RESUMEN
OBJECTIVE: This clinical trial was designed and conducted due to the anti-inflammatory potential of Oleoylethanolamide (OEA) to examine the effect of OEA supplement on glycemic status, oxidative stress, inflammatory factors, and anti-Mullerian hormone (AMH) in women with polycystic ovary syndrome (PCOS). METHOD: This study was a randomized clinical trial, double-blinded, placebo-controlled that was carried out on 90 women with PCOS. Patients were divided into two groups: receiving an OEA supplement (n = 45) or a placebo (n = 45). The intervention group received 125 mg/day OEA and the placebo group received the wheat flour for 8 weeks. Demographic data were collected through questionnaires. Fasting blood sugar (FBS), insulin resistance (IR), total antioxidant capacity (TAC), malondialdehyde (MDA), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and AMH were measured before and after the study. RESULTS: Data analysis of food recall and physical activity questionnaires, showed no significant differences between the two groups (p > 0.05). Biochemical factors including glycemic status, MDA, inflammatory factors, and AMH decreased significantly (p < 0.05). TAC increased remarkably (p < 0.05) in comparison between the two groups, after the intervention. CONCLUSION: OEA supplement with anti-inflammatory characteristics could be efficient independent of diet changes and physical activity in improving disrupted biochemical factors, so both supplementation or food resources of this fatty acid could be considered as a compensatory remedy in patients with PCOS. TRIAL REGISTRATION: This study was retrospectively (09-01-2022) registered in the Iranian website ( www.irct.ir ) for registration of clinical trials (IRCT20141025019669N20).
Asunto(s)
Hormona Antimülleriana , Glucemia , Suplementos Dietéticos , Endocannabinoides , Inflamación , Ácidos Oléicos , Estrés Oxidativo , Síndrome del Ovario Poliquístico , Humanos , Femenino , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/sangre , Estrés Oxidativo/efectos de los fármacos , Adulto , Ácidos Oléicos/uso terapéutico , Ácidos Oléicos/farmacología , Inflamación/tratamiento farmacológico , Inflamación/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Hormona Antimülleriana/sangre , Adulto Joven , Resistencia a la Insulina , Método Doble Ciego , Antioxidantes/farmacología , Antioxidantes/uso terapéuticoRESUMEN
Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.
Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Ácidos Oléicos , Animales , Bovinos , Humanos , Ratones , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Productos Lácteos , Ácidos Grasos Volátiles/farmacología , Ácidos Grasos Volátiles/uso terapéutico , Leche/química , Neoplasias/dietoterapia , Neoplasias/inmunología , Ácidos Oléicos/farmacología , Ácidos Oléicos/uso terapéutico , Carne Roja , OvinosRESUMEN
Neurodegenerative diseases involve an exacerbated neuroinflammatory response led by microglia that triggers cytokine storm and leukocyte infiltration into the brain. PPARα agonists partially dampen this neuroinflammation in some models of brain insult, but neuronal loss was not the triggering cause in any of them. This study examines the anti-inflammatory and immunomodulatory properties of the PPARα agonist oleoylethanolamide (OEA) in the Purkinje Cell Degeneration (PCD) mouse, which exhibits striking neuroinflammation caused by aggressive loss of cerebellar Purkinje neurons. Using real-time quantitative polymerase chain reaction and immunostaining, we quantified changes in pro- and anti-inflammatory markers, microglial density and marker-based phenotype, and overall leukocyte recruitment at different time points after OEA administration. OEA was found to modulate cerebellar neuroinflammation by increasing the gene expression of proinflammatory mediators at the onset of neurodegeneration and decreasing it over time. OEA also enhanced the expression of anti-inflammatory and neuroprotective factors and the Pparα gene. Regarding microgliosis, OEA reduced microglial density-especially in regions where it is preferentially located in PCD mice-and shifted the microglial phenotype towards an anti-inflammatory state. Finally, OEA prevented massive leukocyte infiltration into the cerebellum. Overall, our findings suggest that OEA may change the environment to protect neurons from degeneration caused by exacerbated inflammation.
