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Tihăuan BM, Onisei T, Slootweg W, Gună D, Iliescu C, Chifiriuc MC. Cannabidiol-A friend or a foe? Eur J Pharm Sci 2025; 208:107036. [PMID: 39929375 DOI: 10.1016/j.ejps.2025.107036] [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: 12/20/2024] [Revised: 01/21/2025] [Accepted: 02/06/2025] [Indexed: 03/23/2025]
Abstract
Cannabidiol (CBD), one of the main actives from Cannabis sativa has been perpetually explored lately for its therapeutic effects. Its main attributes, such as anti-inflammatory and antioxidant effects, snowball into pain management, epilepsy and seizure alleviation, anxiety relief, as well as numerous other implications through the entire metabolism. However, conventional administration routes challenge its therapeutic potential, with reported poor water solubility, hepatic degradation, gastric instability and erratic bioavailability observed in oral administration. As a result, the transdermal delivery systems have emerged as a promising alternative to oral or inhaled routes, offering improved bioavailability and targeted effects. The medical use of CBD throughout Europe, UK, USA or Australia is extensive and usually represented by pharmaceutical preparations recommended after conventional treatment routs fail. The non-medical use is limited by each country's own legislation, a wider range of products being available, but the irregular regulatory landscape coupled with the growing market of cannabinoid-infused products, emphasizes the need for standardized formulations and further clinical research. The present work critically examines the transdermal administration of cannabidiol, explores the skin's potential as a route and the strategies involved in using it for systemic targeting. We highlighted key challenges and provided insights into CBD`s variable bioavailability based on different administration routes and methods, thus compiling a literature-based absorption, distribution, metabolism, and excretion (ADME) study. We also explore the role of the endocannabinoid system, its function in various medical conditions, and the therapeutic effects associated with CBD, particularly in light of the varying legislation across countries. While the breadth of potential benefits is compelling, it is essential to emphasize the ongoing nature of CBD research as individual responses to it can vary significantly.
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Affiliation(s)
- Bianca-Maria Tihăuan
- Research Institute of the University of Bucharest-ICUB, 91-95 Spl. Independentei, 50567 Bucharest, Romania; National Institute for Research and Development in Food Bioresources, Dinu Vintilă Street, No.6, 021102 Bucharest, Romania; eBio-hub Research Centre, National University for Science and Technology Politehnica Bucharest, Bucharest, Romania; Academy of Romanian Scientists, Bucharest, Romania
| | - Tatiana Onisei
- National Institute for Research and Development in Food Bioresources, Dinu Vintilă Street, No.6, 021102 Bucharest, Romania
| | - Walter Slootweg
- QB3 Research & Development, Spaarndammerstraaat 4d, 1013SV Amsterdam, Netherlands
| | - Daniel Gună
- S.C. Absolute Essential Oils Ltd. (AEO), Adunații Copăceni Village, Giurgiu County, 38 Troitei Street, 087005, Romania
| | - Ciprian Iliescu
- eBio-hub Research Centre, National University for Science and Technology Politehnica Bucharest, Bucharest, Romania; Academy of Romanian Scientists, Bucharest, Romania; National Institute for Microtechnologies, 126A Erou Iancu Nicolae Street, Voluntari 077190, Romania.
| | - Mariana-Carmen Chifiriuc
- Research Institute of the University of Bucharest-ICUB, 91-95 Spl. Independentei, 50567 Bucharest, Romania.
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Creoli M, Di Paola A, Tarallo A, Aziz S, Miele E, Martinelli M, Casertano M, Colucci A, Cenni S, Marrapodi MM, Staiano A, Rossi F, Strisciuglio C. Effects of CB2 Receptor Modulation on Macrophage Polarization in Pediatric Inflammatory Bowel Disease. Int J Mol Sci 2025; 26:3720. [PMID: 40332343 PMCID: PMC12027514 DOI: 10.3390/ijms26083720] [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: 02/28/2025] [Revised: 04/09/2025] [Accepted: 04/14/2025] [Indexed: 05/08/2025] Open
Abstract
Macrophages play a crucial role in maintaining intestinal homeostasis and can exhibit either pro-inflammatory M1 or anti-inflammatory M2 phenotypes. The cannabinoid receptor type 2 (CB2) is involved in immune regulation and may represent a therapeutic target in inflammatory bowel disease (IBD). Our study investigates the phenotype of circulating macrophages and CB2 expression in children with IBD, assessing the role of CB2 stimulation in macrophage polarization, iron metabolism, and intestinal barrier function. Macrophages were isolated from 17 children with ulcerative colitis (UC), 21 with Crohn's disease (CD), and 12 healthy controls (CTR). Cells were treated with a CB2 agonist (JWH-133) and an inverse agonist (AM630). CB2 expression and macrophage polarization were assessed by Western blot. Iron metabolism was evaluated through IL-6, hepcidin levels, FPN-1 expression, and iron concentration. Inflammation was assessed by cytokine release. An in vitro "immunocompetent gut" model was used to study the effects of CB2 stimulation on macrophage polarization and intestinal barrier function. CB2 expression was reduced in IBD macrophages. Compared to controls, IBD patients showed increased M1 markers and pro-inflammatory cytokines, with a reduction in M2 markers and IL-13. Altered iron metabolism was observed, with increased [Fe3+], hepcidin release, and DMT1 expression, and reduced FPN-1. CB2 stimulation restored iron metabolism, induced M2 polarization, and improved intestinal barrier function. CB2 could represent a novel therapeutic target for IBD by modulating macrophage function, iron metabolism, and mucosal barrier restoration.
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Affiliation(s)
- Mara Creoli
- Department of Woman, Child and General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Via Luigi de Crecchio 2, 80138 Naples, Italy; (M.C.); (A.D.P.); (A.C.); (M.M.M.); (C.S.)
| | - Alessandra Di Paola
- Department of Woman, Child and General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Via Luigi de Crecchio 2, 80138 Naples, Italy; (M.C.); (A.D.P.); (A.C.); (M.M.M.); (C.S.)
- Department of Life Sciences, Health and Health Professions, Link Campus University, Via del Casale di San Pio V, 00165 Rome, Italy
| | - Antonietta Tarallo
- Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Via S. Pansini 5, 80131 Naples, Italy; (A.T.); (E.M.); (M.M.); (M.C.); (A.S.)
| | - Sohail Aziz
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Santa Maria di Costantinopoli 16, 80138 Naples, Italy; (S.A.); (S.C.)
| | - Erasmo Miele
- Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Via S. Pansini 5, 80131 Naples, Italy; (A.T.); (E.M.); (M.M.); (M.C.); (A.S.)
| | - Massimo Martinelli
- Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Via S. Pansini 5, 80131 Naples, Italy; (A.T.); (E.M.); (M.M.); (M.C.); (A.S.)
| | - Marianna Casertano
- Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Via S. Pansini 5, 80131 Naples, Italy; (A.T.); (E.M.); (M.M.); (M.C.); (A.S.)
| | - Antonio Colucci
- Department of Woman, Child and General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Via Luigi de Crecchio 2, 80138 Naples, Italy; (M.C.); (A.D.P.); (A.C.); (M.M.M.); (C.S.)
| | - Sabrina Cenni
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Santa Maria di Costantinopoli 16, 80138 Naples, Italy; (S.A.); (S.C.)
| | - Maria Maddalena Marrapodi
- Department of Woman, Child and General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Via Luigi de Crecchio 2, 80138 Naples, Italy; (M.C.); (A.D.P.); (A.C.); (M.M.M.); (C.S.)
| | - Annamaria Staiano
- Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Via S. Pansini 5, 80131 Naples, Italy; (A.T.); (E.M.); (M.M.); (M.C.); (A.S.)
| | - Francesca Rossi
- Department of Woman, Child and General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Via Luigi de Crecchio 2, 80138 Naples, Italy; (M.C.); (A.D.P.); (A.C.); (M.M.M.); (C.S.)
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Via Luigi de Crecchio 2, 80138 Naples, Italy; (M.C.); (A.D.P.); (A.C.); (M.M.M.); (C.S.)
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Habersham LL, Townsel C, Terplan M, Hurd YL. Substance use and use disorders during pregnancy and the postpartum period. Am J Obstet Gynecol 2025; 232:337-353.e1. [PMID: 39798910 DOI: 10.1016/j.ajog.2025.01.007] [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: 07/22/2024] [Revised: 12/20/2024] [Accepted: 01/02/2025] [Indexed: 01/15/2025]
Abstract
Substance use and substance use disorders among pregnant and postpartum individuals have risen dramatically, necessitating enhanced clinician education and intervention strategies. This expert review offers obstetricians and gynecologists a comprehensive overview of substance use during the prenatal and postpartum periods. We discuss the epidemiology, maternal and fetal adverse effects, as well as treatment approaches for major substances: nicotine, cannabis, alcohol, benzodiazepines, stimulants, and opioids. Additionally, we address the ethical and legal implications of substance use during pregnancy and emphasize the importance of equitable and nonstigmatizing care. By integrating evidence-based practices, we aim to support obstetricians and gynecologists in providing optimal care for pregnant and postpartum individuals affected by substance use disorders.
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Affiliation(s)
- Leah L Habersham
- Department of Obstetrics, Gynecology, & Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY.
| | - Courtney Townsel
- Department of Obstetrics & Gynecology, University of Maryland School of Medicine, Baltimore, MD
| | | | - Yasmin L Hurd
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY
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Ekambaram S, Wang J, Dokholyan NV. CANDI: a web server for predicting molecular targets and pathways of cannabis-based therapeutics. J Cannabis Res 2025; 7:13. [PMID: 40016810 PMCID: PMC11866588 DOI: 10.1186/s42238-025-00268-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 02/07/2025] [Indexed: 03/01/2025] Open
Abstract
BACKGROUND Cannabis sativa L. with a rich history of traditional medicinal use, has garnered significant attention in contemporary research for its potential therapeutic applications in various human diseases, including pain, inflammation, cancer, and osteoarthritis. However, the specific molecular targets and mechanisms underlying the synergistic effects of its diverse phytochemical constituents remain elusive. Understanding these mechanisms is crucial for developing targeted, effective cannabis-based therapies. METHODS To investigate the molecular targets and pathways involved in the synergistic effects of cannabis compounds, we utilized DRIFT, a deep learning model that leverages attention-based neural networks to predict compound-target interactions. We considered both whole plant extracts and specific plant-based formulations. Predicted targets were then mapped to the Reactome pathway database to identify the biological processes affected. To facilitate the prediction of molecular targets and associated pathways for any user-specified cannabis formulation, we developed CANDI (Cannabis-derived compound Analysis and Network Discovery Interface), a web-based server. This platform offers a user-friendly interface for researchers and drug developers to explore the therapeutic potential of cannabis compounds. RESULTS Our analysis using DRIFT and CANDI successfully identified numerous molecular targets of cannabis compounds, many of which are involved in pathways relevant to pain, inflammation, cancer, and other diseases. The CANDI server enables researchers to predict the molecular targets and affected pathways for any specific cannabis formulation, providing valuable insights for developing targeted therapies. CONCLUSIONS By combining computational approaches with knowledge of traditional cannabis use, we have developed the CANDI server, a tool that allows us to harness the therapeutic potential of cannabis compounds for the effective treatment of various disorders. By bridging traditional pharmaceutical development with cannabis-based medicine, we propose a novel approach for botanical-based treatment modalities.
