RESUMEN
Phosphoethanolamine (pEtN) cellulose is a naturally occurring modified cellulose produced by several Enterobacteriaceae. The minimal components of the E. coli cellulose synthase complex include the catalytically active BcsA enzyme, a hexameric semicircle of the periplasmic BcsB protein, and the outer membrane (OM)-integrated BcsC subunit containing periplasmic tetratricopeptide repeats (TPR). Additional subunits include BcsG, a membrane-anchored periplasmic pEtN transferase associated with BcsA, and BcsZ, a periplasmic cellulase of unknown biological function. While cellulose synthesis and translocation by BcsA are well described, little is known about its pEtN modification and translocation across the cell envelope. We show that the N-terminal cytosolic domain of BcsA positions three BcsG copies near the nascent cellulose polymer. Further, the semicircle's terminal BcsB subunit tethers the N-terminus of a single BcsC protein in a trans-envelope secretion system. BcsC's TPR motifs bind a putative cello-oligosaccharide near the entrance to its OM pore. Additionally, we show that only the hydrolytic activity of BcsZ but not the subunit itself is necessary for cellulose secretion, suggesting a secretion mechanism based on enzymatic removal of translocation incompetent cellulose. Lastly, protein engineering introduces cellulose pEtN modification in orthogonal cellulose biosynthetic systems. These findings advance our understanding of pEtN cellulose modification and secretion.
Asunto(s)
Celulosa , Proteínas de Escherichia coli , Escherichia coli , Etanolaminas , Glucosiltransferasas , Celulosa/biosíntesis , Celulosa/metabolismo , Glucosiltransferasas/metabolismo , Glucosiltransferasas/genética , Etanolaminas/metabolismo , Escherichia coli/metabolismo , Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Membrana Celular/metabolismo , Pared Celular/metabolismo , Periplasma/metabolismo , Celulasa/metabolismo , Celulasa/genéticaRESUMEN
This narrative review provides an overview of current knowledge on the impact of nutritional strategies on chronic craniofacial pain associated with temporomandibular disorders (TMDs). Individuals experiencing painful TMDs alter their dietary habits, avoiding certain foods, possibly due to chewing difficulties, which might lead to nutrient deficiencies. Our literature investigation revealed that the causal links between nutritional changes and craniofacial pain remain unclear. However, clinical and preclinical studies suggest that nutraceuticals, including vitamins, minerals, polyphenols, omega-3 fatty acids, isoprenoids, carotenoids, lectins, polysaccharides, glucosamines, and palmitoylethanolamides, could have beneficial effects on managing TMDs. This is described in 12 clinical and 38 preclinical articles since 2000. Clinical articles discussed the roles of vitamins, minerals, glucosamine, and palmitoylethanolamides. The other nutraceuticals were assessed solely in preclinical studies, using TMD models, mostly craniofacial inflammatory rodents, with 36 of the 38 articles published since 2013. Our investigation indicates that current evidence is insufficient to assess the efficacy of these nutraceuticals. However, the existing data suggest potential for therapeutic intervention in TMDs. Further support from longitudinal and randomized controlled studies and well-designed preclinical investigations is necessary to evaluate the efficacy of each nutraceutical intervention and understand their underlying mechanisms in TMDs.
Asunto(s)
Dolor Crónico , Suplementos Dietéticos , Dolor Facial , Trastornos de la Articulación Temporomandibular , Trastornos de la Articulación Temporomandibular/dietoterapia , Humanos , Dolor Facial/dietoterapia , Dolor Facial/etiología , Dolor Crónico/dietoterapia , Dolor Crónico/terapia , Animales , Ácidos Grasos Omega-3/administración & dosificación , Glucosamina/administración & dosificación , Vitaminas/administración & dosificación , Amidas , Etanolaminas , Ácidos PalmíticosRESUMEN
Palmitoylethanolamide (PEA) is a highly lipophilic molecule with low solubility, making absorption difficult. Recent techniques like micronisation, ultra-micronisation and combining PEA with solvents have improved their bioavailability and stability. Our study analysed particle size differences and absorption kinetics using specific solvents (PEAΩ and PEA DynoΩ) over time (0.5 h-6 h) in a dose-dependent manner (200 mg-1800 mg). The results showed that PEAΩ and PEA DynoΩ achieved 82-63% absorption at 3 h, compared to 30-60% for micronised, ultra-micronised PEA and a commercial product, highlighting the optimal dose range of 300 mg-600 mg. In addition, a 3D model of the peripheral nerve was utilised to explain the efficacy after gut passage and support the most effective dose (300 mg or 600 mg) achieved at the gut level. PEAΩ and PEA DynoΩ, which are associated with better intestinal bioavailability compared to PEA-micronised, PEA ultra-micronised and a commercial product, have allowed not only a reduction in the inflammatory context but also an improvement of peripheral nerve well-being by increasing specific markers like MPZ (26-36% vs. 8-15%), p75 (25-32% vs. 13-16%) and NRG1 (22-29.5% vs. 11-14%). These results highlight the potential of advanced PEA formulations to overcome solubility challenges and maintain in vitro efficacy, modulating peripheral nerve well-being.
