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(A) physiological processes and functions that the endocannabinoid system (ECS) takes part in. In this figure, we gathered probably the most crucial ones in terms of potential therapeutic applications, described in detail in this review; (B) components of the ECS; (C) simplified biochemical pathways of the two main endocannabinoids: 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine, also called anandamide (AEA). Blue shapes depict enzymes associated mainly with 2-AG, pink ones—with AEA. Green arrows indicate activation of specific receptors by the endocannabinoids. Abbreviations: 2-AG, 2-arachidonoylglycerol; AA, arachidonic acid; ABHD6/12, α/β hydrolase domain 6 or 12; AEA, N-arachidonoylethanolamine (anandamide); AMT, anandamide membrane transporter; CB1/2, cannabinoid receptor type 1 or 2; COX-2, cyclooxygenase 2; DAG, diacylglycerol; DAGL, diacylglycerol lipase; FAAH, fatty acid amide hydrolase; FABPs, fatty-acid-binding proteins; GPR18/55/119, G protein-coupled receptor 18 or 55 or 119; HSP70s, 70 kilodalton heat shock proteins; MAGL, monoacylglycerol lipase; NAAA, N-acylethanolamine acid amidase; NAPE, N-acylphosphatidylethanolamine; NAPE-PLD, N-acylphosphatidylethanolamine-hydrolyzing phospholipase D; OEA, oleoylethanolamine; PEA, palmitoylethanolamide; PPARγ, peroxisome proliferator-activated receptor γ; TRPV1, transient receptor potential vanilloid type 1 channel.
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The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and prol...
Citations
... Furthermore, CBD potentiates the signaling of type 1 (CB1) and type 2 (CB2) cannabinoid receptors, key components of the endocannabinoid system [26]. This system plays a pivotal role in regulating a wide range of physiological functions, making it a potential target for the development of new treatments [27]. ...
Cell-based therapy using mesenchymal stem cells (MSCs) shows promise for treating several diseases due to their anti-inflammatory and immunomodulatory properties. To enhance the therapeutic potential of MSCs, in vitro priming strategies have been explored. Cannabidiol (CBD), a non-psychoactive compound derived from cannabis, may influence MSC proliferation, differentiation, and immunomodulatory properties. This study evaluates the immunomodulatory potential of equine adipose tissue-derived MSCs (EqAT-MSCs) primed with a CBD-rich cannabis extract. EqAT-MSCs (P3) were primed with CBD concentrations of 5 µM and 7 µM for 24 h. Morphological analysis, MTT assay, β-galactosidase activity, apoptosis assays, and gene expression of interleukins IL-1β, IL-6, IL-10, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) were conducted. Additionally, cannabinoid receptor 1 (CB1) and 2 (CB2) expression were evaluated in naïve EqAT-MSCs (P2–P5). The naïve EqAT-MSCs expressed CB1 and CB2 receptors. Priming with 5 µM significantly increased the expression of IL-10, TNF-α, and IFN-γ, while 7 µM decreased IL-1β and IL-6 expression. No significant changes were observed in other cytokines, MTT, β-galactosidase activity, or apoptosis. These findings demonstrate that naïve EqAT-MSCs express CB1 and CB2 receptors and priming with the extract modulates the expression of pro- and anti-inflammatory cytokines, highlighting its potential immunomodulatory role in EqAT-MSC-based therapies.
... Their higher receptor efficacy results in more potent pharmacological effects, including exacerbated toxicities (e.g., neurotoxicity and cardiotoxicity), increased adverse effects, and elevated abuse potential compared to THC [2][3][4], 2 of 12 contributing to significant public health risks. Therefore, it is important to study the affinity of SCs for CB1 receptors in order to understand their mechanism of action, predict toxicity levels, and develop antagonists [5]. ...
Synthetic cannabinoids (SCs), a class of widely abused new psychoactive substances, are characterized by their structural diversity and rapid evolution. Structure–affinity relationships are crucial for predicting pharmacological effects and potential toxicity. Traditional methods for affinity testing are often complex and less applicable to newly modified compounds. In contrast, Surface Plasmon Resonance (SPR) is a sensitive and label-free technology that detects molecular interactions by measuring refractive index changes on a metallic surface with the advantages of high sensitivity, low sample consumption, and high-throughput capability. In this study, we used SPR to determine the receptor affinity constants of 10 SCs, including some first-reported substances, and analyzed their structure–affinity relationships to validate the method’s reliability. The results showed that (1) indazole-based SCs exhibited stronger CB1 receptor affinity compared to their indole counterparts, (2) the head structure of p-fluorophenyl enhanced affinity relative to 5-fluoropentyl, (3) and the affinity rankings obtained from SPR experiments were consistent with those derived from traditional methods. These results collectively demonstrate the reliability and effectiveness of SPR in assessing CB1 receptor affinity and differentiating affinity differences among structurally similar analogs, with promising application prospects in drug research, particularly in the development and screening of therapeutic agents targeting cannabinoid receptors.