Asunto(s)
Enfermedades Neuroinflamatorias , PPAR alfa , Ratones , Animales , PPAR alfa/metabolismo , Modelos Animales de Enfermedad , Ácidos Oléicos/farmacología , Ácidos Oléicos/uso terapéutico , Endocannabinoides/farmacología , Cerebelo/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
Glioblastoma multiforme (GBM) is the deadliest brain tumor with a poor prognosis and limited therapeutic options. Temozolomide (TMZ) is the first-line chemotherapeutic agent used for the treatment of GBM; however, it suffers from several limitations, including short half-life, rapid metabolism, <1% brain bioavailability, methyl guanine methyl transferase (MGMT) based chemoresistance, and hematological toxicities. Several approaches have been adopted to overcome these limitations, particularly by using nanotechnology-based systems, but its physicochemical properties make TMZ challenging to load into these nanocarriers. In the current research, we conjugated TMZ with different fatty acids, i.e., linoleic acid (LA), oleic acid (OA), and palmitic acid (PA), to obtain TMZ-fatty acid conjugates, which are comparatively hydrophobic, less prone to degradation and potent. These conjugates were thoroughly characterized using 1H NMR spectroscopy, high-resolution mass spectrometry (HR-MS), and reverse phase-high performance liquid chromatography (RP-HPLC). The synthesized conjugates, namely Temozolomide-oleic acid (TOA,6R1), Temozolomide-linoleic acid (TLA, 6R2), and Temozolomide-palmitic acid (TPA, 6R3), showed an IC50 of 101.4, 67.97, and 672.04 µM, respectively in C6 cells and 428.257, 366.43 and 413.69 µM, respectively in U87-MG cells. On the other hand, the free TMZ showed an IC50 of >1000 µM and 564.23 µM in C6 and U87-MG, respectively. Further, the in vivo efficacy of the TMZ-fatty acid conjugates was evaluated in the C6-induced orthotropic rat glioblastoma model, wherein the TMZ-fatty acid conjugate showed improved survival rate (1.6 folds) and overall health of the animals. Collectively, the conjugation of fatty acids with TMZ improves its anticancer potential against glioblastoma multiforme (GBM).
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Ratas , Animales , Temozolomida/uso terapéutico , Glioblastoma/metabolismo , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/farmacología , Ácidos Grasos , Línea Celular Tumoral , Neoplasias Encefálicas/metabolismo , Ácidos Linoleicos/uso terapéutico , Ácidos Palmíticos/uso terapéutico , Ácidos Oléicos/uso terapéutico , Resistencia a Antineoplásicos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Sophorolipids are biosurfactants derived from the nonpathogenic yeasts such as Starmerella bombicola with potential efficacy in anticancer applications. Simple and cost-effective synthesis of these drugs makes them a promising alternative to traditional chemotherapeutics, pending their success in preliminary drug-screening. Drug-screening typically utilizes 2D cell monolayers due to their simplicity and ease of high-throughput assessment. However, 2D assays fail to capture the complexity and 3D context of the tumor microenvironment and have consequently been implicated in the high percentage of drugs investigated in vitro that later fail in clinical trials. Herein, we screened two sophorolipid candidates and a clinically-used chemotherapeutic, doxorubicin, on in vitro breast cancer models ranging from 2D monolayers to 3D spheroids, employing optical coherence tomography to confirm these morphologies. We calculated corresponding IC50 values for these drugs and found one of the sophorolipids to have comparable toxicities to the chemotherapeutic control. Our findings show increased drug resistance associated with model dimensionality, such that all drugs tested showed that 3D spheroids exhibited higher IC50 values than their 2D counterparts. These findings demonstrate promising preliminary data to support the use of sophorolipids as a more affordable alternative to traditional clinical interventions and demonstrate the importance of 3D tumor models in assessing drug response.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Ácidos Oléicos/uso terapéutico , Microambiente TumoralRESUMEN
Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the therapeutic potential of nitro-oleic acid (NO2-OA), a regulator of metabolic and inflammatory signaling pathways, to mitigate allergen and obesity-induced lung function decline in a murine model of asthma. Bile acids were measured in the plasma of healthy subjects and individuals with asthma and serum and lung tissue of mice with and without allergic airway disease (AAD). Lung function, indices of inflammation and hepatic bile acid enzyme expression were measured in obese mice with house dust mite-induced AAD treated with vehicle or NO2-OA. Serum levels of glycocholic acid and glycoursodeoxycholic acid clinically correlate with body mass index and airway hyperreactivity whereas murine levels of ß-muricholic acid and tauro-ß-muricholic acid were significantly increased and positively correlated with impaired lung function in obese mice with AAD. NO2-OA reduced murine bile acid levels by modulating hepatic expression of bile acid synthesis enzymes, with a concomitant reduction in small airway resistance and tissue elastance. Bile acids correlate to body mass index and lung function decline and the signaling actions of nitroalkenes can limit AAD by modulating bile acid metabolism, revealing a potential pharmacologic approach to improving the current standard of care.
