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1.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500646

RESUMO

Arachidonylethanolamide (anandamide) acts as an endogenous ligand of cannabinoid receptors, while other N-acylethanolamines (NAEs), such as palmitylethanolamide and oleylethanolamide, show analgesic, anti-inflammatory, and appetite-suppressing effects through other receptors. In mammalian tissues, NAEs, including anandamide, are produced from glycerophospholipid via N-acyl-phosphatidylethanolamine (NAPE). The ɛ isoform of cytosolic phospholipase A2 (cPLA2) functions as an N-acyltransferase to form NAPE. Since the cPLA2 family consists of six isoforms (α, ß, γ, δ, ɛ, and ζ), the present study investigated a possible involvement of isoforms other than ɛ in the NAE biosynthesis. Firstly, when the cells overexpressing one of the cPLA2 isoforms were labeled with [14C]ethanolamine, the increase in the production of [14C]NAPE was observed only with the ɛ-expressing cells. Secondly, when the cells co-expressing ɛ and one of the other isoforms were analyzed, the increase in [14C]N-acyl-lysophosphatidylethanolamine (lysoNAPE) and [14C]NAE was seen with the combination of ɛ and γ isoforms. Furthermore, the purified cPLA2γ hydrolyzed not only NAPE to lysoNAPE, but also lysoNAPE to glycerophospho-N-acylethanolamine (GP-NAE). Thus, the produced GP-NAE was further hydrolyzed to NAE by glycerophosphodiesterase 1. These results suggested that cPLA2γ is involved in the biosynthesis of NAE by its phospholipase A1/A2 and lysophospholipase activities.


Assuntos
Etanolaminas/metabolismo , Fosfolipases A2/metabolismo , Isoformas de Proteínas/metabolismo , Aciltransferases/metabolismo , Amidas/metabolismo , Animais , Ácidos Araquidônicos/metabolismo , Linhagem Celular , Endocanabinoides/metabolismo , Etanolamina/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Oleicos/metabolismo , Ácidos Palmíticos/metabolismo , Fosfatidiletanolaminas/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Alcamidas Poli-Insaturadas/metabolismo
2.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299330

RESUMO

The ability of endocannabinoid (eCB) to change functional microglial phenotype can be explored as a possible target for therapeutic intervention. Since the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA), may provide beneficial effects in mice model of Alzheimer's disease (AD)-like pathology, we aimed at determining whether the FAAH inhibitor URB597 might target microglia polarization and alter the cytoskeleton reorganization induced by the amyloid-ß peptide (Aß). The morphological evaluation showed that Aß treatment increased the surface area of BV-2 cells, which acquired a flat and polygonal morphology. URB597 treatment partially rescued the control phenotype of BV-2 cells when co-incubated with Aß. Moreover, URB597 reduced both the increase of Rho protein activation in Aß-treated BV-2 cells and the Aß-induced migration of BV-2 cells, while an increase of Cdc42 protein activation was observed in all samples. URB597 also increased the number of BV-2 cells involved in phagocytosis. URB597 treatment induced the polarization of microglial cells towards an anti-inflammatory phenotype, as demonstrated by the decreased expression of iNOS and pro-inflammatory cytokines along with the parallel increase of Arg-1 and anti-inflammatory cytokines. Taken together, these data suggest that FAAH inhibition promotes cytoskeleton reorganization, regulates phagocytosis and cell migration processes, thus driving microglial polarization towards an anti-inflammatory phenotype.


Assuntos
Amidoidrolases/antagonistas & inibidores , Benzamidas/farmacologia , Carbamatos/farmacologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amidoidrolases/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Animais , Ácidos Araquidônicos/metabolismo , Linhagem Celular , Movimento Celular/fisiologia , Polaridade Celular/fisiologia , Citocinas/metabolismo , Citoesqueleto/metabolismo , Modelos Animais de Doenças , Endocanabinoides/metabolismo , Camundongos , Microglia/patologia , Alcamidas Poli-Insaturadas/metabolismo
3.
Eur J Endocrinol ; 185(2): 231-239, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34061772