Asunto(s)
Amidas , Etanolaminas , Ácidos Palmíticos , Ácidos Palmíticos/química , Ácidos Palmíticos/farmacología , Etanolaminas/química , Amidas/química , Humanos , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Suplementos Dietéticos , Animales , Nervios Periféricos/efectos de los fármacos , Tamaño de la PartículaRESUMEN
Fibromyalgia is characterized by chronic widespread pain, fatigue, and sleep disturbances. Recent theories attribute fibromyalgia to central sensitization syndromes, suggesting altered nociceptive processing leads to hyperalgesia and allodynia. Standardized effective treatments are currently lacking. Palmitoylethanolamide and melatonin have shown pain-relieving effects in chronic pain conditions, including fibromyalgia, with excellent safety. Our open-label study assessed the impact of a daily combination of 1200 mg of palmitoylethanolamide and 0.2 mg of melatonin on pain, sleep, and quality of life in fibromyalgia patients. Between June 2023 and March 2024, 50 patients (2016 ACR criteria) were treated and evaluated at baseline, 1 month, 3 months, and 4 months (1 month discontinuation). The assessments included VAS for pain, ISI for insomnia, HAQ for health assessments, and a tender points evaluation. The patients, averaging 54.12 years old with a 3:1 female-to-male ratio, showed significant improvements in VAS, ISI, and HAQ scores relative to their own baselines and a reduction in tender points at 1 and 3 months, which was maintained at 4 months. No adverse events were reported. This study is the first to demonstrate the efficacy of a palmitoylethanolamide and melatonin combination as an adjunct therapy in fibromyalgia, highlighting its potential to reduce pain and improve sleep and quality of life.
Asunto(s)
Amidas , Combinación de Medicamentos , Etanolaminas , Fibromialgia , Melatonina , Ácidos Palmíticos , Calidad de Vida , Humanos , Melatonina/administración & dosificación , Fibromialgia/tratamiento farmacológico , Femenino , Ácidos Palmíticos/administración & dosificación , Ácidos Palmíticos/uso terapéutico , Persona de Mediana Edad , Proyectos Piloto , Masculino , Etanolaminas/administración & dosificación , Amidas/administración & dosificación , Adulto , Anciano , Sueño/efectos de los fármacos , Resultado del Tratamiento , Dimensión del Dolor , Manejo del Dolor/métodos , Dolor Crónico/tratamiento farmacológicoRESUMEN
Purpose: In response to hypoxia, sympathetic fibers to the retina activate ß-adrenoceptors (ß-ARs) that play an important role in the regulation of vascular and neuronal functions. We investigated the role of ß3-AR using the mouse model of oxygen-induced retinopathy (OIR). Methods: Mouse pups were exposed to 75% oxygen at postnatal day 7 (PD7) followed by a return to room air at PD12. The ß3-AR preferential agonist BRL37344 was subcutaneously administered once daily at different times after the return to room air. At PD17, the OIR mice underwent flash and pattern electroretinogram. After sacrifice, retinal wholemounts were used for vessel staining or immunohistochemistry for astrocytes, Müller cells, or retinal ganglion cells (RGCs). In retinal homogenates, the levels of markers associated with neovascularization (NV), the blood-retinal barrier (BRB), or astrocytes were determined by western blot, and quantitative reverse-transcription polymerase chain reaction was used to assess ß3-AR messenger. Administration of the ß3-AR antagonist SR59230A was performed to verify BRL37344 selectivity. Results: ß3-AR expression is upregulated in response to hypoxia, but its increase is prevented by BRL37344, which counteracts NV by inhibiting the pro-angiogenic pathway, activating the anti-angiogenic pathway, recovering BRB-associated markers, triggering nitric oxide production, and favoring revascularization of the central retina through recovered density of astrocytes that ultimately counteracts NV in the midperiphery. Vasculature rescue prevents dysfunctional retinal activity and counteracts OIR-associated retinal ganglion cell loss. Conclusions: ß3-AR has emerged as a crucial intermediary in hypoxia-dependent NV, suggesting a role of ß3-AR agonists in the treatment of proliferative retinopathies.