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Modulatory pathways of the ECS in asthma pathophysiology. In allergen-sensitized patients, antigen exposure results in IgE-FcεRI cross-linking in the surface of mast cells and basophils that lead to the release of their anaphylactogenic mediators, causing increased vascular permeability, bronchoconstriction, and/or mucus production. Following this early process, APC-activated Th2 cells and alarmin-activated ILC2s produce large amounts of Th2 cytokines (IL-4, IL-13, IL-5, and IL-9) that contribute to the activation and recruitment of eosinophils and other inflammatory cells, contraction of smooth muscle, and bronchial hyperreactivity. If the inflammatory environment persists, it may trigger the remodelling of the airways. The contribution of the ECS to the different asthma pathways is highlighted with the corresponding arrow.
Source publication
The human endocannabinoid system (ECS) is a complex signalling network involved in many key physiological processes. The ECS includes the cannabinoid receptors, the endocannabinoid ligands, and the enzymes related to their synthesis and degradation. Other cannabinoids encompass the phytocannabinoids from Cannabis sativaL.(marijuana) and the synthet...
Contexts in source publication
Context 1
... summary, the ECS seems to be clearly involved in the pathophysiology of asthma by acting in structural cells and by regulating immune responses (Fig. 3). Different strategies targeting immune cells with different types of immunomodulators have been previously shown as promising therapies for allergic diseases [128][129][130]. Thus, the rational design of novel immunomodulatory drugs targeting the ECS may be of potential interest for the development of new therapies for allergic asthma ...
Context 2
... summary, the ECS seems to be clearly involved in the pathophysiology of asthma by acting in structural cells and by regulating immune responses (Fig. 3). Different strategies targeting immune cells with different types of immunomodulators have been previously shown as promising therapies for allergic diseases [128][129][130]. Thus, the rational design of novel immunomodulatory drugs targeting the ECS may be of potential interest for the development of new therapies for allergic asthma ...
Similar publications
Like most modern molecular biology and natural product chemistry, understanding cannabinoid pharmacology centres around molecular interactions; in this case, between the cannabinoids and their putative targets, the G-protein coupled receptors (GPCRs) cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). Understanding the complex structure...
Citations
... Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in the generation of pTregs. Immature or mature DCs conditioned by pathogen-derived molecules, FOXP3 + Tregs, and exogenous signals such as vitamin D3 metabolites [26], adenosine, histamine [27,28], retinoid acid, mannan [29,30], cannabinoids [31][32][33][34], or heparan sulfate-related proteoglycan [35], promote the generation of Tregs through mechanisms involving soluble molecules such as TGF-β, retinoic acid, the enzyme indoleamine 2,3-deoxygenase (IDO), and surface-binding co-stimulatory molecules such as programmed death ligand 1 or inducible co-stimulatory molecule ligand. In addition, plasmacytoid DCs (pDCs) might well display intrinsic tolerogenic capacity to promote Tregs [36]. ...
b> Background: Allergy represents a major health problem of increasing prevalence worldwide with a high socioeconomic impact. Our knowledge on the molecular mechanisms underlying allergic diseases and their treatments has significantly improved over the last years. The generation of allergen-specific regulatory T cells (Tregs) is crucial in the induction of healthy immune responses to allergens, preventing the development and worsening of allergic diseases. Summary: In the last decades, intensive research has focused on the study of the molecular mechanisms involved in Treg development and Treg-mediated suppression. These mechanisms are essential for the induction of sustained tolerance by allergen-specific immunotherapy (AIT) after treatment discontinuation. Compelling experimental evidence demonstrated altered suppressive capacity of Tregs in patients suffering from allergic rhinitis, allergic asthma, food allergy, or atopic dermatitis, as well as the restoration of their numbers and functionality after successful AIT. Key Message: The better understanding of the molecular mechanisms involved in Treg generation during allergen tolerance induction might well contribute to the development of novel strategies for the prevention and treatment of allergic diseases.
... However, there are other biochemically and structurally related eCBs. These include PEA, 2-arachidonylglycerol ether (noladin ether, 2-AGE), o-arachidonoylethanolamine (virodhamine), and N-arachidonoyldopamine (NADA) (Fig. 2) (Angelina et al., 2020). ...