... Cannabinoids are a class of compounds that have been attracting considerable research interest, mainly because of their interaction with the endocannabinoid system through CB1 and CB2 receptors 48 . Hyperactivation of CB1 has been observed in multiple types of cancer, and extensive research has demonstrated its association with the progression of cancer and its clinical outcomes 49 . Importantly, high CBR1 expression have been observed in OC tissue, and the expression level of CB1R is positively correlated with the malignant potential of OC cells 50 . ...
Ovarian cancer (OC) is the most deadly gynecological tumor. OC cells utilize cellular metabolic reprogramming to gain a survival advantage, particularly through aberrant lipid metabolic process. As the primary ingredient in exogenous cannabinoids, cannabidiol (CBD) has been confirmed to exhibit antitumor activity in preclinical studies. However, it is still unclear whether CBD can disrupt fatty acid metabolism and induce apoptosis in OC cells. In this study, we have demonstrated that CBD significantly inhibits the proliferation of OCs through a cannabinoid receptor type 1 (CB1R)-mediated manner. Fatty acid metabolic profiling and flow cytometry analysis revealed that CBD has the ability to decrease fatty acid levels and significantly suppress the transcription of genes involved in fatty acid uptake and synthesis in ES-2 cells. In addition, the analysis from RNA-seq and real-time RT-PCR revealed that CBD activated the endoplasmic reticulum (ER) stress pathway. Conversely, by supplementation with unsaturated fatty acid or blocking CB1R, ER stress or reactive oxygen species (ROS) signals with specific inhibitors could significantly relieve CBD induced, dose-dependent, ER stress associated apoptosis, G0-G1 phase arrest, and mitochondrial dysfunction. Taken collectively, these data indicate that CBD may disrupt lipid metabolism, and lead to ER stress-related apoptosis in OCs. Our findings may provide a theoretical mechanism for anti-ovarian cancer using CBD.
... Moreover, biochemical reactions that can change the activity and toxicity of exogenous compounds can thereby shape the host's response to drugs, xenobiotics and cannabinoids [4,5]. The endocannabinoid system (ECS) of receptors that can act as molecular targets has been reported and suggested as a strategic targeting approach that may improve drug delivery [6]. The ECS is an essential neuromodulatory system that comprises a complex intercellular signaling network, with actions that extend from neural development to modulating the tone of mature synaptic plasticity [7,8]. ...
Historically, the multiple uses of cannabis as a medicine, food, and for recreational purposes as a psychoactive drug span several centuries. The various components of the plant (i.e., seeds, roots, leaves and flowers) have been utilized to alleviate symptoms of inflammation and pain (e.g., osteoarthritis, rheumatoid arthritis), mood disorders such as anxiety, and intestinal problems such as nausea, vomiting, abdominal pain and diarrhea. It has been established that the intestinal microbiota progresses neurological, endocrine, and immunological network effects through the gut–microbiota–brain axis, serving as a bilateral communication pathway between the central and enteric nervous systems. An expanding body of clinical evidence emphasizes that the endocannabinoid system has a fundamental connection in regulating immune responses. This is exemplified by its pivotal role in intestinal metabolic and immunity equilibrium and intestinal barrier integrity. This neuromodulator system responds to internal and external environmental signals while also serving as a homeostatic effector system, participating in a reciprocal association with the intestinal microbiota. We advance an exogenous cannabinoid–intestinal microbiota–endocannabinoid system axis potentiated by the intestinal microbiome and medicinal cannabinoids supporting the mechanism of action of the endocannabinoid system. An integrative medicine model of patient care is advanced that may provide patients with beneficial health outcomes when prescribed medicinal cannabis.
... A decrease in CB 2 R activation and M1 macrophage infiltration leads to significant downregulation of gene and protein levels of M1-related markers and cytokines, including IL-6, IL-12, CD86, and iNOS (Du et al., 2018). CB 2 R activation elicits anti-inflammatory effects by inhibiting leukocyte recruitment, reducing the synthesis and release of chemokines, reactive oxygen species and pro-inflammatory cytokines (Stasiulewicz et al., 2020). Cannabinoids can activate CB 2 R in AtT20 cells, and the CB 2 R antagonist AM630 can modulate CB 2 R activation (Udoh et al., 2019). ...