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Modelos Animales de Enfermedad , Electrorretinografía , Ratones Endogámicos C57BL , Oxígeno , Receptores Adrenérgicos beta 3 , Neovascularización Retiniana , Animales , Ratones , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/prevención & control , Neovascularización Retiniana/patología , Oxígeno/toxicidad , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Animales Recién Nacidos , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Etanolaminas/farmacología , Vasos Retinianos/efectos de los fármacos , Retinopatía de la Prematuridad/metabolismo , Retinopatía de la Prematuridad/tratamiento farmacológico , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Inmunohistoquímica , AngiogénesisRESUMEN
This study investigates the efficacy of nebivolol (NBV) in experimental models of toxoplasmosis, focusing on parasite burden reduction and neuronal protection. In the acute model of experimental toxoplasmosis, Swiss mice infected with RH strain tachyzoites received oral NBV chlorhydrate doses of 2 mg/kg/day and 4 mg/kg/day for 8 days. Treatment with NBV significantly reduced parasite burden compared to vehicle and standard drug (PYR) groups. In the chronic model of experimental toxoplasmosis, C57/BL6 mice infected with the ME49 strain received NBV chlorhydrate 41 days post-infection and were evaluated after 10 days of treatment. NBV chlorhydrate effectively reduced cyst number and area, as well as bradyzoite burden compared to controls. Histological analysis demonstrated that NBV chlorhydrate preserved neuronal count, with the 4 mg/kg/day dose yielding counts similar to non-infected mice. Statistical analysis confirmed significant differences compared to control groups. Furthermore, immunohistochemical analysis revealed a significant reduction in iNOS labeling in the brains of mice treated with NBV chlorhydrate, indicating a decrease in nitric oxide production compared to control groups. These findings suggest NBV's potential as a promising candidate for toxoplasmosis treatment, highlighting its ability to reduce parasite burden and protect neuronal integrity. Further research is warranted to elucidate NBV's mechanisms of action and its clinical application in managing toxoplasmosis.
Asunto(s)
Encéfalo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Nebivolol , Carga de Parásitos , Toxoplasmosis Animal , Animales , Nebivolol/farmacología , Nebivolol/uso terapéutico , Ratones , Toxoplasmosis Animal/tratamiento farmacológico , Toxoplasmosis Animal/parasitología , Encéfalo/parasitología , Encéfalo/patología , Encéfalo/efectos de los fármacos , Femenino , Neuronas/efectos de los fármacos , Neuronas/parasitología , Etanolaminas/farmacología , Etanolaminas/uso terapéutico , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Antiprotozoarios/administración & dosificación , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Resultado del Tratamiento , Óxido Nítrico/metabolismo , Toxoplasma/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismoRESUMEN
Plasma levels of endocannabinoids (eCBs) are very dynamic and variable in different circumstances and pathologies. The aim of the study was to determine the levels of the main eCBs and N-acylethanolamines (NAEs) in COVID-19 patients during the acute and post-acute phase of SARS-CoV-2 infection. Samples collected before December 31, 2020 were used for the determination of circulating eCB levels by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The association between plasma eCB measurements and biochemical and hematological parameters, as well as serum IL-6 levels, was evaluated. Samples of 64 individuals were analysed, n = 18 healthy donors, n = 30 acute, and n = 16 post-acute patients. Plasma levels of 2-arachidonoylglycerol (2-AG), were significantly elevated in COVID-19 patients when compared to healthy individuals. Plasma N-palmitoylethanolamide (PEA) and N-arachidonoylethanolamide (AEA) levels were found to be decreased in post-acute patient samples. These results suggest that 2-AG plays an important role in the inflammatory cascade in COVID-19 disease; in addition, eCBs might be involved in the post-acute pathogenesis of COVID-19. This study provides evidence of altered levels of circulating eCBs as a consequence of SARS-CoV-2 infection.