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Affiliation(s)
- Srinivasan Ekambaram
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033, USA
- Department of Neuroscience & Experimental Therapeutics, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Jian Wang
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033, USA
- Department of Neuroscience & Experimental Therapeutics, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Nikolay V Dokholyan
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033, USA.
- Department of Neuroscience & Experimental Therapeutics, Penn State College of Medicine, Hershey, PA, 17033, USA.
- Department of Biochemistry & Molecular Biology, Penn State College of Medicine, Hershey, PA, 17033, USA.
- Department of Chemistry, Penn State University, University Park, PA, 16802, USA.
- Department of Biomedical Engineering, Penn State University, University Park, PA, 16802, USA.
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5
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Rodríguez-Serrano LM, Chávez-Hernández ME. The Administration of Cannabinoid Receptor 2 Agonist Decreases Binge-like Intake of Palatable Food in Mice. Int J Mol Sci 2025; 26:1981. [PMID: 40076606 PMCID: PMC11900424 DOI: 10.3390/ijms26051981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/19/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
Binge eating disorder (BED) is characterized by uncontrollable episodes of eating in a short period of time, with a subjective loss of control of overconsumption behavior. The role CB2 cannabinoid receptor (CB2R) plays in binge-like intake has not yet been identified. In this regard, the present study aims to evaluate the effect of the administration of CB2R agonist, antagonist, or both on binge-like intake of palatable food (PF) in adolescent mice. We used 35 C57BL6/J male mice of 30 postnatal days in this research; all animals were housed individually and had ad libitum access to a standard diet (SD) and water. Animals were evaluated for a total of 15 sessions of the Binge Eating Test (BET), which consisted of 1 h access to PF (chocolate sandwich cookies) according to intermittent diet protocol, with one-day access/one-day no-access. PF and SD caloric intake, as well as the PF binge index (defined as consuming ≥20% of total caloric intake per day during the 1 h access to PF), were analyzed. Mice were randomly assigned to one of the following treatment groups: (1) control; (2) vehicle; (3) HU308, selective CB2R agonist; (4) AM630, selective CB2R antagonist; (5) AM630+HU308 coadministration of antagonist and agonists of CB2R. All treatments were administered intraperitoneally before BET sessions. Our results show that HU308 significantly reduced binge-like intake of PF, while no significant differences were found in the rest of the groups. These results suggest that activation of the CB2R decreases the binge-like intake in adolescent mice and that chronic overconsumption in conditions of non-homeostatic feeding can be modulated by the CB2R. Furthermore, the activation of CB2R may also modulate reward pathways, reducing binge-like behavior, which could be further explored in future studies as a treatment for BED.
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Affiliation(s)
- Luis Miguel Rodríguez-Serrano
- Facultad de Psicología, Universidad Anáhuac México, Universidad Anáhuac Avenue #46, Lomas Anáhuac, Huixquilucan 52786, Mexico;
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Xu W, Gao L, Zou W, Tang X, Nian W, Zheng W, Huang R, Wang P. Compound kushen injection improves radiation enteritis via cannabinoid receptor 1 in rats. BMC Complement Med Ther 2025; 25:70. [PMID: 39987176 PMCID: PMC11847357 DOI: 10.1186/s12906-025-04820-2] [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: 06/01/2024] [Accepted: 02/06/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Clinical studies have shown that Compound Kushen Injection (CKI) can alleviate the inflammatory symptoms of radiation enteritis. However, the mechanism of action remains unclear. The aim of this study was to explore the possible targets and mechanisms of CKI in the treatment of radiation enteritis. METHODS Network pharmacology was used to predict the potential targets of CKI for the treatment of radiation enteritis, and GO and KEGG enrichment analyses were subsequently performed. SD rats were randomly divided into one of the following groups: control, model, CB1 agonist, CKI and CKI + CB1 antagonist. Except for the control group, the remaining groups were irradiated the abdomen with 6 MV medical high-energy x-ray linear accelerator to establish the model of radiation enteritis. After one week of treatment, the expression of inflammatory factors, SOD and GSH-Px activities, MDA, ROS and NO contents; NF-κB signaling activation and the expression of NOX4, CB1, p38 MAPK, p-p38 MAPK in the ileal tissues of rats were examined to assess the therapeutic effect and possible mechanism of CKI on radiation enteritis, respectively. RESULTS According to network pharmacology, CB1 might be a target of CKI. GO and KEGG enrichment analyses revealed that CKI was significantly enriched in analgesic, endocannabinoid and inflammatory pathways. In the rat model, Compared with that in the radiotherapy group, the extent of ileal injury was significantly improved in the CKI group compared to the control group. In addition, the infiltration of CD68 and CD16b was significantly reduced, and the expression of MCP1, TNF-α, IL-1β and IL-10 was significantly decreased. In addition, the activities of SOD and GSH-Px were increased, and the activities of MDA, ROS and NO were decreased. The CKI group also showed inhibition of NF-κB signaling and a significant decrease in the expression of NOX4, CB1 and p-p38 MAPK/p38 MAPK. The use of a CB1 agonist could also alleviate radiation enteritis, whereas the addition of a CB1 antagonist could interfere with the ameliorative effect of CKI on radiation enteritis. CONCLUSIONS CKI might exert an anti-radiation enteritis effect by targeting the cannabinoid receptor 1.
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Affiliation(s)
- Wenjing Xu
- Precision Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
- Department of Oncology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China
| | - Liping Gao
- Department of Oncology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China
| | - Wenjuan Zou
- Department of Oncology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China
| | - Xiaohui Tang
- Department of Oncology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China
| | - Weiqi Nian
- Department of Oncology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China
| | - Weiqin Zheng
- Department of Oncology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China
| | - Rongzhong Huang
- Precision Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
| | - Pei Wang
- Department of Oncology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China.
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7
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Kang H, Schmoyer CJ, Weiss A, Lewis JD. Meta-analysis of the Therapeutic Impact of Cannabinoids in Inflammatory Bowel Disease. Inflamm Bowel Dis 2025; 31:450-460. [PMID: 39197096 DOI: 10.1093/ibd/izae158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Indexed: 08/30/2024]
Abstract
BACKGROUND With the increasing legalization of medical and recreational cannabis, patients and providers have growing interest in the role of cannabinoids in treating inflammatory bowel disease. Prior meta-analysis has shown inconclusive evidence for efficacy of cannabinoids. We sought to produce an up-to-date meta-analysis that pools new data to evaluate the therapeutic effects of cannabinoids in both Crohn's disease (CD) and ulcerative colitis (UC). METHODS PubMed, Embase, CENTRAL and CINAHL were queried for randomized-controlled trials evaluating the impact cannabinoids in CD or UC. Random effects modeling was used to compute pooled estimates of risk difference. Heterogeneity was assessed using I2. RESULTS Eight studies, including 4 studies of CD, 3 studies of UC, and 1 study of both diseases met inclusion criteria. Among 5 studies of CD, a statistically significant decrease in clinical disease activity following intervention was observed (risk ratios [RR], -0.91; 95% CI, CI:1.54 to CI:0.28, I2 = 71.9%). Clinical disease activity in UC was not significantly lower in the pooled analysis (RR, -2.13; 95% CI, -4.80 to 0.55; I2 = 90.3%). Improvement in quality of life (QoL) was observed in both CD and UC combined (RR, 1.79; 95% CI, 0.92-0.2.66; I2 = 82.8%), as well as individually. No differences were observed in the analysis on endoscopic disease activity and inflammatory markers. CONCLUSIONS This meta-analysis of clinical trials suggests that cannabinoids are associated with improved quality of life in both CD and UC, as well as improved disease activity but not inflammation.
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Affiliation(s)
- Hansol Kang
- Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Christopher J Schmoyer
- Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Alexandra Weiss
- Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - James D Lewis
- Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Almeida MM, Calviño C, Reis-Gomes CF, Lombardi I, Brand ALM, Pazos-Moura CC, Garrett R, Alves MA, Trevenzoli IH. Maternal obesity changes the small intestine endocannabinoid system and fecal metabolites of weanling rats associated with reduced intestinal permeability and impaired glucose homeostasis. J Nutr Biochem 2025; 136:109802. [PMID: 39547267 DOI: 10.1016/j.jnutbio.2024.109802] [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: 05/16/2024] [Revised: 10/18/2024] [Accepted: 11/07/2024] [Indexed: 11/17/2024]
Abstract
The small intestine, including the endocannabinoid system (ECS), regulates the energy homeostasis. If maternal obesity modifies the intestinal ECS of the offspring favoring metabolic disorders throughout life is unexplored. Regardless maternal insults, overaction of the ECS has been related to obesity, mainly via type 1 cannabinoid receptor (CB1) signaling, while type 2 cannabinoid receptor (CB2) signaling and the endocannabinoid-like compounds, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), have been associated with anti-inflammatory effects. We hypothesized that maternal obesity changes the ECS in the small intestine of weanling rat offspring in a sex-specific manner associated with altered fecal metabolites. Female rats received a control diet (C; 9% fat) or an obesogenic diet (OD; 37.2% fat, 11.8% sucrose) 9 weeks before mating, gestation and lactation. Offspring were euthanized at weaning. Maternal obesity increased CB2 protein content and mRNA levels of monocyte chemoattractant protein-1 in the small intestine in male offspring, while decreased fecal content of PEA and OEA in both sexes. Maternal obesity decreased gut permeability, but impaired glycemic homeostasis. Concerning fecal levels of γ-aminobutyric acid, amino acids and hypoxanthine, maternal obesity induced a fecal signature related to inflammatory and glycemic homeostasis impairment and dysbiosis. Maternal obesity induced intestinal inflammation and the signaling of CB2, PEA, and OEA might be part of a counter-regulatory response, contributing to reduced gut permeability, but not enough to avoid overweight and glycemic impairment in the offspring at weaning. Our findings provide molecular insights into the intestinal and fecal biomarkers for metabolic disorders.
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Affiliation(s)
- Mariana M Almeida
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil; Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Minas Gerais, Brasil.
| | - Camila Calviño
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
| | - Clara F Reis-Gomes
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
| | - Isabelle Lombardi
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
| | - Ana Laura Macedo Brand
- Instituto de Química (IQ), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
| | - Carmen C Pazos-Moura
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
| | - Rafael Garrett
- Instituto de Química (IQ), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
| | - Marina A Alves
- Instituto de Pesquisa de Produtos Naturais Walter Mors (IPPN), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
| | - Isis H Trevenzoli
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
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Thapa D, Patil M, Warne LN, Carlessi R, Falasca M. Enhancing Tetrahydrocannabinol's Therapeutic Efficacy in Inflammatory Bowel Disease: The Roles of Cannabidiol and the Cannabinoid 1 Receptor Allosteric Modulator ZCZ011. Pharmaceuticals (Basel) 2025; 18:148. [PMID: 40005963 PMCID: PMC11858241 DOI: 10.3390/ph18020148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 01/20/2025] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Current inflammatory bowel disease (IBD) treatments focus on symptomatic relief, highlighting the need for innovative approaches. Dysregulation of the cannabinoid 1 (CB1) receptor, part of the endocannabinoid system, is linked to colitis. While tetrahydrocannabinol (THC) alleviates colitis via CB1 activation, its psychotropic effects limit clinical use. ZCZ011, a CB1R allosteric modulator, and cannabidiol (CBD), a non-psychoactive cannabinoid, offer alternatives. This study investigated combining sub-therapeutic THC doses with ZCZ011 or CBD in a murine model of dextran sodium sulphate (DSS)-induced colitis. Methods: Acute colitis was induced with 4% DSS for 7 days, followed by 3 days of water. Chronic colitis was modelled over 24 days with alternating DSS concentrations. The combination of 2.5 mg/kg THC with 20 mg/kg ZCZ011 or 10 mg/kg CBD was evaluated. Key markers were assessed to determine efficacy and safety, including disease activity index (DAI), inflammation, cytokine levels, GLP-1, and organ health. Results: DSS-induced colitis resulted in increased DAI scores, cytokines, organ inflammation and dysregulation of GLP-1 and ammonia. THC at 10 mg/kg significantly improved colitis markers but was ineffective at 2.5 and 5 mg/kg. ZCZ011 alone showed transient effects. However, combining 2.5 mg/kg THC with either 20 mg/kg ZCZ011 or 10 mg/kg CBD significantly alleviated colitis markers, restored colon integrity and reestablished GLP-1 homeostasis. This combination also maintained favourable haematological and biochemical profiles, including a notable reduction in colitis-induced elevated ammonia levels. Conclusions: This study demonstrates the synergistic potential of low-dose THC combined with CBD or ZCZ011 as a novel, effective and safer therapeutic strategy for ulcerative colitis.