Avian pathogenic Escherichia coli (APEC) is a bacterial pathogen that threatens poultry reproduction by inciting systemic inflammation and leading to chicken colibacillosis. The endocannabinoid system (ECS) is an immunomodulator system that regulates inflammatory responses. In this study, we aimed to investigate the anti-inflammatory effect of paeoniflorin on APEC-infected HD11 cells and its underlying mechanism. The results showed that paeoniflorin significantly reduced the expression levels of pro-inflammatory factors (IL-1β, IL-6, TNF-α), M1-type macrophage-associated markers (IL-12, iNOS, CD86), and chemokines (CXCL8, CXCL12, CCL1, CCL5, CCL17). Additionally, paeoniflorin significantly reduced the expression of MAGL and restored that of DAGL and CB2R, thereby activating the ECS. Furthermore, we found that paeoniflorin and CB2R exhibited stable conformations through molecular docking and molecular dynamics simulations. The addition of the CB2R inhibitor AM630 notably diminished paeoniflorin's inhibitory effects on the phosphorylation levels of proteins in the NF-κB signaling pathway and on inflammatory responses. These results indicate that the anti-inflammatory effects of paeoniflorin on APEC-induced HD11 cells may be mediated by the inhibition of the NF-κB signaling pathway through the activation of CB2R. This work has the potential to provide a new agent for the control and prevention of chicken colibacillosis, as well as contribute to modern research in traditional Chinese medicine.
... El CB1R se encuentra expresado principalmente en el Sistema Nervioso Central, siendo más abundante en la neurona presináptica de regiones como los ganglios basales, el córtex, cerebelo y el hipocampo, encontrándose también expresado en órganos como la glándula pituitaria, la glándula tiroides, las gónadas, glándula adrenal, vías respiratorias superiores, hígado y útero (Reddy et al., 2020). El CB2R se encuentra expresado en mayor proporción en células inmunes, queratinocitos, retina, corazón, páncreas, tracto digestivo, huesos y en el sistema nervioso central, encontrándose expresado en neuronas postsinápticas, astrocitos y en células gliales (Stasiulewicz et al., 2020). ...
... Las proteínas involucradas son la albúmina, la proteína de choque térmico 70 (HSP-70), la proteína transportadora de esteroles 2 (SCP-2) y dos proteínas miembros de la familia de proteínas unidoras a ácidos grasos denominadas Proteínas 5 unidora a ácidos grasos (FABP5) y Proteína 7 unidora a ácidos grasos (FABP7) ( Una vez que los endocannabinoides cumplen su función, son recapturados hacia el interior de las células para poder ser metabolizados. El ingreso de los endocannabinoides al espacio intracelular para su biotransformación se da principalmente por medio de una difusión facilitada por transportadores en la cual se involucra una proteína transportadora (que aún no ha sido adecuadamente caracterizada) denominada transportador membranal de endocannabinoides (EMT) (Reddy et al., 2020;Stasiulewicz et al., 2020;Biró et al., 2009). La AEA puede ser degradada tanto por la FAAH como por la ciclooxigenasa-2 (COX-2) en cuyo caso da origen a prostamidas, las cuales están relacionadas con procesos inflamatorios. ...
... El sistema de recaptura de endocannabinoides se ha planteado como una diana farmacológica de interés para el tratamiento de numerosos padecimientos, esto debido a que al poder interferir con este sistema se permite prolongar la disponibilidad de los endocannabinoides sobre sus dianas moleculares (los CBR) de este modo prolongar y potenciar sus efectos (Reddy et al., 2020;Stasiulewicz et al., 2020;Biró et al., 2009). El ECS ejerce efectos antiinflamatorios que son capaces de regular funciones clave en la fisiopatología del acné como lo son el crecimiento, la proliferación y la diferenciación de distintos tipos celulares, entre los que se encuentran los sebocitos (Oláh et al., 2016). ...