RESUMO

Objective: Patients with craniopharyngioma (CP) frequently suffer from morbid obesity. Endocannabinoids (ECs) are involved in weight gain and rewarding behavior but have not been investigated in this context. Design: Cross-sectional single-center study. Methods: Eighteen patients with CP and 16 age- and sex-matched controls were included. Differences in endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and endocannabinoid-like molecules (oleoyl ethanolamide (OEA), palmitoylethanolamide (PEA), and arachidonic acid (AA) were measured at baseline and following endurance exercise. We further explored ECs-dynamics in relation to markers of HPA-axis activity (ACTH, cortisol, copeptin) and hypothalamic damage. Results: Under resting conditions, independent of differences in BMI, 2-AG levels were more than twice as high in CP patients compared to controls. In contrast, 2-AG and OEA level increased in response to exercise in controls but not in CP patients, while AEA levels decreased in controls. As expected, exercise increased ACTH and copeptin levels in controls only. In a mixed model analysis across time and group, HPA measures did not provide additional information for explaining differences in 2-AG levels. However, AEA levels were negatively influenced by ACTH and copeptin levels, while OEA levels were negatively predicted by copeptin levels only. There were no significant differences in endocannabinoids depending on hypothalamic involvement. Conclusion: Patients with CP show signs of a dysregulated endocannabinoid system under resting conditions as well as following exercise in comparison to healthy controls. Increased 2-AG levels under resting conditions and the missing response to physical activity could contribute to the metabolic phenotype of CP patients.


Assuntos
Craniofaringioma , Endocanabinoides/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Neoplasias Hipofisárias , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Ácido Araquidônico/metabolismo , Ácidos Araquidônicos/metabolismo , Estudos de Casos e Controles , Craniofaringioma/metabolismo , Craniofaringioma/fisiopatologia , Estudos Transversais , Treino Aeróbico , Exercício Físico/fisiologia , Feminino , Glicerídeos/metabolismo , Glicopeptídeos/metabolismo , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Hipotálamo/patologia , Hipotálamo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ácidos Oleicos/metabolismo , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/fisiopatologia , Alcamidas Poli-Insaturadas/metabolismo , Adulto Jovem
4.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067475

RESUMO

Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents, AKI can be effectively prevented through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans), longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, particularly arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.


Assuntos
Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Endocanabinoides/metabolismo , Adulto , Idoso , Animais , Ácidos Araquidônicos/metabolismo , Caenorhabditis elegans/metabolismo , Restrição Calórica/métodos , Modelos Animais de Doenças , Feminino , Humanos , Rim/metabolismo , Longevidade/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Alcamidas Poli-Insaturadas/metabolismo , Traumatismo por Reperfusão/metabolismo
5.
Molecules ; 26(7)2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917316

RESUMO

The cannabinoid system is independently affected by stress and chronic ethanol exposure. However, the extent to which co-occurrence of traumatic stress and chronic ethanol exposure modulates the cannabinoid system remains unclear. We examined levels of cannabinoid system components, anandamide, 2-arachidonoylglycerol, fatty acid amide hydrolase, and monoacylglycerol lipase after mouse single-prolonged stress (mSPS) or non-mSPS (Control) exposure, with chronic intermittent ethanol (CIE) vapor or without CIE vapor (Air) across several brain regions using ultra-high-performance liquid chromatography tandem mass spectrometry or immunoblotting. Compared to mSPS-Air mice, anandamide and 2-arachidonoylglycerol levels in the anterior striatum were increased in mSPS-CIE mice. In the dorsal hippocampus, anandamide content was increased in Control-CIE mice compared to Control-Air, mSPS-Air, or mSPS-CIE mice. Finally, amygdalar anandamide content was increased in Control-CIE mice compared to Control-Air, or mSPS-CIE mice, but the anandamide content was decreased in mSPS-CIE compared to mSPS-Air mice. Based on these data we conclude that the effects of combined traumatic stress and chronic ethanol exposure on the cannabinoid system in reward pathway regions are driven by CIE exposure and that traumatic stress affects the cannabinoid components in limbic regions, warranting future investigation of neurotherapeutic treatment to attenuate these effects.


Assuntos
Canabinoides/metabolismo , Etanol/efeitos adversos , Sistema Límbico/metabolismo , Recompensa , Transtornos de Estresse Pós-Traumáticos/metabolismo , Amidoidrolases/metabolismo , Animais , Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Monoacilglicerol Lipases/metabolismo , Alcamidas Poli-Insaturadas/metabolismo
6.
Clin Sci (Lond) ; 135(1): 185-200, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33393630

