•Dietary n-3 LC-PUFA supplementation modulates hippocampal oxylipins profile.•Dietary n-3 LC-PUFA supplementation decreases hippocampal pro-inflammatory cytokines induced by LPS.•Oxylipin profile ...depending on dietary intake could orchestrate inflammatory response to LPS.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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.
Highlight • Our work confirmed that the concept of “resting” and “activated” microglia is misleading since microglia might present a high morpho-functional plasticity in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
J. Neurochem. (2011) 118, 490–498.
A substantial body of data was reported between 1984 and 2000 demonstrating that the neuropeptide N‐acetylaspartylglutamate (NAAG) not only functions as a ...neurotransmitter but also is the third most prevalent transmitter in the mammalian nervous system behind glutamate and GABA. By 2005, this conclusion was validated further through a series of studies in vivo and in vitro. The primary enzyme responsible for the inactivation of NAAG following its synaptic release had been cloned, characterized and knocked out. Potent inhibitors of this enzyme were developed and their efficacy has been extensively studied in a series of animal models of clinical conditions, including stroke, peripheral neuropathy, traumatic brain injury, inflammatory and neuropathic pain, cocaine addiction, and schizophrenia. Considerable progress also has been made in defining further the mechanism of action of these peptidase inhibitors in elevating synaptic levels of NAAG with the consequent inhibition of transmitter release via the activation of pre‐synaptic metabotropic glutamate receptor 3 by this peptide. Very recent discoveries include identification of two different nervous system enzymes that mediate the synthesis of NAAG from N‐acetylaspartate and glutamate and the finding that one of these enzymes also mediates the synthesis of a second member of the NAAG family of neuropeptides, N‐acetylaspartylglutamylglutamate.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The most widely validated animal models of the positive, negative and cognitive symptoms of schizophrenia involve administration of d-amphetamine or the open channel NMDA receptor blockers, ...dizocilpine (MK-801), phencyclidine (PCP) and ketamine. The drug ZJ43 potently inhibits glutamate carboxypeptidase II (GCPII), an enzyme that inactivates the peptide transmitter N-acetylaspartylglutamate (NAAG) and reduces positive and negative behaviors induced by PCP in several of these models. NAAG is an agonist at the metabotropic glutamate receptor 3 (mGluR3). Polymorphisms in this receptor have been associated with expression of schizophrenia. This study aimed to determine whether two different NAAG peptidase inhibitors are effective in dopamine models, whether their efficacy was eliminated in GCPII knockout mice and whether the efficacy of these inhibitors extended to MK-801-induced cognitive deficits as assessed using the novel object recognition test. ZJ43 blocked motor activation when given before or after d-amphetamine treatment. (R,S)-2-phosphono-methylpentanedioic acid (2-PMPA), another potent NAAG peptidase inhibitor, also reduced motor activation induced by PCP or d-amphetamine. 2-PMPA was not effective in GCPII knockout mice. ZJ43 and 2-PMPA also blocked MK-801-induced deficits in novel object recognition when given before, but not after, the acquisition trial. The group II mGluR antagonist LY341495 blocked the effects of NAAG peptidase inhibition in these studies. 2-PMPA was more potent than ZJ43 in a test of NAAG peptidase inhibition in vivo. By bridging the dopamine and glutamate theories of schizophrenia with two structurally different NAAG peptidase inhibitors and demonstrating their efficacy in blocking MK-801-induced memory deficits, these data advance the concept that NAAG peptidase inhibition represents a potentially novel antipsychotic therapy.