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Affiliation(s)
- Dinesh Thapa
- Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
| | - Mohan Patil
- Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
| | - Leon N Warne
- Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
- College of Science, Health, Engineering and Education, Murdoch University, Perth, WA 6150, Australia
| | - Rodrigo Carlessi
- Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Marco Falasca
- College of Science, Health, Engineering and Education, Murdoch University, Perth, WA 6150, Australia
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy
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Senthil Kumar KJ, Gokila Vani M, Dakpa G, Wang SY. Dietary limonene promotes gastrointestinal barrier function via upregulating tight/adherens junction proteins through cannabinoid receptor type-1 antagonistic mechanism and alters cellular metabolism in intestinal epithelial cells. Biofactors 2025; 51:e2106. [PMID: 39143845 DOI: 10.1002/biof.2106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 01/25/2024] [Indexed: 08/16/2024]
Abstract
Limonene, a dietary monocyclic monoterpene commonly found in citrus fruits and various aromatic plants, has garnered increasing interest as a gastrointestinal protectant. This study aimed to assess the effects of limonene on intestinal epithelial barrier function and investigate the involvement of cannabinoid receptor type-1 (CB1R) in vitro. Additionally, the study focused on examining the metabolomic changes induced by limonene in the intestinal epithelial cells (Caco-2). Initial analysis of transepithelial electrical resistance (TEER) revealed that both l-limonene and d-limonene, isomers of limonene, led to a dose- and time-dependent increase in TEER in normal cells and those inflamed by pro-inflammatory cytokines mixture (CytoMix). Furthermore, both types of limonene reduced CytoMix-induced paracellular permeability, as demonstrated by a decrease in Lucifer yellow flux. Moreover, d-limonene and l-limonene treatment increased the expression of tight junction molecules (TJs) such as occludin, claudin-1, and ZO-1, at both the transcriptional and translational levels. d-Limonene upregulates E-cadherin, a molecule involved in adherens junctions (AJs). Mechanistic investigations demonstrated that d-limonene and l-limonene treatment significantly inhibited CB1R at the protein, while the mRNA level remained unchanged. Notably, the inhibitory effect of d-limonene on CB1R was remarkably similar to that of pharmacological CB1R antagonists, such as rimonabant and ORG27569. d-limonene also alters Caco-2 cell metabolites. A substantial reduction in β-glucose and 2-succinamate was detected, suggesting limonene may impact intestinal epithelial cells' glucose uptake and glutamate metabolism. These findings suggest that d-limonene's CB1R antagonistic property could effectively aid in the recovery of intestinal barrier damage, marking it a promising gastrointestinal protectant.
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Affiliation(s)
- K J Senthil Kumar
- Bachelor Program of Biotechnology, National Chung Hsing University, Taichung, Taiwan
- Center for General Education, National Chung Hsing University, Taichung, Taiwan
| | - M Gokila Vani
- Department of Forestry, National Chung Hsing University, Taichung, Taiwan
| | - Gyaltsen Dakpa
- Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan
- Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan
| | - Sheng-Yang Wang
- Department of Forestry, National Chung Hsing University, Taichung, Taiwan
- Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
- Special Crop and Metabolome Discipline Cluster, Academy of Circle Economy, National Chung Hsing University, Taichung, Taiwan
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11
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Portman A, Bukovich E, Bissex J, Flanagan M, Pojednic R. The Perceived Effectiveness of Cannabidiol on Adult Women with Inflammatory Bowel Disease. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:2059. [PMID: 39768938 PMCID: PMC11680051 DOI: 10.3390/medicina60122059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/07/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025]
Abstract
Background and Objectives: In this study we analyzed the perceived effectiveness of cannabidiol (CBD) in adult women with inflammatory bowel disease (IBD). Materials and Methods: We conducted an online cross-sectional survey which assessed disease severity and quality of life (QOL) in women with IBD (Crohn's disease and ulcerative colitis) who used CBD versus those who did not. The survey included: the Harvey-Bradshaw Index, Partial Mayo Score, Short Inflammatory Bowel Disease Questionnaire, Bristol Stool Scale, and the Prime Screen Short Food Frequency Questionnaire. CBD utilization practices were also examined. STROBE reporting outcomes were followed. Statistical methods included Pearson and Spearman's correlations and chi-square analyses. Results: Seventy-one (n = 71) women were included. Twenty-five (n = 25) were CBD users and forty-six (n = 46) were past/never users. Most current users ingested CBD once per day (40%), acquired CBD from a dispensary (56%), and utilized an oral tincture (40%) at a dose of 25 mg or less (56%). There was no statistical association between CBD use and disease severity, quality of life (QOL), fecal consistency, or food intake. However, CBD users reported decreases in IBD-related pain and nausea (76% and 64%, respectively), and improvement in appetite (60%). Overall, disease severity and QOL were inversely correlated (past/never users: p = 0.000, r = -0.544; current users: p = 0.042, r = -0.427). Conclusions: Women with IBD who use CBD insignificantly trended toward improved disease-related symptoms, appetite, and QOL compared to non-users. Disease severity and QOL were inversely associated, regardless of CBD use. These preliminary outcomes indicate the need for further research on CBD use in women with IBD.
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Affiliation(s)
- Ayelet Portman
- Department of Nutrition, College of Natural, Behavioral and Health Sciences, Simmons University, Boston, MA 02115, USA
| | - Emily Bukovich
- Department of Nutrition, College of Natural, Behavioral and Health Sciences, Simmons University, Boston, MA 02115, USA
| | - Janice Bissex
- Department of Nutrition, College of Natural, Behavioral and Health Sciences, Simmons University, Boston, MA 02115, USA
| | - Molly Flanagan
- Department of Health and Human Performance, Norwich University, Northfield, VT 05663, USA
| | - Rachele Pojednic
- Department of Nutrition, College of Natural, Behavioral and Health Sciences, Simmons University, Boston, MA 02115, USA
- Department of Health and Human Performance, Norwich University, Northfield, VT 05663, USA
- Stanford Lifestyle Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA
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12
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Cheng J, Venkatesh S, Ke K, Barratt MJ, Gordon JI. A human gut Faecalibacterium prausnitzii fatty acid amide hydrolase. Science 2024; 386:eado6828. [PMID: 39446943 PMCID: PMC11572954 DOI: 10.1126/science.ado6828] [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: 02/15/2024] [Accepted: 08/14/2024] [Indexed: 10/26/2024]
Abstract
Undernutrition in Bangladeshi children is associated with disruption of postnatal gut microbiota assembly; compared with standard therapy, a microbiota-directed complementary food (MDCF) substantially improved their ponderal and linear growth. Here, we characterize a fatty acid amide hydrolase (FAAH) from a growth-associated intestinal strain of Faecalibacterium prausnitzii cultured from these children. This enzyme, expressed and purified from Escherichia coli, hydrolyzes a variety of N-acylamides, including oleoylethanolamide (OEA), neurotransmitters, and quorum sensing N-acyl homoserine lactones; it also synthesizes a range of N-acylamides, notably N-acyl amino acids. Treating germ-free mice with N-oleoylarginine and N-oleolyhistidine, major products of FAAH OEA metabolism, markedly affected expression of intestinal immune function pathways. Administering MDCF to Bangladeshi children considerably reduced fecal OEA, a satiety factor whose levels were negatively correlated with abundance and expression of their F. prausnitzii FAAH. This enzyme, structurally and catalytically distinct from mammalian FAAH, is positioned to regulate levels of a variety of bioactive molecules.
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Affiliation(s)
- Jiye Cheng
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110 USA
- The Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO 63110 USA
| | - Siddarth Venkatesh
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110 USA
- The Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO 63110 USA
| | - Ke Ke
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110 USA
- The Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO 63110 USA
| | - Michael J. Barratt
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110 USA
- The Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO 63110 USA
| | - Jeffrey I. Gordon
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110 USA
- The Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO 63110 USA
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13
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Spigarelli R, Calabrese C, Spisni E, Vinciguerra S, Saracino IM, Dussias NK, Filippone E, Valerii MC. Palmitoylethanolamide (PEA) for Prevention of Gastroesophageal Inflammation: Insights from In Vitro Models. Life (Basel) 2024; 14:1221. [PMID: 39459521 PMCID: PMC11508466 DOI: 10.3390/life14101221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 09/04/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
Gastroesophageal reflux disease (GERD) is a digestive disorder that can lead to chronic mucosal damage, causing esophagitis, Barrett's esophagus and esophageal cancer. GERD currently affects about 13% of the world's population and represent a major public health concern due to the increasing prevalence and incidence. The aim of this study was to explore complementary strategies for GERD management based the natural compound palmitoylethanolamide (PEA), alone or associated with plant extracts with demonstrated anti-GERD activity (Zingiber officinale, Musa × paradisiaca, Opuntia ficus-indica and Olea europaea). For this purpose, two in vitro models based on the esophageal mucosa CP-B cell line were chosen. The first one was based on the exposure of esophageal cells to HCl, while the second one was based on lipopolysaccharide (LPS) treatment to cause a strong inflammatory cell response. Inflammation induced was assessed using a Luminex® assay, measuring the secretion of IL-1β, IL-6, IL-10, IL-8 and TNF-α. Results obtained demonstrate that PEA strongly decreased the inflammatory response elicited by HCl exposure. Moreover, the effect of PEA was enhanced by the presence of natural extracts of Zingiber officinale, Musa × paradisiaca, Opuntia ficus-indica and Olea europaea. PEA should be considered as an anti-GERD natural compound of interest.
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Affiliation(s)
- Renato Spigarelli
- Department of Biological, Geological and Environmental Sciences, University of Bologna, Via Selmi 3, 40126 Bologna, Italy; (R.S.); (E.S.); (S.V.)
| | - Carlo Calabrese
- IBD Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (C.C.); (N.K.D.); (E.F.)
- Department of Medical and Surgical and Sciences, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Enzo Spisni
- Department of Biological, Geological and Environmental Sciences, University of Bologna, Via Selmi 3, 40126 Bologna, Italy; (R.S.); (E.S.); (S.V.)
| | - Sara Vinciguerra
- Department of Biological, Geological and Environmental Sciences, University of Bologna, Via Selmi 3, 40126 Bologna, Italy; (R.S.); (E.S.); (S.V.)
| | - Ilaria Maria Saracino
- Microbiology Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy;
| | - Nikolas Kostantine Dussias
- IBD Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (C.C.); (N.K.D.); (E.F.)