Asunto(s)
Ácidos Araquidónicos , COVID-19 , Endocannabinoides , Glicéridos , Inflamación , SARS-CoV-2 , Humanos , Endocannabinoides/sangre , COVID-19/sangre , COVID-19/virología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Ácidos Araquidónicos/sangre , Inflamación/sangre , Glicéridos/sangre , Alcamidas Poliinsaturadas/sangre , Etanolaminas/sangre , Anciano , Interleucina-6/sangre , Ácidos Palmíticos/sangre , Espectrometría de Masas en Tándem , Amidas , Cromatografía LiquidaRESUMEN
When coordinating and adhering to a surface, microorganisms produce a biofilm matrix consisting of extracellular DNA, lipids, proteins, and polysaccharides that are intrinsic to the survival of bacterial communities. Indeed, bacteria produce a variety of structurally diverse polysaccharides that play integral roles in the emergence and maintenance of biofilms by providing structural rigidity, adhesion, and protection from environmental stressors. While the roles that polysaccharides play in biofilm dynamics have been described for several bacterial species, the difficulty in isolating homogeneous material has resulted in few structures being elucidated. Recently, Cegelski and co-workers discovered that uropathogenic Escherichia coli (UPEC) secrete a chemically modified cellulose called phosphoethanolamine cellulose (pEtN cellulose) that plays a vital role in biofilm assembly. However, limited chemical tools exist to further examine the functional role of this polysaccharide across bacterial species. To address this critical need, we hypothesized that we could design and synthesize an unnatural glycopolymer to mimic the structure of pEtN cellulose. Herein, we describe the synthesis and evaluation of a pEtN cellulose glycomimetic which was generated using ring-opening metathesis polymerization. Surprisingly, the synthetic polymers behave counter to native pEtN cellulose in that the synthetic polymers repress biofilm formation in E. coli laboratory strain 11775T and UPEC strain 700415 with longer glycopolymers displaying greater repression. To evaluate the mechanism of action, changes in biofilm and cell morphology were visualized using high resolution field-emission gun scanning electron microscopy which further revealed changes in cell surface appendages. Our results suggest synthetic pEtN cellulose glycopolymers act as an antiadhesive and inhibit biofilm formation across E. coli strains, highlighting a potential new inroad to the development of bioinspired, biofilm-modulating materials.
Asunto(s)
Biopelículas , Celulosa , Etanolaminas , Biopelículas/efectos de los fármacos , Celulosa/química , Celulosa/farmacología , Etanolaminas/química , Etanolaminas/farmacología , Escherichia coli Uropatógena/efectos de los fármacos , Escherichia coli Uropatógena/fisiología , Adhesión Bacteriana/efectos de los fármacosRESUMEN
Depression and anxiety are prominent symptoms of withdrawal syndrome, often caused by the abuse of addictive drugs like morphine. N-palmitoylethanolamide (PEA), a biologically active lipid, is utilized as an anti-inflammatory and analgesic medication. Recent studies have highlighted PEA's role in mitigating cognitive decline and easing depression resulting from chronic pain. However, it remains unknown whether PEA can influence negative emotions triggered by morphine withdrawal. This study seeks to explore the impact of PEA on such emotions and investigate the underlying mechanisms. Mice subjected to morphine treatment underwent a 10-day withdrawal period, followed by assessments of the effect of PEA on anxiety- and depression-like behaviors using various tests. Enzyme-linked immunosorbent assay was conducted to measure levels of monoamine neurotransmitters in specific brain regions. The findings indicate that PEA mitigated anxiety and depression symptoms and reduced 5-hydroxytryptamine, noradrenaline, and dopamine levels in the hippocampus and prefrontal cortex. In summary, PEA demonstrates a significant positive effect on negative emotions associated with morphine withdrawal, accompanied with the reduction in levels of monoamine neurotransmitters in key brain regions. These insights could be valuable for managing negative emotions arising from morphine withdrawal.
Asunto(s)
Amidas , Ansiedad , Depresión , Etanolaminas , Morfina , Ácidos Palmíticos , Síndrome de Abstinencia a Sustancias , Animales , Síndrome de Abstinencia a Sustancias/psicología , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Etanolaminas/farmacología , Ácidos Palmíticos/farmacología , Ratones , Masculino , Morfina/farmacología , Depresión/metabolismo , Depresión/tratamiento farmacológico , Depresión/psicología , Depresión/etiología , Amidas/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Ansiedad/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Emociones/efectos de los fármacos , Serotonina/metabolismo , Dependencia de Morfina/metabolismo , Dependencia de Morfina/psicología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Norepinefrina/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacosRESUMEN
Phosphoethanoamine (pEtN) cellulose is a chemically modified cellulose present in some bacterial biofilms. To deepen our understanding of this biopolymer and its biological function, access to chemically defined pEtN-cellulose oligosaccharides is desirable. Herein, we report an on resin protocol for the fast synthesis of tailor-made pEtN-celluloses. The cellulose backbone is prepared by automated glycan assembly and then specifically functionalized with pEtN groups, allowing for access to a collection of ten pEtN-cellulose oligomers with different amount and pattern of pEtN.
Asunto(s)
Celulosa , Etanolaminas , Celulosa/química , Celulosa/síntesis química , Etanolaminas/química , Etanolaminas/síntesis química , Compuestos Organofosforados/química , Compuestos Organofosforados/síntesis químicaRESUMEN
Ethylamine, ethanolamine and methylamine are biogenic amines (BA) - active metabolites that, despite having important biological functions, may accumulate at toxic concentrations in certain foods. Very little information exists on the toxicity of these BA in this context. This study provides new insights into their cytotoxicity with respect to a human intestinal epithelial cell line, as assessed using real-time cell analyzer technology. A preliminary evaluation of the cytotoxic mode of action was also performed. The present results show that only ethylamine was cytotoxic for these cells at food concentrations. These new data should help establish legal limits for these BA in foods.
