Elliot D Mock
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Einsteinweg 55, Leiden 2333 CC, The Netherlands
| | - Berend Gagestein
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Einsteinweg 55, Leiden 2333 CC, The Netherlands
| | - Mario van der Stelt
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
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The Enteric Glia and Its Modulation by the Endocannabinoid System, a New Target for Cannabinoid-Based Nutraceuticals? MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27196773. [PMID: 36235308 PMCID: PMC9570628 DOI: 10.3390/molecules27196773] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/21/2022] [Accepted: 09/26/2022] [Indexed: 11/29/2022]
Abstract
The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.
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Animal Models and Pathogenesis of Ulcerative Colitis. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:5927384. [PMID: 35860188 PMCID: PMC9293489 DOI: 10.1155/2022/5927384] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/09/2022] [Accepted: 06/17/2022] [Indexed: 01/30/2023]
Abstract
Background Ulcerative colitis (UC) is a kind of inflammatory bowel disease which is needed to be predicted. Objective To analyze various animal models of UC conditions and summarizes the animal selection, model progression, and pathogenic mechanisms of UC animal models. Methods We surveyed the research papers published in PubMed, Google Scholar, Baidu Scholar, CNKI, SciFinder, and Web of Science in the past 5 years and discussed the experimental animals, modeling methods, and pathogenic mechanisms. Results In the selection of experimental animals, rats are considered the best experimental animals. The mainstream modeling methods can be categorized into the chemical stimulation method, immune stimulation method, and compound method, among which the compound method is the most successful. In the study of the pathogenesis of UC, the pathogenesis of UC is due to various pathogenic factors, such as nitric oxide (NO), prostaglandins (PG), proinflammatory factors (IL, TNF-α), and intestinal flora. Conclusion The method of building an animal model of UC is well-established, providing a more targeted selection of animal models for future related experiments.
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Cuddihey H, MacNaughton WK, Sharkey KA. Role of the Endocannabinoid System in the Regulation of Intestinal Homeostasis. Cell Mol Gastroenterol Hepatol 2022; 14:947-963. [PMID: 35750314 PMCID: PMC9500439 DOI: 10.1016/j.jcmgh.2022.05.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/09/2022] [Accepted: 05/25/2022] [Indexed: 12/15/2022]
Abstract
The maintenance of intestinal homeostasis is fundamentally important to health. Intestinal barrier function and immune regulation are key determinants of intestinal homeostasis and are therefore tightly regulated by a variety of signaling mechanisms. The endocannabinoid system is a lipid mediator signaling system widely expressed in the gastrointestinal tract. Accumulating evidence suggests the endocannabinoid system is a critical nexus involved in the physiological processes that underlie the control of intestinal homeostasis. In this review we will illustrate how the endocannabinoid system is involved in regulation of intestinal permeability, fluid secretion, and immune regulation. We will also demonstrate a reciprocal regulation between the endocannabinoid system and the gut microbiome. The role of the endocannabinoid system is complex and multifaceted, responding to both internal and external factors while also serving as an effector system for the maintenance of intestinal homeostasis.
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Affiliation(s)
- Hailey Cuddihey
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada,Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Wallace K. MacNaughton
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada,Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada,Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Keith A. Sharkey
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada,Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada,Correspondence Address correspondence to: Keith Sharkey, PhD, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
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13
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Shi L, Zhang P, Jin R, Chen X, Dong L, Chen W. Dioscin ameliorates inflammatory bowel disease by up-regulating miR-125a-5p to regulate macrophage polarization. J Clin Lab Anal 2022; 36:e24455. [PMID: 35524480 PMCID: PMC9169194 DOI: 10.1002/jcla.24455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 04/13/2022] [Accepted: 04/16/2022] [Indexed: 11/08/2022] Open
Abstract
PURPOSE Dioscin has been proven to have anti-cancer, anti-inflammatory, and anti-infection roles. However, the role of Dioscin in inflammatory bowel disease (IBD) and its related mechanisms is unclear and needs further study. METHODS The colitis model in mice was established. After Dioscin (20, 40, or 80 mg/kg) treatment, the colon length was measured by a ruler. Histopathology, inflammatory cytokines, gut permeability, tight junction proteins, macrophage infiltration, macrophage polarization, and miR-125a-5p level were detected by hematoxylin-eosin staining, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction (qRT-PCR), FITC-dextran, Western blot, and flow cytometry. In vitro experiments, after RAW264.7 cells induced by lipopolysaccharide (LPS)/interleukin-4 (IL-4), were treated with Dioscin and miR-125a-5p inhibitor, miR-125a-5p level, cell vitality, inflammatory cytokines, and M1/M2 marker genes were measured by qRT-PCR and MTT assay. RESULTS Dioscin (20, 40, or 80 mg/kg) relieved DSS-triggered colitis and restrained the serum and colon of pro-inflammatory cytokines expression. Meanwhile, different concentrations' Dioscin weakened M1 macrophage polarization but facilitated tight junction protein expressions, M2 macrophage polarization, and miR-125a-5p level in colitic mice. Moreover, miR-125a-5p inhibitor reversed the modulation of Dioscin on miR-125a-5p expression, cell vitality, and inflammatory cytokines in lipopolysaccharide (LPS)-induced RAW264.7 cells. We further discovered that Dioscin restrained M1 marker gene (CD16) expression while intensifying M2 marker genes (CD206 and Arginase-1) expressions in vitro, which was reversed by miR-125a-5p inhibitor. CONCLUSION Dioscin modulated macrophage polarization by increasing miR-125a-5p, thereby improving the intestinal epithelial barrier function and reducing IBD.
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Affiliation(s)
- Lingyan Shi
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
- Department of GastroenterologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Peichen Zhang
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Ruifang Jin
- Department of GastroenterologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Xiaowei Chen
- Department of GastroenterologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Lemei Dong
- Department of GastroenterologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Weichang Chen
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
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14
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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: 18] [Impact Index Per Article: 6.0] [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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15
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Hurrell BP, Helou DG, Shafiei-Jahani P, Howard E, Painter JD, Quach C, Akbari O. Cannabinoid receptor 2 engagement promotes group 2 innate lymphoid cell expansion and enhances airway hyperreactivity. J Allergy Clin Immunol 2022; 149:1628-1642.e10. [PMID: 34673048 PMCID: PMC9013728 DOI: 10.1016/j.jaci.2021.09.037] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 09/10/2021] [Accepted: 09/17/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Cannabinoids modulate the activation of immune cells and physiologic processes in the lungs. Group 2 innate lymphoid cells (ILC2s) are central players in type 2 asthma, but how cannabinoids modulate ILC2 activation remains to be elucidated. OBJECTIVE Our goal was to investigate the effects of cannabinoids on ILC2s and their role in asthma. METHODS A combination of cannabinoid receptor (CB)2 knockout (KO) mice, CB2 antagonist and agonist were used in the mouse models of IL-33, IL-25, and Alternaria alternata ILC2-dependent airway inflammation. RNA sequencing was performed to assess transcriptomic changes in ILC2s, and humanized mice were used to assess the role of CB2 signaling in human ILC2s. RESULTS We provide evidence that CB2 signaling in ILC2s is important for the development of ILC2-driven airway inflammation in both mice and human. We showed that both naive and activated murine pulmonary ILC2s express CB2. CB2 signaling did not affect ILC2 homeostasis at steady state, but strikingly it stimulated ILC2 proliferation and function upon activation. As a result, ILC2s lacking CB2 induced lower lung inflammation, as we made similar observations using a CB2 antagonist. Conversely, CB2 agonism remarkably exacerbated ILC2-driven airway hyperreactivity and lung inflammation. Mechanistically, transcriptomic and protein analysis revealed that CB2 signaling induced cyclic adenosine monophosphate-response element binding protein (CREB) phosphorylation in ILC2s. Human ILC2s expressed CB2, as CB2 antagonism and agonism showed opposing effects on ILC2 effector function and development of airway hyperreactivity in humanized mice. CONCLUSION Collectively, our results define CB2 signaling in ILC2s as an important modulator of airway inflammation.
