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Molecular Relationship between Endocannabinoid System and Disease
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Molecular Relationship between Endocannabinoid System and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 29726

Special Issue Editor

Dr. Chiara Laezza

E-Mail Website
Guest Editor
Institute of Endocrinology and Experimental Oncology, IEOS CNR, Via Pansini 5, 80131 Naples, Italy
Interests: mevalonate pathway; prenylation proteins; cannabinoid and cancer; cell cycle; cancer-related biochemical pathways; cell proliferation; cell signaling; breast cancer; glioblastoma multiforme
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The endocannabinoid system (ECS) is a biological system involved in the regulation of multiple pathophysiological processes. Alterations of ECS expression and activity have been described in many pathological conditions, including cancers and neurological disorders. Therefore, its pharmaceutical modulation has attracted considerable attention as a target for the development of novel therapeutics. This Special Issue focuses on the molecular relationships between the ECS and diseases including cancers as well as neurological, metabolic, and autoimmune pathologies, with emphasis on recent breakthroughs in the field. The aim of this Special Issue is to encourage studies on the therapeutic potential of cannabinoids in preclinical studies and their possible use in the treatment of the diseases mentioned above. Authors are invited to submit high-quality original research articles and reviews contributing to the knowledge on the role of the endocannabinoid system in the pathological processes.

Dr. Chiara Laezza
Guest Editor

Manuscript Submission Information

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Keywords

  • cannabinoids
  • endocannabinoids
  • endocannabinoid system
  • neurological diseases
  • metabolic disorders
  • autoimmune diseases
  • cancer progression

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Related Special Issue

Published Papers (7 papers)