RESUMO

Obesity is believed to be associated with a dysregulated endocannabinoid system which may reflect enhanced inflammation. However, reports of this in human white adipose tissue (WAT) are limited and inconclusive. Marine long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) have anti-inflammatory actions and therefore may improve obesity-associated adipose tissue inflammation. Therefore, fatty acid (FA) concentrations, endocannabinoid concentrations, and gene expression were assessed in subcutaneous WAT (scWAT) biopsies from healthy normal weight individuals (BMI 18.5-25 kg/m2) and individuals living with metabolically healthy obesity (BMI 30-40 kg/m2) prior to and following a 12-week intervention with 3 g fish oil/day (1.1 g eicosapentaenoic acid (EPA) + 0.8 g DHA) or 3 g corn oil/day (placebo). WAT from individuals living with metabolically healthy obesity had higher n-6 PUFAs and EPA, higher concentrations of two endocannabinoids (anandamide (AEA) and eicosapentaenoyl ethanolamide (EPEA)), higher expression of phospholipase A2 Group IID (PLA2G2D) and phospholipase A2 Group IVA (PLA2G4A), and lower expression of CNR1. In response to fish oil intervention, WAT EPA increased to a similar extent in both BMI groups, and WAT DHA increased by a greater extent in normal weight individuals. WAT EPEA and docosahexaenoyl ethanolamide (DHEA) increased in normal weight individuals only and WAT 2-arachidonyl glycerol (2-AG) decreased in individuals living with metabolically healthy obesity only. Altered WAT fatty acid, endocannabinoid, and gene expression profiles in metabolically healthy obesity at baseline may be linked. WAT incorporates n-3 PUFAs when their intake is increased which affects the endocannabinoid system; however, effects appear greater in normal weight individuals than in those living with metabolically healthy obesity.


Assuntos
Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Endocanabinoides/metabolismo , Obesidade Metabolicamente Benigna/tratamento farmacológico , Gordura Subcutânea/efeitos dos fármacos , Adolescente , Adulto , Ácidos Araquidônicos/metabolismo , Método Duplo-Cego , Combinação de Medicamentos , Inglaterra , Feminino , Fosfolipases A2 do Grupo II/metabolismo , Fosfolipases A2 do Grupo IV/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Metabolicamente Benigna/diagnóstico , Obesidade Metabolicamente Benigna/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Gordura Subcutânea/metabolismo , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
7.
Pharm Dev Technol ; 26(1): 69-80, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33059499

RESUMO

Piper species is one of the most widely consumed spices for culinary purposes. Piperine (PIP) present in Piper species has a wide range of therapeutic activity including hepatoprotection. However, the major biological limitation of PIP is its low bioavailability after oral administration. Purpose of the study was to prepare an optimized and adequately characterized PIP-phospholipid complex (PPC) as a delivery system to overcome these limitations and to investigate the pharmacokinetics and hepato-protectivity of the formulation in the animal model. Response surface methodology was adopted to optimize the process parameters for PPC preparation. FT-IR, DTA, PXRD, SEM, molecular docking etc. were used for characterization. Solubility, log P, dissolution efficiency and in vivo pharmacokinetics were also investigated. PPC showed enhanced hepatoprotective potential as compared to pure PIP at the same dose level (25 and 50 mg/kg). PPC restored the levels of serum marker and antioxidant enzymes. PPC also increased the bioavailability of PIP in rat serum by 10.40-fold in comparison with pure PIP at the same dose level and enhanced the elimination half-life (t1/2 el) from 0.477 ± 1.76 to 9.80 ± 1.98 h. Results concluded that PPC enhanced the hepatoprotection of PIP which may be due to the improved bioavailability and pharmacokinetics of PIP in rats.


Assuntos
Alcaloides/administração & dosagem , Alcaloides/metabolismo , Benzodioxóis/administração & dosagem , Benzodioxóis/metabolismo , Fígado/metabolismo , Fosfolipídeos/administração & dosagem , Fosfolipídeos/metabolismo , Piperidinas/administração & dosagem , Piperidinas/metabolismo , Alcamidas Poli-Insaturadas/administração & dosagem , Alcamidas Poli-Insaturadas/metabolismo , Alcaloides/síntese química , Animais , Benzodioxóis/síntese química , Disponibilidade Biológica , Fígado/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular/métodos , Fosfolipídeos/síntese química , Piperidinas/síntese química , Alcamidas Poli-Insaturadas/síntese química , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/síntese química , Substâncias Protetoras/metabolismo , Ratos , Ratos Wistar
8.
Int J Mol Sci ; 22(1)2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33379212

RESUMO

The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the ventral tegmental area (VTA) and the nucleus accumbens (NAC) (reward/reinforcement). The significant mutual interaction between these systems in food intake has been documented; however, the possible role of ghrelin/GHS-R1A in the cannabinoid reinforcement effects and addiction remain unclear. Therefore, the principal aim of the present study was to investigate whether pretreatment with GHS-R1A antagonist/JMV2959 could reduce the CB1R agonist/WIN55,212-2-induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. The synthetic aminoalklylindol cannabinoid WIN55,212-2 administration into the posterior VTA induced significant accumbens dopamine release, which was significantly reduced by the 3 mg/kg i.p. JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by the JMV2959 pretreament. The intracerebral WIN55,212-2 administration also increased the endocannabinoid arachidonoylethanolamide/anandamide and the 2-arachidonoylglycerol/2-AG extracellular levels in the NACSh, which was moderately but significantly attenuated by the JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens γ-aminobutyric acid/gamma-aminobutyric acid levels was reversed by the JMV2959 pretreatment. The behavioural study in the LABORAS cage showed that 3 mg/kg JMV2959 pretreatment also significantly reduced the systemic WIN55,212-2-induced behavioural stimulation. Our results demonstrate that the ghrelin/GHS-R1A system significantly participates in the rewarding/reinforcing effects of the cannabinoid/CB1 agonist that are involved in cannabinoid addiction processing.