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Affiliation(s)
- Benjamin P Hurrell
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif
| | - Doumet Georges Helou
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif
| | - Pedram Shafiei-Jahani
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif
| | - Emily Howard
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif
| | - Jacob D Painter
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif
| | - Christine Quach
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
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16
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Kiran S, Rakib A, Moore BM, Singh UP. Cannabinoid Receptor 2 (CB2) Inverse Agonist SMM-189 Induces Expression of Endogenous CB2 and Protein Kinase A That Differentially Modulates the Immune Response and Suppresses Experimental Colitis. Pharmaceutics 2022; 14:pharmaceutics14050936. [PMID: 35631522 PMCID: PMC9147685 DOI: 10.3390/pharmaceutics14050936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/22/2022] [Accepted: 04/24/2022] [Indexed: 12/25/2022] Open
Abstract
The causes of Crohn’s disease (CD) and ulcerative colitis (UC), the two most common forms of inflammatory bowel disease (IBD), are multi-factorial and include dysregulation of immune cells in the intestine. Cannabinoids mediate protection against intestinal inflammation by binding to the G-protein coupled cannabinoid receptors 1 and 2 (CB1 and CB2). Here, we investigate the effects of the CB2 inverse agonist SMM-189 on dextran sodium sulfate (DSS)-induced experimental colitis. We observed that SMM-189 effectively attenuated the overall clinical score, reversed colitis-associated pathogenesis, and increased both body weight and colon length. Treatment with SMM-189 also increased the expression of CB2 and protein kinase A (PKA) in colon lamina propria lymphocytes (LPLs). We noticed alterations in the percentage of Th17, neutrophils, and natural killer T (NKT) cells in the spleen, mesenteric lymph nodes (MLNs), and LPLs of mice with DSS-induced colitis after treatment with SMM-189 relative to DSS alone. Further, myeloid-derived suppressor cells (MDSCs) during colitis progression increased with SMM-189 treatment as compared to DSS alone or with control cohorts. These findings suggest that SMM-189 may ameliorate experimental colitis by inducing the expression of endogenous CB2 and PKA in LPLs, increasing numbers of MDSCs in the spleen, and reducing numbers of Th17 cells and neutrophils in the spleen, MLNs, and LPLs. Taken together, these data support the idea that SMM-189 may be developed as a safe novel therapeutic target for IBD.
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17
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Sionov RV, Steinberg D. Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles. Biomedicines 2022; 10:biomedicines10030631. [PMID: 35327432 PMCID: PMC8945038 DOI: 10.3390/biomedicines10030631] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/06/2022] [Accepted: 03/08/2022] [Indexed: 12/12/2022] Open
Abstract
Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites of plants possess anti-bacterial activities, and especially the phytocannabinoids of the Cannabis sativa L. varieties have reached a renaissance and attracted much attention for their anti-microbial and anti-biofilm activities at concentrations below the cytotoxic threshold on normal mammalian cells. Accordingly, many synthetic cannabinoids have been designed with the intention to increase the specificity and selectivity of the compounds. The structurally unrelated endocannabinoids have also been found to have anti-microbial and anti-biofilm activities. Recent data suggest for a mutual communication between the endocannabinoid system and the gut microbiota. The present review focuses on the anti-microbial activities of phytocannabinoids and endocannabinoids integrated with some selected issues of their many physiological and pharmacological activities.
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18
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Rao Q, Ma GC, Wu H, Li M, Xu W, Wang GJ, Wang D, Zhang CE, Ma ZJ, Zhang ZT. Dendritic cell combination therapy reduces the toxicity of triptolide and ameliorates colitis in murine models. Drug Deliv 2022; 29:679-691. [PMID: 35225120 PMCID: PMC8890574 DOI: 10.1080/10717544.2022.2044935] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Triptolide (TP) exerts a promising effect in the treatment of ulcerative colitis (UC). However, its toxicity seriously hinders its application in the clinic. Previous studies indicated that dendritic cells (DCs) are the main target through which TP exerts its immunoregulatory effect. Thus, we designed an approach to target DCs in vitro to avoid the direct exposure of organs to TP. Our results revealed that DCs pretreated with TP (DCTP) exerted satisfactory therapeutic effects in mice with colitis, resulting in improved colonic inflammation and alleviated local lesion damage. In addition, no obvious toxicity was observed. DCTP also reshaped the immune milieu by decreasing CD4+ T cell numbers and increasing regulatory T cell numbers in the spleen, mesenteric lymph nodes, peripheral blood and colon; these effects were further confirmed in vitro. Downregulation of CD80/86, ICAM-1, MHCI, TLR2/4, TNF-α, and IL-6 expression and upregulation of programmed cell death ligand 1 (PDL1) and IL-10 expression were observed, indicating that DCs were converted into tolerogenic DCs. In conclusion, DCTP can effectively reduce toxicity and alleviate colonic inflammation and local lesion damage in mice with colitis. The immune mechanism underlying the effects of DCTP included the conversion of DCs into tolerogenic DCs and the alteration of T cell differentiation to produce immunoinhibitory rather than immunostimulatory T cells.
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Affiliation(s)
- Quan Rao
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Guang-Chao Ma
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, China
| | - Hao Wu
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Meng Li
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wei Xu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Guo-Jun Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Dong Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Cong-En Zhang
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhi-Jie Ma
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhong-Tao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
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19
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Khan RN, Maner-Smith K, A. Owens J, Barbian ME, Jones RM, R. Naudin C. At the heart of microbial conversations: endocannabinoids and the microbiome in cardiometabolic risk. Gut Microbes 2022; 13:1-21. [PMID: 33896380 PMCID: PMC8078674 DOI: 10.1080/19490976.2021.1911572] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cardiometabolic syndrome encompasses intertwined risk factors such as hypertension, dyslipidemia, elevated triglycerides, abdominal obesity, and other maladaptive metabolic and inflammatory aberrations. As the molecular mechanisms linking cardiovascular disease and metabolic disorders are investigated, endocannabinoids have emerged as molecules of interest. The endocannabinoid system (ECS) of biologically active lipids has been implicated in several conditions, including chronic liver disease, osteoporosis, and more recently in cardiovascular diseases. The gut microbiome is a major regulator of inflammatory and metabolic signaling in the host, and if disrupted, has the potential to drive metabolic and cardiovascular diseases. Extensive studies have unraveled the impact of the gut microbiome on host physiology, with recent reports showing that gut microbes exquisitely control the ECS, with significant influences on host metabolic and cardiac health. In this review, we outline how modulation of the gut microbiome affects host metabolism and cardiovascular health via the ECS, and how these findings could be exploited as novel therapeutic targets for various metabolic and cardiac diseases.
