RESUMEN
Maternal immune activation (MIA) and poor maternal nutritional habits are risk factors for the occurrence of neurodevelopmental disorders (NDD). Human studies show the deleterious impact of prenatal inflammation and low n-3 polyunsaturated fatty acid (PUFA) intake on neurodevelopment with long-lasting consequences on behavior. However, the mechanisms linking maternal nutritional status to MIA are still unclear, despite their relevance to the etiology of NDD. We demonstrate here that low maternal n-3 PUFA intake worsens MIA-induced early gut dysfunction, including modification of gut microbiota composition and higher local inflammatory reactivity. These deficits correlate with alterations of microglia-neuron crosstalk pathways and have long-lasting effects, both at transcriptional and behavioral levels. This work highlights the perinatal period as a critical time window, especially regarding the role of the gut-brain axis in neurodevelopment, elucidating the link between MIA, poor nutritional habits, and NDD.
Asunto(s)
Ácidos Grasos Omega-3 , Efectos Tardíos de la Exposición Prenatal , Animales , Conducta Animal , Encéfalo , Femenino , Humanos , Inflamación , Microglía , EmbarazoRESUMEN
Brain aging is characterized by a decline in cognitive functions, which can lead to the development of neurodegenerative pathologies. Age-related spatial learning and memory deficits are associated with a chronic low-grade inflammation. Anxiety disorders and stress response alterations, occurring for a part of the elderly, have also been linked to an increased neuroinflammation and thus, an accelerated cognitive decline. Nutrition is an innovative strategy to prevent age-related cognitive impairments. Among the nutrients, n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides from proteins, especially those from marine resources, are good candidates for their immunomodulatory, anxiolytic and neuroprotective properties. The aim of this study is to determine the combined effect of n-3 LC-PUFAs and low molecular weight peptides on cognitive functions, and their mechanism of action. We are the first to show that a dietary supplementation with a fish hydrolysate containing n-3 LC-PUFAs and low molecular weight peptides prevented the age-related spatial short-term memory deficits and modulated navigation strategies adopted during spatial learning. In addition, the fish hydrolysate displayed anxiolytic activities with the reduction of anxiety-like behaviour in aged mice, restored the plasmatic corticosterone levels similar to adult animals following an acute stress and modulated the hypothalamic stress response. These effects on behaviour can be explained by the immunomodulatory and neuroprotective properties of the fish hydrolysate that limited microgliosis in vivo, decreased LPS-induced expression of pro-inflammatory cytokines and increased the expression of growth factors such as BDNF and NGF in vitro. Thus, n-3 LC-PUFAs and low molecular weight peptides contained in the fish hydrolysate can play an important role in the limitation of neuroinflammation and stress response alterations during aging and represent a potential strategy for the prevention of age-related cognitive decline.
Asunto(s)
Ácidos Grasos Omega-3 , Memoria a Corto Plazo , Animales , Dieta , Suplementos Dietéticos , Trastornos de la Memoria/prevención & control , RatonesRESUMEN
Omega-3 fatty acids (n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in Humans. However, the n-3 PUFAs deficiency-mediated mechanisms affecting the development of the central nervous system are poorly understood. Active microglial engulfment of synapses regulates brain development. Impaired synaptic pruning is associated with several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development in mice. Our results show that maternal dietary n-3 PUFA deficiency increases microglia-mediated phagocytosis of synaptic elements in the rodent developing hippocampus, partly through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, altering neuronal morphology and affecting cognitive performance of the offspring. These findings provide a mechanistic insight into neurodevelopmental defects caused by maternal n-3 PUFAs dietary deficiency.