Allergic reactions are highly prevalent pathologies initiated by the production of IgE antibodies against harmless antigens (allergens) and the activation of the high-affinity IgE receptor (FcεRI) expressed in the surface of basophils and mast cells (MCs). Research on the mechanisms of negative control of those exacerbated inflammatory reactions has been intense in recent years. Endocannabinoids (eCBs) show important regulatory effects on MC-mediated immune responses, mainly inhibiting the production of pro-inflammatory mediators. However, the description of the molecular mechanisms involved in eCB control of MC activation is far from complete. In this review, we aim to summarize the available information regarding the role of eCBs in the modulation of FcεRI-dependent activation of that cell type, emphasizing the description of the eCB system and the existence of some of its elements in MCs. Unique characteristics of the eCB system and cannabinoid receptors (CBRs) localization and signaling in MCs are mentioned. The described and putative points of cross-talk between CBRs and FcεRI signaling cascades are also presented. Finally, we discuss some important considerations in the study of the effects of eCBs in MCs and the perspectives in the field.
... Within the plant materials the acid becomes decarboxylated and the presence of an odd number of carbon atoms can be recognised within the structure. Figure 3: Working mechanism of cannabinoids Source: [6] According to some previously conducted experiments it can be stated that cannabinoids have the capability to act against inflammation. This anti-inflammatory mechanism follows a specific pathway which includes some Toll-like receptors. ...
... These receptors can activate the MAPK signalling pathway and NF-κB activation, which should induce the proinflammatory genes. The stimulation of macrophage, monocyte and macroglia, after the signalling pathway, is able to generate LPS stimulation [6]. During inflammation, the molecules of cannabinoids support the signalling process of TLR. ...
The study has clearly provided an idea of anti inflammatory responses of Cannabinoids against respiratory disorders. In that case, asthma can be considered as one of the major diseases and most of the individuals have been suffering from it. In that case, “human endocannabinoid system” can be considered as one of the complicated structures that are mainly responsible for producing signals. Therefore, the entire system of ECS includes ligand, enzymes, synthesis process and degradation. Cannabinoids can be obtained from the plant Cannabis Sativa plant. On the other hand, cannabinoids have the anti-inflammatory properties which can exacerbate the activation of CB2 signalling pathways. The study also demonstrates the derivative substances of cannabinoids has involved the inflammation process and also focuses on the immune responses. In this study, there were mainly two types of receptors mentioned and both of them belong from the G protein family. CB2 cells mainly activate and release proinflammatory mediators, which mainly act on the respiratory inflammation and also help in reducing the impact. In contrast, the activation of CB1 receptors directly impacts the bronchial nerve endings and it can be taken as a positive aspect for treating asthma.
... Alternative CBRs include other orphan GPCRs (GPCR55, GPCR119 and GPCR18), transient receptor potential cation channels (TRPVs), or nuclear peroxisome proliferatoractivated receptors (PPARs) [16][17][18] . Phytocannabinoids from Cannabis sativa L., marijuana, (THC, Δ 9 -tetrahydrocannabinol) and synthetic cannabinoids (HU210, WIN55212-2 or HU308) also activate CBRs and downstream signalling pathways regulating proliferation, differentiation, cell survival, metabolism or immunity 15,[19][20][21] . Different preclinical and clinical studies pointed out cannabinoids as potential therapeutic tools in cancer 15,22 , neurological 23 and inflammatory diseases 19,21 . ...
... Phytocannabinoids from Cannabis sativa L., marijuana, (THC, Δ 9 -tetrahydrocannabinol) and synthetic cannabinoids (HU210, WIN55212-2 or HU308) also activate CBRs and downstream signalling pathways regulating proliferation, differentiation, cell survival, metabolism or immunity 15,[19][20][21] . Different preclinical and clinical studies pointed out cannabinoids as potential therapeutic tools in cancer 15,22 , neurological 23 and inflammatory diseases 19,21 . Human and mice DCs express functional CBRs [24][25][26] , but how cannabinoids regulate functional properties of DCs is not yet completely understood. ...