- Department of Medical and Surgical and Sciences, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Eleonora Filippone
- IBD Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (C.C.); (N.K.D.); (E.F.)
| | - Maria Chiara Valerii
- Department of Biological, Geological and Environmental Sciences, University of Bologna, Via Selmi 3, 40126 Bologna, Italy; (R.S.); (E.S.); (S.V.)
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14
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Ekambaram S, Wang J, Dokholyan NV. CANDI: A Web Server for Predicting Molecular Targets and Pathways of Cannabis-Based Therapeutics. RESEARCH SQUARE 2024:rs.3.rs-4744915. [PMID: 39149470 PMCID: PMC11326374 DOI: 10.21203/rs.3.rs-4744915/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Background Cannabis sativa with a rich history of traditional medicinal use, has garnered significant attention in contemporary research for its potential therapeutic applications in various human diseases, including pain, inflammation, cancer, and osteoarthritis. However, the specific molecular targets and mechanisms underlying the synergistic effects of its diverse phytochemical constituents remain elusive. Understanding these mechanisms is crucial for developing targeted, effective cannabis-based therapies. Methods To investigate the molecular targets and pathways involved in the synergistic effects of cannabis compounds, we utilized DRIFT, a deep learning model that leverages attention-based neural networks to predict compound-target interactions. We considered both whole plant extracts and specific plant-based formulations. Predicted targets were then mapped to the Reactome pathway database to identify the biological processes affected. To facilitate the prediction of molecular targets and associated pathways for any user-specified cannabis formulation, we developed CANDI (Cannabis-derived compound Analysis and Network Discovery Interface), a web-based server. This platform offers a user-friendly interface for researchers and drug developers to explore the therapeutic potential of cannabis compounds. Results Our analysis using DRIFT and CANDI successfully identified numerous molecular targets of cannabis compounds, many of which are involved in pathways relevant to pain, inflammation, cancer, and other diseases. The CANDI server enables researchers to predict the molecular targets and affected pathways for any specific cannabis formulation, providing valuable insights for developing targeted therapies. Conclusions By combining computational approaches with knowledge of traditional cannabis use, we have developed the CANDI server, a tool that allows us to harness the therapeutic potential of cannabis compounds for the effective treatment of various disorders. By bridging traditional pharmaceutical development with cannabis-based medicine, we propose a novel approach for botanical-based treatment modalities.
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15
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Wiącek J, Podgórski T, Kusy K, Łoniewski I, Skonieczna-Żydecka K, Karolkiewicz J. Evaluating the Impact of Probiotic Therapy on the Endocannabinoid System, Pain, Sleep and Fatigue: A Randomized, Double-Blind, Placebo-Controlled Trial in Dancers. Int J Mol Sci 2024; 25:5611. [PMID: 38891799 PMCID: PMC11171887 DOI: 10.3390/ijms25115611] [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: 04/26/2024] [Revised: 05/16/2024] [Accepted: 05/19/2024] [Indexed: 06/21/2024] Open
Abstract
Emerging research links the endocannabinoid system to gut microbiota, influencing nociception, mood, and immunity, yet the molecular interactions remain unclear. This study focused on the effects of probiotics on ECS markers-cannabinoid receptor type 2 (CB2) and fatty acid amide hydrolase (FAAH)-in dancers, a group selected due to their high exposure to physical and psychological stress. In a double-blind, placebo-controlled trial (ClinicalTrials.gov NCT05567653), 15 dancers were assigned to receive either a 12-week regimen of Lactobacillus helveticus Rosell-52 and Bifidobacterium longum Rosell-17 or a placebo (PLA: n = 10, PRO: n = 5). There were no significant changes in CB2 (probiotic: 0.55 to 0.29 ng/mL; placebo: 0.86 to 0.72 ng/mL) or FAAH levels (probiotic: 5.93 to 6.02 ng/mL; placebo: 6.46 to 6.94 ng/mL; p > 0.05). A trend toward improved sleep quality was observed in the probiotic group, while the placebo group showed a decline (PRO: from 1.4 to 1.0; PLA: from 0.8 to 1.2; p = 0.07841). No other differences were noted in assessed outcomes (pain and fatigue). Probiotic supplementation showed no significant impact on CB2 or FAAH levels, pain, or fatigue but suggested potential benefits for sleep quality, suggesting an area for further research.
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Affiliation(s)
- Jakub Wiącek
- Department of Food and Nutrition, Poznan University of Physical Education, 61-871 Poznan, Poland
| | - Tomasz Podgórski
- Department of Biochemistry and Physiology, Poznan University of Physical Education, 61-871 Poznan, Poland;
| | - Krzysztof Kusy
- Department of Athletics, Strength and Conditioning, Poznan University of Physical Education, 61-871 Poznan, Poland;
| | - Igor Łoniewski
- Department of Biochemical Science, Pomeranian Medical University in Szczecin, Broniewskiego 24, 71-460 Szczecin, Poland; (I.Ł.); (K.S.-Ż.)
| | - Karolina Skonieczna-Żydecka
- Department of Biochemical Science, Pomeranian Medical University in Szczecin, Broniewskiego 24, 71-460 Szczecin, Poland; (I.Ł.); (K.S.-Ż.)
| | - Joanna Karolkiewicz
- Department of Food and Nutrition, Poznan University of Physical Education, 61-871 Poznan, Poland
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16
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Spathakis M, Dovrolis N, Filidou E, Kandilogiannakis L, Tarapatzi G, Valatas V, Drygiannakis I, Paspaliaris V, Arvanitidis K, Manolopoulos VG, Kolios G, Vradelis S. Exploring Microbial Metabolite Receptors in Inflammatory Bowel Disease: An In Silico Analysis of Their Potential Role in Inflammation and Fibrosis. Pharmaceuticals (Basel) 2024; 17:492. [PMID: 38675452 PMCID: PMC11054721 DOI: 10.3390/ph17040492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/09/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Metabolites produced by dysbiotic intestinal microbiota can influence disease pathophysiology by participating in ligand-receptor interactions. Our aim was to investigate the differential expression of metabolite receptor (MR) genes between inflammatory bowel disease (IBD), healthy individuals (HIs), and disease controls in order to identify possible interactions with inflammatory and fibrotic pathways in the intestine. RNA-sequencing datasets containing 643 Crohn's disease (CD) patients, 467 ulcerative colitis (UC) patients and 295 HIs, and 4 Campylobacter jejuni-infected individuals were retrieved from the Sequence Read Archive, and differential expression was performed using the RaNA-seq online platform. The identified differentially expressed MR genes were used for correlation analysis with up- and downregulated genes in IBD, as well as functional enrichment analysis using a R based pipeline. Overall, 15 MR genes exhibited dysregulated expression in IBD. In inflamed CD, the hydroxycarboxylic acid receptors 2 and 3 (HCAR2, HCAR3) were upregulated and were associated with the recruitment of innate immune cells, while, in the non-inflamed CD ileum, the cannabinoid receptor 1 (CNR1) and the sphingosine-1-phospate receptor 4 (S1PR4) were downregulated and were involved in the regulation of B-cell activation. In inflamed UC, the upregulated receptors HCAR2 and HCAR3 were more closely associated with the process of TH-17 cell differentiation, while the pregnane X receptor (NR1I2) and the transient receptor potential vanilloid 1 (TRPV1) were downregulated and were involved in epithelial barrier maintenance. Our results elucidate the landscape of metabolite receptor expression in IBD, highlighting associations with disease-related functions that could guide the development of new targeted therapies.
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Affiliation(s)
- Michail Spathakis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Nikolas Dovrolis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Eirini Filidou
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Leonidas Kandilogiannakis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Gesthimani Tarapatzi
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Vassilis Valatas
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Gastroenterology and Hepatology Research Laboratory, Medical School, University of Crete, 71003 Heraklion, Greece;
| | - Ioannis Drygiannakis
- Gastroenterology and Hepatology Research Laboratory, Medical School, University of Crete, 71003 Heraklion, Greece;
| | | | - Konstantinos Arvanitidis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Vangelis G. Manolopoulos
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - George Kolios
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Stergios Vradelis
- Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
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Zhou L, Tian M, Zhang B, Cao X, Huo X, Yang F, Cao P, Feng L, Ma X, Tian X. Lysosome targeting fluorescent probe for NAAA imaging and its applications in the drug development for anti-inflammatory. Int J Biol Macromol 2024; 263:130307. [PMID: 38382784 DOI: 10.1016/j.ijbiomac.2024.130307] [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: 07/18/2023] [Revised: 02/04/2024] [Accepted: 02/18/2024] [Indexed: 02/23/2024]
Abstract
N-acylethanolamine acid amidase (NAAA) is a nucleophilic lysosomal cysteine hydrolase, which primarily mediates the hydrolytic inactivation of endogenous palmitoylethanolamide (PEA), which further influences the inflammatory process by regulating peroxisome proliferator-activated receptor-α (PPAR-α). Herein, a novel lysosome (Lyso)-targeting fluorescent probe (i.e., PMBD) was designed and synthesized for detecting endogenous NAAA selectively and sensitively, allowing real-time visual monitoring of endogenous NAAA in living cells. Moreover, PMBD can target Lyso with a high colocalization in Lyso Tracker. Finally, a high-throughput assay method for NAAA inhibitor screening was established using PMBD, and the NAAA-inhibitory effects of 42 anti-inflammatory Traditional Chinese medicines were evaluated. A novel potent inhibitor of NAAA, ellagic acid, was isolated from Cornus officinalis, which can suppress LPS-induced iNOS upregulation and NO production in RAW264.7 cells that display anti-inflammatory activities. PMBD, a novel Lyso-targeting fluorescent probe for visually imaging NAAA, could serve as a useful molecular tool for exploring the physiological functions of NAAA and drug development based on NAAA-related diseases.
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Affiliation(s)
- Limin Zhou
- Second Affiliated Hospital, Dalian Medical University, Dalian 116023, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Manman Tian
- Second Affiliated Hospital, Dalian Medical University, Dalian 116023, China
| | - Baojing Zhang
- Second Affiliated Hospital, Dalian Medical University, Dalian 116023, China
| | - Xudong Cao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xiaokui Huo
- Second Affiliated Hospital, Dalian Medical University, Dalian 116023, China
| | - Fangyu Yang
- General Hospital of Northern Theater Command, Department of Neurosurgery, Shenyang, China
| | - Peng Cao
- General Hospital of Northern Theater Command, Department of Neurosurgery, Shenyang, China.
| | - Lei Feng
- Second Affiliated Hospital, Dalian Medical University, Dalian 116023, China; School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China.
| | - Xiaochi Ma
- Second Affiliated Hospital, Dalian Medical University, Dalian 116023, China
| | - Xiangge Tian
- Second Affiliated Hospital, Dalian Medical University, Dalian 116023, China.