Asunto(s)
Aminas Biogénicas , Etanolamina , Metilaminas , Humanos , Etanolamina/química , Etanolamina/toxicidad , Metilaminas/toxicidad , Metilaminas/química , Aminas Biogénicas/análisis , Aminas Biogénicas/toxicidad , Contaminación de Alimentos/análisis , Etilaminas/química , Etilaminas/toxicidad , Etanolaminas/química , Etanolaminas/toxicidad , Supervivencia Celular/efectos de los fármacosRESUMEN
BACKGROUND: The mental health benefits of cannabidiol (CBD) are promising but can be inconsistent, in part due to challenges in defining an individual's effective dosage. In schizophrenia, alterations in anandamide (AEA) concentrations, an endocannabinoid (eCB) agonist of the eCB system, reflect positively on treatment with CBD. Here, we expanded this assessment to include eCBs alongside AEA congeners, comparing phytocannabinoids and dosage in a clinical setting. METHODS: Liquid chromatography-tandem mass spectrometry quantified changes in serum levels of AEA, 2-arachidonoylglycerol (2-AG), alongside AEA-related compounds oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which were attained from two independent, parallel-designed, clinical trials investigating single, oral CBD (600 or 800 mg), delta-9-tetrahydrocannabinol (Δ9-THC, 10 or 20 mg) and combination administration (CBD|800 mg+Δ9-THC|20 mg) in healthy volunteers (HVs, n=75). Concentrations were measured at baseline (t=0), 65 and 160 min post administration. RESULTS: CBD-led increases in AEA (1.6-fold), OEA and PEA (1.4-fold) were observed following a single 800 mg (pcorr<0.05) but not 600 mg dosage. Declining AEA was observed with Δ9-THC at 10 mg (-1.3-fold) and 20 mg (-1.4-fold) but restored to baseline levels by 160 min. CBD+Δ9-THC yielded the highest increases in AEA (2.1-fold), OEA (1.9-fold) and PEA (1.8-fold) without reaching a maximal response. CONCLUSION: CBD-administered effects towards AEA, OEA and PEA are consistent with phase II trials reporting clinical improvement for acute schizophrenia (CBD≥800 mg). Including Δ9-THC appears to enhance the CBD-induced response towards AEA and its congeners. Our results warrant further investigations into the potential of these lipid-derived mediators as metabolic measures for CBD dose prescription and co-cannabinoid administration.
Asunto(s)
Ácidos Araquidónicos , Cannabidiol , Relación Dosis-Respuesta a Droga , Dronabinol , Endocannabinoides , Etanolaminas , Voluntarios Sanos , Alcamidas Poliinsaturadas , Humanos , Endocannabinoides/sangre , Ácidos Araquidónicos/sangre , Ácidos Araquidónicos/administración & dosificación , Cannabidiol/administración & dosificación , Cannabidiol/sangre , Adulto , Masculino , Alcamidas Poliinsaturadas/sangre , Alcamidas Poliinsaturadas/administración & dosificación , Etanolaminas/administración & dosificación , Etanolaminas/sangre , Dronabinol/sangre , Dronabinol/administración & dosificación , Dronabinol/farmacocinética , Femenino , Adulto Joven , Administración Oral , Persona de Mediana Edad , Amidas , Ácidos PalmíticosRESUMEN
BACKGROUND: The burden of malaria persists in sub-Saharan Africa and the emergence of artemisinin resistance has introduced complexity to control efforts. Monitoring the efficacy of artemisinin-based treatment for malaria is crucial to address this challenge. This study assessed treatment efficacy of artemether-lumefantrine (AL) and genetic diversity of Plasmodium falciparum isolates in a Nigerian population. METHODS: Participants presenting with clinical symptoms of uncomplicated malaria at a health centre in Lagos, Nigeria, were screened for P. falciparum. Enrolled participants were treated with AL and monitored through scheduled check-up visits, clinical and laboratory examinations for 28 days. Parasite clearance and genetic diversity were assessed through polymerase chain reaction (PCR) analysis of merozoite surface proteins (msp1 and msp2). The prevalence of drug resistance mutations was assessed by P. falciparum multidrug resistance gene 1 (mdr1) genotyping followed by P. falciparum ubiquitin-specific protease 1 (ubp1) gene sequencing. RESULTS: The PCR-uncorrected treatment outcome revealed 94.4% adequate clinical and parasitological response (ACPR) and 5.6% late parasitological failure (LPF) rates. After PCR correction, no suspected LPF case was detected and ACPR 67/67 (100%) was achieved in all the individuals. Moreover, a high prevalence of wild-type alleles for mdr1 N86Y (93.7%), and mdr1 D1246Y (87.5%) was observed. Genetic diversity analysis revealed predominant K1 allelic family for msp1 (90.2%) and FC27 for msp2 (64.4%). Estimated multiplicity of infection (MOI) was 1.7, with the highest MOI observed in the 5-15 years age group. ubp1 sequence analysis identified one nonsynonymous E1528D polymorphism at a low frequency (1.6%). CONCLUSION: The study demonstrated sustained efficacy of AL for treating uncomplicated P. falciparum malaria. Genetic diversity analysis revealed various allelic types, suggesting occurrences of polyclonal infections. Nonetheless, the detection of a significant ubp1 polymorphism could have future implications for the epidemiology of anti-malarial drug resistance in the population.