The generation of functional regulatory T cells (Tregs) is essential to keep tissue homeostasis and restore healthy immune responses in many biological and inflammatory contexts. Cannabinoids have been pointed out as potential therapeutic tools for several diseases. Dendritic cells (DCs) express the endocannabinoid system, including the cannabinoid receptors CB1 and CB2. However, how cannabinoids might regulate functional properties of DCs is not completely understood. We uncover that the triggering of cannabinoid receptors promote human tolerogenic DCs that are able to prime functional FOXP3+ Tregs in the context of different inflammatory diseases. Mechanistically, cannabinoids imprint tolerogenicity in human DCs by inhibiting NF-κB, MAPK and mTOR signalling pathways while inducing AMPK and functional autophagy flux via CB1- and PPARα-mediated activation, which drives metabolic rewiring towards increased mitochondrial activity and oxidative phosphorylation. Cannabinoids exhibit in vivo protective and anti-inflammatory effects in LPS-induced sepsis and also promote the generation of FOXP3+ Tregs. In addition, immediate anaphylactic reactions are decreased in peanut allergic mice and the generation of allergen-specific FOXP3+ Tregs are promoted, demonstrating that these immunomodulatory effects take place in both type 1- and type 2-mediated inflammatory diseases. Our findings might open new avenues for novel cannabinoid-based interventions in different inflammatory and immune-mediated diseases.
... Although the detailed mechanisms of cannabinoid-PPAR interactions are not completely elucidated, there is some evidence that PPAR are also involved in immune cell regulation. [70]. ...
... The enzymes involved in the degradation of ECs are fatty acid-amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) [23, [74][75][76][77]. FAAH and MAGL represent possible therapeutic targets for the treatment of several disorders [70]. In some tissues, ECs can also undergo oxidative catabolism through the lipoxygenase, cyclooxygenase 2 (COX-2), and cytochrome P450 isoenzymes [78]. ...
... Almost all immune cells express and interact with members of the ECS [160]. Human peripheral blood immune cells (i.e., B cells, NK cells, monocytes, neutrophils, eosinophils and CD8 + and CD4 + lym-phocytes) express different degrees of CB receptors [34,70]. The state of cellular activation modulates the different expression of CB receptors. ...
The therapeutic potential of Cannabis sativa has been recognized since ancient times. Phytocannabinoids, endocannabinoids and synthetic cannabinoids activate two major G protein-coupled receptors, subtype 1 and 2 (CB1 and CB2). Cannabinoids (CBs) modulate several aspects of cancer cells, such as apoptosis, autophagy, proliferation, migration, epithelial-to-mesenchymal transition and stemness. Moreover, agonists of CB1 and CB2 receptors inhibit angiogenesis and lymphangiogenesis in vitro and in vivo. Low-grade inflammation is a hallmark of cancer in the tumor microenvironment (TME), which contains a plethora of innate and adaptive immune cells. These cells play a central role in tumor initiation and growth and the formation of metastasis. CB2 and, to a lesser extent, CB1 receptors are expressed on a variety of immune cells present in TME (e.g., T cells, macrophages, mast cells, neutrophils, NK cells, dendritic cells, monocytes, eosinophils). The activation of CB receptors modulates a variety of biological effects on cells of the adaptive and innate immune system. The expression of CB2 and CB1 on different subsets of immune cells in TME and hence in tumor development is incompletely characterized. The recent characterization of the human cannabinoid receptor CB2-Gi signaling complex will likely aid to design potent and specific CB2/CB1 ligands with therapeutic potential in cancer.
... The immunomodulatory effects of endocannabinoids are shortlived. However, it has been shown that immune cells can produce endocannabinoids themselves providing immediate action when required [82,[106][107][108][109][110][111]. Other effects have been observed involving receptors of the endocannabinoid system. ...
As an integral part of the innate immune system, the epithelial membrane is exposed to an array of insults that may trigger an immune response. One of the immune system’s main functions is to regulate the level of communications between the mucosa and the lumen of various tissues. While it is clear that inhaled or ingested substances, or microorganisms may induce changes that affect the epithelial barrier in various ways, the proteins involved in the signaling cascades and physiological events leading to the regulation and maintenance of the barrier are not always well characterized. We review here some of the signaling components involved in regulating the barrier’s paracellular permeability, and their potential effects on the activation of an immune response. While an effective immune response must be launched against pathogenic insults, tolerance must also be maintained for non-pathogenic antigens such as those in the commensal flora or for endogenous metabolites. Along with other members of the innate and adaptive immunity, the endocannabinoid system also plays an instrumental role in maintaining the balance between inflammation and tolerance. We discuss the potential effects of endo- and phytocannabinoids on epithelial permeability and how the dysregulation of this system could be involved in diseases and targeted for therapy.
... 2-AG belongs to the endocannabinoid system consisting of endocannabinoid ligands, endocannabinoid receptors, and enzymes related to their synthesis and degradation. While many studies depict the roles of the endocannabinoid system in allergic diseases, their actual contribution remains controversial [250]. 2-AG binds to and activates GPCRs such as the cannabinoid receptor 1 and 2 (CB1, CB2). ...