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Research

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19 pages, 1578 KiB  
Article
Blood Levels of Endocannabinoids, Oxylipins, and Metabolites Are Altered in Hemodialysis Patients
by Bruce A. Watkins, Allon N. Friedman, Jeffrey Kim, Kamil Borkowski, Shaun Kaiser, Oliver Fiehn and John W. Newman
Int. J. Mol. Sci. 2022, 23(17), 9781; https://doi.org/10.3390/ijms23179781 - 29 Aug 2022
Cited by 6 | Viewed by 2142
Abstract
Hemodialysis patients (HDPs) have higher blood pressure, higher levels of inflammation, a higher risk of cardiovascular disease, and unusually low plasma n-3 polyunsaturated fatty acid (PUFA) levels compared to healthy subjects. The objective of our investigation was to examine the levels of endocannabinoids [...] Read more.
Hemodialysis patients (HDPs) have higher blood pressure, higher levels of inflammation, a higher risk of cardiovascular disease, and unusually low plasma n-3 polyunsaturated fatty acid (PUFA) levels compared to healthy subjects. The objective of our investigation was to examine the levels of endocannabinoids (eCBs) and oxylipins (OxLs) in female HDPs compared to healthy matched female controls, with the underlying hypothesis that differences in specific PUFA levels in hemodialysis patients would result in changes in eCBs and OxLs. Plasma phospholipid fatty acids were analyzed by gas chromatography. Plasma was extracted and analyzed using ultra-performance liquid chromatography followed by electrospray ionization and tandem MS for eCBs and OxLs. The global untargeted metabolite profiling of plasma was performed by GCTOF MS. Compared to the controls, HDPs showed lower levels of plasma EPA and the associated OxL metabolites 5- and 12-HEPE, 14,15-DiHETE, as well as DHA derived 19(20)-EpDPE. Meanwhile, no changes in arachidonylethanolamide or 2-arachidonylglycerol in the open circulation were detected. Higher levels of multiple N-acylethanolamides, monoacylglycerols, biomarkers of progressive kidney disease, the nitric oxide metabolism-linked citrulline, and the uremic toxins kynurenine and creatine were observed in HDP. These metabolic differences in cCBs and OxLs help explain the severe inflammatory and cardiovascular disease manifested by HDPs, and they should be explored in future studies. Full article
(This article belongs to the Special Issue Molecular Relationship between Endocannabinoid System and Disease)
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15 pages, 2006 KiB  
Article
Regulation of Expression of Cannabinoid CB2 and Serotonin 5HT1A Receptor Complexes by Cannabinoids in Animal Models of Hypoxia and in Oxygen/Glucose-Deprived Neurons
by Jaume Lillo, Iu Raïch, Laura Silva, David A. Zafra, Alejandro Lillo, Carlos Ferreiro-Vera, Verónica Sánchez de Medina, José Martínez-Orgado, Rafael Franco and Gemma Navarro
Int. J. Mol. Sci. 2022, 23(17), 9695; https://doi.org/10.3390/ijms23179695 - 26 Aug 2022
Cited by 7 | Viewed by 2767
Abstract
Background: Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate. CBD targets a variety of proteins, cannabinoid CB2 and serotonin 5HT1A receptors included. These two receptors may interact [...] Read more.
Background: Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate. CBD targets a variety of proteins, cannabinoid CB2 and serotonin 5HT1A receptors included. These two receptors may interact to form heteromers (CB2–5HT1A-Hets) that are also a target of CBD. Aims: We aimed to assess whether the expression and function of CB2–5HT1A-Hets is affected by CBD in animal models of hypoxia of the neonate and in glucose- and oxygen-deprived neurons. Methods: We developed a quantitation of signal transduction events in a heterologous system and in glucose/oxygen-deprived neurons. The expression of receptors was assessed by immuno-cyto and -histochemistry and, also, by using the only existing technique to visualize CB2–5HT1A-Hets fixed cultured cells and tissue sections (in situ proximity ligation PLA assay). Results: CBD and cannabigerol, which were used for comparative purposes, affected the structure of the heteromer, but in a qualitatively different way; CBD but not CBG increased the affinity of the CB2 and 5HT1A receptor–receptor interaction. Both cannabinoids regulated the effects of CB2 and 5HT1A receptor agonists. CBD was able to revert the upregulation of heteromers occurring when neurons were deprived of oxygen and glucose. CBD significantly reduced the increased expression of the CB2–5HT1A-Het in glucose/oxygen-deprived neurons. Importantly, in brain sections of a hypoxia/ischemia animal model, administration of CBD led to a significant reduction in the expression of CB2–5HT1A-Hets. Conclusions: Benefits of CBD in the hypoxia of the neonate are mediated by acting on CB2–5HT1A-Hets and by reducing the aberrant expression of the receptor–receptor complex in hypoxic-ischemic conditions. These results reinforce the potential of CBD for the therapy of the hypoxia of the neonate. Full article