Asunto(s)
Antimaláricos , Combinación Arteméter y Lumefantrina , Resistencia a Medicamentos , Malaria Falciparum , Plasmodium falciparum , Combinación Arteméter y Lumefantrina/uso terapéutico , Nigeria , Humanos , Plasmodium falciparum/genética , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/uso terapéutico , Antimaláricos/farmacología , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Femenino , Masculino , Niño , Preescolar , Adolescente , Adulto , Adulto Joven , Resistencia a Medicamentos/genética , Persona de Mediana Edad , Lactante , Resultado del Tratamiento , Artemisininas/uso terapéutico , Artemisininas/farmacología , Variación Genética , Anciano , Proteínas Protozoarias/genética , Combinación de Medicamentos , Proteína 1 de Superficie de Merozoito/genética , Etanolaminas/uso terapéutico , Fluorenos/uso terapéuticoRESUMEN
Traumatic brain injuries (TBI) of varying severity are becoming more frequent all over the world. The process of neuroinflammation, in which macrophages and microglia are key players, underlies all types of brain damage. The present study focuses on evaluating the therapeutic potential of N-docosahexaenoylethanolamine (DHEA, synaptamide), which is an endogenous metabolite of docosahexaenoic acid in traumatic brain injury. Previously, several in vitro and in vivo models have shown significant anti-neuroinflammatory and synaptogenic activity of synaptamide. The results of the present study show that synaptamide by subcutaneous administration (10 mg/kg/day, 7 days) exerts anti-inflammatory and anti-apoptotic effects in the thalamus and cerebral cortex of experimental animals (male C57BL/6 mice). Were analyzed the dynamics of changes in the activity of Iba-1- and CD68-positive microglia/macrophages, the level of production of pro-inflammatory cytokines (IL1ß, IL6, TNFα) and pro-apoptotic proteins (Bad, Bax), the expression of pro- and anti-inflammatory markers (CD68, CD206, arg-1). ATF3 transcription factor distribution and neuronal state in the thalamus and cerebral cortex of animals with craniotomy, traumatic brain injury, and therapy are quantitatively assessed. The obtained data showed that synaptamide: (1) has no effect on the total pool of microglia/macrophages; (2) inhibits the activity of pro-inflammatory microglia/macrophages and cytokines they produce; (3) increases the expression of CD206 but not arg-1; (4) has anti-apoptotic effect and (5) improves the morphological state of neurons. The results obtained confirm the high therapeutic potential of synaptamide in the therapy of traumatic brain injury.
Asunto(s)
Apoptosis , Lesiones Traumáticas del Encéfalo , Corteza Cerebral , Ratones Endogámicos C57BL , Microglía , Neuronas , Animales , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Apoptosis/efectos de los fármacos , Ratones , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Antiinflamatorios/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Tálamo/efectos de los fármacos , Tálamo/metabolismo , Tálamo/patología , Citocinas/metabolismo , Etanolaminas/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismoRESUMEN
Dysregulation of energy balance leading to obesity is a significant risk factor for cardiometabolic diseases such as diabetes, non-alcoholic fatty liver disease and atherosclerosis. In rodents and several other vertebrates, feeding has been shown to induce a rapid rise in the intestinal levels of N-acyl-ethanolamines (NAEs) and the chronic consumption of a high fat diet abolishes this rise. Administering NAEs to rodents consuming a high fat diet reduces their adiposity, in part by reducing food intake and enhancing fat oxidation, so that feeding-induced intestinal NAE biosynthesis appears to be critical to appropriate regulation of energy balance. However, the contribution of feeding-induced intestinal NAE biosynthesis to appropriate energy balance remains poorly understood in part because there are multiple enzymes that can contribute to NAE biosynthesis and the specific enzyme(s) that are responsible for feeding-induced intestinal NAE biosynthesis have not been identified. The rate-limiting step in the intestinal biosynthesis of NAEs is formation of their immediate precursors, the N-acyl-phosphatidylethanolamines (NAPEs), by phosphatidylethanolamine N-acyltransferases (NATs). At least six NATs are found in humans and multiple homologs of these NATs are found in most vertebrate species. In recent years, the fecundity and small size of zebrafish (Danio rerio), as well as their similarities in feeding behavior and energy balance regulation with mammals, have led to their use to model key features of cardiometabolic disease. We therefore searched the Danio rerio genome to identify all NAT homologs and found two additional NAT homologs besides the previously reported plaat1, rarres3, and rarres3l, and used CRISPR/cas9 to delete these two NAT homologs (plaat1l1 and plaat1l2). While wild-type fish markedly increased their intestinal NAPE levels in response to a meal after fasting, this response was completely ablated in plaat1l1-/-fish. Furthermore, plaat1l1-/- fish fed a standard flake diet had increased weight gain and glucose intolerance compared to wild-type fish. The results support a critical role for feeding-induced NAPE and NAE biosynthesis in regulating energy balance and suggest that restoring this response in obese animals could potentially be used to treat obesity and cardiometabolic disease.
