Silencing or amplification of endocannabinoid signaling in blastocysts via CB1 compromises trophoblast cell migration
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE36399 | GEO | 2012/07/26
SECONDARY ACCESSION(S): PRJNA153291
REPOSITORIES: GEO
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Project description:Endocannabinoid signaling plays a key role in multiple events in female reproduction. In this investigation, we discovered an interesting phenomenon that mice with either elevated or silenced endocannabinoid signaling show similar defects in multiple pregnancy events, including preimplantation embryo development. To unravel the underlying mechanisms, microarray studies were was conducted using RNAs collected from WT, Cnr1-/- and Faah-/- mouse blastocysts on day 4 of pregnancy. The results show that about 100 genes showed unidirectional changes under either elevated or silenced endocannabinoid signaling. Analysis of functional grouping of these genes revealed that multiple biological functions and pathways are affected under aberrant endocannabinoid signaling, including cell migration. Several genes from the microarray data were confirmed by quantitative RT-PCR. Cell motility assays validated the predicted compromised cell migration in Cnr1-/- and Faah-/- trophoblast stem cells. This study provides molecular basis for biphasic effects of endocannabinoid signaling in female reproduction To generate Cnr1-/-, Faah-/- and WT embryos, mutant and WT females were mated with males of the same genotypes. On day 4 of pregnancy at 1500h, embryos were collected from oviducts and uteri of pregnant females, because Cnr1-/- and Faah-/- females show aberrant oviductal transport of embryos. As expected, WT embryos were mostly at the blastocyst stage and all of them were collected from uteri. However, Cnr1-/- and Faah-/- females had higher percentages of embryos at the morula stage, and some of them were still in the oviduct. Since gene expression profiles greatly vary depending on the embryonic development stage, morulae were not included in gene expression analysis; only RNAs from blastocysts were used to better understand the effects solely arising from disrupted cannabinoid signaling in blastocysts.
2012-07-25 | E-GEOD-36399 | biostudies-arrayexpress
Project description:Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cellspecific effects in this disease are not well understood. Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1 deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sexspecific differences in proliferation were dependent on estrogen receptor (ER)α estradiol signaling. Kinase activity profiling revealed a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further unveiled chromatin modifications, mRNA processing and mitochondrial respiration among the key processes affected by CB1 signaling, which was supported by metabolic flux assays. Chronic administration of the peripherally-restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism and inflammatory markers, hinting to a possible implication of CB1-dependent regulation in human pathophysiology. In conclusion, impaired macrophage CB1 signaling is atheroprotective by limiting their arterial recruitment, proliferation and inflammatory reprogramming. The importance of macrophage CB1 signaling seems to be more pronounced in male mice.
2023-12-07 | GSE249503 | GEO
Project description:Diacylglycerol lipase-beta (DAGLB) serves as a principal 2-arachidonoylglycerol (2-AG) biosynthetic enzyme regulating endocannabinoid and eicosanoid metabolism in immune cells including macrophages and dendritic cells. Genetic or pharmacological inactivation of DAGLb ameliorates inflammation and hyper-nociception in preclinical models of pathogenic pain. These beneficial effects have been assigned principally to reductions in downstream pro-inflammatory lipid signaling, leaving alternative mechanisms of regulation largely underexplored. Here, we apply quantitative chemical- and phospho-proteomics to discover that disruption of DAGLb in primary macrophages leads to LKB1-AMPK signaling activation, resulting in reprogramming of the phosphoproteome and bioenergetics. Notably, AMPK inhibition reversed the antinociceptive effects of DAGLb blockade, thereby directly supporting DAGLβ-AMPK crosstalk in vivo. Our findings uncover signaling between endocannabinoid biosynthetic enzymes and ancient energy sensing kinases to mediate cell biological and pain responses.
2024-01-02 | GSE249312 | GEO
Project description:We evaluated cutaneous contact hypersensitivity (CHS) in Cnr1-/-/Cnr2-/- animals using the obligate contact allergen 2,4-dinitrofluorobenzene (DNFB), which generates a specific cutaneous T-cell mediated allergic response upon repeated allergen contact. Allergic contact dermatitis affects about 5% of men and 11% of women in industrialized countries and is one of the leading causes for occupational diseases. In an animal model for cutaneous contact hypersensitivity we show that mice lacking both known cannabinoid receptors display exacerbated allergic inflammation. In contrast, fatty acid amide hydrolase deficient mice, which have increased levels of the endocannabinoid anandamide, displayed reduced allergic responses in the skin. Cannabinoid receptor antagonists exacerbated whereas receptor agonists attenuated allergic inflammation. These results demonstrate a protective role of the endocannabinoid system in contact allergy in the skin, and suggest a novel target for therapeutic intervention. Experiment Overall Design: Three wildtype mice (Wt) and three Cnr1-/-/Cnr2-/- (Ko) mice were used. Contact hypersensitivity was determined always at the right ears, which therefore were treated with DNFB (Tr). Left ears of mice were kept untreated and served as control ears (C). A total of 12 hybridizations were performed (2 strains x 2 treatments X 3 biological replicates) in this experiment.
2009-04-23 | E-GEOD-7694 | biostudies-arrayexpress
Project description:To analyse the effect of endocannabinoid AEA on the expression of inflammation related miRNAs in HIV1 TAT activated Normal Human Astrocytes.