Assuntos
Benzoxazinas/administração & dosagem , Dopamina/metabolismo , Grelina/metabolismo , Glicina/análogos & derivados , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Triazóis/administração & dosagem , Animais , Ácidos Araquidônicos/metabolismo , Avaliação Pré-Clínica de Medicamentos , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Glicina/administração & dosagem , Masculino , Núcleo Accumbens/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Ratos Wistar , Ácido gama-Aminobutírico/metabolismo
9.
Int J Mol Sci ; 21(19)2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33023013

RESUMO

BACKGROUND: Cannabinoids induce biphasic effects on memory depending on stress levels. We previously demonstrated that different stress intensities, experienced soon after encoding, impaired rat short-term recognition memory in a time-of-day-dependent manner, and that boosting endocannabinoid anandamide (AEA) levels restored memory performance. Here, we examined if two different stress intensities and time-of-day alter hippocampal endocannabinoid tone, and whether these changes modulate short-term memory. METHODS: Male Sprague-Dawley rats were subjected to an object recognition task and exposed, at two different times of the day (i.e., morning or afternoon), to low or high stress conditions, immediately after encoding. Memory retention was assessed 1 hr later. Hippocampal AEA and 2-arachidonoyl glycerol (2-AG) content and the activity of their primary degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), were measured soon after testing. RESULTS: Consistent with our previous findings, low stress impaired 1-hr memory performance only in the morning, whereas exposure to high stress impaired memory independently of testing time. Stress exposure decreased AEA levels independently of memory alterations. Interestingly, exposure to high stress decreased 2-AG content and, accordingly, increased MAGL activity, selectively in the afternoon. Thus, to further evaluate 2-AG's role in the modulation of short-term recognition memory, rats were given bilateral intra-hippocampal injections of the 2-AG hydrolysis inhibitor KML29 immediately after training, then subjected to low or high stress conditions and tested 1 hr later. CONCLUSIONS: KML29 abolished the time-of-day-dependent impairing effects of stress on short-term memory, ameliorating short-term recognition memory performance.


Assuntos
Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Hipocampo/metabolismo , Memória de Curto Prazo/fisiologia , Amidoidrolases/genética , Animais , Ácidos Araquidônicos/antagonistas & inibidores , Ácidos Araquidônicos/genética , Benzodioxóis/farmacologia , Emoções/fisiologia , Endocanabinoides/antagonistas & inibidores , Endocanabinoides/genética , Glicerídeos/antagonistas & inibidores , Glicerídeos/genética , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Masculino , Monoacilglicerol Lipases/genética , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genética
10.
Int J Mol Sci ; 21(19)2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33036283

RESUMO

Osteoarthritis (OA) is a degenerative joint disease manifested by movement limitations and chronic pain. Endocannabinoid system (ECS) may modulate nociception via cannabinoid and TRPV1 receptors. The purpose of our study was to examine alterations in the spinal and joint endocannabinoid system during pain development in an animal model of OA. Wistar rats received intra-articular injection of 3mg of sodium monoiodoacetate (MIA) into the knee joint. Animals were sacrificed on day 2, 7, 14, 21, 28 after injection and lumbar spinal cord, cartilage and synovium were collected. Changes in the transcription levels of the ECS elements were measured. At the spinal level, gene expression levels of the cannabinoid and TRPV1 receptors as well as enzymes involved in anandamide synthesis and degradation were elevated in the advanced OA phase. In the joint, an important role of the synovium was demonstrated, since cartilage degeneration resulted in attenuation of the changes in the gene expression. Enzymes responsible for anandamide synthesis and degradation were upregulated particularly in the early stages of OA, presumably in response to early local joint inflammation. The presented study provides missing information about the MIA-induced OA model and encourages the development of a therapy focused on the molecular role of ECS.