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Affiliation(s)
- Ramsha Nabihah Khan
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Kristal Maner-Smith
- Emory Integrated Metabolomics and Lipidomics Core, Emory University, Atlanta, Georgia, USA
| | - Joshua A. Owens
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Maria Estefania Barbian
- Division of Neonatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Rheinallt M. Jones
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Crystal R. Naudin
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA,CONTACT Crystal R. Naudin Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA30322, United States of America
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20
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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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21
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On the Biomedical Properties of Endocannabinoid Degradation and Reuptake Inhibitors: Pre-clinical and Clinical Evidence. Neurotox Res 2021; 39:2072-2097. [PMID: 34741755 DOI: 10.1007/s12640-021-00424-z] [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: 07/19/2021] [Revised: 09/14/2021] [Accepted: 09/28/2021] [Indexed: 10/19/2022]
Abstract
The endocannabinoid system (ECS) is composed of endogenous cannabinoids; components involved in their synthesis, transport, and degradation; and an expansive variety of cannabinoid receptors. Hypofunction or deregulation of the ECS is related to pathological conditions. Consequently, endogenous enhancement of endocannabinoid levels and/or regulation of their metabolism represent promising therapeutic approaches. Several major strategies have been suggested for the modulation of the ECS: (1) blocking endocannabinoids degradation, (2) inhibition of endocannabinoid cellular uptake, and (3) pharmacological modulation of cannabinoid receptors as potential therapeutic targets. Here, we focused in this review on degradation/reuptake inhibitors over cannabinoid receptor modulators in order to provide an updated synopsis of contemporary evidence advancing mechanisms of endocannabinoids as pharmacological tools with therapeutic properties for the treatment of several disorders. For this purpose, we revisited the available literature and reported the latest advances regarding the biomedical properties of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors in pre-clinical and clinical studies. We also highlighted anandamide and 2-arachidonoylglycerol reuptake inhibitors with promising results in pre-clinical studies using in vitro and animal models as an outlook for future research in clinical trials.
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22
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Sinclair J, Collett L, Abbott J, Pate DW, Sarris J, Armour M. Effects of cannabis ingestion on endometriosis-associated pelvic pain and related symptoms. PLoS One 2021; 16:e0258940. [PMID: 34699540 PMCID: PMC8547625 DOI: 10.1371/journal.pone.0258940] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 10/07/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The use of cannabis for symptoms of endometriosis was investigated utilising retrospective archival data from Strainprint Technologies Ltd., a Canadian data technology company with a mobile phone application that tracks a range of data including dose, mode of administration, chemovar and their effects on various self-reported outcomes, including pelvic pain. METHODS A retrospective, electronic record-based cohort study of StrainprintTM users with self-reported endometriosis was conducted. Self-rated cannabis efficacy, defined as a function of initial and final symptom ratings, was investigated across the included symptom clusters of cramps, pelvic pain, gastrointestinal pain, nausea, depression, and low libido. Cannabis dosage form, dose and cannabinoid ratio information was also recorded. RESULTS A total number of 252 participants identifying as suffering endometriosis recorded 16193 sessions using cannabis between April 2017 and February 2020. The most common method of ingestion was inhalation (n = 10914, 67.4%), with pain as the most common reported symptom being treated by cannabis (n = 9281, 57.3%). Gastrointestinal symptoms, though a less common reason for cannabis usage (15.2%), had the greatest self-reported improvement after use. Inhaled forms had higher efficacy for pain, while oral forms were superior for mood and gastrointestinal symptoms. Dosage varied across ingestion methods, with a median dose of 9 inhalations (IQR 5 to 11) for inhaled dosage forms and 1 mg/mL (IQR 0.5 to 2) for other ingested dosage forms. The ratio of THC to CBD had a statistically significant, yet clinically small, differential effect on efficacy, depending on method of ingestion. CONCLUSIONS Cannabis appears to be effective for pelvic pain, gastrointestinal issues and mood, with effectiveness differing based on method of ingestion. The greater propensity for use of an inhaled dosage delivery may be due to the rapid onset of pain-relieving effects versus the slower onset of oral products. Oral forms appeared to be superior compared to inhaled forms in the less commonly reported mood or gastrointestinal categories. Clinical trials investigating the tolerability and effectiveness of cannabis for endometriosis pain and associated symptoms are urgently required.
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Affiliation(s)
- Justin Sinclair
- NICM Health Research Institute, Western Sydney University, Sydney, NSW, Australia
| | - Laura Collett
- Bristol Trials Centre, University of Bristol, Bristol, United Kingdom
| | - Jason Abbott
- School of Women’s and Children’s Health, UNSW, Sydney, NSW, Australia
| | - David W. Pate
- NICM Health Research Institute, Western Sydney University, Sydney, NSW, Australia
| | - Jerome Sarris
- NICM Health Research Institute, Western Sydney University, Sydney, NSW, Australia
- Professorial Unit, The Melbourne Clinic, Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia
| | - Mike Armour
- NICM Health Research Institute, Western Sydney University, Sydney, NSW, Australia
- Translational Health Research Institute, Western Sydney University, Sydney, NSW, Australia
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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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Giorgi V, Marotto D, Batticciotto A, Atzeni F, Bongiovanni S, Sarzi-Puttini P. Cannabis and Autoimmunity: Possible Mechanisms of Action. Immunotargets Ther 2021; 10:261-271. [PMID: 34322454 PMCID: PMC8313508 DOI: 10.2147/itt.s267905] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 06/25/2021] [Indexed: 12/11/2022] Open
Abstract
Medical cannabis (MC) describes the usually inhaled or ingested use of a cannabis plant or cannabis extract for medicinal purposes. The action of whole cannabis plants is extremely complex because their large number of active compounds not only bind to a plethora of different receptors but also interact with each other both synergistically and otherwise. Renewed interest in the medicinal properties of cannabis has led to increasing research into the practical uses of cannabis derivatives, and it has been found that the endocannabinoid system (particularly CB2 receptor activation) is a possible target for the treatment of inflammatory and the autoimmune diseases related to immune cell activation. However, in vivo findings still lack, creating difficulties in applying translational cannabinoid research to human immune functions. In this review, we summarized the main mechanisms of action of medical cannabis plant especially regarding the immune system and the endocannabinoid system, looking at preliminary clinical data in three most important autoimmune diseases of three different specialities: rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.
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Affiliation(s)
- Valeria Giorgi
- Rheumatology Unit, Internal Medicine Department, ASST Fatebenefratelli-Sacco, Milan University School of Medicine, Milan, Italy
| | - Daniela Marotto
- Rheumatology Unit, ATS Sardegna, P. Dettori Hospital, Tempio Pausania, Italy
| | - Alberto Batticciotto
- Rheumatology Unit, Internal Medicine Department, ASST Settelaghi, Ospedale Di Circolo - Fondazione Macchi, Varese, Italy
| | - Fabiola Atzeni
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Sara Bongiovanni
- Rheumatology Unit, Internal Medicine Department, ASST Fatebenefratelli-Sacco, Milan University School of Medicine, Milan, Italy
| | - Piercarlo Sarzi-Puttini
- Rheumatology Unit, Internal Medicine Department, ASST Fatebenefratelli-Sacco, Milan University School of Medicine, Milan, Italy
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25
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Rahaman O, Ganguly D. Endocannabinoids in immune regulation and immunopathologies. Immunology 2021; 164:242-252. [PMID: 34053085 DOI: 10.1111/imm.13378] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 04/19/2021] [Accepted: 05/10/2021] [Indexed: 12/12/2022] Open
Abstract
Endocannabinoids are key bioactive components of the endocannabinoid system, and the profound influence of endocannabinoids on the modulation of the immune system is being increasingly appreciated. The knowledge of endocannabinoid-immune cell crosstalk will pave the way to therapeutic implications of modulators of this pathway in autoimmune and chronic inflammatory disorders. Endocannabinoids seem to exert both anti-inflammatory and pro-inflammatory effects in specific contexts, based on specific receptor engagement and the downstream signalling pathways involved. In this review, we summarized the biosynthesis, signalling and degradation of two well-studied endocannabinoids-anandamide and 2-arachidonylglycerol in immune cells. Then, we discussed the effects of these two endocannabinoids on the functioning of major innate and adaptive immune cells, along with the choice of receptors employed in such interactions. Finally, we outline our current knowledge on the involvement of anandamide and 2-arachidonylglycerol in context of inflammation, allergies, autoimmunity and metabolic disorders.