Asunto(s)
Encéfalo/efectos de los fármacos , Ácidos Grasos Omega-3/farmacología , Microglía/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Fagocitosis/efectos de los fármacos , Animales , Encéfalo/crecimiento & desarrollo , Suplementos Dietéticos , Ácidos Grasos Omega-3/deficiencia , Ácidos Grasos Omega-3/genética , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Hipocampo/citología , Hipocampo/crecimiento & desarrollo , Homeostasis , Humanos , Lipooxigenasa , Masculino , Ratones , Trastornos del NeurodesarrolloRESUMEN
Neurological involvement is frequent in inherited metabolic disease of the intoxication type. Hyperammonemic coma related to these diseases may cause severe neurological sequelae. Early optimal treatment is mandatory combining metabolite scavengers (MS) and sometimes continuous veno-venous hemodialysis (CVVHD). We aimed to describe the therapeutic management of hyperammonemia in neonates upon diagnosis of their metabolic disease and to compare neonates managed with MS alone or with both MS and CVVHD. We conducted a retrospective study including all neonates admitted for initial hyperammonemia to the pediatric intensive care unit of a Reference Center of Inherited Metabolic Diseases, between 2001 and 2012. The study included 35 neonates. Before admission, MS were initiated for 11 neonates. At admission, the median ammonia levels were 391 µmol/L and were significantly lower in neonates who received MS before admission. At admission, ammonia levels were 644 µmol/L in dialyzed and 283 µmol/L in non-dialyzed neonates. The median time to reach a 50% decrease of the initial ammonia levels was significantly shorter in dialyzed neonates; however, the normalization of ammonia levels was similar between dialyzed and non-dialyzed neonates. Hemodynamic disorders were more frequent in dialyzed neonates. CONCLUSION: MS represent an effective treatment for hyperammonemia and should be available in all pediatric units to avoid the need for CVVHD. Although CVVHD enhances the kinetics of toxic metabolite decrease, it is associated with adverse hemodynamic effects.
Asunto(s)
Antimetabolitos/uso terapéutico , Terapia de Reemplazo Renal Continuo/métodos , Hiperamonemia/terapia , Diálisis Renal/métodos , Terapia Combinada , Enfermedad Crítica , Femenino , Humanos , Hiperamonemia/diagnóstico , Recién Nacido , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The brain is highly enriched in long chain polyunsaturated fatty acids (LC-PUFAs) that display immunomodulatory properties in the brain. At the periphery, the modulation of inflammation by LC-PUFAs occurs through lipid mediators called oxylipins which have anti-inflammatory and pro-resolving activities when derived from n-3 LC-PUFAs and pro-inflammatory activities when derived from n-6 LC-PUFAs. However, whether a diet rich in LC-PUFAs modulates oxylipins and neuroinflammation in the brain has been poorly investigated. In this study, the effect of a dietary n-3 LC-PUFA supplementation on oxylipin profile and neuroinflammation in the brain was analyzed. Mice were given diets deficient or supplemented in n-3 LC-PUFAs for a 2-month period starting at post-natal day 21, followed by a peripheral administration of lipopolysaccharide (LPS) at adulthood. We first showed that dietary n-3 LC-PUFA supplementation induced n-3 LC-PUFA enrichment in the hippocampus and subsequently an increase in n-3 PUFA-derived oxylipins and a decrease in n-6 PUFA-derived oxylipins. In response to LPS, n-3 LC-PUFA deficient mice presented a pro-inflammatory oxylipin profile whereas n-3 LC-PUFA supplemented mice displayed an anti-inflammatory oxylipin profile in the hippocampus. Accordingly, the expression of cyclooxygenase-2 and 5-lipoxygenase, the enzymes implicated in pro- and anti-inflammatory oxylipin synthesis, was induced by LPS in both diets. In addition, LPS-induced pro-inflammatory cytokine increase was reduced by dietary n-3 LC-PUFA supplementation. These results indicate that brain n-3 LC-PUFAs increase by dietary means and promote the synthesis of anti-inflammatory derived bioactive oxylipins. As neuroinflammation plays a key role in all brain injuries and many neurodegenerative disorders, the present data suggest that dietary habits may be an important regulator of brain cytokine production in these contexts.