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Metabolismo Energético , Pez Cebra , Animales , Pez Cebra/metabolismo , Etanolaminas/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Aciltransferasas/metabolismo , Aciltransferasas/genéticaRESUMEN
Fatty acid amide hydrolase (FAAH) is a conserved hydrolase in eukaryotes with promiscuous activity toward a range of acylamide substrates. The native substrate repertoire for FAAH has just begun to be explored in plant systems outside the model Arabidopsis thaliana. Here, we used ex vivo lipidomics to identify potential endogenous substrates for Medicago truncatula FAAH1 (MtFAAH1). We incubated recombinant MtFAAH1 with lipid mixtures extracted from M. truncatula and resolved their profiles via gas chromatography-mass spectrometry (GC-MS). Data revealed that besides N-acylethanolamines (NAEs), sn-1 or sn-2 isomers of monoacylglycerols (MAGs) were substrates for MtFAAH1. Combined with in vitro and computational approaches, our data support both amidase and esterase activities for MtFAAH1. MAG-mediated hydrolysis via MtFAAH1 may be linked to biological roles that are yet to be discovered.
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Amidohidrolasas , Lipidómica , Medicago truncatula , Monoglicéridos , Medicago truncatula/enzimología , Medicago truncatula/metabolismo , Medicago truncatula/genética , Amidohidrolasas/metabolismo , Amidohidrolasas/química , Amidohidrolasas/genética , Especificidad por Sustrato , Lipidómica/métodos , Monoglicéridos/metabolismo , Monoglicéridos/química , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/química , Etanolaminas/metabolismo , Etanolaminas/química , Cromatografía de Gases y Espectrometría de Masas , HidrólisisRESUMEN
BACKGROUND: The Mediterranean diet (MedDiet) has demonstrated efficacy in preventing age-related cognitive decline and modulating plasma concentrations of endocannabinoids (eCBs) and N-acylethanolamines (NAEs, or eCB-like compounds), which are lipid mediators involved in multiple neurological disorders and metabolic processes. Hypothesizing that eCBs and NAEs will be biomarkers of a MedDiet intervention and will be related to the cognitive response, we investigated this relationship according to sex and apolipoprotein E (APOE) genotype, which may affect eCBs and cognitive performance. METHODS: This was a prospective cohort study of 102 participants (53.9% women, 18.8% APOE-É4 carriers, aged 65.6 ± 4.5 years) from the PREDIMED-Plus-Cognition substudy, who were recruited at the Hospital del Mar Research Institute (Barcelona). All of them presented metabolic syndrome plus overweight/obesity (inclusion criteria of the PREDIMED-Plus) and normal cognitive performance at baseline (inclusion criteria of this substudy). A comprehensive battery of neuropsychological tests was administered at baseline and after 1 and 3 years. Plasma concentrations of eCBs and NAEs, including 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and N-docosahexaenoylethanolamine (DHEA), were also monitored. Baseline cognition, cognitive changes, and the association between eCBs/NAEs and cognition were evaluated according to gender (crude models), sex (adjusted models), and APOE genotype. RESULTS: At baseline, men had better executive function and global cognition than women (the effect size of gender differences was - 0.49, p = 0.015; and - 0.42, p = 0.036); however, these differences became nonsignificant in models of sex differences. After 3 years of MedDiet intervention, participants exhibited modest improvements in memory and global cognition. However, greater memory changes were observed in men than in women (Cohen's d of 0.40 vs. 0.25; p = 0.017). In men and APOE-ε4 carriers, 2-AG concentrations were inversely associated with baseline cognition and cognitive changes, while in women, cognitive changes were positively linked to changes in DHEA and the DHEA/AEA ratio. In men, changes in the OEA/AEA and OEA/PEA ratios were positively associated with cognitive changes. CONCLUSIONS: The MedDiet improved participants' cognitive performance but the effect size was small and negatively influenced by female sex. Changes in 2-AG, DHEA, the OEA/AEA, the OEA/PEA and the DHEA/AEA ratios were associated with cognitive changes in a sex- and APOE-dependent fashion. These results support the modulation of the endocannabinoid system as a potential therapeutic approach to prevent cognitive decline in at-risk populations. TRIAL REGISTRATION: ISRCTN89898870.