Assuntos
Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Osteoartrite/metabolismo , Dor/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Ácidos Araquidônicos/genética , Modelos Animais de Doenças , Progressão da Doença , Endocanabinoides/genética , Regulação da Expressão Gênica , Injeções Intra-Articulares , Ácido Iodoacético/efeitos adversos , Ácido Iodoacético/toxicidade , Articulação do Joelho/metabolismo , Osteoartrite/complicações , Osteoartrite/genética , Dor/etiologia , Dor/genética , Ratos , Ratos Wistar , Canais de Cátion TRPV/genética
11.
Int J Mol Sci ; 21(19)2020 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-32992491

RESUMO

Different Follicle Stimulating Hormone (FSH) formulation and Luteinizing Hormone (LH) are used in Assisted Reproductive Technology (ART) to induce follicles development and oocytes maturation, but it is still under debate which protocol is to be preferred. In the present study, the different effects on cumulus cells (CCs) of three controlled ovarian stimulation (COS) protocols, based on urinary FSH, recombinant FSH, or human Menopausal Gonadotropin (hMG) administration, were assessed. CCs were obtained from 42 normal-responders women undergoing COS, randomly divided into three groups according to the used gonadotropin formulation. Differences were found in the expression of genes belonging to the endocannabinoid system (the receptors CNR1, CNR2 and TRPV1, and the enzymes involved in the metabolisms of anandamide, NAPE-PLD and FAAH, and 2-acylglycerol, DAGL and MAGL); consistently, changes in lipid (PPARα, and FASN) and carbohydrate (GLUT1 and GLUT9) metabolisms, in CCs' macromolecules composition (highlighted by Fourier Transform Infrared Microspectroscopy, FTIRM), and in the number of retrieved oocytes were found. For the first time, statistically significant evidence on the differences related to each COS protocol on the endocannabinoid system, metabolism and macromolecular composition of CCs was found, representing a proof of concept to be further confirmed in a larger cohort of patients.


Assuntos
Células do Cúmulo/efeitos dos fármacos , Células do Cúmulo/metabolismo , Endocanabinoides/metabolismo , Hormônio Foliculoestimulante Humano/farmacologia , Menotropinas/farmacologia , Indução da Ovulação/métodos , Transdução de Sinais/efeitos dos fármacos , Urofolitropina/farmacologia , Adulto , Ácidos Araquidônicos/genética , Ácidos Araquidônicos/metabolismo , Células Cultivadas , Estudos de Coortes , Endocanabinoides/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Recuperação de Oócitos , Alcamidas Poli-Insaturadas/metabolismo , Proteínas Recombinantes/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
12.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1865(12): 158807, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32829065

RESUMO

Cannabis use has been increasing worldwide for recreational and medical purposes. Consumption by pregnant women is associated with disturbances in pregnancy outcome, such as low birth weight, prematurity and intrauterine growth retardation, though the underlying biochemical mechanisms are unknown. The endocannabinoid system is involved in several reproductive events and the disruption of its homeostasis by ∆9-tetrahydrocannabinol (THC), the main psychoactive cannabinoid, may lead to a negative gestational outcome. In human placenta, THC impairs the levels of the endocannabinoid anandamide (AEA). The other major endocannabinoid, 2-arachidonoylglycerol (2-AG) also plays an important role on proper placentation and pregnancy success. However, THC impact on 2-AG homeostasis has never been addressed. Hence, the effects of THC in 2-AG levels and metabolic enzymes expression were explored. Long-term treatment impairs the expression of the main 2-AG synthetic and degradative enzymes. Curiously, with the highest concentration, despite the maintenance of diacylglycerol lipase alpha (DAGLα) and the decrease in monoacylglycerol lipase (MAGL) expression, 2-AG levels remain constant. Given the endocannabinoid signalling local tight regulation, we hypothesize the involvement of other 2-AG degradative enzymes. Indeed, THC increases the expression of the hydrolyzing enzymes alpha beta hydrolase domain-6 (ABHD6) and -12 (ABHD12), that we firstly describe in human placental tissues. The results show that THC, depending on time of exposure, induces alterations in 2-AG metabolic enzymes expression in placental explants, highlighting the importance of 2-AG regulation and endocannabinoid signalling in placental development. Alterations in this homeostasis may explain the negative pregnancy outcome related to cannabis consumption.


Assuntos
Dronabinol/farmacologia , Endocanabinoides/metabolismo , Monoacilglicerol Lipases/metabolismo , Placenta/efeitos dos fármacos , Psicotrópicos/farmacologia , Ácidos Araquidônicos/metabolismo , Feminino , Glicerídeos/metabolismo , Humanos , Placenta/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Gravidez
13.
Essays Biochem ; 64(3): 485-499, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32648908