Asunto(s)
Ácidos Grasos Omega-3/metabolismo , Oxilipinas/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Citocinas/metabolismo , Dieta , Suplementos Dietéticos , Ácidos Grasos , Ácidos Grasos Omega-3/fisiología , Ácidos Grasos Omega-6 , Ácidos Grasos Insaturados/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inflamación/metabolismo , Lipopolisacáridos/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos AnimalesRESUMEN
Maternal immune activation (MIA) is a common environmental insult on the developing brain and represents a risk factor for neurodevelopmental disorders. Animal models of in utero inflammation further revealed a causal link between maternal inflammatory activation during pregnancy and behavioural impairment relevant to neurodevelopmental disorders in the offspring. Accumulating evidence point out that proinflammatory cytokines produced both in the maternal and fetal compartments are responsible for social, cognitive and emotional behavioral deficits in the offspring. Polyunsaturated fatty acids (PUFAs) are essential fatty acids with potent immunomodulatory activities. PUFAs and their bioactive derivatives can promote or inhibit many aspects of the immune and inflammatory response. PUFAs of the n-3 series ('n-3 PUFAs', also known as omega-3) exhibit anti-inflammatory/pro-resolution properties and promote immune functions, while PUFAs of the n-6 series ('n-6 PUFAs' or omega-6) favor pro-inflammatory responses. The present study aimed at providing insight into the effects of n-3 PUFAs on the consequences of MIA on brain development. We hypothesized that a reduction in n-3 PUFAs exacerbates both maternal and fetal inflammatory responses to MIA and later-life defects in memory in the offspring. Based on a lipopolysaccharide (LPS) model of MIA (LPS injection at embryonic day 17), we showed that n-3 PUFA deficiency 1) alters fatty acid composition of the fetal and adult offspring brain; 2) exacerbates maternal and fetal inflammatory processes with no significant alteration of microglia phenotype, and 3) induces spatial memory deficits in the adult offspring. We also showed a strong negative correlation between brain content in n-3 PUFA and cytokine production in MIA-exposed fetuses. Overall, our study is the first to address the deleterious effects of n-3 PUFA deficiency on brain lipid composition, inflammation and memory performances in MIA-exposed animals and indicates that it should be considered as a potent environmental risk factor for the apparition of neurodevelopmental disorders.
Asunto(s)
Ácidos Grasos Omega-3/deficiencia , Ácidos Grasos Omega-3/metabolismo , Memoria Espacial/efectos de los fármacos , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Citocinas/efectos de los fármacos , Suplementos Dietéticos , Modelos Animales de Enfermedad , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-6/metabolismo , Ácidos Grasos Omega-6/fisiología , Femenino , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Trastornos del Neurodesarrollo/etiología , Trastornos del Neurodesarrollo/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/inmunología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Conducta SocialRESUMEN
In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) account for up to 25% of cases and are associated with a poor outcome. In order to better target this AML subtype, a comprehensive view of how FLT3-ITD impacts AML cell biology is required. Here, we found that FLT3-ITD expression increased basal autophagy in AML cells, and that both pharmacological and genetic inhibition of the receptor reduced autophagy in primary AML samples and cell lines. Conditional expression of shRNAs against key autophagy proteins demonstrated that autophagy is required for AML cell proliferation in vitro and for leukemic cells survival in a mouse model of xenograft. Importantly, autophagy inhibition also overcame FLT3 inhibitor resistance both in vitro and in vivo. The transcription factor ATF4 was identified as an essential actor of FLT3-ITD-induced autophagy. Cellular levels of ATF4 were highly dependent on FLT3-ITD activity, and downregulation of ATF4 inhibited autophagy-dependent AML cell proliferation and improved overall mouse survival similarly to autophagy inhibition. These results suggest that targeting autophagy or ATF4 in patients expressing FLT3 mutations may represent a novel promising and innovative therapeutic strategy for AML.
Asunto(s)
Factor de Transcripción Activador 4/metabolismo , Autofagia , Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/patología , Tirosina Quinasa 3 Similar a fms/metabolismo , Factor de Transcripción Activador 4/genética , Animales , Biomarcadores de Tumor/genética , Proliferación Celular , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Secuencias Repetidas en Tándem , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Within the central nervous system the traditional role of microglia has been in brain infection and disease, phagocytosing debris and secreting factors to modify disease progression. More recently, microglia have been found to be important for normal brain development, circuit refinement, and synaptic plasticity in ways that were previously unsuspected. Hence, the brain innate immune system appears to be key in all situations, ranging from physiology to pathology. This unique feature of microglia is established by the wide array of receptors it is equipped with to sense molecular patterns. This includes receptors to most if not all neurotransmitters, neuromodulators and purines. We here review novel, yet extensive literature on a new class of microglia modulators, namely bioactive fatty acids. These lipids are issued from metabolism of nutrients and can cross the blood brain barrier to reach the CNS. They appear to be direct modulators of microglial activity, triggering/inhibiting inflammatory processes or enhancing/inhibiting the ability of these cells to respond to hazardous agents.
