2-arachidonoyl glycerol (2-AG) modulated miRNAs expression in human cholangiocarcinoma
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ABSTRACT:
ORGANISM(S): Mus musculus Rattus norvegicus Homo sapiens
PROVIDER: GSE188863 | GEO | 2022/05/01
REPOSITORIES: GEO
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Project description:To elucidate the specific molecular signals associated with the activation or blockade of CB1 and CB2 receptors in this glial cell, mass spectrometry-based proteomics and in silico biology tools were used to determine which signaling pathways and molecular mechanisms are triggered in a human oligodendrocytic cell line (MO3.13) by several pharmacological stimuli: the phytocannabinoid cannabidiol (CBD); CB1 and CB2 agonists WIN55,212-2, ACEA, and HU308; CB1 and CB2 antagonists AM251 and AM630; and endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG).
2022-06-09 | PXD031923 | Pride
Project description:The United States is currently facing a severe opioid epidemic, therefore addressing how opioids induce rewarding behaviors could be key to a solution for this medical and societal crisis. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how chronic opioid exposure may affect this system. In the present study, we investigated how chronic morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA), a critical region in the mesolimbic reward circuitry. Our studies found that the VTA expresses 32 different proteins or genes related to the endogenous cannabinoid system; 3 of these proteins or genes were significantly affected after chronic morphine exposure. We also investigated the effects of acute and chronic morphine treatment on the production of the primary endocannabinoids, 2-Arachidonoylglycerol (2-AG) and anandamide (AEA), and identified that acute, but not chronic, morphine treatment significantly reduced AEA production in the VTA; 2-AG levels were unchanged in either condition. Lastly, our studies exhibited a systemic enhancement of 2-AG tone via inhibition of monoacylglycerol lipase (MAGL)-mediated degradation and the pharmacological activation of cannabinoid receptor 2 (CB2R) significantly suppressed chronic morphine-induced conditioned place preference. Taken together, our studies offer a broad picture of chronic morphine-induced alterations of the VTA endogenous cannabinoid system, provide several uncharacterized targets that could be used to develop novel therapies, and identify how manipulation of the endocannabinoid system can mitigate opioid reward to directly address the ongoing opioid epidemic.
2021-04-08 | PXD023096 | Pride
Project description:The endocannabinoid system (ECS), named after the chemical compounds found in the cannabis plant, is a regulatory network of neurotransmitters, receptors, and enzymes that plays crucial roles in skin health and disease. Endogenous ligands of the ECS, called endocannabinoids, have proven to be important regulators of immune responses. One of the most prevalent endocannabinoids, arachidonoylethanolamide (also known as anandamide), is known for its anti-inflammatory effects. It reduces the production of pro-inflammatory cytokines in various immune cells, weakens both humoral and cellular immune responses, and promotes cell migration. Langerhans cells (LCs) are the sole antigen-presenting cells present in the human epidermis. They serve as the first line of defense against invading pathogens and are essential for the skin's specific immune responses and play a critical role in maintaining tissue homeostasis; however, little is known about the effect of endocannabinoids, specifically anandamide, on the biological functions of these cells. Our research aimed to provide the connection between monocyte-derived Langerhans cells (moLCs) and the ECS, shedding light on their collaborative roles in immune homeostasis and inflammation. Anandamide did not significantly affect the viability of moLCs up to 10 µM. When applied during the differentiation process it had only a negligible effect on CD207 expression, the prototypic marker of LCs; however, there was an observed reduction in CD1a expression by moLCs. Anandamide had no significant effects on the maturation status of moLCs, nor did it affect the maturation induced by TLR3 and TLR7/8 agonists. moLCs differentiated in the presence of anandamide did however show decreased production of CXCL8, IL-6, IL-10 and IL-12 cytokines induced by TLR3 and TLR7/8 activation. Anandamide-treated moLCs showed an increased capability to activate naïve T cells; however, not to the level seen with combined TLR agonism. RNAseq analysis of moLCs differentiated with anandamide showed modest changes to the transcriptome of the cells but did reveal an inhibitory effect on oxidative phosphorylation specifically in activated moLCs. Anandamide also promoted the polarization of naïve T cells towards a Th1 phenotype. Our results show that anandamide has nuanced effects on the differentiation, maturation, cytokine secretion, metabolism and function of activated moLCs. Among these changes the decrease in CD1a expression on moLCs holds promise to selectively dampen inflammation induced by CD1a restricted T cells, which have been implicated as drivers of inflammation in common inflammatory skin conditions such as psoriasis, atopic dermatitis and contact dermatitis.