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18
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Stemmer E, Zahavi T, Kellerman M, Sinberger LA, Shrem G, Salmon‐Divon M. Exploring potential biomarkers and therapeutic targets in inflammatory bowel disease: insights from a mega-analysis approach. Front Immunol 2024; 15:1353402. [PMID: 38510241 PMCID: PMC10951083 DOI: 10.3389/fimmu.2024.1353402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/20/2024] [Indexed: 03/22/2024] Open
Abstract
Background Understanding the molecular pathogenesis of inflammatory bowel disease (IBD) has led to the discovery of new therapeutic targets that are more specific and effective. Our aim was to explore the molecular pathways and genes involved in IBD pathogenesis and to identify new therapeutic targets and novel biomarkers that can aid in the diagnosis of the disease. Methods To obtain the largest possible number of samples and analyze them comprehensively, we used a mega-analysis approach. This involved reprocessing raw data from multiple studies and analyzing them using bioinformatic and machine learning techniques. Results We analyzed a total of 697 intestinal biopsies of Ulcerative Colitis (n = 386), Crohn's disease (n = 183) and non-IBD controls (n = 128). A machine learning analysis detected 34 genes whose collective expression effectively distinguishes inflamed biopsies of IBD patients from non-IBD control samples. Most of these genes were upregulated in IBD. Notably, among these genes, three novel lncRNAs have emerged as potential contributors to IBD development: ENSG00000285744, ENSG00000287626, and MIR4435-2HG. Furthermore, by examining the expression of 29 genes, among the 34, in blood samples from IBD patients, we detected a significant upregulation of 12 genes (p-value < 0.01), underscoring their potential utility as non-invasive diagnostic biomarkers. Finally, by utilizing the CMap library, we discovered potential compounds that should be explored in future studies for their therapeutic efficacy in IBD treatment. Conclusion Our findings contribute to the understanding of IBD pathogenesis, suggest novel biomarkers for IBD diagnosis and offer new prospects for therapeutic intervention.
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Affiliation(s)
- Edia Stemmer
- Department of Molecular Biology, Ariel University, Ariel, Israel
| | - Tamar Zahavi
- Department of Molecular Biology, Ariel University, Ariel, Israel
| | - Maoz Kellerman
- Department of Molecular Biology, Ariel University, Ariel, Israel
- Kaleidoo, Bar Lev High Tech Park, Misgav, Israel
| | | | - Guy Shrem
- Obstetrics, Gynecology and Infertility (OB&GYN) Department Maccabi Healthcare Services, Tel Aviv, Israel
| | - Mali Salmon‐Divon
- Department of Molecular Biology, Ariel University, Ariel, Israel
- Adelson School of Medicine, Ariel University, Ariel, Israel
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19
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Al-Khazaleh AK, Jaye K, Chang D, Münch GW, Bhuyan DJ. Buds and Bugs: A Fascinating Tale of Gut Microbiota and Cannabis in the Fight against Cancer. Int J Mol Sci 2024; 25:872. [PMID: 38255944 PMCID: PMC10815411 DOI: 10.3390/ijms25020872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/08/2024] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Emerging research has revealed a complex bidirectional interaction between the gut microbiome and cannabis. Preclinical studies have demonstrated that the gut microbiota can significantly influence the pharmacological effects of cannabinoids. One notable finding is the ability of the gut microbiota to metabolise cannabinoids, including Δ9-tetrahydrocannabinol (THC). This metabolic transformation can alter the potency and duration of cannabinoid effects, potentially impacting their efficacy in cancer treatment. Additionally, the capacity of gut microbiota to activate cannabinoid receptors through the production of secondary bile acids underscores its role in directly influencing the pharmacological activity of cannabinoids. While the literature reveals promising avenues for leveraging the gut microbiome-cannabis axis in cancer therapy, several critical considerations must be accounted for. Firstly, the variability in gut microbiota composition among individuals presents a challenge in developing universal treatment strategies. The diversity in gut microbiota may lead to variations in cannabinoid metabolism and treatment responses, emphasising the need for personalised medicine approaches. The growing interest in understanding how the gut microbiome and cannabis may impact cancer has created a demand for up-to-date, comprehensive reviews to inform researchers and healthcare practitioners. This review provides a timely and invaluable resource by synthesizing the most recent research findings and spotlighting emerging trends. A thorough examination of the literature on the interplay between the gut microbiome and cannabis, specifically focusing on their potential implications for cancer, is presented in this review to devise innovative and effective therapeutic strategies for managing cancer.
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Affiliation(s)
- Ahmad K. Al-Khazaleh
- NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia; (A.K.A.-K.); (K.J.); (D.C.)
| | - Kayla Jaye
- NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia; (A.K.A.-K.); (K.J.); (D.C.)
| | - Dennis Chang
- NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia; (A.K.A.-K.); (K.J.); (D.C.)
| | - Gerald W. Münch
- Pharmacology Unit, School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia
| | - Deep Jyoti Bhuyan
- NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia; (A.K.A.-K.); (K.J.); (D.C.)
- School of Science, Western Sydney University, Penrith, NSW 2751, Australia
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20
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Kumawat VS, Kaur G. Cannabinoid receptor 2 (CB 2) agonists and L-arginine ameliorate diabetic nephropathy in rats by suppressing inflammation and fibrosis through NF-κβ pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:381-393. [PMID: 37450015 DOI: 10.1007/s00210-023-02597-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 06/21/2023] [Indexed: 07/18/2023]
Abstract
Diabetic nephropathy (DN) is a condition that leads to end-stage chronic kidney disease characterized by inflammation and a deficiency of nitric oxide (NO). Cannabinoid receptor (CB2) activation by specific agonist reduces nuclear factor kappa beta (NF-κβ) expression. Beta caryophyllene (BCP), a natural CB2 receptor activator, protects kidney function in several diseases. L-Arginine (LA) modulates several physiological processes by donating nitric oxide (NO). Hence, we tested a novel BCP-LA combination to treat DN and investigated its molecular mechanisms. BCP, LA, and combinations of both were evaluated in LPS-induced RAW 264.7 macrophage inflammation as well as in streptozotocin (55 mg/kg)-induced diabetes in SD rats. Diabetic rats were administered 200 mg/kg of BCP, 100 mg/kg of LA, and combination of both orally for 28 days. Biochemical markers and inflammatory cytokines were assessed in plasma; also, kidney tissue was examined for renal oxidative stress injury, NF-κβ expression, and histology. After 28 days of treatment, BCP and LA combination significantly lowered plasma glucose levels than the disease control group. BCP and LA also normalized renal markers and oxidative stress of diabetic rats. Plasma and RAW macrophage cell lines showed reduced levels of IL-6 and TNF-α (P < 0.001). Histopathological evaluations revealed that BCP and LA together decreased renal fibrosis and collagen deposition also improved nephrotic indices. Meanwhile, the effect of BCP and LA together significantly reduced the NF-κβ (P < 0.01) against diabetic rats. These results indicate that the innovative regimen BCP with LA may be a therapeutic treatment for DN, as it protects kidney tissue from diabetes via NF-κβ inhibition.
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Affiliation(s)
- Vivek S Kumawat
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, 400056, India
| | - Ginpreet Kaur
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, 400056, India.
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21
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Kumar R, Singh S, Maharshi V. Effect of cannabinoids in mild-to-moderate cases of Crohn's disease as compared to placebo: a systematic review and meta-analysis of randomised controlled trials. J Basic Clin Physiol Pharmacol 2024; 35:15-24. [PMID: 38409768 DOI: 10.1515/jbcpp-2023-0137] [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: 05/23/2023] [Accepted: 01/15/2024] [Indexed: 02/28/2024]
Abstract
INTRODUCTION In view of limited treatment options (those too may fail) for Crohn's disease, cannabinoids have been tried as a therapeutic. However, their efficacy is not unequivocally established. This systematic review and meta-analysis was planned to pool data from randomised controlled trials (RCTs) evaluating effect of cannabinoids in Crohn's disease with an intention to take this uncertainty away. CONTENT Following literature search in Medline, EMBASE, Scopus and Google Scholar databases, RCTs assessing the effect of cannabinoids on mild-to-moderate Crohn's disease in adults were included. Crohns' disease activity index (CDAI), QoL (Quality of life), number participants achieving full remission and serum CRP at eight weeks of treatment were the outcomes considered for meta-analysis. Quality of studies was assessed using Cochrane's RoB2 tool. Random effect model was applied for meta-analysis. Heterogeneity was assessed by Cochrane 'Q' statistics and I2 test. Sensitivity analysis was performed to identify the major contributor(s) to heterogeneity and assess robustness of the results. SUMMARY Risk of bias for the four included studies varied from 'low' to 'some concern'. Overall effect estimate (SMD -0.92; 95 % CI -1.80, -0.03) indicated a statistically significant effect of cannabinoids as compared to control (p<0.05) on CDAI score. Effect of cannabinoids on rest of the outcome parameters was comparable to that of placebo. Magnitude of heterogeneity for different outcome parameters ranged from 'low' to 'substantial'. OUTLOOK Cannabinoids were superior to placebo for favourably affecting the disease severity in terms of CDAI score. However, no statistically significant difference was found between the two for improving QoL, causing full disease-remission and reducing inflammatory markers. The results must be interpreted with caution in view of relatively high heterogeneity among the studies.
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Affiliation(s)
- Rajesh Kumar
- Department of Pharmacology, All India Institute of Medical Sciences, Patna, Bihar, India
| | - Shruti Singh
- Department of Pharmacology, All India Institute of Medical Sciences, Patna, Bihar, India
| | - Vikas Maharshi
- Department of Pharmacology, All India Institute of Medical Sciences, Patna, Bihar, India
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22
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Wilson G, Yang L, Su X, Ding S, Li L, Yang Y, Wang X, Wang W, Sa Y, Zhang Y, Chen J, Ma X. Exploring the therapeutic potential of natural compounds modulating the endocannabinoid system in various diseases and disorders: review. Pharmacol Rep 2023; 75:1410-1444. [PMID: 37906390 DOI: 10.1007/s43440-023-00544-7] [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: 07/21/2023] [Revised: 10/07/2023] [Accepted: 10/09/2023] [Indexed: 11/02/2023]
Abstract
Cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes involved in the biosynthesis and degradation of the endocannabinoids make up the endocannabinoid system (ECS). The components of the ECS are proven to modulate a vast bulk of various physiological and pathological processes due to their abundance throughout the human body. Such discoveries have attracted the researchers' attention and emerged as a potential therapeutical target for the treatment of various diseases. In the present article, we reviewed the discoveries of natural compounds, herbs, herbs formula, and their therapeutic properties in various diseases and disorders by modulating the ECS. We also summarize the molecular mechanisms through which these compounds elicit their properties by interacting with the ECS based on the existing findings. Our study provides the insight into the use of natural compounds that modulate ECS in various diseases and disorders, which in turn may facilitate future studies exploiting natural lead compounds as novel frameworks for designing more effective and safer therapeutics.
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Affiliation(s)
- Gidion Wilson
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Lingling Yang
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Xiaojuan Su
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Shuqin Ding
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Liuyan Li
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Youyue Yang
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Xiaoying Wang
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Weibiao Wang
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Yuping Sa
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Yue Zhang
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Jianyu Chen
- Fujian University of Traditional Chinese Medicine, No. 1, Huatuo Road, Minhoushangjie, Fuzhou, 350122, China.
| | - Xueqin Ma
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China.
