1,721,024 research outputs found
Anandamide increases swelling and reduces calcium sensitivity of mitochondria
No full textThe endocannabinoid anandamide alters mitochondria-dependent signal transduction, thus controlling key cellular events like energy homeostasis and induction of apoptosis. Here, the ability of anandamide to directly affect the integrity of mitochondria was investigated on isolated organelles. We found that anandamide dose-dependently increases mitochondrial swelling, and reduces cytochrome c release induced by calcium ions. The effects of anandamide were independent of its target receptors (e.g., cannabinoid or vanilloid receptors), and were paralleled by decreased membrane potential and increased membrane fluidity. Overall, our data suggest that anandamide can impact mitochondrial physiology, by reducing calcium sensitivity and perturbing membrane properties of these organelles.[...
Endocannabinoids as biomarkers of human reproduction.
Full text linkInfertility is a condition of the reproductive system that affects ∼10-15% of couples attempting to conceive a baby. More than half of all cases of infertility are a result of female conditions, while the remaining cases can be attributed to male factors, or to a combination of both. The search for suitable biomarkers of pregnancy outcome is a challenging issue in human reproduction, aimed at identifying molecules with predictive significance of the reproductive potential of male and female gametes. Among the various candidates, endocannabinoids (eCBs), and in particular anandamide (AEA), represent potential biomarkers of human fertility disturbances. Any perturbation of the balance between synthesis and degradation of eCBs will result in local changes of their tone in human female and male reproductive tracts, which in turn regulates various pathophysiological processes, oocyte and sperm maturation included.METHODSPubMed and Web of Science databases were searched for papers using relevant keywords like 'biomarker', 'endocannabinoid', 'infertility', 'pregnancy' and 'reproduction'.RESULTSIn this review, we discuss different studies on the measurements of AEA and related eCBs in human reproductive cells, tissues and fluids, where the local contribution of these bioactive lipids could be critical in ensuring normal sperm fertilizing ability and pregnancy.CONCLUSIONBased on the available data, we suggest that the AEA tone has the potential to be exploited as a novel diagnostic biomarker of infertility, to be used in association with assays of conventional hormones (e.g. progesterone, β-chorionic gonadotrophin) and semen analysis. However further quantitative research of its predictive capacity is required
The endocannabinoid system in gp120-mediated insults and HIV-associated dementia
No full textEndocannabinoids (eCBs) include a group of lipid mediators that act as endogenous agonists at cannabinoid (CB(1), CB(2)) and vanilloid (TRPV1) receptors. In the last two decades a number of eCBs-metabolizing enzymes have been discovered that, together with eCBs and congeners, target receptors and proteins responsible for their transport and intracellular trafficking form the so-called "endocannabinoid system" (ECS). Within the central nervous system ECS elements participate in neuroprotection against neuroinflammatory/neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. More recently, a role for eCBs has been documented also in human immunodeficiency virus-1 (HIV-1) envelope glycoprotein gp120-mediated insults, and in HIV-associated dementia (HAD). The modulation of ECS in the latter disease conditions is the subject of this review, that will also address the molecular mechanisms underlying the neuroprotective effects of eCBs. In particular, the interactions between neurons and glia during neuroinflammation, and the alterations of ECS in these cells upon gp120 insults and HAD will be discussed, along with the potential therapeutic exploitation of ECS-oriented drugs for the treatment of HAD and related disorders
Neuroprotection by (endo)cannabinoids in glaucoma and retinal neurodegenerative diseases
No full textAbstract: Background: Emerging neuroprotective strategies are being explored to preserve
the retina from degeneration, that occurs in eye pathologies like glaucoma, diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosa. Incidentally, neuroprotection of retina is a defending mechanism designed to prevent or delay neuronal cell death, and to maintain neural function following an initial insult, thus avoiding loss of vision. Methods: Numerous studies have investigated potential neuroprotective properties of plant-derived phytocannabinoids, as well as of their endogenous counterparts collectively termed endocannabinoids (eCBs), in several degenerative diseases of the retina. eCBs are a group of neuromodulators that, mainly by activating G protein-coupled type-1 and type-2 cannabinoid (CB1 and CB2) receptors, trigger multiple signal transduction cascades that modulate central and peripheral cell functions. A fine balance between biosynthetic and degrading enzymes that control the right concentration of eCBs has been shown to provide neuroprotection in traumatic, ischemic, inflammatory and neurotoxic damage of the brain. Results: Since the existence of eCBs and their binding receptors was documented in the retina of numerous species (from fishes to primates), their involvement in the visual processing has been demonstrated, more recently with a focus on retinal neurodegeneration and neuroprotection. Conclusion: The aim of this review is to present a modern view of the endocannabinoid system, in order to discuss in a better perspective available data from preclinical studies on the use of eCBs as new neuroprotective agents, potentially useful to prevent glaucoma and retinal neurodegenerative diseases
Activity of anandamide (AEA) metabolic enzymes in rat placental bed
No full textEndocannabinoids are endogenous lipid mediators, with anandamide (AEA) being the first member identified. It is now widely accepted that AEA influences early pregnancy events and its levels, which primarily depend on its synthesis by an N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and degradation by a fatty acid amide hydrolase (FAAH), must be tightly regulated. Previous studies demonstrated that AEA levels require in situ regulation of these respective metabolic enzymes, and thus, any disturbance in AEA levels may impact maternal remodeling processes occurring during placental development. In this study, the activities of the AEA-metabolic enzymes that result in the establishment of proper local AEA levels during rat gestation were examined. Here, we demonstrate that during placentation NAPE-PLD and FAAH activities change in a temporal manner. Our findings suggest that NAPE-PLD and FAAH create the appropriate AEA levels required for tissue remodeling in the placental bed, a process essential to pregnancy maintenance