Asunto(s)
Asma/metabolismo , Asma/fisiopatología , Ácidos y Sales Biliares/metabolismo , Ácidos Grasos/fisiología , Pulmón/fisiopatología , Nitrocompuestos/uso terapéutico , Obesidad/metabolismo , Ácidos Oléicos/uso terapéutico , Adolescente , Adulto , Animales , Antiasmáticos/uso terapéutico , Antígenos Dermatofagoides/toxicidad , Asma/tratamiento farmacológico , Asma/etiología , Dieta Alta en Grasa/efectos adversos , Evaluación Preclínica de Medicamentos , Ácidos Grasos/química , Femenino , Volumen Espiratorio Forzado , Ácido Glicocólico/sangre , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/fisiopatología , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/tratamiento farmacológico , Hipersensibilidad Respiratoria/metabolismo , Delgadez , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/sangre , Capacidad Vital , Adulto JovenRESUMEN
Obesity is currently a major epidemic in the developed world. However, we lack a wide range of effective pharmacological treatments and therapies against obesity, and those approved are not devoid of adverse effects. Dietary components such as palmitoleic acid have been proposed to improve metabolic disbalance in obesity, although the mechanisms involved are not well understood. Both palmitoleic acid (POA) and oleic acid (OA) can be transformed in N-acylethanolamines (NAEs), mediating the effects of dietary POA and OA. To test this hypothesis, here, we study the effects on food intake and body weight gain of palmitoleylethanolamide (POEA) and the OA-derived NAE analogue, oleoylethanolamide (OEA), in Sprague-Dawley rats with a hypercaloric cafeteria diet (HFD). Plasma biochemical metabolites, inflammatory mediators, and lipogenesis-associated liver protein expression were also measured. The results indicate that POEA is able to improve health status in diet-induced obesity, decreasing weight, liver steatosis, inflammation, and dyslipemia. The action of POEA was found to be almost identical to that of OEA, which is an activator of the nuclear peroxisome proliferator receptor alpha (PPARα), and it is structurally related to POEA. These results suggest that the dietary administration of either POA or POEA might be considered as nutritional intervention as complementary treatment for complicated obesity in humans.
Asunto(s)
Ácidos Grasos Monoinsaturados/farmacología , Ácidos Grasos Monoinsaturados/uso terapéutico , Obesidad/tratamiento farmacológico , Ácidos Oléicos/farmacología , Ácidos Oléicos/uso terapéutico , Animales , Peso Corporal , Citocinas , Dieta , Endocannabinoides , Etanolaminas , Ácidos Grasos , Hígado Graso/metabolismo , Humanos , Resistencia a la Insulina , Lipogénesis , Hígado/metabolismo , Masculino , Ácido Oléico/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
Nitro-oleic acid (NO2-OA), a nitric oxide (NO)- and nitrite (NO2-)-derived electrophilic fatty acid metabolite, displays anti-inflammatory and anti-fibrotic signaling actions and therapeutic benefit in murine models of ischemia-reperfusion, atrial fibrillation, and pulmonary hypertension. Muscle LIM protein-deficient mice (Mlp-/-) develop dilated cardiomyopathy (DCM), characterized by impaired left ventricular function and increased ventricular fibrosis at the age of 8 weeks. This study investigated the effects of NO2-OA on cardiac function in Mlp-/- mice both in vivo and in vitro. Mlp-/- mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneous osmotic minipumps. Wildtype (WT) littermates treated with vehicle served as controls. Mlp-/- mice exhibited enhanced TGFß signalling, fibrosis and severely reduced left ventricular systolic function. NO2-OA treatment attenuated interstitial myocardial fibrosis and substantially improved left ventricular systolic function in Mlp-/- mice. In vitro studies of TGFß-stimulated primary cardiac fibroblasts further revealed that the anti-fibrotic effects of NO2-OA rely on its capability to attenuate fibroblast to myofibroblast transdifferentiation by inhibiting phosphorylation of TGFß downstream targets. In conclusion, we demonstrate a substantial therapeutic benefit of NO2-OA in a murine model of DCM, mediated by interfering with endogenously activated TGFß signaling.