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23
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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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24
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Calzadilla N, Qazi A, Sharma A, Mongan K, Comiskey S, Manne J, Youkhana AG, Khanna S, Saksena S, Dudeja PK, Alrefai WA, Gill RK. Mucosal Metabolomic Signatures in Chronic Colitis: Novel Insights into the Pathophysiology of Inflammatory Bowel Disease. Metabolites 2023; 13:873. [PMID: 37512580 PMCID: PMC10386370 DOI: 10.3390/metabo13070873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/19/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023] Open
Abstract
Inflammatory bowel diseases (IBD) involve complex interactions among genetic factors, aberrant immune activation, and gut microbial dysbiosis. While metabolomic studies have focused on feces and serum, fewer investigations have examined the intestinal mucosa despite its crucial role in metabolite absorption and transport. The goals of this study were twofold: to test the hypothesis that gut microbial dysbiosis from chronic intestinal inflammation leads to mucosal metabolic alterations suitable for therapeutic targeting, and to address gaps in metabolomic studies of intestinal inflammation that have overlooked the mucosal metabolome. The chronic DSS colitis was induced for five weeks in 7-9-week-old wild-type C57BL/6J male mice followed by microbial profiling with targeted 16srRNA sequencing service. Mucosal metabolite measurements were performed by Metabolon (Morrisville, NC). The data were analyzed using the bioinformatic tools Pathview, MetOrigin, and Metaboanalyst. The novel findings demonstrated increases in several host- and microbe-derived purine, pyrimidine, endocannabinoid, and ceramide metabolites in colitis. Origin analysis revealed that microbial-related tryptophan metabolites kynurenine, anthranilate, 5-hydroxyindoleacetate, and C-glycosyltryptophan were significantly increased in colon mucosa during chronic inflammation and strongly correlated with disease activity. These findings offer new insights into the pathophysiology of IBD and provide novel potential targets for microbial-based therapeutics.
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Affiliation(s)
- Nathan Calzadilla
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Aisha Qazi
- Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Anchal Sharma
- Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Kai Mongan
- Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Shane Comiskey
- Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Jahnavi Manne
- Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Alvin G Youkhana
- Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Sonam Khanna
- Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Seema Saksena
- Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
| | - Pradeep K Dudeja
- Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
| | - Waddah A Alrefai
- Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
| | - Ravinder K Gill
- Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
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25
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Saidman J, Rubin S, Swaminath A. Inflammatory bowel disease and cannabis: key counseling strategies. Curr Opin Gastroenterol 2023; 39:301-307. [PMID: 37144523 DOI: 10.1097/mog.0000000000000946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
PURPOSE OF REVIEW Cannabis use is becoming more frequent in patients with inflammatory bowel disease (IBD). Because of the increased usage, gastroenterologists need to be cognizant of the benefits and risks associated with cannabis use in the IBD-patient population. RECENT FINDINGS Recent studies have attempted to determine whether cannabis can improve biomarkers or endoscopic findings of inflammation in patients with IBD, but the results have been inconclusive. However, cannabis has been shown to have an impact on the symptoms and quality of life of individuals with IBD. Despite these benefits, the use of cannabis in IBD is not without risks, including the potential for systemic illness, toxin ingestion and significant drug interactions. SUMMARY In this review article, we use a case-based approach to discuss the critical clinical data that informs us of the benefits and risks of cannabis use in IBD. The endocannabinoid system plays a crucial role in regulating various physiological functions including the gastrointestinal tract. Studies have investigated the impact of cannabis on various medical conditions, including IBD. Clinicians must be aware of the most recent data to properly educate their patients on the benefits and risks of its use.
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Affiliation(s)
- Jakob Saidman
- Division of Gastroenterology and Hepatobiliary Diseases, Westchester Medical Center, Valhalla
| | | | - Arun Swaminath
- Division of Gastroenterology, Lenox Hill Hospital, New York, New York, USA
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26
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Fordjour E, Manful CF, Sey AA, Javed R, Pham TH, Thomas R, Cheema M. Cannabis: a multifaceted plant with endless potentials. Front Pharmacol 2023; 14:1200269. [PMID: 37397476 PMCID: PMC10308385 DOI: 10.3389/fphar.2023.1200269] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 05/30/2023] [Indexed: 07/04/2023] Open
Abstract
Cannabis sativa, also known as "hemp" or "weed," is a versatile plant with various uses in medicine, agriculture, food, and cosmetics. This review attempts to evaluate the available literature on the ecology, chemical composition, phytochemistry, pharmacology, traditional uses, industrial uses, and toxicology of Cannabis sativa. So far, 566 chemical compounds have been isolated from Cannabis, including 125 cannabinoids and 198 non-cannabinoids. The psychoactive and physiologically active part of the plant is a cannabinoid, mostly found in the flowers, but also present in smaller amounts in the leaves, stems, and seeds. Of all phytochemicals, terpenes form the largest composition in the plant. Pharmacological evidence reveals that the plants contain cannabinoids which exhibit potential as antioxidants, antibacterial agents, anticancer agents, and anti-inflammatory agents. Furthermore, the compounds in the plants have reported applications in the food and cosmetic industries. Significantly, Cannabis cultivation has a minimal negative impact on the environment in terms of cultivation. Most of the studies focused on the chemical make-up, phytochemistry, and pharmacological effects, but not much is known about the toxic effects. Overall, the Cannabis plant has enormous potential for biological and industrial uses, as well as traditional and other medicinal uses. However, further research is necessary to fully understand and explore the uses and beneficial properties of Cannabis sativa.
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Affiliation(s)
- Eric Fordjour
- School of Science and the Environment, Memorial University of Newfoundland, Corner Brook, NL, Canada
- Biotron Experimental Climate Change Research Centre/Department of Biology, University of Western Ontario, London, ON, Canada
| | - Charles F. Manful
- School of Science and the Environment, Memorial University of Newfoundland, Corner Brook, NL, Canada
| | - Albert A. Sey
- School of Science and the Environment, Memorial University of Newfoundland, Corner Brook, NL, Canada
| | - Rabia Javed
- School of Science and the Environment, Memorial University of Newfoundland, Corner Brook, NL, Canada
| | - Thu Huong Pham
- School of Science and the Environment, Memorial University of Newfoundland, Corner Brook, NL, Canada
| | - Raymond Thomas
- Biotron Experimental Climate Change Research Centre/Department of Biology, University of Western Ontario, London, ON, Canada
| | - Mumtaz Cheema
- School of Science and the Environment, Memorial University of Newfoundland, Corner Brook, NL, Canada
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27
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Venneri T, Giorgini G, Leblanc N, Flamand N, Borrelli F, Silvestri C, Di Marzo V. Altered endocannabinoidome bioactive lipid levels accompany reduced DNBS-induced colonic inflammation in germ-free mice. Lipids Health Dis 2023; 22:63. [PMID: 37189092 DOI: 10.1186/s12944-023-01823-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 04/24/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND Gut microbiota are involved in the onset and development of chronic intestinal inflammation. The recently described endocannabinoidome (eCBome), a diverse and complex system of bioactive lipid mediators, has been reported to play a role in various physio-pathological processes such as inflammation, immune responses and energy metabolism. The eCBome and the gut microbiome (miBIome) are closely linked and form the eCBome - miBIome axis, which may be of special relevance to colitis. METHODS Colitis was induced in conventionally raised (CR), antibiotic-treated (ABX) and germ-free (GF) mice with dinitrobenzene sulfonic acid (DNBS). Inflammation was assessed by Disease Activity Index (DAI) score, body weight change, colon weight-length ratio, myeloperoxidase (MPO) activity and cytokine gene expression. Colonic eCBome lipid mediator concentrations were measured by HPLC-MS /MS. RESULTS GF mice showed increased levels of anti-inflammatory eCBome lipids (LEA, OEA, DHEA and 13- HODE-EA) in the healthy state and higher MPO activity. DNBS elicited reduced inflammation in GF mice, having lower colon weight/length ratios and lower expression levels of Il1b, Il6, Tnfa and neutrophil markers compared to one or both of the other DNBS-treated groups. Il10 expression was also lower and the levels of several N-acyl ethanolamines and 13-HODE-EA levels were higher in DNBS-treated GF mice than in CR and ABX mice. The levels of these eCBome lipids negatively correlated with measures of colitis and inflammation. CONCLUSIONS These results suggest that the depletion of the gut microbiota and subsequent differential development of the gut immune system in GF mice is followed by a compensatory effect on eCBome lipid mediators, which may explain, in part, the observed lower susceptibility of GF mice to develop DNBS-induced colitis.
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Affiliation(s)
- Tommaso Venneri
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Giada Giorgini
- Joint International Research Unit (JIRU) for Chemical and Biomolecular Research on the Microbiome and its impact on Metabolic Health and Nutrition (MicroMeNu) between Université Laval and the Consiglio Nazionale delle Ricerche (CNR), Institute of Biomolecular Chemistry, Pozzuoli, NA, Italy
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada
| | - Nadine Leblanc
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada
| | - Nicolas Flamand
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada
| | - Francesca Borrelli
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Cristoforo Silvestri
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada.
- Centre NUTRISS, École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, Canada.
| | - Vincenzo Di Marzo
- Joint International Research Unit (JIRU) for Chemical and Biomolecular Research on the Microbiome and its impact on Metabolic Health and Nutrition (MicroMeNu) between Université Laval and the Consiglio Nazionale delle Ricerche (CNR), Institute of Biomolecular Chemistry, Pozzuoli, NA, Italy.
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada.
- Centre NUTRISS, École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, Canada.
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, Canada.
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Zielińska A, da Ana R, Fonseca J, Szalata M, Wielgus K, Fathi F, Oliveira MBPP, Staszewski R, Karczewski J, Souto EB. Phytocannabinoids: Chromatographic Screening of Cannabinoids and Loading into Lipid Nanoparticles. Molecules 2023; 28:molecules28062875. [PMID: 36985847 PMCID: PMC10058297 DOI: 10.3390/molecules28062875] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/13/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) are receiving increasing interest as an approach to encapsulate natural extracts to increase the physicochemical stability of bioactives. Cannabis extract-derived cannabidiol (CBD) has potent therapeutic properties, including anti-inflammatory, antioxidant, and neuroprotective properties. In this work, physicochemical characterization was carried out after producing Compritol-based nanoparticles (cSLN or cNLC) loaded with CBD. Then, the determination of the encapsulation efficiency (EE), loading capacity (LC), particle size (Z-Ave), polydispersity index (PDI), and zeta potential were performed. Additionally, the viscoelastic profiles and differential scanning calorimetry (DSC) patterns were recorded. As a result, CBD-loaded SLN showed a mean particle size of 217.2 ± 6.5 nm, PDI of 0.273 ± 0.023, and EE of about 74%, while CBD-loaded NLC showed Z-Ave of 158.3 ± 6.6 nm, PDI of 0.325 ± 0.016, and EE of about 70%. The rheological analysis showed that the loss modulus for both lipid nanoparticle formulations was higher than the storage modulus over the applied frequency range of 10 Hz, demonstrating that they are more elastic than viscous. The crystallinity profiles of both CBD-cSLN (90.41%) and CBD-cNLC (40.18%) were determined. It may justify the obtained encapsulation parameters while corroborating the liquid-like character demonstrated in the rheological analysis. Scanning electron microscopy (SEM) study confirmed the morphology and shape of the developed nanoparticles. The work has proven that the solid nature and morphology of cSLN/cNLC strengthen these particles' potential to modify the CBD delivery profile for several biomedical applications.