ANXIOLYTIC LIKE PROPERTIES OF ST4070 A NOVEL, POTENT AND SELECTIVE REVERSIBLE INHIBITOR OF FAAH
No full textIntroduction: Current management of anxiety, a common and debilitating disorder with a high social and personal cost, is far from satisfactory. Therefore, in the last years an urgent need for novel pharmacological approaches has emerged. One such strategy involves targeting the endocannabinoid system (ECS), and there is now considerable evidence for the central role played by ECS in coping with the regulation of stress and emotions. More recently, attention has moved from directly targeting type-1 cannabinoid (CB1) receptors to indirectly enhancing the content of their endogenous ligands, a more valuable strategy that preserves the spatiotemporal specificity of endocannabinoid activity. Despite recent evidence suggesting the benefits of inhibiting fatty acid amide hydrolase (FAAH), the enzyme that degradates the endogenous CB1 agonist arachidonoylethanolamide (anandamide), further research is needed to demonstrate the therapeutic efficacy of FAAH inhibitors, and their putative translation into the clinic. Methods: ST4070, a novel, potent and selective reversible inhibitor of FAAH, was administered per os in CD1 male mice (3 to 30 mg/10 ml/kg), that were tested in the elevated-plus maze, and in Wistar male rats (3 to 30 mg/2.5 ml/kg), that were tested in the light-dark apparatus. In addition, the effect of ST4070 on FAAH activity and on the content of FAAH substrates (anandamide and palmitoylethanolamide) in selected brain regions was assessed by radiochromatography and LC-MS analysis. Results: ST4070 showed clear anxiolytic-like properties in both rodent models, and in parallel it also produced a clear inhibition of FAAH activity, and a significant increase of anandamide and palmitoylethanolamide in behaviorally-relevant brain regions. Conclusions: Investigation into novel pharmacological targets for the management of anxiety holds the promise to further our understanding of its aetiology, and to develop new and more effective anxiolytic drugs, like the reversible FAAH inhibitor ST4070. [...
Carotid Body as a model for aging studies: is there a link between oxygen and aging ?
No full textThe carotid body (CB) is the site in the body that triggers awareness of changes in blood oxygen pressure. Aging is characterized by a decrease in oxygen supply to tissues, in reduction of tissue Po2, and in the activity of several enzymes and metabolic factors. The ventilatory response to hypoxia is attenuated with aging related to the age-dependent structure modifications including the basal reduction of oxygen requirements. The aged CB shows an increase in extracellular matrix, a reduction in number and volume of type I cells, and a reduction in volume of mitochondria that was consistent with and similar to that during chronic hypoxia; this phenomenon seems to operate also during aging as shown by the reduced volume of mitochondria in the aged CB. During chronic hypoxia, CB hypertrophy is less evident in aged CB than in young CB. Therefore, hypoxia and aging seem to share some type of link at different cell sites. CB represents an experimental model adequate for studying aging processes because of its high blood flow and metabolism, and thus it serves as a means to understanding the oxygen modulation of the aging process
Effect of RNAlater on lipoxygenase activity and expression, and immune cell apoptosis: opening the gate to the "ROALD" experiment aboard the space shuttle
No full textDetailed characterization of the endocannabinoid system in human macrophages and foam cells, and anti-inflammatory role of type-2 cannabinoid receptor.
No full textOBJECTIVE:
Cannabinoid receptors are activated in murine macrophages upon exposure to oxidized low-density lipoproteins (oxLDL), and type-1 cannabinoid receptor (CB1R) is considered as a risk factor in atherosclerosis, because it promotes cholesterol accumulation and release of inflammatory mediators. Conversely, accumulated evidence suggests a protective role for type-2 cannabinoid receptor (CB2R). Here, we sought to ascertain whether different elements of the endocannabinoid system (ECS) were activated in human lipid-laden macrophages, and whether CB2R played any role in atherogenesis and inflammation of these cells.
METHODS AND RESULTS:
Human macrophages were exposed to oxLDL in order to obtain lipid-laden foam cells. Liquid chromatography/mass spectrometry (LC/MS) was used to measure the production of the endocannabinoids in both macrophages and foam cells, and radiometric assays were performed to measure cannabinoid receptor binding and activity of endocannabinoid metabolizing enzymes. OxLDL accumulation was investigated by confocal imaging, and cytokine production and release were measured by means of flow cytometry and ELISA. The results showed that human macrophages possess a fully functional ECS, which was modulated by oxLDL. Selective CB2R activation reduced cellular oxLDL accumulation, which was associated with decreased expression of CD36 scavenger receptor, and decreased production of TNFα, IL-12 and IL-10. These anti-atherogenic and anti-inflammatory effects were reverted by the selective CB2R antagonist SR144528.
CONCLUSIONS:
A fully active ECS is present in human macrophages and macrophage-derived foam cells. Selective activation of CB2R reduces CD36-dependent oxLDL accumulation and modulates production of inflammatory cytokines, thus representing a potential therapeutic strategy to combat atherosclerosis
Regulation of female fertility by the endocannabinoid system
No full textThe role of endocannabinoids in mammalian reproduction is an emerging concept. Cannabinoids have been always identified as being harmful drugs, because of their negative effects on female reproduction. The discovery of endocannabinoids, endogenous lipids that bind to cannabinoid receptors, and of their involvement in procreation permitted better understanding of the significance of cannabinoid/endocannabinoid signalling in fertilization, preimplantation embryo development, implantation and postimplantation embryonic growth. These studies have also opened new perspectives in clinical applications, pointing to endocannabinoid signalling as a new target for correcting infertility, and for improving reproductive health in humans. This review will present endocannabinoids, their target receptors and metabolic enzymes, and will discuss the involvement of these bioactive lipids in female mammalian reproduction
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