Asunto(s)
Encéfalo/citología , Ácidos Grasos/metabolismo , Microglía/fisiología , Neuroinmunomodulación/fisiología , Animales , Encéfalo/metabolismo , Ácidos Grasos/farmacología , Humanos , Microglía/efectos de los fármacosRESUMEN
The aim of the study was to determine the effect of maternal diets administered since day 1 of gestation and containing dairy lipids or vegetable oils differing in the supply of n-3 polyunsaturated fatty acids (n-3 PUFAs) (equilibrated or deficient) and of Lactobacillus fermentum (L. fermentum) on the docosahexaenoic acid (DHA) accretion in the pups at postnatal day 14 in the prefrontal cortex (PFC) and hippocampus (HC) for brain structures and in the liver and adipose tissue for peripheral tissues. Maternal milk fatty acid composition was also assessed by analyzing the fatty acid composition of the gastric content of the pups. DHA was higher in mice supplemented with L. fermentum than in mice in the deficient group in HC and PFC and also in liver and adipose tissue. This increase could be linked to the slight but significant increase in C18:3n-3 in the maternal milk. This proportion was comparable in the dairy lipid group for which the brain DHA level was the highest. L. fermentum may have a key role in the protection of the brain during the perinatal period via the neuronal accretion of n-3 PUFAs, especially during n-3 PUFA deficiency.
Asunto(s)
Tejido Adiposo/metabolismo , Encéfalo/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Limosilactobacillus fermentum/fisiología , Hígado/metabolismo , Leche/química , Aceites de Plantas/administración & dosificación , Animales , Animales Lactantes , Suplementos Dietéticos , Ácidos Grasos/análisis , Femenino , Hipocampo/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos , Ratones , Corteza Prefrontal/metabolismo , Embarazo , Distribución TisularRESUMEN
Polyunsaturated fatty acids (PUFAs) are essential fatty acids, which are critical for brain development and later life cognitive functions. The main brain PUFAs are docosahexaenoic acid (DHA) for the n-3 family and arachidonic acid (ARA) for the n-6 family, which are provided to the post-natal brain by breast milk or infant formula. Recently, the use of dairy lipids (DL) in replacement of vegetable lipids (VL) was revealed to potently promote the accretion of DHA in the developing brain. Brain DHA, in addition to be a key component of brain development, display potent anti-inflammatory activities, which protect the brain from adverse inflammatory events. In this work, we evaluated the protective effect of partial replacement of VL by DL, supplemented or not with DHA and ARA, on post-natal inflammation and its consequence on memory. Mice were fed with diets poor in vegetal n-3 PUFA (Def VL), balanced in vegetal n-3/n-6 PUFA (Bal VL), balanced in dairy lipids (Bal DL) or enriched in DHA and ARA (Supp VL; Supp DL) from the first day of gestation until adulthood. At post-natal day 14 (PND14), pups received a single administration of the endotoxin lipopolysaccharide (LPS) and brain cytokine expression, microglia phenotype and neurogenesis were measured. In a second set of experiments, memory and neurogenesis were measured at adulthood. Overall, our data showed that lipid quality of the diet modulates early life LPS effect on microglia phenotype, brain cytokine expression and neurogenesis at PND14 and memory at adulthood. In particular, Bal DL diet protects from the adverse effect of early life LPS exposure on PND14 neurogenesis and adult spatial memory.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Discapacidades para el Aprendizaje/prevención & control , Lipopolisacáridos/efectos adversos , Memoria Espacial/efectos de los fármacos , Animales , Animales Recién Nacidos , Ácido Araquidónico/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Grasas de la Dieta/farmacología , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/metabolismo , Discapacidades para el Aprendizaje/inducido químicamente , Ratones , Neurogénesis/efectos de los fármacos , Aceites de Plantas/administración & dosificación , Aceites de Plantas/farmacologíaRESUMEN
Mimicking the breast milk lipid composition appears to be necessary for infant formula to cover the brain's needs in n-3 PUFA. In this study, we evaluated the impact of partial replacement of vegetable oil (VL) in infant formula by dairy fat (DL) on docosahexaenoic acid (DHA) brain level, neuroplasticity and corticosterone in mice. Mice were fed with balanced VL or balanced DL diets enriched or not in DHA and arachidonic acid (ARA) from the first day of gestation. Brain DHA level, microglia number, neurogenesis, corticosterone and glucocorticoid receptor expression were measured in the offsprings. DL diet increased DHA and neuroplasticity in the brain of mice at postnatal day (PND) 14 and at adulthood compared to VL. At PND14, ARA and DHA supplementation increased DHA in VL but not in DL mice brain. Importantly, DHA and ARA supplementation further improved neurogenesis and decreased corticosterone level in DL mice at adulthood. In conclusion, dairy lipids improve brain DHA level and neuroplasticity.