Microglial cells are an integral part of central nervous system networks. They were considered “resting,” but it has recently become evident that they actively sense neuronal microenvironment. In the ...developing brain, they contribute directly to the establishment of neuronal networks by eliminating or maintaining synapses. Morphofunctional plasticity of microglial cells is finely tuned in order to keep brain homeostasis and to ensure such developmental activity. N-6 and n-3 polyunsaturated fatty acids are essential fatty acids that have to be provided through the diet. They are precursors of bioactive lipid messengers involved in the regulation of inflammation and microglial activity. We previously demonstrated that depleting the diet in n-3 fatty acids from the first day of gestation alters some neuronal functions of the offspring at adulthood. We here hypothesized this is due to an alteration of microglial morphofunctional activity in the developing brain. Mice were submitted to a diet deficient or not in n-3 throughout gestation and lactation. Microglial morphology, phenotypes and functions were determined in the brain of pups at post-natal day 21. Microglial cells from mice fed with an n-3 deficient diet presented a drastic change of phenotype and a dysregulated activity. All together, our results show that dietary n-3 deficiency is likely to impair brain innate immune system activity at weaning. The outcome of such microglial impairment on brain function is discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Through-mask electrochemical micromachining has been employed to fabricate well-defined three-dimensional topographies in titanium. Well-controlled shapes with a smooth surface finish were obtained ...using optimized electrolyte composition and electrochemical parameters. The shape change resulting from electrochemical etching through patterned photoresists were numerically simulated using the boundary element method, assuming the rate of titanium dissolution to be diffusion controlled. A satisfactory agreement was found between experimentally measured and simulated etched profiles.
The mechanism of electropolishing of titanium in methanol-sulfuric acid electrolytes is studied by steady-state measurements and by ac-impedance spectroscopy using a rotating disk electrode. The ...effect of applied potential, electrode rotation rate, temperature, and electrolyte composition on the response of the system is investigated at the mass-transport-limited current plateau. Both steady-state measurements and impedance data suggest that the rate of reaction is controlled by mass transport of tetravalent titanium species from the anode surface to the bulk electrolyte. The impedance data confirm the presence of a compact film at the anode surface during titanium dissolution at the limiting current.
To date, no studies have reported nationwide adoption of acute care surgery (ACS) or identified structural and/or process variations for the care of emergency general surgery (EGS) patients within ...such models.
We surveyed surgeons responsible for EGS coverage at University Health Systems Consortium hospitals using an eight-page postal/e-mail questionnaire querying respondents on hospital and EGS structure/process measures. Survey responses were analyzed using descriptive statistics, univariate comparisons, and multivariable regression models.
Of 319 potential respondents, 258 (81%) completed the surveys. A total of 81 hospitals (31%) had implemented ACS, while 134 (52%) had a traditional general surgeon on-call (GSOC) model. Thirty-eight hospitals (15%) had another model (hybrid). Larger-bed, university-based, teaching hospitals with Level 1 trauma center verification status located in urban areas were more likely to have adopted ACS. In multivariable modeling, hospital type, setting, and trauma center verification predicted ACS implementation. EGS processes of care varied, with 28% of the GSOC hospitals having block time versus 67% of the ACS hospitals (p < 0.0001), 45% of the GSOC hospitals providing ICU intensive care unit care to EGS patients in a surgical/trauma ICU versus 93% of the ACS hospitals (p < 0.0001), 5.7 ± 3.2 surgeons sharing call at GSOC hospitals versus 7.9 ± 2.3 surgeons at ACS hospitals (p < 0.0001), and 13% of the GSOC hospitals requiring in-house EGS call versus 75% of the ACS hospitals (p < 0.0001). Among ACS hospitals, there were variations in patient cohorting (EGS patients alone, 25%; EGS + trauma, 21%; EGS + elective, 17%; and EGS + trauma + elective, 30%), data collection (26% had prospective EGS registries), patient hand-offs (56% had attending surgeon presence), and call responsibilities (averaging 4.8 ± 1.3 calls per month, with 60% providing extra call stipend and 40% with no postcall clinical duties).
The potential of the ACS on the national crisis in access to EGS care is not fully met. Variations in EGS processes of care among adopters of ACS suggest that standardized criteria for ACS implementation, much like trauma center verification criteria, may be beneficial.
A model for predicting leveling during electrodeposition in the presence of an inhibiting additive is presented. Based on a diffusion-adsorption mechanism, the model assumes that the additive is ...consumed at the cathode by electroreduction. Using the approximation of a flat, stagnant diffusion layer, leveling during metal electrodeposition into triangular and semicircular grooves is simulated. The variation of the leveling agent concentration along the groove profile is determined by solving a concentration field problem with a boundary element method, and the advancement of the groove profile is simulated with a flexible moving-boundary algorithm. Leveling performance depends on three dimensionless groups characterizing leveling-agent reduction, metal-ion reduction, and the geometrical ratio of the diffusion layer thickness to groove depth. Experiments (done in part II of this study) were done with nickel deposition.
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