RESUMO

Thirty years ago, the discovery of a cannabinoid (CB) receptor that interacts with the psychoactive compound in Cannabis led to the identification of anandamide, an endogenous receptor ligand or endocannabinoid. Research on endocannabinoids has since exploded, and additional receptors along with their lipid mediators and signaling pathways continue to be revealed. Specifically, in humans, the release of endocannabinoids from membrane lipids occurs on demand and the signaling process is rapidly attenuated by the breakdown of the ligand suggesting a tight regulation of the endocannabinoid system (ECS). Additionally, the varying distribution of CB receptors between the central nervous system and other tissues allows for the ECS to participate in a wide range of cognitive and physiological processes. Select plant-derived 'phyto'cannabinoids such as Δ-9-tetrahydrocannabinol (Δ9-THC) bind to the CB receptors and trigger the ECS, and in the case of Δ9-THC, while it has therapeutic value, can also produce detrimental effects. Current research is aimed at the identification of additional phytocannabinoids with minimal psychotropic effects with potential for therapeutic development. Although decades of research on the ECS and its components have expanded our understanding of the mechanisms and implications of endocannabinoid signaling in mammals, it continues to evolve. Here, we provide a brief overview of the ECS and its overlap with other related lipid-mediated signaling pathways.


Assuntos
Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Animais , Cannabis/química , Sistema Nervoso Central/metabolismo , Dronabinol/metabolismo , Humanos , Ligantes , Extratos Vegetais/metabolismo , Transdução de Sinais
14.
Nutrients ; 12(6)2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32599787

RESUMO

Black pepper (Piper nigrum L.) has been employed in medicine (epilepsy, headaches, and diabetes), where its effects are mainly attributed to a nitrogen alkaloid called piperidine (1-(1-[1,3-benzodioxol-5-yl]-1-oxo-2,4 pentenyl) piperidine). Piperine co-administered with vitamins and minerals has improved its absorption. Therefore, this study aimed to describe the impact of the joint administration of iron (Fe) plus black pepper in physically active healthy individuals. Fe is a micronutrient that aids athletic performance by influencing the physiological functions involved in endurance sports by improving the transport, storage, and utilization of oxygen. Consequently, athletes have risk factors for Fe depletion, Fe deficiency, and eventually, anemia, mainly from mechanical hemolysis, gastrointestinal disturbances, and loss of Fe through excessive sweating. Declines in Fe stores have been reported to negatively alter physical capacities such as aerobic capacity, strength, and skeletal muscle recovery in elite athletes. Thus, there is a need to maintain Fe storage, even if Fe intake meets the recommended daily allowance (RDA), and Fe supplementation may be justified in physically active individuals, in states of Fe deficiency, with or without anemia. Females, in particular, should monitor their Fe hematological profile. The recommended oral Fe supplements are ferrous or ferric salts, sulfate, fumarate, and gluconate. These preparations constitute the first line of treatment; however, the high doses administered have gastrointestinal side effects that reduce tolerance and adherence to treatment. Thus, a strategy to counteract these adverse effects is to improve the bioavailability of Fe. Therefore, piperine may benefit the absorption of Fe through its bioavailability enhancement properties. Three research studies of Fe associated with black pepper have reported improvements in parameters related to the metabolism of Fe, without adverse effects. Although more research is needed, this could represent an advance in oral Fe supplementation for physically active individuals.


Assuntos
Alcaloides , Benzodioxóis , Ferro , Compostos Fitoquímicos , Piper nigrum , Piperidinas , Alcamidas Poli-Insaturadas , Alcaloides/efeitos adversos , Alcaloides/química , Alcaloides/metabolismo , Alcaloides/farmacocinética , Animais , Benzodioxóis/efeitos adversos , Benzodioxóis/química , Benzodioxóis/metabolismo , Benzodioxóis/farmacocinética , Disponibilidade Biológica , Suplementos Nutricionais , Exercício Físico , Humanos , Ferro/química , Ferro/metabolismo , Ferro/farmacocinética , Compostos Fitoquímicos/efeitos adversos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacocinética , Alcamidas Poli-Insaturadas/efeitos adversos , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/metabolismo , Alcamidas Poli-Insaturadas/farmacocinética , Ratos
15.
Sci Rep ; 10(1): 11134, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636441

RESUMO

The use of cannabinoids to treat fibrotic skin diseases is an emergent issue. Therefore, we aimed to evaluate systemic and skin endocannabinoid responses in the wound-healing process in humans. A prospective study was performed in 50 patients who underwent body-contouring surgery. Anandamide (N-arachidonoylethanolamine, AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were quantified using LC-MS/MS. Ten (20%) patients developed hypertrophic (HT) scars. No significant changes were observed between the normal (N) scar and HT scar groups in terms of plasma and skin endocannabinoids. Nevertheless, a positive correlation between plasma and skin AEA concentrations was found in the N group (r = 0.38, p = 0.015), which was absent in the HT group. Moreover, the AEA concentration was significantly lower in HT scar tissue than in normal scar tissue (0.77 ± 0.12 ng/g vs 1.15 ± 0.15 ng/g, p < 0.001). Interestingly, in all patients, the surgical intervention produced a time-dependent effect with a U shape for AEA, PEA and OEA plasma concentrations. In contrast, 2-AG plasma concentrations increased 5 days after surgery and were reduced and stabilized 3 months later. These results suggest crosstalk between systemic and local skin endocannabinoid systems during human wound healing. AEA appears to be the most likely candidate for this link, which is deficient in patients with HT scars.