... 2-AG binds to and activates GPCRs such as the cannabinoid receptor 1 and 2 (CB1, CB2). Moreover, 2-AG may be converted to arachidonic acid via the monoacylglycerol lipase (MGL) pathway leading to eicosanoid production [250]. Human leukocytes were found to differentially express CB1 and CB2 receptors as well as MGL [251][252][253]. ...
... Similar findings were observed in human eosinophils in vitro, where MGL inhibition prevented the migration of primed eosinophils in response to 2-AG, suggesting potential anti-inflammatory actions of MGL inhibitors in lung inflammation and allergy [66]. The involvement of the endocannabinoid system in allergic diseases was comprehensively described by Angelina et al. in a recent Collegium Internationale Allergologicum update [250]. ...
Eosinophils are important effector cells involved in allergic inflammation. When stimulated , eosinophils release a variety of mediators initiating, propagating, and maintaining local inflammation. Both, the activity and concentration of secreted and cytosolic phospholipases (PLAs) are increased in allergic inflammation, promoting the cleavage of phospholipids and thus the production of reactive lipid mediators. Eosinophils express high levels of secreted phospholipase A2 compared to other leukocytes, indicating their direct involvement in the production of lipid mediators during allergic inflammation. On the other side, eosinophils have also been recognized as crucial mediators with regulatory and homeostatic roles in local immunity and repair. Thus, targeting the complex network of lipid mediators offer a unique opportunity to target the over-activation and 'pro-inflammatory' phenotype of eosinophils without compromising the survival and functions of tissue-resident and homeostatic eosinophils. Here we provide a comprehensive overview of the critical role of phospholipase-derived lipid mediators in modulating eosinophil activity in health and disease. We focus on lysophospholipids, polyunsaturated fatty acids, and eicosanoids with exciting new perspectives for future drug development.
... 2 Cannabinoids are lipid-derived mediators with anti-inflammatory properties in different disorders. 4 Cannabinoid receptor 1 (CB1) agonists inhibited the development of arthritis by restoring the intestinal barrier in the in the pre-phase of arthritis. 5 CB1 expression is significantly increased in atopic patients. ...
... Rimonabant has been first approved for obesity due to its strong anorexigenic effects [354,355], but an unacceptable suicide rate has been detected during its post-market clinical trial (CRESCENDO), being withdraw from the market [356]. However, learnings from the CB system encouraged further investigations for the development of improved drugs without psychiatric effects, and has demonstrated mitigation of low-grade inflammation typically observed in obesity [357,358], beneficial effects on the RAAS [359,360], and immunomodulation [361][362][363], which allowed to propose rimonabant as a candidate for first and second stages in COVID-19 [364,365], although it could only be tested for strict experimental purposes, since it has been banished since 2010. ...
Background
Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2.
Main text
While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19.
The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed.
Conclusion
While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.
Our study investigates the molecular link between COVID‐19 and Alzheimer's disease (AD). We aim to elucidate the mechanisms by which COVID‐19 may influence the onset or progression of AD. Using bioinformatic tools, we analyzed gene expression datasets from the Gene Expression Omnibus (GEO) database, including GSE147507, GSE12685, and GSE26927. Intersection analysis was utilized to identify common differentially expressed genes (CDEGs) and their shared biological pathways. Consensus clustering was conducted to group AD patients based on gene expression, followed by an analysis of the immune microenvironment and variations in shared pathway activities between clusters. Additionally, we identified transcription factor‐binding sites shared by CDEGs and genes in the common pathway. The activity of the pathway and the expression levels of the CDEGs were validated using GSE164805 and GSE48350 datasets. Six CDEGs (MAL2, NECAB1, SH3GL2, EPB41L3, MEF2C, and NRGN) were identified, along with a downregulated pathway, the endocannabinoid (ECS) signaling pathway, common to both AD and COVID‐19. These CDEGs showed a significant correlation with ECS activity ( p < 0.05) and immune functions. The ECS pathway was enriched in healthy individuals' brains and downregulated in AD patients. Validation using GSE164805 and GSE48350 datasets confirmed the differential expression of these genes in COVID‐19 and AD tissues. Our findings reveal a potential pathogenetic link between COVID‐19 and AD, mediated by CDEGs and the ECS pathway. However, further research and multicenter evidence are needed to translate these findings into clinical applications.