2024-06-21 | GSE266075 | GEO
Project description:The endocannabinoid system plays important roles in the modulation of gastrointestinal motility and secretions. These effects are mainly mediated by the activation by the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) of CB1 receptors expressed on cholinergic neurons. Cannabis sativa extracts also perform these activities, through the detection of CB1 receptors by the phytocannabinoids they contain, in particular delta9-tetrahydrocannabinol.
CB1 receptors are abundantly expressed at the synaptic terminals of excitatory motor neurons and cholinergic secretomotor neurons and their activation induces prejunctional inhibition of acetylcholine release. It is thought that the endocannabinoids AEA and 2-AG, by activating these receptors, may exert a physiological control on gastrointestinal contractility and secretions.
This research hypothesizes that drugs capable of inhibiting the biosynthetic and catabolic enzymes of endocannabinoids, of inhibiting the transmembrane transport of endocannabinoids or of allosterically modulating CB1 receptors induce important regulating effects of basal contractility and excitatory motor responses, induced by activation of neurons intramural cholinergics, of colonic circular smooth muscle.
The effects of drugs acting on CB receptors, endocannabinoid biosynthetic and catabolic enzymes and endocannabinoid membrane transporters on basal contractility or induced by neuronal activation of colonic preparations in vitro will be evaluated.
The study will enroll patients affected by colorectal cancer to undergo elective resective surgery at any stage, undergoing upfront surgery or after neo-adjuvant therapy with a therapeutic interval greater than 6 weeks. In the selected patients (see inclusion/exclusion criteria), a fresh sample of about 2.5 cm of healthy colon (healthy resection margin) will be taken, which will be taken in the operating room and sent to the laboratory for in vitro study.
Expected results: The study is expected to provide new evidence regarding the induction of pharmacological effects by allosteric receptor modulators of CB1 receptors, inhibitors of endocannabinoid biosynthetic and catabolic enzymes, and inhibitors of cannabinoid transporters in the human colon, which may open interesting perspectives regarding the development of new therapeutic strategies for the treatment of constipation, diarrhea and irritable bowel syndrome.
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Project description:Background: The regular use of cannabis by young men has been associated with an increased incidence of testicular germ cell tumors (TGCT). TGCT, the most common cancer in young adults, is believed to arise from an alteration of testicular fetal germ cells differentiation during development, with a possible subsequent environmental trigger (eg drugs or other chemicals) during puberty or adulthood leading to cancer. Cannabis consumption by pregnant women is currently increasing worldwide, and legalization for its recreational and therapeutic purposes is debated in numerous countries. In this context, we aimed to determine whether cannabis exposure can affect development of the fetal testis. Methods: Since phytocannabinoids act on an endogenous system called the endocannabinoid system (ECS), we first investigated these signaling pathways in the human fetal testis, from 6 to 17 developmental weeks. We next investigated the effects of the two main components of cannabis, (−)-Δ9-trans-tetrahydrocannabinol (THC) and cannabidiol (CBD), on the human fetal testis ex vivo. Results: We show the presence of two key endocannabinoids, 2-arachidonylglycerol (2-AG) and anandamide (AEA), albeit with lower levels. The human fetal testis also expressed several enzymes and receptors of this signaling pathway. Human fetal testicular explants collected from first trimester were exposed to CBD, THC or CBD/THC [ratio 1:1] at concentrations ranging from 10-7 to 10-5M during 72h to 14 days. Phytocannabinoids treatments affected fetal testicular cell proliferation and viability, as well as testosterone secretion by Leydig cells and AMH secretion by Sertoli cells. Transcriptomic analysis performed by BRB-seq on exposed versus unexposed fetal testis explants showed 187 differentially expressed genes (DEGs), some of which involved in toxic substances response and steroid synthesis. Conclusions: Our study provides the first evidence of the presence of ECS in human fetal testis and support a potential adverse effect of cannabis consumption in pregnant women on the male reproductive function development.