Asunto(s)
Encéfalo/crecimiento & desarrollo , Corticosterona/metabolismo , Grasas de la Dieta/administración & dosificación , Ácidos Docosahexaenoicos/metabolismo , Aceites de Plantas/administración & dosificación , Animales , Ácido Araquidónico/metabolismo , Encéfalo/metabolismo , Productos Lácteos , Grasas de la Dieta/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Lactante , Fórmulas Infantiles/química , Ratones , Modelos Animales , Plasticidad Neuronal/efectos de los fármacos , Aceites de Plantas/farmacología , Receptores de Glucocorticoides/efectos de los fármacosRESUMEN
Sustained inflammation in the brain together with microglia activation can lead to neuronal damage. Hence limiting brain inflammation and activation of microglia is a real therapeutic strategy for inflammatory disease. Resolvin D1 (RvD1) and resolvin E1 (RvE1) derived from n-3 long chain polyunsaturated fatty acids are promising therapeutic compounds since they actively turn off the systemic inflammatory response. We thus evaluated the anti-inflammatory activities of RvD1 and RvE1 in microglia cells in vitro. BV2 cells were pre-incubated with RvD1 or RvE1 before lipopolysaccharide (LPS) treatment. RvD1 and RvE1 both decreased LPS-induced proinflammatory cytokines (TNF-α, IL-6 and IL-1ß) gene expression, suggesting their proresolutive activity in microglia. However, the mechanisms involved are distinct as RvE1 regulates NFκB signaling pathway and RvD1 regulates miRNAs expression. Overall, our findings support that pro-resolving lipids are involved in the resolution of brain inflammation and can be considered as promising therapeutic agents for brain inflammation.
Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/análogos & derivados , Inflamación/tratamiento farmacológico , Interleucina-6/metabolismo , MicroARNs/metabolismo , Microglía/efectos de los fármacos , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Animales , Ácido Eicosapentaenoico/farmacología , RatonesRESUMEN
Due to the implication of docosahexaenoic acid (DHA) in neurogenesis, synaptogenesis, neurite outgrowth and to its high incorporation into the brain, this n-3 long chain polyunsaturated fatty acid (LCPUFA) is considered as crucial in the development and maintenance of the learning memory performance throughout life. In the present chapter we aimed at reviewing data investigating the relation between DHA and cognition during the perinatal period, young adult- and adulthood and neurodegenerative diseases such as Alzheimer disease (AD). In Humans, dietary DHA supplementation from the perinatal period to adulthood does not reveal a clear and consistent memory improvement whereas it is the case in animal studies. The positive effects observed in animal models may have been enhanced by using n-3 PUFA deficient animal models as controls. In animal models of AD, a general consensus on the beneficial effects of n-3 LCPUFA in attenuating cognitive impairment was established. These studies make DHA a potential suitable micronutrient for the maintenance of cognitive performance at all periods of life.
Asunto(s)
Cognición/efectos de los fármacos , Suplementos Dietéticos , Ácidos Docosahexaenoicos/administración & dosificación , Adulto , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Niño , Cognición/fisiología , Femenino , Feto , Humanos , Lactante , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , EmbarazoRESUMEN
Within the central nervous system (CNS) the traditional role of microglia has been in brain infection and disease, phagocytosing debris and secreting factors to modify disease progression. This led to the concept of "resting" versus "activated" microglia. However, this is misleading because multiple phenotypic and morphological stages of microglia can influence neuronal structure and function in any condition and recent evidence extends their role to healthy brain homeostasis. The present work was thus aimed at reappraising the concept of morphofunctional activity of microglia in a context of peripheral acute immune challenge, where microglial activity is known to be modified, using the new state-of-the-art techniques available. To do so, mice were injected peripherally with lipopolysaccharide, a potent inducer of cerebral inflammation, and we assessed early cytokines production, phenotype, motility and morphology of microglial cells. Our results showed that LPS induced a widespread inflammatory response both peripherally and centrally, as revealed by the quantification of cytokines levels. We also found an alteration of microglial motility that was confirmed by in vivo studies showing an overall reduction of microglial processes length in the hippocampus of LPS-treated animals. Finally, analysis of various surface receptors expression revealed that LPS did not significantly impact microglial phenotype 2h after the injection but rather induced an increase of CD11b(+)/CD45(high) cells. These latter may be at the vasculature, at the CNS vicinity, or may have invaded the CNS.