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Affiliation(s)
- Oindrila Rahaman
- Dendritic Cell Biology Laboratory, IICB-Translational Research Unit of Excellence, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Dipyaman Ganguly
- Dendritic Cell Biology Laboratory, IICB-Translational Research Unit of Excellence, CSIR-Indian Institute of Chemical Biology, Kolkata, India
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26
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Osafo N, Yeboah OK, Antwi AO. Endocannabinoid system and its modulation of brain, gut, joint and skin inflammation. Mol Biol Rep 2021; 48:3665-3680. [PMID: 33909195 DOI: 10.1007/s11033-021-06366-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023]
Abstract
The discovery of endogenous cannabinoid receptors CB1 and CB2 and their endogenous ligands has generated interest in the endocannabinoid system and has contributed to the understanding of the role of the endocannabinoid system. Its role in the normal physiology of the body and its implication in pathological states such as cardiovascular diseases, neoplasm, depression and pain have been subjects of scientific interest. In this review the authors focus on the endogenous cannabinoids, and the critical role of cannabinoid receptor signaling in neurodegeneration and other inflammatory responses such as gut, joint and skin inflammation. This review also discusses the potential of endocannabinoid pathways as drug targets in the amelioration of some inflammatory conditions. Though the exact role of the endocannabinoid system is not fully understood, the evidence found much clearly points to a great potential in exploiting both its central and peripheral pathways in disease management. Cannabinoid therapy has proven promising in several preclinical and clinical trials.
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Affiliation(s)
- Newman Osafo
- Department of Pharmacology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
| | - Oduro K Yeboah
- Department of Pharmacology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Aaron O Antwi
- Department of Pharmacology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
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27
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Vecchiarelli HA, Morena M, Keenan CM, Chiang V, Tan K, Qiao M, Leitl K, Santori A, Pittman QJ, Sharkey KA, Hill MN. Comorbid anxiety-like behavior in a rat model of colitis is mediated by an upregulation of corticolimbic fatty acid amide hydrolase. Neuropsychopharmacology 2021; 46:992-1003. [PMID: 33452437 PMCID: PMC8115350 DOI: 10.1038/s41386-020-00939-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/11/2020] [Accepted: 12/06/2020] [Indexed: 01/29/2023]
Abstract
Peripheral inflammatory conditions, including those localized to the gastrointestinal tract, are highly comorbid with psychiatric disorders such as anxiety and depression. These behavioral symptoms are poorly managed by conventional treatments for inflammatory diseases and contribute to quality of life impairments. Peripheral inflammation is associated with sustained elevations in circulating glucocorticoid hormones, which can modulate central processes, including those involved in the regulation of emotional behavior. The endocannabinoid (eCB) system is exquisitely sensitive to these hormonal changes and is a significant regulator of emotional behavior. The impact of peripheral inflammation on central eCB function, and whether this is related to the development of these behavioral comorbidities remains to be determined. To examine this, we employed the trinitrobenzene sulfonic acid-induced model of colonic inflammation (colitis) in adult, male, Sprague Dawley rats to produce sustained peripheral inflammation. Colitis produced increases in behavioral measures of anxiety and elevations in circulating corticosterone. These alterations were accompanied by elevated hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which hydrolyzes the eCB anandamide (AEA), throughout multiple corticolimbic brain regions. This elevation of FAAH activity was associated with broad reductions in the content of AEA, whose decline was driven by central corticotropin releasing factor type 1 receptor signaling. Colitis-induced anxiety was reversed following acute central inhibition of FAAH, suggesting that the reductions in AEA produced by colitis contributed to the generation of anxiety. These data provide a novel perspective for the pharmacological management of psychiatric comorbidities of chronic inflammatory conditions through modulation of eCB signaling.
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Affiliation(s)
- Haley A. Vecchiarelli
- grid.22072.350000 0004 1936 7697Neuroscience Graduate Program, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB T2N4N1 Canada
| | - Maria Morena
- grid.22072.350000 0004 1936 7697Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Psychiatry, University of Calgary, Calgary, AB T2N4N1 Canada
| | - Catherine M. Keenan
- grid.22072.350000 0004 1936 7697Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1 Canada
| | - Vincent Chiang
- grid.22072.350000 0004 1936 7697Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Psychiatry, University of Calgary, Calgary, AB T2N4N1 Canada
| | - Kaitlyn Tan
- grid.22072.350000 0004 1936 7697Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Psychiatry, University of Calgary, Calgary, AB T2N4N1 Canada
| | - Min Qiao
- grid.22072.350000 0004 1936 7697Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Psychiatry, University of Calgary, Calgary, AB T2N4N1 Canada
| | - Kira Leitl
- grid.22072.350000 0004 1936 7697Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Psychiatry, University of Calgary, Calgary, AB T2N4N1 Canada
| | - Alessia Santori
- grid.22072.350000 0004 1936 7697Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Psychiatry, University of Calgary, Calgary, AB T2N4N1 Canada
| | - Quentin J. Pittman
- grid.22072.350000 0004 1936 7697Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1 Canada
| | - Keith A. Sharkey
- grid.22072.350000 0004 1936 7697Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1 Canada
| | - Matthew N. Hill
- grid.22072.350000 0004 1936 7697Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB T2N4N1 Canada ,grid.22072.350000 0004 1936 7697Department of Psychiatry, University of Calgary, Calgary, AB T2N4N1 Canada
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The Endocannabinoid, Anandamide, Acts as a Novel Inhibitor of LPS-Induced Inflammasome Activation in Human Gastric Cancer AGS Cell Line: Involvement of CB1 and TRPV1 Receptors. Mediators Inflamm 2021. [DOI: 10.1155/2021/6698049] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Inflammasome activation is a pivotal step for the maturation of IL-1β, which is involved in the development and progression of gastric cancer (GC). Endocannabinoids, such as anandamide (AEA), are emerging as new anticancer therapeutic agents; however, their effects on inflammasome components and underlying mechanisms have not been well elucidated. This study was designed to investigate the effects of AEA on the expression of inflammasome components in lipopolysaccharide- (LPS-) stimulated AGS cells. Moreover, we explored the involvement of cannabinoid receptors (CRs), including CB1R and TRPV1R, in the observed effects of AEA. Our results showed that inflammation was induced by LPS (10 μg/ml) in AGS cells, and inflammasome components (NLRP3, MLRC4, ASC, IL-18, and IL-1β) were overexpressed. Exposure to AEA (10 μM, 24 h) before or after inflammation induction downregulated the expression of inflammasome components and attenuated inflammasome activation as demonstrated by cleavage of caspase 1 and matured IL-1β secretion, although AEA pretreatment showed more reducing effects on the inflammasome activation. In addition, blocking of CB1R and TRPV1R by application of AM-251 and AMG-9810 antagonists remarkably reversed the observed effects of AEA and revealed that NLRP3, NLRC4, and IL-1β genes were mainly regulated via CB1R, while TRPV1R could only regulate the expression of IL-1β and IL-18 genes. In conclusion, our results would indicate a novel anticancer effect of anandamide by attenuation of inflammasome activation and consequently reducing IL-1β production in human AGS cancer cell line via CB1R and TRPV1R.