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Affiliation(s)
- Aleksandra Zielińska
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznan, Poland
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Raquel da Ana
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Joel Fonseca
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Milena Szalata
- Department of Biotechnology, Institute of Natural Fibres and Medicinal Plants, National Research Institute, Wojska Polskiego 71B, 60-630 Poznan, Poland
| | - Karolina Wielgus
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna 27/33, 60-572 Poznan, Poland
| | - Faezeh Fathi
- REQUIMTE/LAQV, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira No. 280, 4050-313 Porto, Portugal
| | - M Beatriz P P Oliveira
- REQUIMTE/LAQV, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira No. 280, 4050-313 Porto, Portugal
| | - Rafał Staszewski
- Department of Hypertension Angiology and Internal Medicine, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Jacek Karczewski
- Department of Environmental Medicine, Poznan University of Medical Sciences, 61-701 Poznan, Poland
- Department of Gastroenterology, Dietetics and Internal Diseases, H. Swiecicki University Hospital, Poznan University of Medical Sciences, 60-355 Poznan, Poland
| | - Eliana B Souto
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
- REQUIMTE/UCIBIO, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
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29
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Velez-Santiago A, Alvarez-Torres E, Martinez-Rodriguez R, Candal-Rivera E, Muniz-Camacho L, Ramos-Burgos L, Torres EA. A Survey of Cannabis Use among Patients with Inflammatory Bowel Disease (IBD). INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:5129. [PMID: 36982049 PMCID: PMC10049263 DOI: 10.3390/ijerph20065129] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/20/2023] [Accepted: 03/02/2023] [Indexed: 06/18/2023]
Abstract
Inflammatory bowel diseases (IBDs) are chronic conditions of unknown cause or cure. Treatment seeks to reduce symptoms and induce and maintain remission. Many patients have turned to alternatives, such as cannabis, to alleviate living with IBD. This study reports the demographics, prevalence, and perception on cannabis use of patients attending an IBD clinic. Patients agreed to participate and completed an anonymous survey during their visit or online. Descriptive analysis, Fisher's exact test, and Wilcoxon-Mann-Whitney rank-sum test were used. One hundred and sixty-two adults (85 males, 77 with CD) completed the survey. Sixty (37%) reported use of cannabis, of which 38 (63%) used it to relieve their IBD. A value of 77% reported low to moderate knowledge about cannabis, and 15% reported little to no knowledge. Among cannabis users, 48% had discussed use with their physician, but 88% said they would feel comfortable discussing medical cannabis for IBD. Most saw improvement of their symptoms (85.7%). A considerable number of patients with IBD use medical cannabis for their disease, unknown to their physician. The study reinforces the importance that physicians understand the role of cannabis in the treatment of IBD in order to appropriately counsel patients.
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Affiliation(s)
- Alondra Velez-Santiago
- Department of Medicine, School of Medicine, University of Puerto Rico Medical Sciences Campus, PR Medical Center, San Juan, PR 00935, USA; (A.V.-S.); (E.A.-T.); (R.M.-R.)
| | - Edwin Alvarez-Torres
- Department of Medicine, School of Medicine, University of Puerto Rico Medical Sciences Campus, PR Medical Center, San Juan, PR 00935, USA; (A.V.-S.); (E.A.-T.); (R.M.-R.)
| | - Ricardo Martinez-Rodriguez
- Department of Medicine, School of Medicine, University of Puerto Rico Medical Sciences Campus, PR Medical Center, San Juan, PR 00935, USA; (A.V.-S.); (E.A.-T.); (R.M.-R.)
| | - Emmanuel Candal-Rivera
- Veterans Affairs Caribbean Health System, 10 Calle Casia, San Juan, PR 00921-3201, USA; (E.C.-R.); (L.M.-C.)
| | - Luis Muniz-Camacho
- Veterans Affairs Caribbean Health System, 10 Calle Casia, San Juan, PR 00921-3201, USA; (E.C.-R.); (L.M.-C.)
| | - Luis Ramos-Burgos
- Massachussetts General Hospital, 55 Fruit St., Boston, MA 02114, USA;
| | - Esther A. Torres
- Department of Medicine, School of Medicine, University of Puerto Rico Medical Sciences Campus, PR Medical Center, San Juan, PR 00935, USA; (A.V.-S.); (E.A.-T.); (R.M.-R.)
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30
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Yang J, Wang L, Mei M, Guo J, Yang X, Liu S. Electroacupuncture repairs intestinal barrier by upregulating CB1 through gut microbiota in DSS-induced acute colitis. Chin Med 2023; 18:24. [PMID: 36894930 PMCID: PMC9999655 DOI: 10.1186/s13020-023-00733-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 03/05/2023] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND A few studies have reported that electroacupuncture (EA) can repair the intestinal barrier through unknown mechanisms. Cannabinoid receptor 1 (CB1) was shown to play an important role in the protection of the gut barrier in recent studies. Gut microbiota can influence the expression of CB1. In this study, we explored the effect of EA on the gut barrier in acute colitis and its mechanism. METHODS A dextran sulfate sodium (DSS)-induced acute colitis model, CB1 antagonist model and fecal microbiota transplantation (FMT) model were used in this study. The disease activity index (DAI) score, colon length, histological score, and inflammatory factors were detected to evaluate colonic inflammation. Methods for detecting intestinal barrier functions included the expression of tight junction proteins, intestinal permeability, and the number of goblet cells. Moreover, 16S rRNA sequencing was applied to analyze alterations in the gut microbiota. Western blotting and RT-PCR were performed to assess the levels of CB1 and autophagy-related proteins. Autophagosomes were observed by transmission electron microscopy. RESULTS EA reduced the DAI score, histological score, levels of inflammatory factors, and restored the colon length. Moreover, EA increased the expression of tight junction proteins and the number of goblet cells, and decreased intestinal permeability. In addition, EA remodeled the community structure of the gut microbiota, increased the expression of CB1, and enhanced the degree of autophagy. However, the therapeutic effects were reversed by CB1 antagonists. In addition, FMT in the EA group exhibited similar effects to EA and upregulated CB1. CONCLUSIONS We concluded that EA may protect intestinal barrier functions by increasing the expression of CB1 to enhance autophagy through gut microbiota in DSS-induced acute colitis.
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Affiliation(s)
- Jingze Yang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lingli Wang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Minhui Mei
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jinlu Guo
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xin Yang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shi Liu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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31
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Bialkowski S, Toschi A, Yu LE, Schlitzkus L, Mann P, Grilli E, Li Y. Effects of microencapsulated blend of organic acids and botanicals on growth performance, intestinal barrier function, inflammatory cytokines, and endocannabinoid system gene expression in broiler chickens. Poult Sci 2023; 102:102460. [PMID: 36680863 PMCID: PMC10014334 DOI: 10.1016/j.psj.2022.102460] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 12/12/2022] [Accepted: 12/25/2022] [Indexed: 12/30/2022] Open
Abstract
With restricted usage of growth-promoting antibiotics, identifying alternative feed additives that both improve intestinal barrier function and reduce inflammation is the center to improve chickens' health. This study examined the effects of a microencapsulated feed additive containing citric acid, sorbic acids, thymol, and vanillin on intestinal barrier function and inflammation status. A total of 240 birds were assigned to either a commercial control diet or control diet supplemented with 500 g/MT of the microencapsulated additive product. Birds were raised by feeding a 2-phase diet (starter, d 1 to d 21; and grower, d 15 to d 42). Growth performance was recorded weekly. At d 21 and d 42, total gastrointestinal tract permeability was evaluated by FITC-dextran (FD4) oral gavage. Jejunum-specific barrier functions were evaluated by Ussing chamber. Intestinal gene expression of selected epithelial cell markers, tight junction (TJ) proteins, inflammatory cytokines, and endocannabinoid system (ECS) markers were determined by RT-PCR. Statistical analysis was performed using Student t test. Results showed significant improvement of feed efficiency in the birds supplemented with the blend of organic acids and botanicals. At d 21, both oral and jejunal FD4 permeability were lower in the supplemented group. Jejunal transepithelial resistance was higher in the supplemented birds. At d 21, expression of TJs mRNA (CLDN1 and ZO2) was both upregulated in the jejunum and ileum of supplemented birds, while CLDN2 was downregulated in cecum. Proliferating cell marker SOX9 was higher expressed in jejunum and ceca. Goblet cell marker (MUC2) was upregulated, while Paneth cell marker (LYZ) was downregulated in the ileum. Proinflammatory cytokine expressions of IL1B, TNFA, and IFNG were downregulated in jejunum, while anti-inflammatory IL10 expression was higher in jejunum, ileum, cecum, and cecal tonsil. The ECS markers expressions were upregulated in most intestinal regions. Together, these results demonstrated that the blend of organic acids and botanical supplementation reduced inflammation, improved the TJs expression and intestinal barrier function, and thus improved chicken feed efficiency. The activated ECS may play a role in reducing intestinal tissue inflammation.
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Affiliation(s)
- Sofia Bialkowski
- Department of Animal and Food Sciences, University of Delaware, Newark, DE, USA
| | | | - Liang-En Yu
- Department of Animal and Food Sciences, University of Delaware, Newark, DE, USA
| | - Lydia Schlitzkus
- Department of Animal and Food Sciences, University of Delaware, Newark, DE, USA
| | - Peter Mann
- Department of Animal and Food Sciences, University of Delaware, Newark, DE, USA
| | - Ester Grilli
- DIMEVET, University of Bologna, 40064 Ozzano Emilia, Bologna, Italy; Vetagro Inc., 60604 Chicago, IL, USA
| | - Yihang Li
- Department of Animal and Food Sciences, University of Delaware, Newark, DE, USA.
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32
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Sharma A, Junge O, Szymczak S, Rühlemann MC, Enderle J, Schreiber S, Laudes M, Franke A, Lieb W, Krawczak M, Dempfle A. Network-based quantitative trait linkage analysis of microbiome composition in inflammatory bowel disease families. Front Genet 2023; 14:1048312. [PMID: 36755569 PMCID: PMC9901208 DOI: 10.3389/fgene.2023.1048312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 01/09/2023] [Indexed: 01/24/2023] Open
Abstract
Introduction: Inflammatory bowel disease (IBD) is characterized by a dysbiosis of the gut microbiome that results from the interaction of the constituting taxa with one another, and with the host. At the same time, host genetic variation is associated with both IBD risk and microbiome composition. Methods: In the present study, we defined quantitative traits (QTs) from modules identified in microbial co-occurrence networks to measure the inter-individual consistency of microbial abundance and subjected these QTs to a genome-wide quantitative trait locus (QTL) linkage analysis. Results: Four microbial network modules were consistently identified in two cohorts of healthy individuals, but three of the corresponding QTs differed significantly between IBD patients and unaffected individuals. The QTL linkage analysis was performed in a sub-sample of the Kiel IBD family cohort (IBD-KC), an ongoing study of 256 German families comprising 455 IBD patients and 575 first- and second-degree, non-affected relatives. The analysis revealed five chromosomal regions linked to one of three microbial module QTs, namely on chromosomes 3 (spanning 10.79 cM) and 11 (6.69 cM) for the first module, chr9 (0.13 cM) and chr16 (1.20 cM) for the second module, and chr13 (19.98 cM) for the third module. None of these loci have been implicated in a microbial phenotype before. Discussion: Our study illustrates the benefit of combining network and family-based linkage analysis to identify novel genetic drivers of microbiome composition in a specific disease context.