Asunto(s)
Citocinas/metabolismo , Lipopolisacáridos/toxicidad , Microglía/citología , Microglía/fisiología , Animales , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Inflamación/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacosRESUMEN
AIM: The composition of the meibum of blepharitis patients is characterised by increased levels of branched-chain fatty acids (BCFAs) that return to normal values in patients treated with cyclins and lid hygiene. The aim of this study was to determine if BCFAs had toxic effects on conjunctival cells related to the disease. METHODS: Chang and IOBA-NHC conjunctival human cells were treated with BCFAs (isoC16 and isoC20) or palmitic acid as a control for 4 h or 24 h at 50 microM or 100 microM. Morphological and functional changes were investigated by measuring mitochondrial dehydrogenase activity, cell permeability, mitochondrial depolarisation, chromatin condensation, IL-1beta and reactive oxygen species production. RESULTS: None of the fatty acids modified the parameters of cytotoxicity in conjunctival cells in Chang or IOBA-NHC cell lines. Only the mitochondrial dehydrogenase activity was significantly decreased in relation to the isoC20 concentration increase. CONCLUSIONS: The increase in BCFAs in the tears of blepharitis patients does not consistently participate in the conjunctival cell changes throughout the course of the disease. Instead, it is likely an adaptive response of the ocular surface to the lack of tears, possibly increasing meibum fluidity, thus enhancing lacrimal film stability.
Asunto(s)
Blefaritis/metabolismo , Conjuntiva/efectos de los fármacos , Ácidos Grasos/farmacología , Lágrimas/metabolismo , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular , Conjuntiva/citología , Conjuntiva/metabolismo , Relación Dosis-Respuesta a Droga , Ácidos Grasos/metabolismo , Ácidos Grasos/farmacocinética , Humanos , Interleucina-1beta/biosíntesis , Especies Reactivas de Oxígeno/metabolismoRESUMEN
AIMS: To assess the changes in ocular surface abnormalities and meibomian fatty acid composition in patients suffering from meibomian gland dysfunction (MGD) after treatment with oral minocycline associated with lid hygiene versus lid hygiene only. METHODS: We evaluated the break-up time, corneal staining and quality of meibomian excreta, and collected meibomian oil in 20 individuals suffering from MGD before and after 8 weeks of minocycline associated with lid hygiene (n = 10) or lid hygiene only (n = 10). Meibomian fatty acids were directly transmethylated and analysed by gas chromatography (GC) and GC mass spectrometry. RESULTS: The meibomian fatty acid composition was slightly modified after 8 weeks in both groups. The decrease in a branched-chain fatty acid (isoC20) was greater after minocycline treatment than after lid hygiene only (-65% and -25%, respectively; p<0.05). Other fatty acids were unchanged. A significant improvement in the BUT was observed after minocycline treatment (p = 0.03). CONCLUSION: This study showed better tear film stability after minocycline treatment and a biological effect on meibomian fatty acid composition in MGD patients. Minocycline was more effective than lid hygiene alone. Both interventions partly corrected fatty acid composition abnormalities. Among the fatty acids, isoC20 could be a biological marker of MGD.
Asunto(s)
Antibacterianos/administración & dosificación , Enfermedades de los Párpados/tratamiento farmacológico , Ácidos Grasos/metabolismo , Glándulas Tarsales/metabolismo , Minociclina/administración & dosificación , Administración Oral , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Antibacterianos/uso terapéutico , Blefaritis/tratamiento farmacológico , Blefaritis/metabolismo , Enfermedades de los Párpados/terapia , Ácidos Grasos/análisis , Femenino , Humanos , Higiene , Masculino , Glándulas Tarsales/efectos de los fármacos , Persona de Mediana Edad , Minociclina/uso terapéutico , Lágrimas , Resultado del TratamientoRESUMEN
AIMS: To evaluate the differences in meibomian fatty acid composition in healthy subjects and in patients suffering from meibomian gland dysfunction or aqueous-deficient dry eye. METHODS: We collected meibomian oil using a sterile Schirmer paper in healthy individuals (n = 20), dry eye patients (aqueous-deficient) (n = 32) and meibomian gland dysfunction (MGD) patients (n = 25) after gentle massage of the lid margin. Meibomian fatty acids were directly transmethylated and analysed using gas chromatography (GC) and GC mass spectrometry. RESULTS: Meibomian fatty acids were similar in healthy individuals and in dry eye patients but were different in MGD patients, who showed significantly higher levels of branched-chain fatty acids (29.8% vs 20.2%) (p<0.0001) and lower levels of saturated fatty acids (9.3 vs 24.6%) (p<0.0001), in particular lower levels of palmitic (C16) and stearic (C18) acids. CONCLUSION: The increase in branched-chain fatty acids may reflect greater quantities of wax and cholesterol esters and triglycerides in meibomian gland excreta. Since wax and cholesterol esters are the main lipids of meibum, these differences may have physical consequences for tear-film lipid-layer fluidity and stability. Meibomian fatty acid composition and particularly the increase in branched chains could be a marker for meibomian gland dysfunction.