Asunto(s)
Antiinflamatorios/uso terapéutico , Cardiomiopatía Dilatada/tratamiento farmacológico , Nitrocompuestos/uso terapéutico , Ácidos Oléicos/uso terapéutico , Función Ventricular Izquierda/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/patología , Evaluación Preclínica de Medicamentos , Fibroblastos/metabolismo , Fibrosis , Corazón/efectos de los fármacos , Proteínas con Dominio LIM/genética , Ratones , Proteínas Musculares/genética , Miocardio/metabolismo , Nitrocompuestos/farmacología , Ácidos Oléicos/farmacología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Oleoylethanolamide (OEA) is an endocannabinoid that has been proposed to prevent neuronal damage and neuroinflammation. In this study, we evaluated the effects of OEA on the disruption of both cerebellar structure and physiology and on the behavior of Purkinje cell degeneration (PCD) mutant mice. These mice exhibit cerebellar degeneration, displaying microtubule alterations that trigger the selective loss of Purkinje cells and consequent behavioral impairments. The effects of different doses (1, 5, and 10 mg/kg, i.p.) and administration schedules (chronic and acute) of OEA were assessed at the behavioral, histological, cellular, and molecular levels to determine the most effective OEA treatment regimen. Our in vivo results demonstrated that OEA treatment prior to the onset of the preneurodegenerative phase prevented morphological alterations in Purkinje neurons (the somata and dendritic arbors) and decreased Purkinje cell death. This effect followed an inverted U-shaped time-response curve, with acute administration on postnatal day 12 (10 mg/kg, i.p.) being the most effective treatment regimen tested. Indeed, PCD mice that received this specific OEA treatment regimen showed improvements in motor, cognitive and social functions, which were impaired in these mice. Moreover, these in vivo neuroprotective effects of OEA were mediated by the PPARα receptor, as pretreatment with the PPARα antagonist GW6471 (2.5 mg/kg, i.p.) abolished them. Finally, our in vitro results suggested that the molecular effect of OEA was related to microtubule stability and structure since OEA administration normalized some alterations in microtubule features in PCD-like cells. These findings provide strong evidence supporting the use of OEA as a pharmacological agent to limit severe cerebellar neurodegenerative processes.
Asunto(s)
Muerte Celular/efectos de los fármacos , Enfermedades Cerebelosas/tratamiento farmacológico , Modelos Animales de Enfermedad , Endocannabinoides/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Ácidos Oléicos/uso terapéutico , Células de Purkinje/efectos de los fármacos , Animales , Muerte Celular/fisiología , Células Cultivadas , Enfermedades Cerebelosas/genética , Enfermedades Cerebelosas/patología , Endocannabinoides/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Ratones Transgénicos , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Ácidos Oléicos/farmacología , Células de Purkinje/patologíaRESUMEN
Oleoylethanolamide (OEA) is a naturally occurring bioactive lipid belonging to the family of N-acylethanolamides. A variety of beneficial effects have been attributed to OEA, although the greater interest is due to its potential role in the treatment of obesity, fatty liver, and eating-related disorders. To better clarify the mechanism of the antiadipogenic effect of OEA in the liver, using a lipidomic study performed by 1H-NMR, LC-MS/MS and thin-layer chromatography analyses we evaluated the whole lipid composition of rat liver, following a two-week daily treatment of OEA (10 mg kg-1 i.p.). We found that OEA induced a significant reduction in hepatic triacylglycerol (TAG) content and significant changes in sphingolipid composition and ceramidase activity. We associated the antiadipogenic effect of OEA to decreased activity and expression of key enzymes involved in fatty acid and TAG syntheses, such as acetyl-CoA carboxylase, fatty acid synthase, diacylglycerol acyltransferase, and stearoyl-CoA desaturase 1. Moreover, we found that both SREBP-1 and PPARγ protein expression were significantly reduced in the liver of OEA-treated rats. Our findings add significant and important insights into the molecular mechanism of OEA on hepatic adipogenesis, and suggest a possible link between the OEA-induced changes in sphingolipid metabolism and suppression of hepatic TAG level.