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Affiliation(s)
- Arunabh Sharma
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
| | - Olaf Junge
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
| | - Silke Szymczak
- Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany
| | - Malte Christoph Rühlemann
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany,Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Janna Enderle
- Institute of Epidemiology, Kiel University, Kiel, Germany
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany,Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Matthias Laudes
- Institute of Diabetology and Clinical Metabolic Research, Kiel University, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - Wolfgang Lieb
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Michael Krawczak
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
| | - Astrid Dempfle
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany,*Correspondence: Astrid Dempfle,
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Oshaghi M, Kourosh-Arami M, Roozbehkia M. Role of neurotransmitters in immune-mediated inflammatory disorders: a crosstalk between the nervous and immune systems. Neurol Sci 2023; 44:99-113. [PMID: 36169755 DOI: 10.1007/s10072-022-06413-0] [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: 05/11/2022] [Accepted: 09/14/2022] [Indexed: 02/07/2023]
Abstract
Immune-mediated inflammatory diseases (IMIDs) are a group of common heterogeneous disorders, characterized by an alteration of cellular homeostasis. Primarily, it has been shown that the release and diffusion of neurotransmitters from nervous tissue could result in signaling through lymphocyte cell-surface receptors and the modulation of immune function. This finding led to the idea that the neurotransmitters could serve as immunomodulators. It is now manifested that neurotransmitters can also be released from leukocytes and act as autocrine or paracrine modulators. Increasing data indicate that there is a crosstalk between inflammation and alterations in neurotransmission. The primary goal of this review is to demonstrate how these two pathways may converge at the level of the neuron and glia to involve in IMID. We review the role of neurotransmitters in IMID. The different effects that these compounds exert on a variety of immune cells are also reviewed. Current and future developments in understanding the cross-talk between the immune and nervous systems will undoubtedly identify new ways for treating immune-mediated diseases utilizing agonists or antagonists of neurotransmitter receptors.
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Affiliation(s)
- Mojgan Oshaghi
- Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Kourosh-Arami
- Department of Neuroscience, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Maryam Roozbehkia
- Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
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Dalavaye N, Erridge S, Nicholas M, Pillai M, Bapir L, Holvey C, Coomber R, Rucker JJ, Hoare J, Sodergren MH. The effect of medical cannabis in inflammatory bowel disease: analysis from the UK Medical Cannabis Registry. Expert Rev Gastroenterol Hepatol 2023; 17:85-98. [PMID: 36562418 DOI: 10.1080/17474124.2022.2161046] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Cannabis-based medicinal products (CBMPs) have shown promising preclinical activity in inflammatory bowel disease (IBD). However, clinical trials have not demonstrated effects on inflammation. This study aims to analyze changes in health-related quality of life (HRQoL) and adverse events in IBD patients prescribed CBMPs. METHODS A case series from the UK Medical Cannabis Registry was performed. Primary outcomes included changes from baseline in the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), Generalized Anxiety Disorder-7 (GAD-7), Single-Item Sleep Quality Scale (SQS), and EQ-5D-5L Index score at 1 and 3 months. Statistical significance was defined using p < 0.050. RESULTS Seventy-six patients with Crohn's disease (n = 51; 67.11%) and ulcerative colitis (n = 25; 32.89%) were included. The median baseline SIBDQ score improved at 1 and 3 months. EQ-5D-5L index values, GAD-7, and SQS also improved after 3 months (p < 0.050). Sixteen (21.05%) patients reported adverse events with the majority being classified as mild to moderate in severity. CONCLUSION Patients treated with CBMPs for refractory symptoms of Crohn's disease and ulcerative colitis demonstrated a short-term improvement in IBD-specific and general HRQoL. Prior cannabis consumers reported greater improvement compared to cannabis-naïve individuals.
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Affiliation(s)
- Nishaanth Dalavaye
- Imperial College Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Simon Erridge
- Imperial College Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, UK.,Sapphire Medical Clinics, London, UK
| | - Martha Nicholas
- Imperial College Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Manaswini Pillai
- Imperial College Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Lara Bapir
- Imperial College Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, UK
| | | | - Ross Coomber
- Sapphire Medical Clinics, London, UK.,St. George's Hospital NHS Trust, London, UK
| | - James J Rucker
- Sapphire Medical Clinics, London, UK.,Department of Psychological Medicine, Kings College London, London, UK.,South London & Maudsley NHS Foundation Trust, London, UK
| | - Jonathan Hoare
- Imperial College Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, UK.,Sapphire Medical Clinics, London, UK
| | - Mikael H Sodergren
- Imperial College Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, UK.,Sapphire Medical Clinics, London, UK
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35
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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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36
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Abdulla M, Mohammed N. A Review on Inflammatory Bowel Diseases: Recent Molecular Pathophysiology Advances. Biologics 2022; 16:129-140. [PMID: 36118798 PMCID: PMC9481278 DOI: 10.2147/btt.s380027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/27/2022] [Indexed: 11/24/2022]
Abstract
Inflammatory bowel diseases are considered immune disorders with a complex genetic architecture involving constantly changing endogenous and exogenous factors. The rapid evolution of genomic technologies and the emergence of newly discovered molecular actors are compelling the research community to reevaluate the knowledge and molecular processes. The human intestinal tract contains intestinal human microbiota consisting of commensal, pathogenic, and symbiotic strains leading to immune responses that can contribute and lead to both systemic and intestinal disorders including IBD. In this review, we attempted to highlight some updates of the new IBD features related to genomics, microbiota, new emerging therapies and some major established IBD risk factors.
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Affiliation(s)
- Maheeba Abdulla
- Internal Medicine Department, Ibn AlNafees Hospital, Arabian Gulf University, Manama, Bahrain
- Correspondence: Maheeba Abdulla, Consultant Gastroenterologist, Internal Medicine Department, Ibn AlNafees Hospital, Arabian Gulf University, Manama, Bahrain, Email
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37
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Shute A, Bihan DG, Lewis IA, Nasser Y. Metabolomics: The Key to Unraveling the Role of the Microbiome in Visceral Pain Neurotransmission. Front Neurosci 2022; 16:917197. [PMID: 35812241 PMCID: PMC9260117 DOI: 10.3389/fnins.2022.917197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 05/30/2022] [Indexed: 11/29/2022] Open
Abstract
Inflammatory bowel disease (IBD), comprising Crohn's disease and Ulcerative colitis, is a relapsing and remitting disease of the gastrointestinal tract, presenting with chronic inflammation, ulceration, gastrointestinal bleeding, and abdominal pain. Up to 80% of patients suffering from IBD experience acute pain, which dissipates when the underlying inflammation and tissue damage resolves. However, despite achieving endoscopic remission with no signs of ongoing intestinal inflammation or damage, 30-50% of IBD patients in remission experience chronic abdominal pain, suggesting altered sensory neuronal processing in this disorder. Furthermore, effective treatment for chronic pain is limited such that 5-25% of IBD outpatients are treated with narcotics, with associated morbidity and mortality. IBD patients commonly present with substantial alterations to the microbial community structure within the gastrointestinal tract, known as dysbiosis. The same is also true in irritable bowel syndrome (IBS), a chronic disorder characterized by altered bowel habits and abdominal pain, in the absence of inflammation. An emerging body of literature suggests that the gut microbiome plays an important role in visceral hypersensitivity. Specific microbial metabolites have an intimate relationship with host receptors that are highly expressed on host cell and neurons, suggesting that microbial metabolites play a key role in visceral hypersensitivity. In this review, we will discuss the techniques used to analysis the metabolome, current potential metabolite targets for visceral hypersensitivity, and discuss the current literature that evaluates the role of the post-inflammatory microbiota and metabolites in visceral hypersensitivity.
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Affiliation(s)
- Adam Shute
- Department of Medicine, Cumming School of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Dominique G. Bihan
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - Ian A. Lewis
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - Yasmin Nasser
- Department of Medicine, Cumming School of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
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Srivastava RK, Lutz B, Ruiz de Azua I. The Microbiome and Gut Endocannabinoid System in the Regulation of Stress Responses and Metabolism. Front Cell Neurosci 2022; 16:867267. [PMID: 35634468 PMCID: PMC9130962 DOI: 10.3389/fncel.2022.867267] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/14/2022] [Indexed: 11/26/2022] Open
Abstract
The endocannabinoid system, with its receptors and ligands, is present in the gut epithelium and enteroendocrine cells, and is able to modulate brain functions, both indirectly through circulating gut-derived factors and directly through the vagus nerve, finally acting on the brain’s mechanisms regarding metabolism and behavior. The gut endocannabinoid system also regulates gut motility, permeability, and inflammatory responses. Furthermore, microbiota composition has been shown to influence the activity of the endocannabinoid system. This review examines the interaction between microbiota, intestinal endocannabinoid system, metabolism, and stress responses. We hypothesize that the crosstalk between microbiota and intestinal endocannabinoid system has a prominent role in stress-induced changes in the gut-brain axis affecting metabolic and mental health. Inter-individual differences are commonly observed in stress responses, but mechanisms underlying resilience and vulnerability to stress are far from understood. Both gut microbiota and the endocannabinoid system have been implicated in stress resilience. We also discuss interventions targeting the microbiota and the endocannabinoid system to mitigate metabolic and stress-related disorders.
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Affiliation(s)
- Raj Kamal Srivastava
- Department of Zoology, Indira Gandhi National Tribal University, Anuppur, India
- *Correspondence: Raj Kamal Srivastava,
| | - Beat Lutz
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- Leibniz Institute for Resilience Research (LIR), Mainz, Germany
| | - Inigo Ruiz de Azua
- Leibniz Institute for Resilience Research (LIR), Mainz, Germany
- Inigo Ruiz de Azua,
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Effects of CB2 Receptor Modulation on Macrophage Polarization in Pediatric Celiac Disease. Biomedicines 2022; 10:biomedicines10040874. [PMID: 35453624 PMCID: PMC9029516 DOI: 10.3390/biomedicines10040874] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/04/2022] [Accepted: 04/07/2022] [Indexed: 01/27/2023] Open
Abstract
Celiac Disease (CD) represents an autoimmune disorder triggered by the exposure to gluten in genetically susceptible individuals. Recent studies suggest the involvement of macrophages in CD pathogenesis. Macrophages are immune cells, present as pro-inflammatory classically activated macrophages (M1) or as anti-inflammatory alternatively activated macrophages (M2). The Cannabinoid Receptor 2 (CB2) has important anti-inflammatory and immunoregulatory properties. We previously demonstrated that a common CB2 functional variant, Q63R, causing CB2 reduced function, is associated with several inflammatory and autoimmune diseases The first aim of this study was to investigate the phenotype of macrophages isolated from peripheral blood of CD patients and CB2 expression. The second aim was to evaluate the effects of CB2 pharmacological modulation on CD macrophage polarization. Moreover, by an in vitro model of “immunocompetent gut” we investigated the role of CD macrophages in inducing intestinal barrier damage and the possibility to restore its functionality modulating their polarization. We found an increased expression of M1 macrophages and a CB2 reduced expression. We also demonstrated CD M1 macrophages in inducing the typical mucosal barrier damage of CD. CB2 stimulation switches macrophage polarization towards the anti-inflammatory M2 phenotype thus reducing inflammation but also limiting the epithelial dysfunction. Therefore, we suggest CB2 receptor as a possible novel therapeutic target for CD by regulating macrophages polarization and by preventing mucosal barrier damage.
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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: 24] [Impact Index Per Article: 8.0] [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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