2023-06-15 | GSE223827 | GEO
Project description:Anandamide, or N-arachidonoylethanolamine (AEA), is a signaling lipid that modulates neurotransmitter release via activation of the cannabinoid receptor type 1 (CB1R) in the brain. Termination of anandamide signaling is thought to be mediated via a facilitated cellular reuptake process utilizing an unknown transporter protein. Recently, WOBE437 has been reported as a novel, natural product-based inhibitor of AEA reuptake that is active in cellular and in vivo models. To profile its target interaction landscape, we synthesized pac-WOBE, a photoactivatable probe derivative of WOBE437, and performed chemical proteomics in mouse neuroblastoma Neuro-2a cells. Surprisingly, WOBE437, but not OMDM-1, was found to increase AEA uptake in Neuro-2a cells. In line, WOBE437 reduced cellular levels of AEA and related N-acylethanolamines (NAEs). Using pac-WOBE, we identified saccharopine dehydrogenase-like oxidoreductase (SCCPDH), vesicle amine transport 1 (VAT1) and ferrochelatase (FECH) as WOBE437-interacting proteins in Neuro-2a cells
2022-05-04 | PXD031488 | Pride
Project description:Primary human aortic smooth muscle cells (HAoSMC) were starved over night in 1% FCS. On the next day cells were treated with 100nM Anandamide (AEA) or EtOH as control for 4h in presence of 10µM diclofenac. Subsequently cells were treated with or without 10ng/mL IL-1β for last 1.5h.
2020-04-21 | GSE131732 | GEO
Project description:While it is known that endocannabinoids (eCB) modulate multiple neuronal functions, the molecular mechanism governing their release and transport remains elusive. Here, we propose an “on demand release” model, wherein the formation of microvesicles, a specific group of extracellular vesicles (EVs) containing the eCB, 2-arachidonoylglycerol (2-AG), is the rate-limiting step. A co31 culture model system that combines a reporter cell line expressing the fluorescent eCB sensor,GRABeCB2.0, and neuronal cells revealed that neurons release EVs containing 2-AG, but not anandamide, in a stimulus-dependent process regulated by PKC, DAGL, Arf6, and which was sensitive to inhibitors of eCB facilitated diffusion. A vesicle contained approximately 2000 2-AG molecules. Accordingly, hippocampal eCB-mediated synaptic plasticity was modulated by Arf6 and transport inhibitors. This “on demand release” model, supported by mathematical analysis, offers a cohesive framework for understanding eCB signaling at the molecular level and suggests that microvesicles carrying signaling lipids regulate neuronal functions in parallel to canonical synaptic vesicles. To show the identity and purity of the EVs isolated in this study, the proteome of the EVs and their parental cells were analyzed by LC-MS/MS
2025-02-27 | PXD056498 | Pride
Project description:2-arachidonoyl glycerol (2-AG) modulated miRNAs expression in human cholangiocarcinoma
| PRJNA780527 | ENA
Project description:We generated RRBS data to analyse the DNA methylation profiling among WT-AG-haESCs, DKO-AG-haESCs and round spermatids, we found deletion of H19 and Gtl2 DMRs do not change the methylation patterns in AG-haESCs base on all detected CpG sites.
2015-06-29 | GSE60075 | GEO