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Caioni G, Viscido A, d’Angelo M, Panella G, Castelli V, Merola C, Frieri G, Latella G, Cimini A, Benedetti E. Inflammatory Bowel Disease: New Insights into the Interplay between Environmental Factors and PPARγ. Int J Mol Sci 2021; 22:985. [PMID: 33498177 PMCID: PMC7863964 DOI: 10.3390/ijms22030985] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/14/2021] [Accepted: 01/18/2021] [Indexed: 12/19/2022] Open
Abstract
The pathophysiological processes of inflammatory bowel diseases (IBDs), i.e., Crohn's disease (CD) and ulcerative colitis (UC), are still not completely understood. The exact etiology remains unknown, but it is well established that the pathogenesis of the inflammatory lesions is due to a dysregulation of the gut immune system resulting in over-production of pro-inflammatory cytokines. Increasing evidence underlines the involvement of both environmental and genetic factors. Regarding the environment, the microbiota seems to play a crucial role. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert pleiotropic effects on glucose homeostasis, lipid metabolism, inflammatory/immune processes, cell proliferation, and fibrosis. Furthermore, PPARs modulate interactions with several environmental factors, including microbiota. A significantly impaired PPARγ expression was observed in UC patients' colonic epithelial cells, suggesting that the disruption of PPARγ signaling may represent a critical step of the IBD pathogenesis. This paper will focus on the role of PPARγ in the interaction between environmental factors and IBD, and it will analyze the most suitable in vitro and in vivo models available to better study these relationships.
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Affiliation(s)
- Giulia Caioni
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (G.C.); (A.V.); (M.d.); (G.P.); (V.C.); (G.F.); (G.L.); (A.C.)
| | - Angelo Viscido
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (G.C.); (A.V.); (M.d.); (G.P.); (V.C.); (G.F.); (G.L.); (A.C.)
| | - Michele d’Angelo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (G.C.); (A.V.); (M.d.); (G.P.); (V.C.); (G.F.); (G.L.); (A.C.)
| | - Gloria Panella
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (G.C.); (A.V.); (M.d.); (G.P.); (V.C.); (G.F.); (G.L.); (A.C.)
- Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy;
| | - Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (G.C.); (A.V.); (M.d.); (G.P.); (V.C.); (G.F.); (G.L.); (A.C.)
| | - Carmine Merola
- Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy;
| | - Giuseppe Frieri
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (G.C.); (A.V.); (M.d.); (G.P.); (V.C.); (G.F.); (G.L.); (A.C.)
| | - Giovanni Latella
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (G.C.); (A.V.); (M.d.); (G.P.); (V.C.); (G.F.); (G.L.); (A.C.)
| | - Annamaria Cimini
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (G.C.); (A.V.); (M.d.); (G.P.); (V.C.); (G.F.); (G.L.); (A.C.)
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| | - Elisabetta Benedetti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (G.C.); (A.V.); (M.d.); (G.P.); (V.C.); (G.F.); (G.L.); (A.C.)
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Śledziński P, Nowak-Terpiłowska A, Zeyland J. Cannabinoids in Medicine: Cancer, Immunity, and Microbial Diseases. Int J Mol Sci 2020; 22:E263. [PMID: 33383838 PMCID: PMC7795897 DOI: 10.3390/ijms22010263] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/16/2020] [Accepted: 12/25/2020] [Indexed: 12/12/2022] Open
Abstract
Recently, there has been a growing interest in the medical applications of Cannabis plants. They owe their unique properties to a group of secondary metabolites known as phytocannabinoids, which are specific for this genus. Phytocannabinoids, and cannabinoids generally, can interact with cannabinoid receptors being part of the endocannabinoid system present in animals. Over the years a growing body of scientific evidence has been gathered, suggesting that these compounds have therapeutic potential. In this article, we review the classification of cannabinoids, the molecular mechanisms of their interaction with animal cells as well as their potential application in the treatment of human diseases. Specifically, we focus on the research concerning the anticancer potential of cannabinoids in preclinical studies, their possible use in cancer treatment and palliative medicine, as well as their influence on the immune system. We also discuss their potential as therapeutic agents in infectious, autoimmune, and gastrointestinal inflammatory diseases. We postulate that the currently ongoing and future clinical trials should be accompanied by research focused on the cellular and molecular response to cannabinoids and Cannabis extracts, which will ultimately allow us to fully understand the mechanism, potency, and safety profile of cannabinoids as single agents and as complementary drugs.
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Affiliation(s)
- Paweł Śledziński
- Department of Genome Engineering, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 60-032 Poznan, Poland;
| | | | - Joanna Zeyland
- Department of Biochemistry and Biotechnology, Poznan University of Life Sciences, 60-632 Poznan, Poland;
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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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Ellermann M, Pacheco AR, Jimenez AG, Russell RM, Cuesta S, Kumar A, Zhu W, Vale G, Martin SA, Raj P, McDonald JG, Winter SE, Sperandio V. Endocannabinoids Inhibit the Induction of Virulence in Enteric Pathogens. Cell 2020; 183:650-665.e15. [PMID: 33031742 DOI: 10.1016/j.cell.2020.09.022] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 06/30/2020] [Accepted: 09/08/2020] [Indexed: 12/12/2022]
Abstract
Endocannabinoids are host-derived lipid hormones that fundamentally impact gastrointestinal (GI) biology. The use of cannabis and other exocannabinoids as anecdotal treatments for various GI disorders inspired the search for mechanisms by which these compounds mediate their effects, which led to the discovery of the mammalian endocannabinoid system. Dysregulated endocannabinoid signaling was linked to inflammation and the gut microbiota. However, the effects of endocannabinoids on host susceptibility to infection has not been explored. Here, we show that mice with elevated levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG) are protected from enteric infection by Enterobacteriaceae pathogens. 2-AG directly modulates pathogen function by inhibiting virulence programs essential for successful infection. Furthermore, 2-AG antagonizes the bacterial receptor QseC, a histidine kinase encoded within the core Enterobacteriaceae genome that promotes the activation of pathogen-associated type three secretion systems. Taken together, our findings establish that endocannabinoids are directly sensed by bacteria and can modulate bacterial function.
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Affiliation(s)
- Melissa Ellermann
- Department of Microbiology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Alline R Pacheco
- Department of Microbiology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Angel G Jimenez
- Department of Microbiology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Regan M Russell
- Department of Microbiology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Santiago Cuesta
- Department of Microbiology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Aman Kumar
- Department of Microbiology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Wenhan Zhu
- Department of Microbiology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Gonçalo Vale
- Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sarah A Martin
- Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Prithvi Raj
- Microbiome Research Lab, Department of Immunology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jeffrey G McDonald
- Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sebastian E Winter
- Department of Microbiology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Vanessa Sperandio
- Department of Microbiology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
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Pagano E, Iannotti FA, Piscitelli F, Romano B, Lucariello G, Venneri T, Di Marzo V, Izzo AA, Borrelli F. Efficacy of combined therapy with fish oil and phytocannabinoids in murine intestinal inflammation. Phytother Res 2020; 35:517-529. [PMID: 32996187 DOI: 10.1002/ptr.6831] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/24/2020] [Accepted: 07/13/2020] [Indexed: 12/16/2022]
Abstract
Fish oil (FO) and phytocannabinoids have received considerable attention for their intestinal anti-inflammatory effects. We investigated whether the combination of FO with cannabigerol (CBG) and cannabidiol (CBD) or a combination of all three treatments results in a more pronounced intestinal antiinflammatory action compared to the effects achieved separately. Colitis was induced in mice by 2,4-dinitrobenzenesulfonic acid (DNBS). CBD and CBG levels were detected and quantified by liquid chromatography coupled with time of flight mass spectrometry and ion trap mass spectrometry (LC-MS-IT-TOF). Endocannabinoids and related mediators were assessed by LC-MS. DNBS increased colon weight/colon length ratio, myeloperoxidase activity, interleukin-1β, and intestinal permeability. CBG, but not CBD, given by oral gavage, ameliorated DNBS-induced colonic inflammation. FO pretreatment (at the inactive dose) increased the antiinflammatory action of CBG and rendered oral CBD effective while reducing endocannabinoid levels. Furthermore, the combination of FO, CBD, and a per se inactive dose of CBG resulted in intestinal anti-inflammatory effects. Finally, FO did not alter phytocannabinoid levels in the serum and in the colon. By highlighting the apparent additivity between phytocannabinoids and FO, our preclinical data support a novel strategy of combining these substances for the potential development of a treatment of inflammatory bowel disease.