Asunto(s)
Síndromes de Ojo Seco/metabolismo , Enfermedades de los Párpados/metabolismo , Ácidos Grasos/análisis , Glándulas Tarsales/química , Anciano , Cromatografía de Gases/métodos , Ácidos Grasos/química , Femenino , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
INTRODUCTION: Polyunsaturated fatty acids (PUFAs) are involved in inflammatory pathways via prostaglandins. Conjunctival inflammation is a hallmark of all dry eye syndromes. We investigated the role of dietary n-6 and n-3 fatty acids in patients suffering from ocular dryness. PATIENTS AND METHODS: Seventy-one patients presenting with mild to moderate dry eye syndromes were randomly assigned to Nutrilarm or placebo capsules, twice a day for 6 months. The Schirmer test, BUT, fluorescein staining, and lissamin green stainings were performed at inclusion and after 1, 3, and 6 months. Furthermore, a questionnaire related to the dry eye symptoms and global discomfort was provided at every visit. RESULTS: The Schirmer test, BUT, fluorescein staining, and lissamin green stainings were improved with treatment when compared to placebo but the difference was not statistically significant. The efficacy evaluated by the patients and the investigator were nearly significant (p=0.052 and p=0.054, respectively). For some signs, such as reflex tearing and conjunctival hyperemia, the improvement reached the threshold of significance (p=0.047 and p=0.045, respectively). The same results were found with skin quality and emotional condition, which were improved (61% with treatment versus 36% with placebo). CONCLUSION: This double-masked pilot study shows that PUFAs seem to be an interesting tool to alleviate the symptoms related to dry eye syndrome. These results should be confirmed using a larger study population.
Asunto(s)
Síndromes de Ojo Seco/tratamiento farmacológico , Ácidos Grasos Omega-3/uso terapéutico , Ácidos Grasos Omega-6/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
The pathogenesis of age-related macular degeneration (ARMD) is not clearly understood. Like other age-related diseases, it is associated with abnormal deposits called drusen. These drusens are localized in Bruch's membrane. Recent investigations have shown a link between drusen formation and inflammatory and immunologic reactions. The involvement of oxidative stress is supported by available data as an important contributing factor in the developement of ARMD. The data regarding the nature and the source of the deposits suggest that ARMD may share similar pathways with atherosclerosis. The role of oxydized products of cholesterol, the oxysterols, in the pathogenesis of atherosclerosis is well known. As cholesterol is a constituent of drusens, oxysterols could be involved in retinal pigment epithelium and photoreceptor lesions occurring in ARMD owing to their cytotoxic, pro-inflammatory, and pro-oxydant properties.
Asunto(s)
Aterosclerosis/complicaciones , Colesterol/metabolismo , Degeneración Macular/etiología , Estrés Oxidativo , Aterosclerosis/patología , Humanos , Degeneración Macular/patología , Factores de RiesgoRESUMEN
Pure individual phytosterols were prepared using reversed-phase HPLC in order to obtain the oxidized compounds of sitosterol, campesterol, stigmasterol and brassicasterol. 7-Hydroxy-, 7-keto-, 5,6-epoxy-, 4beta-hydroxy-, 4-ene-6-hydroxy-, 6-keto- and 5alpha,6beta-dihydroxyphytosterols were obtained as well as analogous compounds of cholesterol. The gas chromatographic properties as well as the electronic impact mass spectra of these compounds (as trimethylsilyl ether derivatives) were studied. These data were used to identify oxyphytosterols in a spread enriched in phytosterols: the oxyphytosterols represented no more than 68 microg/g of spread (about 0.08% of phytosterols were oxidised).