(This article belongs to the Special Issue Molecular Relationship between Endocannabinoid System and Disease)
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15 pages, 6019 KiB  
Article
Prolonged Activation of Brain CB2 Signaling Modulates Hypothalamic Microgliosis and Astrogliosis in High Fat Diet-Fed Mice
by Rodrigo Rorato, Nathalia L. Ferreira, Franciane P. Oliveira, Higor J. Fideles, Tays A. Camilo, Jose Antunes-Rodrigues, Andre S. Mecawi and Lucila L. K. Elias
Int. J. Mol. Sci. 2022, 23(10), 5527; https://doi.org/10.3390/ijms23105527 - 16 May 2022
Cited by 4 | Viewed by 2114
Abstract
Low-grade inflammation of the hypothalamus is associated with the disturbance of energy balance. The endocannabinoid system has been implicated in the development and maintenance of obesity as well as in the control of immune responses. The type 2 cannabinoid receptor (CB2) signaling has [...] Read more.
Low-grade inflammation of the hypothalamus is associated with the disturbance of energy balance. The endocannabinoid system has been implicated in the development and maintenance of obesity as well as in the control of immune responses. The type 2 cannabinoid receptor (CB2) signaling has been associated with anti-inflammatory effects. Therefore, in high fat diet (HFD)-induced obese mice, we modulated CB2 signaling and investigated its effects on energy homeostasis and hypothalamic microgliosis/astrogliosis. We observed no effect on caloric intake and body weight gain in control diet-fed animals that received prolonged icv infusion of the CB2 receptor agonist HU308. Interestingly, we observed a decrease in glucose tolerance in HFD-fed animals treated with HU308. Prolonged icv infusion of HU308 increases astrogliosis in the ventromedial nucleus (VMH) of obese animals and reduced HFD-induced microgliosis in the hypothalamic arcuate (ARC) but not in the paraventricular (PVN) or VMH nuclei. These data indicate that central CB2 signaling modulates glucose homeostasis and glial reactivity in obesogenic conditions, irrespective of changes in body weight. Full article
(This article belongs to the Special Issue Molecular Relationship between Endocannabinoid System and Disease)
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13 pages, 2623 KiB  
Article
Distinct Effects of Cannabidiol on Sphingolipid Metabolism in Subcutaneous and Visceral Adipose Tissues Derived from High-Fat-Diet-Fed Male Wistar Rats
by Klaudia Berk, Karolina Konstantynowicz-Nowicka, Tomasz Charytoniuk, Ewa Harasim-Symbor and Adrian Chabowski
Int. J. Mol. Sci. 2022, 23(10), 5382; https://doi.org/10.3390/ijms23105382 - 11 May 2022
Cited by 7 | Viewed by 2509
Abstract
Available data suggest that cannabidiol (CBD) may ameliorate symptoms of insulin resistance by modulating the sphingolipid concentrations in particular organs. However, it is not entirely clear whether its beneficial actions also involve adipose tissues in a state of overnutrition. The aim of the [...] Read more.
Available data suggest that cannabidiol (CBD) may ameliorate symptoms of insulin resistance by modulating the sphingolipid concentrations in particular organs. However, it is not entirely clear whether its beneficial actions also involve adipose tissues in a state of overnutrition. The aim of the study was to evaluate the effect of CBD on sphingolipid metabolism pathways and, as a result, on the development of insulin resistance in subcutaneous (SAT) and visceral (VAT) adipose tissues of an animal model of HFD-induced insulin resistance. Our experiment was performed on Wistar rats that were fed with a high-fat diet and/or received intraperitoneal CBD injections. We showed that CBD significantly lowered the ceramide content in VAT by reducing its de novo synthesis and increasing its catabolism. However, in SAT, CBD decreased the ceramide level through the inhibition of salvage and de novo synthesis pathways. All of these changes restored adipose tissues’ sensitivity to insulin. Our study showed that CBD sensitized adipose tissue to insulin by influencing the metabolism of sphingolipids under the conditions of increased availability of fatty acids in the diet. Therefore, we believe that CBD use may be considered as a potential therapeutic strategy for treating or reducing insulin resistance, T2DM, and metabolic syndrome. Full article
(This article belongs to the Special Issue Molecular Relationship between Endocannabinoid System and Disease)
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Review