Asunto(s)
Endocannabinoides/uso terapéutico , Ácidos Grasos/metabolismo , Hígado/metabolismo , Ácidos Oléicos/uso terapéutico , PPAR gamma/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/metabolismo , Animales , Línea Celular Tumoral , Cromatografía Liquida , Diacilglicerol O-Acetiltransferasa/metabolismo , Lipogénesis , Espectroscopía de Resonancia Magnética , Masculino , Análisis Multivariante , Ratas , Ratas Wistar , Estearoil-CoA Desaturasa/metabolismo , Espectrometría de Masas en TándemRESUMEN
Wernicke-Korsakoff Syndrome (WKS) is a neuropsychiatric disorder whose etiology is a thiamine deficiency (TD), with alcoholism being the main underlying cause. Previous evidence suggests the presence of initial neuroinflammation and oxidative/nitrosative stress in the physiopathology, although the specific molecular mechanisms underlying TD-induced brain damage and behavioral disabilities are unknown. We explored the specific role of the innate immune receptor TLR4 in three murine models of WKS, based on the combination of a thiamine-deficient diet and pyrithiamine injections (0.25 mg/kg, i.p.) over time. The Symptomatic Model (SM) allowed us to describe the complete neurological/neurobehavioral symptomatology over 16 days of TD. Animals showed an upregulation of the TLR4 signaling pathway both in the frontal cortex (FC) and cerebellum and clear motor impairments related with cerebellar dysfunction. However, in the Pre-Symptomatic Model (PSM), 12 days of TD induced the TLR4 pathway upregulation in the FC, which correlated with disinhibited-like behavior, but not in the cerebellum, and no motor impairments. In addition, we tested the effects of the biolipid oleoylethanolamide (OEA, 10 mg/kg, i.p., once daily, starting before any symptom of the pathology is manifested) through the Glucose-Precipitated Model (GPM), which was generated by glucose loading (5 g/kg, i.v., last day) in thiamine-deficient animals to accelerate damage. Pretreatment with OEA prevented the TLR4-induced signature in the FC, as well as an underlying incipient memory disability and disinhibited-like behavior. This study suggests a key role for TLR4 in TD-induced neuroinflammation in the FC and cerebellum, and it reveals different vulnerability of these brain regions in WKS over time. Pre-treatment with OEA counteracts TD-induced TLR4-associated neuroinflammation and may serve as co-adjuvant therapy to prevent WKS-induced neurobehavioral alterations.
Asunto(s)
Cerebelo/metabolismo , Corteza Cerebral/metabolismo , Endocannabinoides/uso terapéutico , Síndrome de Korsakoff/tratamiento farmacológico , Ácidos Oléicos/uso terapéutico , Receptor Toll-Like 4/metabolismo , Animales , Cerebelo/química , Corteza Cerebral/química , Citocinas/análisis , Citocinas/metabolismo , Modelos Animales de Enfermedad , Prueba de Laberinto Elevado , Masculino , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/etiología , Prueba de Campo Abierto , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Prueba de Desempeño de Rotación con Aceleración Constante , Deficiencia de Tiamina/complicaciones , Receptor Toll-Like 4/análisisRESUMEN
Obesity and its related diseases have been associated with oxidative stress. Thus, the search for nutritional strategies to ameliorate oxidative stress in obese individuals seems important. We hypothesized that the supplementation with monounsaturated (2-hydroxyoleic acid (2-OHOA)) and with combined n-3 polyunsaturated (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) fatty acids would ameliorate oxidative stress in different organs, including brain, liver, lungs, and kidneys of adult diet-induced obese (DIO) mice. Adult female ICR-CD1 mice were fed a high-fat diet (HFD) for 14 weeks. During the last 6 weeks of HFD feeding, one group of DIO mice received the same HFD, supplemented with 1500 mg of 2-OHOA per kg of HFD and another group with 1500 mg of EPA and 1500 mg of DHA per kg of HFD. At the end of the experiment, several parameters of oxidative stress were assessed. The supplementation with 2-OHOA or with EPA and DHA in DIO mice was able to revert oxidative stress, enhancing the activities of catalase and glutathione reductase, as well as diminishing the activity of xanthine oxidase, the concentration of thiobarbituric acid reactive substances (TBARS) and the ratio between oxidized glutathione and reduced glutathione in several organs. These reached similar values to those of control mice, which were fed a standard diet. These data suggest that supplementation with 2-OHOA and with EPA and DHA could be an effective nutritional intervention to restore an appropriate redox state in DIO mice.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Ácidos Grasos Omega-3/uso terapéutico , Ácidos Oléicos/uso terapéutico , Animales , Femenino , Ratones , Ratones Obesos , Estrés Oxidativo/efectos de los fármacosRESUMEN
RATIONALE: Oleoyl glycine, a little studied fatty acid amide similar in structure to anandamide, interferes with nicotine addiction in mice and acute naloxone-precipitated morphine withdrawal (MWD) in rats. Because endogenous oleoyl glycine is subject to rapid enzymatic deactivation, we evaluated the potential of more stable analogs to interfere with opiate withdrawal. OBJECTIVES: The potential of monomethylated oleoyl glycine (oleoyl alanine, HU595) to interfere with somatic and aversive effects of acute naloxone-precipitated MWD, its duration, and mechanism of action was assessed in male Sprague Dawley rats. The potential of dimethylated oleoyl glycine (HU596) to interfere with the aversive effects of naloxone-precipitated MWD was also investigated. RESULTS: Oleoyl alanine (HU595) interfered with somatic and aversive effects produced by naloxone-precipitated MWD at equivalent doses (1 and 5 mg/kg, i.p.) as we have reported for oleoyl glycine; however, oleoyl alanine produced a longer lasting (60 min) interference, yet did not produce rewarding or aversive effects on its own and did not modify locomotor activity. HU596 was not effective. The interference with aversive effects of naloxone-precipitated MWD by oleoyl alanine was prevented by both a PPARα antagonist and a CB1 receptor antagonist. Accordingly, the compound was found to inhibit FAAH and activate PPARα in vitro. Finally, oleoyl alanine also reduced acute naloxone-precipitated MWD anhedonia, as measured by decreased saccharin preference. CONCLUSIONS: Oleoyl alanine (also an endogenous fatty acid) may be a more stable and effective treatment for opiate withdrawal than oleoyl glycine.