Assuntos
Ácidos Araquidônicos/metabolismo , Cicatriz Hipertrófica/metabolismo , Endocanabinoides/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Pele/metabolismo , Cicatrização , Adulto , Idoso , Contorno Corporal/efeitos adversos , Cicatriz/metabolismo , Etanolaminas/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Ferida Cirúrgica/metabolismo , Adulto Jovem
16.
Cell Rep ; 31(9): 107710, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32492422

RESUMO

Endocannabinoids protect against seizures, but their mechanism of action is still unclear, as they can have effects independent of known cannabinoid receptors. Using Drosophila melanogaster, which lacks canonical cannabinoid receptors, we report that the endocannabinoids anandamide and 2-arachidonoylglycerol protect against seizures in multiple fly seizure models. Surprisingly, inhibition of anandamide catabolism renders flies insensitive to protection by anandamide, indicating that anandamide metabolites are responsible for seizure protection. Consistent with this finding, arachidonic acid, a direct metabolite of anandamide, protects against seizures. To identify downstream effectors, we test for a role of transient receptor potential (TRP) channels and find that the TRPV1 antagonist capsazepine blocks the protective effect of anandamide. Also, a targeted genetic screen of TRP channels identifies water witch as a mediator of protection by anandamide. Using a Drosophila model, we reveal the role of arachidonic acid in seizure protection and identify a cannabinoid-receptor-1/2-independent mechanism of endocannabinoid seizure protection.


Assuntos
Anticonvulsivantes/uso terapêutico , Ácidos Araquidônicos/uso terapêutico , Proteínas de Drosophila/metabolismo , Endocanabinoides/uso terapêutico , Glicerídeos/uso terapêutico , Convulsões/prevenção & controle , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Ácidos Araquidônicos/metabolismo , Cálcio/metabolismo , Modelos Animais de Doenças , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Endocanabinoides/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Alcamidas Poli-Insaturadas/uso terapêutico , RNA Guia/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Convulsões/patologia , Canais de Potencial de Receptor Transitório/genética
17.
Pharmacol Biochem Behav ; 195: 172965, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32526217

RESUMO

As cannabinoid use among the adolescent population becomes widespread with recent legalizations, understanding more about its effects on the developing brain becomes increasingly important. Adolescent cannabinoid use has been shown to elicit both short and long lasting effects on cortical function, in part due to its impact on maturing brain regions including the prefrontal cortex and associated inputs. This paper provides an overview of current state of knowledge on the lasting impact of repeated cannabinoid exposure on behavior and associated neural circuits in adolescents compared to other age groups. Data obtained from human and rodent literature are integrated to discuss potential neural mechanisms underpinning the enduring negative impact of cannabinoid exposure during this sensitive period of brain development.


Assuntos
Atenção/efeitos dos fármacos , Cognição/efeitos dos fármacos , Dronabinol/farmacologia , Função Executiva/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Adolescente , Animais , Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Humanos , Alcamidas Poli-Insaturadas/metabolismo , Córtex Pré-Frontal/crescimento & desenvolvimento , Assunção de Riscos , Ácido gama-Aminobutírico/metabolismo
18.
Biochem Pharmacol ; 177: 114000, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32353424

RESUMO

Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an IC50 value of 0.88 µM. Isothermal titration calorimetry and thermofluor assay demonstrate the directly interaction between piperine and DHODH. The co-complex crystal structure of DHODH and piperine at 1.98 Å resolution further reveal that Tyr356 residue of DHODH is crucial for piperine binding. Importantly, we show that piperine can inhibit T cell overactivation in a DHODH-dependent manner in concanavalin A-triggered T-cell assay and mixed lymphocyte reaction assay. Finally, piperine exhibits strong preventive and therapeutic effect in the MOG-induced experimental allergic encephalomyelitis (EAE), a useful model for studying potential treatments for MS, by restricting inflammatory cells infiltration into the CNS and preventing myelin destruction and blood-brain barrier (BBB) disruption. Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system, and demonstrate a novel role for piperine in the treatment of MS.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/química , Alcaloides/metabolismo , Animais , Benzodioxóis/química , Benzodioxóis/metabolismo , Produtos Biológicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Cristalografia por Raios X , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Feminino , Humanos , Células Jurkat , Camundongos Endogâmicos C57BL , Modelos Moleculares , Terapia de Alvo Molecular , Bainha de Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidade , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Fragmentos de Peptídeos/toxicidade , Piperidinas/química , Piperidinas/metabolismo , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/metabolismo , Baço/citologia
19.
Pulm Pharmacol Ther ; 62: 101920, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32416152