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15 pages, 951 KiB  
Review
The Endocannabinoid System and Physical Activity—A Robust Duo in the Novel Therapeutic Approach against Metabolic Disorders
by Tomasz Charytoniuk, Hubert Zywno, Klaudia Berk, Wiktor Bzdega, Adrian Kolakowski, Adrian Chabowski and Karolina Konstantynowicz-Nowicka
Int. J. Mol. Sci. 2022, 23(6), 3083; https://doi.org/10.3390/ijms23063083 - 12 Mar 2022
Cited by 7 | Viewed by 5206
Abstract
Rapidly increasing worldwide prevalence of obesity and related pathologies encompassing coronary heart disease, hypertension, metabolic syndrome, or type 2 diabetes constitute serious threats to global health and are associated with a significantly elevated risk of premature death. Considering the enormous burden of these [...] Read more.
Rapidly increasing worldwide prevalence of obesity and related pathologies encompassing coronary heart disease, hypertension, metabolic syndrome, or type 2 diabetes constitute serious threats to global health and are associated with a significantly elevated risk of premature death. Considering the enormous burden of these pathologies, novel therapeutic and preventive patterns are indispensable. Dysregulation of one of the most complex biological systems in the human body namely, the endocannabinoid system (ECS) may result in metabolic imbalance and development of insulin resistance, type 2 diabetes, or non-alcoholic fatty liver disease. Furthermore, many studies showed that physical exercises, depending on their type, intensity, and frequency, exert various alterations within the ECS. Emerging evidence suggests that targeting the ECS via physical activity may produce robust beneficial effects on the course of metabolic pathologies. However, the data showing a direct correlation between the ECS and physical activity in the aspect of metabolic health are very scarce. Therefore, the aim of this review was to provide the most up-to-date state of knowledge about the interplay between the ECS activity and physical exercises in the novel therapeutic and preventive approach toward metabolic pathologies. We believe that this paper, at least in part, will fulfill the existing gap in knowledge and encourage researchers to further explore this very complex yet interesting link between the ECS, its action in physical activity, and subsequent positive outcomes for metabolic health. Full article
(This article belongs to the Special Issue Molecular Relationship between Endocannabinoid System and Disease)
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20 pages, 801 KiB  
Review
New Insights in the Involvement of the Endocannabinoid System and Natural Cannabinoids in Nicotine Dependence
by Rocio Saravia, Marc Ten-Blanco, Inmaculada Pereda-Pérez and Fernando Berrendero
Int. J. Mol. Sci. 2021, 22(24), 13316; https://doi.org/10.3390/ijms222413316 - 10 Dec 2021
Cited by 7 | Viewed by 4215
Abstract
Nicotine, the main psychoactive component in tobacco smoke, plays a major role in tobacco addiction, producing a high morbidity and mortality in the world. A great amount of research has been developed to elucidate the neural pathways and neurotransmitter systems involved in such [...] Read more.
Nicotine, the main psychoactive component in tobacco smoke, plays a major role in tobacco addiction, producing a high morbidity and mortality in the world. A great amount of research has been developed to elucidate the neural pathways and neurotransmitter systems involved in such a complex addictive behavior. The endocannabinoid system, which has been reported to participate in the addictive properties of most of the prototypical drugs of abuse, is also implicated in nicotine dependence. This review summarizes and updates the main behavioral and biochemical data involving the endocannabinoid system in the rewarding properties of nicotine as well as in nicotine withdrawal and relapse to nicotine-seeking behavior. Promising results from preclinical studies suggest that manipulation of the endocannabinoid system could be a potential therapeutic strategy for treating nicotine addiction. Full article
(This article belongs to the Special Issue Molecular Relationship between Endocannabinoid System and Disease)
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21 pages, 1640 KiB  
Review
Molecular Mechanism of Cannabinoids in Cancer Progression
by Cristina Pagano, Giovanna Navarra, Laura Coppola, Maurizio Bifulco and Chiara Laezza
Int. J. Mol. Sci. 2021, 22(7), 3680; https://doi.org/10.3390/ijms22073680 - 1 Apr 2021
Cited by 50 | Viewed by 9478
Abstract
Cannabinoids are a family of heterogeneous compounds that mostly interact with receptors eliciting several physiological effects both in the central and peripheral nervous systems and in peripheral organs. They exert anticancer action by modulating signaling pathways involved in cancer progression; furthermore, the effects [...] Read more.
Cannabinoids are a family of heterogeneous compounds that mostly interact with receptors eliciting several physiological effects both in the central and peripheral nervous systems and in peripheral organs. They exert anticancer action by modulating signaling pathways involved in cancer progression; furthermore, the effects induced by their use depend on both the type of tumor and their action on the components of the endocannabinoid system. This review will explore the mechanism of action of the cannabinoids in signaling pathways involved in cancer proliferation, neovascularisation, migration, invasion, metastasis, and tumor angiogenesis. Full article
(This article belongs to the Special Issue Molecular Relationship between Endocannabinoid System and Disease)
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