Asunto(s)
Alanina/uso terapéutico , Analgésicos Opioides/efectos adversos , Glicina/análogos & derivados , Morfina/efectos adversos , Naloxona/efectos adversos , Ácidos Oléicos/uso terapéutico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Alanina/análogos & derivados , Animales , Glicina/química , Glicina/uso terapéutico , Masculino , Dependencia de Morfina/tratamiento farmacológico , Dependencia de Morfina/psicología , Antagonistas de Narcóticos/efectos adversos , Ácidos Oléicos/química , Ratas , Ratas Sprague-Dawley , Recompensa , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
AIMS: Ovarian cancer (OC) is the most lethal gynecological malignancies and many women develop chemoresistance associated with the inflammatory process. We investigated the effects of P-MAPA and IL-12 on the inflammatory and immune responses in a chemically-induced OC model. MAIN METHODS: OCs were induced with 7,12-dimethylbenz(a)anthracene into the ovarian bursa, and the animals were given P-MAPA (5 mg/kg bw., i.p., twice a week), or IL-12 (300 ng/kg bw., i.p., one a week) for 60 days, or both P-MAPA and IL-12. Immunohistochemistry, western blot, flow cytometry, and multiplex assay were used to examine the effectiveness of immunotherapies in OC. KEY FINDINGS: The combinatory therapy improved the general OC features, reducing inflammatory cells and adipocyte accumulation, in addition to revealing a soft and mobile tissue with no adherences and peritoneal implants. P-MAPA treatment increased the levels of TLR2, TLR4 and TRIF in OCs while decreasing the number of regulatory T (Treg) cells. Additionally, the association of P-MAPA with IL-12 significantly increased the number of CD4+ and CD8+ T effector cells in draining lymph nodes. Regarding the inflammatory mediators, P-MAPA enhanced the levels of the pro-inflammatory cytokine IL-17 while P-MAPA+IL-12 increased the levels of IL-1ß. Treatment with IL-12 enhanced the cytokine levels of IL-17, TNF-α, IL-1ß, and IL-2 in addition to the chemokine MIP-1α. SIGNIFICANCE: We conclude that P-MAPA upregulated TLR2 and TLR4 signaling, possibly activating the non-canonical pathway, while attenuating the tumor immunosuppression. Also, the combination of P-MAPA with IL-12 improves the antitumor immunoresponse, opening a new therapeutic approach for fighting OC.
Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD8-positivos/efectos de los fármacos , Interleucina-12/farmacología , Ácidos Linoleicos/farmacología , Ácidos Oléicos/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , 9,10-Dimetil-1,2-benzantraceno , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Adipocitos/efectos de los fármacos , Animales , Linfocitos T CD8-positivos/metabolismo , Quimiocina CCL3/metabolismo , Citocinas/metabolismo , Sinergismo Farmacológico , Femenino , Inflamación/tratamiento farmacológico , Interleucina-12/uso terapéutico , Ácidos Linoleicos/uso terapéutico , Ácidos Oléicos/uso terapéutico , Neoplasias Ováricas/inducido químicamente , Neoplasias Ováricas/metabolismo , Ratas , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
Venous malformations (VMs) are congenital disorders that constitute about 40% of all vascular anomalies. These lesions do not regress spontaneously and may increase in size during childhood. The case of a 10-year-old girl with an extensive oral VM is reported. Intraoral examination revealed the presence of purplish nodules in the alveolar mucosa and gingiva from anterior maxilla. Doppler ultrasound showed a well-defined hypoechoic image and increased vascularization with low blood flow for the alveolar mucosa lesion. The patient was submitted to intralesional injections of the ethanolamine oleate/mepivacaine sclerosing solution. After four sessions, there was a significant reduction of the lesions. However, the patient abandoned the treatment and the oral VM grew progressively. After 1 year, sclerotherapy was resumed and performed weekly. After 10 session of sclerotherapy, the oral VM totally regressed. The childhood is a critical period for oral VM growth. Doppler ultrasound and sclerotherapy can be effective for the management of extensive lesions in children.