RESUMO

Cannabinoids and the endocannabinoid system significantly contributes to the airway inflammation. Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are two main enzymes responsible for the metabolism of the endocannabinoids anandamide (AEA) and 2-arachydonoyl glycerol (2-AG), respectively. In the present study, we aimed to investigate the effects of local and systemic FAAH and MAGL inhibitor treatments in experimental airway inflammation and tracheal hyperreactivity in mice. Airway inflammation was induced by intranasal (i.n.) lipopolysaccharide (LPS) application (60 µl; 0,1 mg/ml in PBS) to mice and the control group received PBS. Systemic (intraperitoneal (i.p.)) or local (i.n.) FAAH inhibitor URB597 and MAGL inhibitor JZL184 treatments were administered 1h before LPS/PBS application. Fourty 8 h after LPS/PBS application, tracheas were removed to assess airway reactivity, and the lungs and bronchoalveolar lavage (BAL) fluids were isolated for histopathological evaluation, cytokine and endocannabinoid measurements. LPS application lead to an increase in 5-hydroxytryptamine (5-HT) contractions in isolated tracheal rings while carbachol contractions remained unchanged. The increased 5-HT contractions were prevented by both systemic and local URB597 and JZL184 treatments. Systemic treatment with URB597 and JZL184, and local treatment with JZL184 reduced peribronchial and paranchymal inflammation in the LPS group while i.n. application of URB597 worsened the inflammation in the lungs. Systemic URB597 treatment increased lung AEA level whereas it had no effect on 2-AG level. However, JZL184 treatment increased 2-AG level by either systemic or local application, and also elevated AEA level. Inflammation-induced increase in neutrophil numbers was only prevented by systemic URB597 treatment. However, both URB597 and JZL184 treatments abolished the increased TNF-α level either they are administered systemically or locally. These results indicate that FAAH and MAGL inhibition may have a protective effect in airway inflammation and airway hyperreactivity, and therefore their therapeutic potential for airway diseases should be further investigated.


Assuntos
Amidoidrolases/antagonistas & inibidores , Benzamidas/farmacologia , Benzodioxóis/farmacologia , Carbamatos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Piperidinas/farmacologia , Pneumonia/tratamento farmacológico , Animais , Ácidos Araquidônicos/metabolismo , Citocinas/efeitos dos fármacos , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Pulmão/fisiopatologia , Masculino , Camundongos , Pneumonia/induzido quimicamente , Alcamidas Poli-Insaturadas/metabolismo , Hipersensibilidade Respiratória/tratamento farmacológico
20.
Basic Res Cardiol ; 115(3): 34, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32323032

RESUMO

Endocannabinoids are important lipid-signaling mediators. Both protective and deleterious effects of endocannabinoids in the cardiovascular system have been reported but the mechanistic basis for these contradicting observations is unclear. We set out to identify anti-inflammatory mechanisms of endocannabinoids in the murine aorta and in human vascular smooth muscle cells (hVSMC). In response to combined stimulation with cytokines, IL-1ß and TNFα, the murine aorta released several endocannabinoids, with anandamide (AEA) levels being the most significantly increased. AEA pretreatment had profound effects on cytokine-induced gene expression in hVSMC and murine aorta. As revealed by RNA-Seq analysis, the induction of a subset of 21 inflammatory target genes, including the important cytokine CCL2 was blocked by AEA. This effect was not mediated through AEA-dependent interference of the AP-1 or NF-κB pathways but rather through an epigenetic mechanism. In the presence of AEA, ATAC-Seq analysis and chromatin-immunoprecipitations revealed that CCL2 induction was blocked due to increased levels of H3K27me3 and a decrease of H3K27ac leading to compacted chromatin structure in the CCL2 promoter. These effects were mediated by recruitment of HDAC4 and the nuclear corepressor NCoR1 to the CCL2 promoter. This study therefore establishes a novel anti-inflammatory mechanism for the endogenous endocannabinoid AEA in vascular smooth muscle cells. Furthermore, this work provides a link between endogenous endocannabinoid signaling and epigenetic regulation.


Assuntos
Ácidos Araquidônicos/metabolismo , Quimiocina CCL2/biossíntese , Endocanabinoides/metabolismo , Músculo Liso Vascular/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Ácidos Araquidônicos/farmacologia , Quimiocina CCL2/efeitos dos fármacos , Endocanabinoides/farmacologia , Epigênese Genética/efeitos dos fármacos , Humanos , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Transdução de Sinais/efeitos dos fármacos
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