El acné es una afección compleja que afecta a millones de personas en todo el mundo, está constituida por unidades pilosebáceas de la piel y aparece tanto en forma inflamatoria como no inflamatoria. Dada su naturaleza multifactorial, el tratamiento del acné a menudo implica una variedad de terapias integrales, que pueden aumentar los costos. Objetivo: realizar una investigación teórica sobre la fisiopatología del acné y sus características para enfocar dicho conocimiento en el establecimiento de nuevas dianas terapéuticas como el sistema endocannabinoide que mejore el entendimiento para el desarrollo potencial de tratamientos más efectivos contra este padecimiento. Métodos. Se utilizaron plataformas para la búsqueda de la información, considerando algunas palabras clave como: "Endocannabinoid System", "sebaceous glands" and "acne vulgaris". Resultados: Se encontraron alrededor de 3,242 artículos, en el buscador de PubMed, "Acne vulgaris" (1,588), "Endocannabinoid System" (812), "sebaceous glands" (842). En el Google schoolar, se encontraron alrededor de 199,000, 93,800 y 135,000 artículos respectivamente. Los principales hallazgos mencionan que entre los años 1990 – 2022, los estudios epidemiológicos en Europa y Reino Unido mostraron prevalenciea de la cepa Cutibacterium acnes resistente a distintos antibióticos como la eritromicina y clindamicina, siendo los sebocitos, queranocitos cutáneas y mastocitos, las células que presentan componentes del sistema endocannabinoide; reportándose algunos cannabinoides con efecto sobre la lipogénesis de éstas células. Conclusión: El sistema endocannabinoide se considera una diana terapéutica potencial para el tratamiento del acné debido a que las glándulas sebáceas muestran relación con este sistema, presentando efectos antiinflamatorios y antiproliferativos sobre células dérmicas. Millions of people worldwide suffer from acne, a complicated disorder that can be either inflammatory or non-inflammatory and affects the skin's pilosebaceous units. Because acne is complex, treating it frequently entails using a range of integrative therapies, which might raise expenses. Aim: To conduct theoretical research on acne pathophysiology and its features to concentrate that knowledge on identifying novel therapeutic targets, such as the endocannabinoid system, which advances our understanding of the condition and may lead to the creation of more potent treatments. Methods: Information was found using platforms that took into account keywords like "Endocannabinoid System," "sebaceous glands", and "acne vulgaris". Findings: The PubMed search engine yielded about 3,242 articles about "Acne vulgaris" (1,588), "Endocannabinoid System" (812), and "sebaceous glands" (842). Google Scholar yielded about 199,000, 93,800, and 135,000 articles, respectively. The main findings mention that between the years 1990 - 2022, epidemiological studies in Europe and the United Kingdom showed the prevalence of Cutibacterium acnes strain resistant to different antibiotics such as erythromycin and clindamycin, with sebocytes, skin keranocytes and mast cells being the cells that present components of the endocannabinoid system. Therefore, some cannabinoids have been reported to affect the lipogenesis of these cells. Conclusion: Because of its association with the sebaceous glands and its anti-inflammatory and antiproliferative effects on dermal cells, the endocannabinoid system is thought to be a promising therapeutic target for acne treatment.
... These compounds play essential roles in lipid metabolism and inflammation regulation because of their anti-inflammatory functions. PPAR-γ is highly expressed in macrophages, and its expression is increased in IL-4-treated macrophages, thereby reducing inflammatory cell migration, driving an alternating activated phenotype and increasing oxidative metabolism [84,85]. The regulation of polarization also involves epigenetic modifications, such as histone methylation and acetylation. ...
Idiopathic inflammatory myopathies are a group of systemic autoimmune diseases characterized by chronic muscle inflammation and diverse clinical manifestations. Macrophages, pivotal components of innate immunity, are implicated in immune responses, inflammation resolution, and tissue repair. Distinct macrophage polarization states play vital roles in disease progression and resolution. Mechanistically, activated macrophages release proinflammatory cytokines, chemokines, and reactive oxygen species, perpetuating immune responses and tissue damage. Dysregulated macrophage polarization contributes to sustained inflammation. Here, we reviewed the intricate contributions of macrophages to IIM pathogenesis and explored novel therapeutic avenues. We discussed emerging strategies targeting macrophages, including receptor-based interventions and macrophage polarization modulation, for IIM treatment. This review underscores the multifaceted involvement of macrophages in IIM pathogenesis and offers insights into potential therapeutic approaches targeting these immune cells for disease management.
... Esse sistema está fortemente envolvido nos processos do neurodesenvolvimento e saúde cerebral, como a proliferação de progenitores neurais, comprometimento da linhagem, migração neuronal, orientação axonal e plasticidade sináptica (Rodrigues, 2019). Além disso, o ESC atua em vários processos fisiológicos como: nocicepção, regulação do humor, funções cognitivas, neurogênese e neuroproteção, apetite, metabolismo lipídico, bem como crescimento e proliferação celular (Stasiulewicz et al., 2020). ...