Asunto(s)
Malformaciones Vasculares/terapia , Angiografía , Niño , Femenino , Humanos , Inyecciones Intralesiones , Mepivacaína/uso terapéutico , Ácidos Oléicos/uso terapéutico , Soluciones Esclerosantes/uso terapéutico , Escleroterapia , Malformaciones Vasculares/diagnóstico por imagenRESUMEN
The current outbreak of COVID-19 (coronavirus) has been identified by World Health Organization (WHO) as a global pandemic. With the emergence of the COVID-19 virus and considering the lack of effective pharmaceutical treatment for it, there is an urgent need to identify safe and effective drugs or potential adjuvant therapy in this regard. Bioactive lipids with an array of known health-promoting properties can be suggested as effective agents in alleviating acute respiratory stress induced by virus. The bioactive lipid amide, oleoylethanolamide (OEA), due to several distinctive homeostatic properties, including anti-inflammatory activities, modulation of immune response, and anti-oxidant effects can be considered as a novel potential pharmacological alternative for the management of COVID-19.
Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Endocannabinoides/farmacología , Endocannabinoides/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Ácidos Oléicos/farmacología , Ácidos Oléicos/uso terapéutico , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Neumonía Viral/patología , SARS-CoV-2RESUMEN
The effects of oleoylethanolamide (OEA) on NAFLD are yet to be examined in human. The objective of the present study was to examine the effects of OEA supplementation along with weight loss intervention on the expression of PPAR-α, uncoupling proteins 1and 2 (UCP1 and UCP2) genes in the peripheral blood mononuclear cells (PBMCs), metabolic parameters, and anthropometric indices among obese patients with NAFLD. In this triple-blind placebo-controlled randomized clinical trial, 76 obese patients newly diagnosed with NAFLD were randomly allocated into either OEA or placebo group along with calorie-restricted diets for 12 weeks. At pre-and post-intervention phase, mRNA expression levels of PPAR-α, UCP1, and UCP2 genes in the PBMCs, serum levels of metabolic parameters as well as diet and appetite sensations were assessed. There was a significant increase in the expression levels of PPAR-α, UCP1, and UCP2 genes in the PBMCs, compared to the placebo at the endpoint. A significant decrease in the anthropometric indices, energy and carbohydrate intakes, glycemic parameters, except for hemoglobin A1c concentration was also observed in the OEA group, compared to the placebo group. OEA treatment significantly resulted in decreased serum levels of triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST, increased serum levels of high-density lipoprotein cholesterol (HDL-C), and improved appetite sensations. Importantly, a significant improvement in TG, ALT, AST, ALT/AST, HDL-C levels as well as appetite sensations by OEA were under the influence of body mass index (BMI). Although liver steatosis severity was significantly reduced in both groups, the between-group differences did not reach statistical significance (P = 0.061). In conclusion, the present study, for the first time, revealed that OEA supplementation significantly improved anthropometric and metabolic risk factors related to NAFLD.