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Affiliation(s)
- Ester Pagano
- Department of Pharmacy, School of Medicine and Pharmacy, University of Naples Federico II, Naples, Italy.,Endocannabinoid Research Group
| | - Fabio A Iannotti
- Endocannabinoid Research Group.,Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy
| | - Fabiana Piscitelli
- Endocannabinoid Research Group.,Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy
| | - Barbara Romano
- Department of Pharmacy, School of Medicine and Pharmacy, University of Naples Federico II, Naples, Italy.,Endocannabinoid Research Group
| | - Giuseppe Lucariello
- Department of Pharmacy, School of Medicine and Pharmacy, University of Naples Federico II, Naples, Italy
| | - Tommaso Venneri
- Department of Pharmacy, School of Medicine and Pharmacy, University of Naples Federico II, Naples, Italy.,Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Institut Universitaire de Cardiologie et de Pneumologie de Québec and Institut sur la Nutrition et les Aliments Fonctionnels Centre NUTRISS, Université Laval, Quebec City, Canada
| | - Vincenzo Di Marzo
- Endocannabinoid Research Group.,Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy.,Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Institut Universitaire de Cardiologie et de Pneumologie de Québec and Institut sur la Nutrition et les Aliments Fonctionnels Centre NUTRISS, Université Laval, Quebec City, Canada
| | - Angelo A Izzo
- Department of Pharmacy, School of Medicine and Pharmacy, University of Naples Federico II, Naples, Italy.,Endocannabinoid Research Group
| | - Francesca Borrelli
- Department of Pharmacy, School of Medicine and Pharmacy, University of Naples Federico II, Naples, Italy.,Endocannabinoid Research Group
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Szczepaniak A, Fichna J. What role do cannabinoids have in modern medicine as gastrointestinal anti-inflammatory drugs? Expert Opin Pharmacother 2020; 21:1931-1934. [DOI: 10.1080/14656566.2020.1795129] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Adrian Szczepaniak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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Inner Engineering Practices and Advanced 4-day Isha Yoga Retreat Are Associated with Cannabimimetic Effects with Increased Endocannabinoids and Short-Term and Sustained Improvement in Mental Health: A Prospective Observational Study of Meditators. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:8438272. [PMID: 32595741 PMCID: PMC7293737 DOI: 10.1155/2020/8438272] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/08/2020] [Accepted: 04/17/2020] [Indexed: 12/15/2022]
Abstract
Background Anxiety and depression are common in the modern world, and there is growing demand for alternative therapies such as meditation. Meditation can decrease perceived stress and increase general well-being, although the physiological mechanism is not well-characterized. Endocannabinoids (eCBs), lipid mediators associated with enhanced mood and reduced anxiety/depression, have not been previously studied as biomarkers of meditation effects. Our aim was to assess biomarkers (eCBs and brain-derived neurotrophic factor [BDNF]) and psychological parameters after a meditation retreat. Methods This was an observational pilot study of adults before and after the 4-day Isha Yoga Bhava Spandana Program retreat. Participants completed online surveys (before and after retreat, and 1 month later) to assess anxiety, depression, focus, well-being, and happiness through validated psychological scales. Voluntary blood sampling for biomarker studies was done before and within a day after the retreat. The biomarkers anandamide, 2-arachidonoylglycerol (2-AG), 1-arachidonoylglycerol (1-AG), docosatetraenoylethanolamide (DEA), oleoylethanolamide (OLA), and BDNF were evaluated. Primary outcomes were changes in psychological scales, as well as changes in eCBs and BDNF. Results Depression and anxiety scores decreased while focus, happiness, and positive well-being scores increased immediately after retreat from their baseline values (P < 0.001). All improvements were sustained 1 month after BSP. All major eCBs including anandamide, 2-AG, 1-AG, DEA, and BDNF increased after meditation by > 70% (P < 0.001). Increases of ≥20% in anandamide, 2-AG, 1-AG, and total AG levels after meditation from the baseline had weak correlations with changes in happiness and well-being. Conclusions A short meditation experience improved focus, happiness, and positive well-being and reduced depression and anxiety in participants for at least 1 month. Participants had increased blood eCBs and BDNF, suggesting a role for these biomarkers in the underlying mechanism of meditation. Meditation is a simple, organic, and effective way to improve well-being and reduce depression and anxiety.
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Decara J, Rivera P, López-Gambero AJ, Serrano A, Pavón FJ, Baixeras E, Rodríguez de Fonseca F, Suárez J. Peroxisome Proliferator-Activated Receptors: Experimental Targeting for the Treatment of Inflammatory Bowel Diseases. Front Pharmacol 2020; 11:730. [PMID: 32536865 PMCID: PMC7266982 DOI: 10.3389/fphar.2020.00730] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 05/01/2020] [Indexed: 12/17/2022] Open
Abstract
The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that promote ligand-dependent transcription of target genes that regulate energy production, lipid metabolism, and inflammation. The PPAR superfamily comprises three subtypes, PPARα, PPARγ, and PPARβ/δ, with differential tissue distributions. In addition to their different roles in the regulation of energy balance and carbohydrate and lipid metabolism, an emerging function of PPARs includes normal homeostasis of intestinal tissue. PPARα activation represses NF-κB signaling, which decreases the inflammatory cytokine production by different cell types, while PPARγ ligands can inhibit activation of macrophages and the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and Il-1β. In this regard, the anti-inflammatory responses induced by PPAR activation might restore physiopathological imbalances associated with inflammatory bowel diseases (IBD). Thus, PPARs and their ligands have important therapeutic potential. This review briefly discusses the roles of PPARs in the physiopathology and therapies of the most important IBDs, ulcerative colitis (UC), and Crohn's disease (CD), as well some new experimental compounds with PPAR activity as promising drugs for IBD treatment.
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Affiliation(s)
- Juan Decara
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Patricia Rivera
- Departamento de Endocrinología, Fundación Investigación Biomédica del Hospital Infantil Universitario Niño Jesús, Madrid, Spain
| | - Antonio Jesús López-Gambero
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Antonia Serrano
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Francisco Javier Pavón
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) and UGC del Corazón, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Elena Baixeras
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Málaga, IBIMA, Málaga, Spain
| | - Fernando Rodríguez de Fonseca
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Juan Suárez
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
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Cas MD, Roda G, Li F, Secundo F. Functional Lipids in Autoimmune Inflammatory Diseases. Int J Mol Sci 2020; 21:E3074. [PMID: 32349258 PMCID: PMC7246500 DOI: 10.3390/ijms21093074] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/22/2020] [Accepted: 04/24/2020] [Indexed: 12/27/2022] Open
Abstract
Lipids are apolar small molecules known not only as components of cell membranes but also, in recent literature, as modulators of different biological functions. Herein, we focused on the bioactive lipids that can influence the immune responses and inflammatory processes regulating vascular hyperreactivity, pain, leukocyte trafficking, and clearance. In the case of excessive pro-inflammatory lipid activity, these lipids also contribute to the transition from acute to chronic inflammation. Based on their biochemical function, these lipids can be divided into different families, including eicosanoids, specialized pro-resolving mediators, lysoglycerophospholipids, sphingolipids, and endocannabinoids. These bioactive lipids are involved in all phases of the inflammatory process and the pathophysiology of different chronic autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, type-1 diabetes, and systemic lupus erythematosus.