2023-08-05 | GSE210095 | GEO
Project description:Diacylglycerol lipase-beta (DAGLβ) serves as a principal 2-arachidonoylglycerol (2-AG) biosynthetic enzyme regulating endocannabinoid and eicosanoid metabolism in immune cells including macrophages and dendritic cells. Genetic or pharmacological inactivation of DAGLβ ameliorates inflammation and hyper-nociception in preclinical models of pathogenic pain. These beneficial effects have been assigned principally to reductions in downstream proinflammatory lipid signaling, leaving alternative mechanisms of regulation largely underexplored. Here, we apply quantitative chemical- and phospho-proteomics to find that disruption of DAGLβ in primary macrophages leads to LKB1–AMPK signaling activation, resulting in reprogramming of the phosphoproteome and bioenergetics. Notably, AMPK inhibition reversed the antinociceptive effects of DAGLβ blockade, thereby directly supporting DAGLβ–AMPK crosstalk in vivo. Our findings uncover signaling between endocannabinoid biosynthetic enzymes and ancient energy-sensing kinases to mediate cell biological and pain responses.
2024-01-02 | PXD047413 | Pride
Project description:Benson2014 - FAAH inhibitors for the treatment of osteoarthritic pain
Evaluation of fatty acid amide hydrolase (FAAH) as a target for osteoarthritic pain in humans, using an integrated systems pharmacology model.
The SBML version of the model is obtained from the supplementary material of the corresponding paper (see below).
This model is described in the article:
A systems pharmacology perspective on the clinical development of Fatty Acid amide hydrolase inhibitors for pain.
Benson N, Metelkin E, Demin O, Li GL, Nichols D, van der Graaf PH.
CPT Pharmacometrics Syst Pharmacol. 2014 Jan 15;3:e91.
Abstract:
The level of the endocannabinoid anandamide is controlled by fatty acid amide hydrolase (FAAH). In 2011, PF-04457845, an irreversible inhibitor of FAAH, was progressed to phase II clinical trials for osteoarthritic pain. This article discusses a prospective, integrated systems pharmacology model evaluation of FAAH as a target for pain in humans, using physiologically based pharmacokinetic and systems biology approaches. The model integrated physiological compartments; endocannabinoid production, degradation, and disposition data; PF-04457845 pharmacokinetics and pharmacodynamics, and cannabinoid receptor CB1-binding kinetics. The modeling identified clear gaps in our understanding and highlighted key risks going forward, in particular relating to whether methods are in place to demonstrate target engagement and pharmacological effect. The value of this modeling exercise will be discussed in detail and in the context of the clinical phase II data, together with recommendations to enable optimal future evaluation of FAAH inhibitors.
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2014-02-07 | BIOMD0000000512 | BioModels
Project description:The endocannabinoid (eCB) system plays an active role in epidermal homeostasis. Phytocannabinoids such as CBD modulate this system but also act through eCB-independent mechanisms. This study evaluated effects of CBD, bakuchiol (BAK) and ethyl (linoleate/oleate) (ELN) in keratinocytes (KCs) and reconstituted human epidermis (RHE). Molecular docking simulations showed that each compound binds the active site of the eCB carrier fatty-acid-binding protein 5 (FABP5). However, BAK and ethyl linoleate bound this site with highest affinity when combined 1:1 (w/w) and in vitro assays showed that BAK+ELN most effectively inhibited FABP5 and fatty acid amide hydrolase (FAAH). In TNF-stimulated KCs, BAK+ELN reversed TNF-induced expression shifts and uniquely down-regulated type I interferon genes and PTGS2 (COX-2). BAK+ELN also repressed expression of genes linked to KC differentiation but up-regulated those associated with proliferation. Finally, BAK+ELN inhibited cortisol secretion in RHE skin (not observed with CBD). These results support a model in which BAK and ELN synergistically interact to inhibit eCB degradation, favoring eCB mobilization and inhibition of downstream inflammatory mediators (e.g., TNF, COX-2, type I interferon). Topical combination of these ingredients may thus enhance cutaneous eCB tone or potentiate other modulators, suggesting new ways to modulate the eCB system for innovative skincare product development.
2022-11-23 | GSE216614 | GEO
Project description:PHARC is a neurodegenerative disease comprising early onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems; including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyse 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behaviour and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects. Homozygosity mapping using Affymetrix 250K SNP arrays were performed according to the manufacturer's directions on DNA extracted from peripheral blood samples. This accession number contains the data for families 1-5 plus 7 in the article. Supplementary files linked below. The region of interest on chromosome 20 was found using families 1 and 2. The patients in families 3,4 and 5 were then recruited and the patients were homozygous for the same region on chromosome 20 as those in families 1 and 2, showing that all these patients are distantly related. All affected are homozygous for the same mutation. The rest of the chromosomes fall outside the scope of our study. Mutations in ABHD12 Cause the Neurodegenerative Disease PHARC: An Inborn Error of Endocannabinoid Metabolism, Fiskerstrand et al. The American Journal of Human Genetics, 26 August 2010 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B8JDD-50W2K9M-3&_user=6129429&_coverDate=08%2F26%2F2010&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000000150&_version=1&_urlVersion=0&_userid=6129429&md5=234296648f66debd3e2b08e795f2179f
2010-08-26 | E-GEOD-23151 | biostudies-arrayexpress
Project description:PHARC is a neurodegenerative disease comprising early onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems; including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyse 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behaviour and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects.
2010-08-27 | GSE23151 | GEO