Asunto(s)
Suplementos Dietéticos , Endocannabinoides/uso terapéutico , Leucocitos Mononucleares/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Ácidos Oléicos/uso terapéutico , PPAR alfa/metabolismo , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 2/metabolismo , Adulto , Antropometría , Regulación del Apetito , Índice de Masa Corporal , Restricción Calórica , Terapia Combinada , Conducta Alimentaria , Femenino , Regulación de la Expresión Génica , Humanos , Irán , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/diagnóstico , Obesidad/genética , Obesidad/metabolismo , PPAR alfa/genética , Factores de Tiempo , Resultado del Tratamiento , Proteína Desacopladora 1/genética , Proteína Desacopladora 2/genética , Pérdida de Peso , Adulto JovenRESUMEN
Oleoylethanolamide (OEA) is an endogenous peroxisome proliferator-activated receptor α (PPARα) agonist that acts on the peripheral control of energy metabolism. However, its therapeutic potential and related mechanisms in hepatic glucose metabolism under type 2 diabetes mellitus (T2DM) are not clear. Here, OEA treatment markedly improved glucose homeostasis in a PPARα-independent manner. OEA efficiently promoted glycogen synthesis and suppressed gluconeogenesis in mouse primary hepatocytes and liver tissue. OEA enhanced hepatic glycogen synthesis and inhibited gluconeogenesis via liver kinase B1 (LKB1)/5' AMP-activated protein kinase (AMPK) signaling pathways. PPARα was not involved in the roles of OEA in the LKB1/AMPK pathways. We found that OEA exerts its antidiabetic effect by increasing glycogenesis and decreasing gluconeogenesis via the LKB1/AMPK pathway. The ability of OEA to control hepatic LKB1/AMPK pathways may serve as a novel therapeutic approach for the treatment of T2DM. SIGNIFICANCE STATEMENT: Oleoylethanolamide (OEA) exerted a potent antihyperglycemic effect in a peroxisome proliferator-activated receptor α-independent manner. OEA played an antihyperglycemic role primarily via regulation of hepatic glycogen synthesis and gluconeogenesis. The main molecular mechanism of OEA in regulating liver glycometabolism is activating the liver kinase B1/5' AMP-activated protein kinase signaling pathways.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Endocannabinoides/farmacología , Gluconeogénesis/fisiología , Glucógeno/biosíntesis , Hígado/metabolismo , Ácidos Oléicos/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Proteínas Quinasas Activadas por AMP , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inducido químicamente , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Endocannabinoides/uso terapéutico , Gluconeogénesis/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Ácidos Oléicos/uso terapéutico , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Vascular anomalies are common in the head and neck, and oral lesions are most commonly found on the lips, tongue, mucosa, and palate. Monoethanolamine oleate sclerotherapy (MOS) is an option for treatment, although we know of no established protocols yet. We report the prevalence and characteristics of intraoral vascular anomalies (IVA) and the results achieved with the use of 5% MOS, and suggest a clinical guideline. Data from the medical records of patients with IVA were collected (age, sex, ethnicity, site, size, duration, and treatment). Cases treated with MOS were detailed, and data about number of applications, interval between them, dose, adverse effects, and results were recorded. A total of 65 cases of IVA were found. White-skinned women aged from 61 to 70 years (n=21) were most likely to be affected, and the lower lip (n=25) was the most common site. Twenty-seven were treated with MOS using a mean of 1-2 applications with a seven-day interval. The mean dose applied was 0.3ml/section, which was diluted in local anaesthetic in 38 cases. Twenty-two resolved completely. In summary, we found a prevalence of 4.8% of IVA and European women aged 61 to 70 years were most affected. MOS 5% was effective and safe in the treatment of IVA more than 3cm in size, with minimal morbidity and adverse effects. We therefore suggest a sclerotherapy protocol of 0.3ml of the drug (undiluted with anaesthetic) for each 1cm lesion (maximum 3cm), with weekly revaluations and further applications when necessary within a 14-day period.
Asunto(s)
Soluciones Esclerosantes , Escleroterapia , Anciano , Femenino , Humanos , Persona de Mediana Edad , Ácidos Oléicos/uso terapéutico , Estudios Retrospectivos , Soluciones Esclerosantes/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Atherosclerotic plaque rupture is the major trigger of acute cardiovascular risk events, and manipulation of M1/M2 macrophage homeostasis is an effective strategy for regulating atherosclerotic plaque stability. This study was aimed to illuminate the effects of oleoylethanolamide (OEA) on macrophage polarization and plaque stability. METHODS: Macrophages derived from THP-1 were treated with OEA followed by LPS/IFN-γ, and the markers of M1, M2 macrophages were monitored by western blot, real-time PCR and immunofluorescence staining. The effect of OEA on macrophage polarization in the arch of aortic arteries was tested by immunofluorescence staining and western blot, and the plaque stability was completed by Masson's trichrome and hematoxylin and eosin (HE) in apolipoprotein E (ApoE)-/- mice. RESULTS: OEA treatment enhanced the expression of two classic M2 macrophage markers, macrophage mannose receptor (CD206) and transforming growth factor (TGF-ß), while the expression of iNOS (M1 macrophages) was decreased in THP-1-derived macrophages. Blocking of PPARα using siRNA and inhibition of AMP-activated protein kinase (AMPK) by its inhibitor compound C attenuated the OEA-induced expression of M2 macrophage markers. In addition, OEA significantly suppressed M1, promoted M2 macrophage polarization, increased collagen content and decreased necrotic core size in atherosclerotic plaques in ApoE-/- mice, which were linked with the expression of PPARα. CONCLUSIONS: OEA improved atherosclerotic plaque stability through regulating macrophage polarization via AMPK-PPARα pathway.