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Cognición , Dieta Mediterránea , Endocannabinoides , Genotipo , Síndrome Metabólico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Amidas , Apolipoproteínas E/genética , Ácidos Araquidónicos/sangre , Biomarcadores/sangre , Cognición/fisiología , Dieta Mediterránea/estadística & datos numéricos , Endocannabinoides/sangre , Etanolaminas/sangre , Glicéridos/sangre , Síndrome Metabólico/genética , Ácidos Oléicos/sangre , Ácidos Palmíticos/sangre , Alcamidas Poliinsaturadas/sangre , Estudios Prospectivos , Factores SexualesRESUMEN
Palmitoylethanolamide (PEA) emerged over the years as a promising approach in the management of chronic pain. Despite the fact that the efficacy of micron-size PEA formulations appears to be time-dependent, the optimal timing has not yet been elucidated. This systematic review and meta-analysis aim to estimate the possible advantage of an extended treatment in the relief of chronic pain. The literature search was conducted consulting scientific databases, to identify clinical trials in which micron-size PEA was administered for at least 60 days, and pain assessed by the Visual Analogue Scale (VAS) or Numeric Rating Scale (NRS). Nine studies matched the required criteria, for a total of 742 patients involved. The meta-analysis showed a statistically and clinically significant pain intensity reduction after 60 days of micron-size PEA supplementation, compared to 30 days (1.36 points, p < 0.01). The secondary analysis revealed a weighted NRS/VAS score decrease of 2.08 points within the first month of treatment. These two obtained scores corresponded to a 35.1% pain intensity reduction within the first month, followed by a further 35.4% during the second month. Overall, these results confirm the clinically relevant and time-depended pain-relieving effect of micron-size PEA and therefore the advantage of an extended treatment, especially in patient with incomplete pain management.
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Amidas , Dolor Crónico , Etanolaminas , Ácidos Palmíticos , Ácidos Palmíticos/administración & dosificación , Ácidos Palmíticos/uso terapéutico , Humanos , Amidas/administración & dosificación , Etanolaminas/administración & dosificación , Dolor Crónico/tratamiento farmacológico , Dimensión del Dolor , Administración Oral , Resultado del Tratamiento , Analgésicos/administración & dosificaciónAsunto(s)
Antiasmáticos , Asma , Etanolaminas , Fumarato de Formoterol , Humanos , Asma/tratamiento farmacológico , Fumarato de Formoterol/administración & dosificación , Fumarato de Formoterol/uso terapéutico , Antiasmáticos/uso terapéutico , Antiasmáticos/administración & dosificación , Etanolaminas/uso terapéutico , Etanolaminas/administración & dosificación , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Administración por Inhalación , Medicina Basada en la Evidencia , Broncodilatadores/uso terapéutico , Broncodilatadores/administración & dosificación , Resultado del TratamientoRESUMEN
The cationic surfactant triethanolamine-based esterquat (TEAQ) is a main ingredient in commercial fabric softeners and is produced and used in large quantities. However, little information is available for its occurrence in the environment, particularly in sediments. Here, we developed an analytical method for quantifying TEAQ in sediment and investigated TEAQ contamination in Japanese river and lake sediments. In our analytical method, TEAQ concentrations were measured by liquid chromatography-tandem mass spectrometry using a polymer-based size-exclusion column, which resulted in excellent peak shapes. TEAQ was detected at significant levels in procedural blanks, resulting in a method limit of detection in the sediment of 8.9-97 µg/kg-dry for TEAQ monoesters and 0.6-24 µg/kg-dry for TEAQ diesters. TEAQ was detected in 22 out of 26 sediment samples, with the sum of all homologue concentrations being up to 1340 µg/kg-dry. The concentration of TEAQ in sediments was high at locations where the concentrations of benzalkoniums and the organic carbon content were also high. TEAQ was detected in 8 out of 14 commercial fabric softeners at concentrations of 1.7-7.4 wt%. TEAQ homologues containing only saturated fatty acids accounted for 83 ± 5% of the total TEAQ in the sediments, whereas those with unsaturated fatty acids accounted for 71 ± 14% of the total TEAQ in a commercial technical mixture and the softener products. The results of this study will be useful for the environmental risk assessment of esterquats.