... A inibição de FAAH e consecutivo aumento de AEA demonstra atividade pró-nociceptiva pela ativação pré-sináptica do TRPV1 (Receptor Potencial Transiente Vaniloide tipo 1) e efeito analgésico pela ativação de CB1(Malek;Starowicz, 2016). Além disso,Stasiulewicz et al. (2020) ressalta que a AEA é metabolizada também em prostaglandinas pró-inflamatórias pela COX (Cicloxigenase), sendo os inibidores duplos FAAH / TRPV1 e FAAH / COX-2 alvos propostos para a terapia da dor. ...
O canabidiol (CBD) é o fitocanabinóide mais abundante da Cannabis sativa, popularmente conhecida como maconha. Esse fitocanabinóide possuí um grande potencial terapêutico e se destaca por não provocar efeitos psicoativos e dependência, diferentemente do Delta 9-Tetrahidrocanabinol (Δ9-THC). Objetivou-se com esse estudo, revisar os mecanismos de ação propostos para o CBD, bem como os efeitos terapêuticos associados, contribuindo para uma melhor compreensão da sua utilidade clínica. Utilizou-se dados coletados a partir dos bancos de dados disponíveis no PubMed e ScienceDirect. Vinte e sete artigos científicos foram selecionados para o aprofundamento analítico, seguindo critérios como, disponibilidade do trabalho na íntegra, publicação nos últimos oito anos, nos idiomas inglês e português, além de congruência temática com os objetivos do presente estudo. O CBD é considerado como “multialvo”, possuindo uma dinâmica farmacológica consideravelmente complexa, haja vista a descrição de mais de 65 alvos. Os principais efeitos terapêuticos descritos são antiepilépticos, ansiolíticos, antidepressivos, antipsicótico, neuroprotetores, cardioprotetores, anti-apoptóticos, anti-inflamatórios, entre outros. Dessa forma, o canabidiol se apresenta como forte candidato à terapêutica de diversas doenças, porém, são necessários mais dados para esclarecer completamente sua farmacocinética, bem como parte do seu comportamento multialvo e seus efeitos a longo prazo no organismo humano.
... Some of the health effects caused by cannabinoids result from their interaction with the endocannabinoid system, a highly complex regulatory system that governs a multitude of biological processes (Ligresti et al. 2016;Hillard 2018;Marzo et al. 1998;Devane et al. 1992). Dysregulation of the endocannabinoid system is known to play a role in various neuropsychiatric disorders, which partly explains why the therapeutic potential of cannabinoids is of increasing scientific interest (Cristino et al. 2020;Morano et al. 2020;Stasiulewicz et al. 2020). Cannabinoids can also interact, sometimes exclusively, with molecular targets outside of the endocannabinoid system, allowing them to affect more physiological processes than previously thought (Morales et al. 2017;Cristino et al. 2020). ...
Background
Use of cannabis-based products is becoming more frequent, and it is important that healthcare professionals are informed and confident about them when making evidence-based decisions about their use. This study aimed to gain an international perspective on the attitudes, knowledge, and confidence of healthcare professionals about cannabis-based products.
Methods
An online questionnaire regarding these products was completed by 1580 healthcare professionals (neurologists, psychiatrists, general practitioners, pharmacists and nurses) from 16 countries across Asia, Europe, Oceania, South America, and the Middle East.
Results
Respondents expressed a high level of interest in cannabis-based products (median score 9 out of 10) and reported that they felt knowledgeable about them (median score 6 out of 7). They reported a high level of confidence when providing patients with information on cannabis-based products, returning median scores of 6 and 5 out of 7 for their legality and regulations, and their benefits and risks, respectively. Despite this, healthcare professionals sought further information on cannabis-based products across areas including legality, neurobiology, and scientific evidence. Finally, 59% (n = 930) of respondents considered robust clinical trial evidence as the most important factor to ensure patient safety in the context of these products. Few nominally significant differences emerged between healthcare professionals from different specialities or regions.
Conclusion
In conclusion, this large survey of attitudes held by healthcare professionals towards cannabis-based products revealed a high level of interest and a demand for more information. Limitations of this study include potential sample bias and limited external validity.
... The presence of receptors in immune cells to accommodate endocannabinoids influences neural signals, creating a crosstalk between systems in the body, which regulates immune responses in various physiological states [26]. With the dynamic and crucial role ECS plays as an anti-inflammatory and immunomodulatory agent, endocannabinoids and associated compounds have captured the attention of researchers and clinicians at large for their potential therapeutic role in immune-related situations such as arthritis, autoimmune disorders, and organ transplantation to minimize immune rejection [27,28]. ...