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Affiliation(s)
- Michele Dei Cas
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy
| | - Gabriella Roda
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Feng Li
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
| | - Francesco Secundo
- Istituto di Scienze e Tecnologie Chimiche “Giulio Natta”, Consiglio Nazionale delle Ricerche, 20131 Milan, Italy
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38
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Fornelos N, Franzosa EA, Bishai J, Annand JW, Oka A, Lloyd-Price J, Arthur TD, Garner A, Avila-Pacheco J, Haiser HJ, Tolonen AC, Porter JA, Clish CB, Sartor RB, Huttenhower C, Vlamakis H, Xavier RJ. Growth effects of N-acylethanolamines on gut bacteria reflect altered bacterial abundances in inflammatory bowel disease. Nat Microbiol 2020; 5:486-497. [PMID: 31959971 PMCID: PMC7047597 DOI: 10.1038/s41564-019-0655-7] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 12/06/2019] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel diseases (IBD) are associated with alterations in gut microbial abundances and lumenal metabolite concentrations, but the effects of specific metabolites on the gut microbiota in health and disease remain largely unknown. Here, we analysed the influences of metabolites that are differentially abundant in IBD on the growth and physiology of gut bacteria that are also differentially abundant in IBD. We found that N-acylethanolamines (NAEs), a class of endogenously produced signalling lipids elevated in the stool of IBD patients and a T-cell transfer model of colitis, stimulated growth of species over-represented in IBD and inhibited that of species depleted in IBD in vitro. Using metagenomic sequencing, we recapitulated the effects of NAEs in complex microbial communities ex vivo, with Proteobacteria blooming and Bacteroidetes declining in the presence of NAEs. Metatranscriptomic analysis of the same communities identified components of the respiratory chain as important for the metabolism of NAEs, and this was verified using a mutant deficient for respiratory complex I. In this study, we identified NAEs as a class of metabolites that are elevated in IBD and have the potential to shift gut microbiota towards an IBD-like composition.
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Affiliation(s)
| | - Eric A Franzosa
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Jason Bishai
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - John W Annand
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research Inc., Cambridge, MA, USA
| | - Akihiko Oka
- Departments of Medicine, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jason Lloyd-Price
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | | | - Ashley Garner
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | - Henry J Haiser
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research Inc., Cambridge, MA, USA
| | | | - Jeffrey A Porter
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research Inc., Cambridge, MA, USA
| | - Clary B Clish
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - R Balfour Sartor
- Departments of Medicine, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Curtis Huttenhower
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Hera Vlamakis
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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Hossain MZ, Ando H, Unno S, Kitagawa J. Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain. Int J Mol Sci 2020; 21:E1423. [PMID: 32093166 PMCID: PMC7073137 DOI: 10.3390/ijms21041423] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/17/2020] [Accepted: 02/18/2020] [Indexed: 02/06/2023] Open
Abstract
Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP.
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Affiliation(s)
- Mohammad Zakir Hossain
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan; (S.U.); (J.K.)
| | - Hiroshi Ando
- Department of Biology, School of Dentistry, Matsumoto Dental University, 1780 Gobara, Hirooka, Shiojiri, Nagano 399-0781, Japan;
| | - Shumpei Unno
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan; (S.U.); (J.K.)
| | - Junichi Kitagawa
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan; (S.U.); (J.K.)
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Karoly HC, Mueller RL, Bidwell LC, Hutchison KE. Cannabinoids and the Microbiota-Gut-Brain Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders. Alcohol Clin Exp Res 2019; 44:340-353. [PMID: 31803950 DOI: 10.1111/acer.14256] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Abstract
The endocannabinoid system (ECS) has emerged in recent years as a potential treatment target for alcohol use disorders (AUD). In particular, the nonpsychoactive cannabinoid cannabidiol (CBD) has shown preclinical promise in ameliorating numerous clinical symptoms of AUD. There are several proposed mechanism(s) through which cannabinoids (and CBD in particular) may confer beneficial effects in the context of AUD. First, CBD may directly impact specific brain mechanisms underlying AUD to influence alcohol consumption and the clinical features of AUD. Second, CBD may influence AUD symptoms through its actions across the digestive, immune, and central nervous systems, collectively known as the microbiota-gut-brain axis (MGBA). Notably, emerging work suggests that alcohol and cannabinoids exert opposing effects on the MGBA. Alcohol is linked to immune dysfunction (e.g., chronic systemic inflammation in the brain and periphery) as well as disturbances in gut microbial species (microbiota) and increased intestinal permeability. These MGBA disruptions have been associated with AUD symptoms such as craving and impaired cognitive control. Conversely, existing preclinical data suggest that cannabinoids may confer beneficial effects on the gastrointestinal and immune system, such as reducing intestinal permeability, regulating gut bacteria, and reducing inflammation. Thus, cannabinoids may exert AUD harm-reduction effects, at least in part, through their beneficial actions across the MGBA. This review will provide a brief introduction to the ECS and the MGBA, discuss the effects of cannabinoids (particularly CBD) and alcohol in the brain, gut, and immune system (i.e., across the MGBA), and put forth a theoretical framework to inform future research questions.
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Affiliation(s)
- Hollis C Karoly
- Institute of Cognitive Science, University of Colorado Boulder, Boulder, Colorado
| | - Raeghan L Mueller
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado
| | - L Cinnamon Bidwell
- Institute of Cognitive Science, University of Colorado Boulder, Boulder, Colorado.,Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado
| | - Kent E Hutchison
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado
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Bozkurt TE. Endocannabinoid System in the Airways. Molecules 2019; 24:E4626. [PMID: 31861200 PMCID: PMC6943521 DOI: 10.3390/molecules24244626] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/12/2019] [Accepted: 12/15/2019] [Indexed: 12/12/2022] Open
Abstract
Cannabinoids and the mammalian endocannabinoid system is an important research area of interest and attracted many researchers because of their widespread biological effects. The significant immune-modulatory role of cannabinoids has suggested their therapeutic use in several inflammatory conditions. Airways are prone to environmental irritants and stimulants, and increased inflammation is an important process in most of the respiratory diseases. Therefore, the main strategies for treating airway diseases are suppression of inflammation and producing bronchodilation. The ability of cannabinoids to induce bronchodilation and modify inflammation indicates their importance for airway physiology and pathologies. In this review, the contribution of cannabinoids and the endocannabinoid system in the airways are discussed, and the existing data for their therapeutic use in airway diseases are presented.
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Affiliation(s)
- Turgut Emrah Bozkurt
- Department of Pharmacology, Faculty of Pharmacy, Hacettepe University, Ankara 06100, Turkey
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42
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Benzofuran and pyrrole derivatives as cannabinoid receptor modulators with in vivo efficacy against ulcerative colitis. Future Med Chem 2019; 11:3139-3159. [DOI: 10.4155/fmc-2019-0172] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Aim: Highlighting the need for effective therapies for the treatment of ulcerative colitis, novel series of potential CB2 modulators (benzofuran and pyrrole carboxamides) were developed and tested for their functional activities on CB1/CB2 receptors. Results: In the benzofuran series, the cannabinoid (CB) receptor selectivity and the functional profile were dependent on the nature of the amide substituent and the position of the methoxy group, meanwhile the pyrrole derivatives, displayed an exclusive selectivity to the CB2 receptor and a functionality that is controlled by the nature of the pyrrole nitrogen substituent. Conclusion: Remarkably, we succeeded to develop potent and selective pyrrole-based CB2 receptor agonists, represented by compound 25a, which also demonstrated an exquisite anti-inflammatory effect in a dextran sodium sulfate-induced colitis model in mice.
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The Endocannabinoid System in Pediatric Inflammatory and Immune Diseases. Int J Mol Sci 2019; 20:ijms20235875. [PMID: 31771129 PMCID: PMC6928713 DOI: 10.3390/ijms20235875] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 11/19/2019] [Accepted: 11/20/2019] [Indexed: 12/26/2022] Open
Abstract
Endocannabinoid system consists of cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors, their endogenous ligands, and the enzymes responsible for their synthesis and degradation. CB2, to a great extent, and CB1, to a lesser extent, are involved in regulating the immune response. They also regulate the inflammatory processes by inhibiting pro-inflammatory mediator release and immune cell proliferation. This review provides an overview on the role of the endocannabinoid system with a major focus on cannabinoid receptors in the pathogenesis and onset of inflammatory and autoimmune pediatric diseases, such as immune thrombocytopenia, juvenile idiopathic arthritis, inflammatory bowel disease, celiac disease, obesity, neuroinflammatory diseases, and type 1 diabetes mellitus. These disorders have a high social impact and represent a burden for the healthcare system, hence the importance of individuating more innovative and effective treatments. The endocannabinoid system could address this need, representing a possible new diagnostic marker and therapeutic target.
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Holleran G, Scaldaferri F, Gasbarrini A, Currò D. Herbal medicinal products for inflammatory bowel disease: A focus on those assessed in double-blind randomised controlled trials. Phytother Res 2019; 34:77-93. [PMID: 31701598 DOI: 10.1002/ptr.6517] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 08/01/2019] [Accepted: 09/08/2019] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease patients frequently use herbal products as complementary or alternative medicines to current pharmacotherapies and obtain information on them mainly from the internet, social media, or unlicensed practitioners. Clinicians should therefore take a more active role and become knowledgeable of the mechanisms of action and potential drug interactions of herbal medicines for which evidence of efficacy is available. The therapeutic efficacy and safety of several herbal medicines have been studied in double-blind randomised controlled trials (RCTs). Evidence of efficacy is available for Andrographis paniculata extract; curcumin; a combination of myrrh, extract of chamomile flower, and coffee charcoal; and the Chinese herbal medicines Fufangkushen colon-coated capsule and Xilei san in patients with ulcerative colitis; and Artemisia absinthium extract and Boswellia serrata resin extract in patients with Crohn's disease. However, most of this evidence comes from single small RCTs with short follow-up, and the long-term effects and safety of their use have not yet been established. Thus, our findings indicate that further appropriately sized RCTs are necessary prior to the recommended use of these herbal medicines in therapy. In the meantime, increasing awareness of their use, and potential drug interactions among physicians may help to reduce unwanted effects and adverse disease outcomes.
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Affiliation(s)
- Grainne Holleran
- Department of Gastroenterology and Clinical Medicine, Trinity Centre for Health Sciences, Tallaght Hospital, Dublin, Ireland
| | - Franco Scaldaferri
- Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, 00168, Italy
| | - Antonio Gasbarrini
- Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, 00168, Italy.,Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
| | - Diego Currò
- Unità Operativa Complessa di Farmacologia, Direzione Sanitaria, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, 00168, Italy.,Istituto di Farmacologia, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
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45
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Kynurenines and the Endocannabinoid System in Schizophrenia: Common Points and Potential Interactions. Molecules 2019; 24:molecules24203709. [PMID: 31619006 PMCID: PMC6832375 DOI: 10.3390/molecules24203709] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 12/15/2022] Open
Abstract
Schizophrenia, which affects around 1% of the world’s population, has been described as a complex set of symptoms triggered by multiple factors. However, the exact background mechanisms remain to be explored, whereas therapeutic agents with excellent effectivity and safety profiles have yet to be developed. Kynurenines and the endocannabinoid system (ECS) play significant roles in both the development and manifestation of schizophrenia, which have been extensively studied and reviewed previously. Accordingly, kynurenines and the ECS share multiple features and mechanisms in schizophrenia, which have yet to be reviewed. Thus, the present study focuses on the main common points and potential interactions between kynurenines and the ECS in schizophrenia, which include (i) the regulation of glutamatergic/dopaminergic/γ-aminobutyric acidergic neurotransmission, (ii) their presence in astrocytes, and (iii) their role in inflammatory mechanisms. Additionally, promising pharmaceutical approaches involving the kynurenine pathway and the ECS will be reviewed herein.
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Ghonim AE, Ligresti A, Rabbito A, Mahmoud AM, Di Marzo V, Osman NA, Abadi AH. Structure-activity relationships of thiazole and benzothiazole derivatives as selective cannabinoid CB2 agonists with in vivo anti-inflammatory properties. Eur J Med Chem 2019; 180:154-170. [DOI: 10.1016/j.ejmech.2019.07.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 07/01/2019] [Accepted: 07/01/2019] [Indexed: 12/23/2022]
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Sen A, Stark H. Role of cytochrome P450 polymorphisms and functions in development of ulcerative colitis. World J Gastroenterol 2019; 25:2846-2862. [PMID: 31249444 PMCID: PMC6589734 DOI: 10.3748/wjg.v25.i23.2846] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/26/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Cytochromes P450s (CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms (CYP1A1, CYP2D6, CYP2J2, CYP2R1, CYP3A5, CYP3A7, CYP4F3, CYP24A1, CYP26B1 and CYP27B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.
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Affiliation(s)
- Alaattin Sen
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri 38080, Turkey
- Biology Department, Faculty of Arts and Sciences, Pamukkale University, Denizli 20070, Turkey
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf 40225, Germany
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48
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Csekő K, Beckers B, Keszthelyi D, Helyes Z. Role of TRPV1 and TRPA1 Ion Channels in Inflammatory Bowel Diseases: Potential Therapeutic Targets? Pharmaceuticals (Basel) 2019; 12:E48. [PMID: 30935063 PMCID: PMC6630403 DOI: 10.3390/ph12020048] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 03/26/2019] [Accepted: 03/27/2019] [Indexed: 12/20/2022] Open
Abstract
Inflammatory bowel diseases (IBD) have long been recognized to be accompanied by pain resulting in high morbidity. Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) ion channels located predominantly on the capsaicin-sensitive sensory neurons play a complex role in hyperalgesia and neurogenic inflammation. This review provides an overview of their expression and role in intestinal inflammation, in particular colitis, that appears to be virtually inconsistent based on the thorough investigations of the last twenty years. However, preclinical results with pharmacological interventions, as well as scarcely available human studies, more convincingly point out the potential therapeutic value of TRPV1 and TRPA1 antagonists in colitis and visceral hypersensitivity providing future therapeutical perspectives through a complex, unique mechanism of action for drug development in IBD.
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Affiliation(s)
- Kata Csekő
- Department of Pharmacology and Pharmacotherapy, Medical School and Molecular Pharmacology Research Group, Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary.
| | - Bram Beckers
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center (MUMC+), 6202 AZ Maastricht, The Netherlands.
- NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University, 6202 AZ Maastricht, The Netherlands.
| | - Daniel Keszthelyi
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center (MUMC+), 6202 AZ Maastricht, The Netherlands.
- NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University, 6202 AZ Maastricht, The Netherlands.
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School and Molecular Pharmacology Research Group, Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary.
- PharmInVivo Ltd., H-7629 Pécs, Hungary.
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49
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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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50
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Salaga M, Binienda A, Piscitelli F, Mokrowiecka A, Cygankiewicz AI, Verde R, Malecka-Panas E, Kordek R, Krajewska WM, Di Marzo V, Fichna J. Systemic administration of serotonin exacerbates abdominal pain and colitis via interaction with the endocannabinoid system. Biochem Pharmacol 2019; 161:37-51. [DOI: 10.1016/j.bcp.2019.01.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 01/02/2019] [Indexed: 12/24/2022]
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