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Depression is a highly prevalent disorder and a leading cause of disability worldwide. It has a major impact on the affected individual and on society as a whole. Regrettably, current available treatments for this condition are insufficient in many patients. In recent years, the gut microbiome has emerged as a promising alternative target for treating and preventing depressive disorders. However, the microbes that form this ecosystem do not act alone but are part of a complicated network connecting the gut and the brain that influences our mood. Host cells that are in intimate contact with gut microbes, such as the epithelial cells forming the gut barrier and the immune cells in their vicinity, play a key role in the process. These cells continuously shape immune responses to maintain healthy communication between gut microbes and the host. In this article, we review how the interplay among epithelial cells, the immune system, and gut microbes mediates gut-brain communication to influence mood. We also discuss how advances in our knowledge of the mechanisms underlying the gut-brain axis could contribute to addressing depression. SIGNIFICANCE STATEMENT: This review does not aim to systematically describe intestinal microbes that might be beneficial or detrimental for depression. We have adopted a novel point of view by focusing on potential mechanisms underlying the crosstalk between gut microbes and their intestinal environment to control mood. These pathways could be targeted by well defined and individually tailored dietary interventions, microbes, or microbial metabolites to ameliorate depression and decrease its important social and economic impact.
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Eje Cerebro-Intestino , Depresión , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/inmunología , Microbioma Gastrointestinal/fisiología , Animales , Eje Cerebro-Intestino/fisiología , Depresión/inmunología , Depresión/microbiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/metabolismoRESUMEN
Immune cells and the brain have a privileged interaction. Here, we report changes in the hippocampal immune microenvironment at the single cell level after stress, uncovering the tight orchestration of immune cell infiltration into the hippocampus after stress to maintain homeostasis. We show the distribution of several immune cell types in the hippocampus associated with their susceptibility or resilience to the learned helplessness paradigm in a sex- and microbiota-dependent manner using single-cell RNA sequencing and bioinformatic tools, flow cytometry, and immunofluorescence. We uncovered the presence of tissue-resident memory T cells that accumulate over time in the hippocampus of learned helpless mice, and the presence of CD74-expressing myeloid cells. These cells were found by a knockdown approach to be critical to induce resilience to learned helplessness. Altogether, these findings provide a novel overview of the neuro-immune repertoire and its impact on the landscape of the hippocampus after learned helplessness.
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Encéfalo , Hipocampo , Ratones , Animales , Hipocampo/metabolismo , Desamparo Adquirido , Estrés Psicológico/metabolismoRESUMEN
Psychiatric disorders are mental illnesses involving changes in mood, cognition and behavior. Their prevalence has rapidly increased in the last decades. One of the most prevalent psychiatric disorders is major depressive disorder (MDD), a debilitating disease lacking efficient treatments. Increasing evidence shows that microbial and immunological changes contribute to the pathophysiology of depression and both are modulated by stress. This bidirectional relationship constitutes the brain-gut axis involving various neuroendocrine, immunological, neuroenterocrine and autonomic pathways. The present review covers the most recent findings on the relationships between stress, the gut microbiome and the inflammatory response and their contribution to depression.
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Trastorno Depresivo Mayor , Microbioma Gastrointestinal , Humanos , Depresión/metabolismo , Trastorno Depresivo Mayor/metabolismo , Microbioma Gastrointestinal/fisiología , Afecto , Inflamación/metabolismo , Encéfalo/metabolismoRESUMEN
BACKGROUND: Microbiome alterations have been associated with depression, and fecal transfer of depressed patients' microbiomes is sufficient to enhance despair behaviors in rodents. Yet little is known about the potential mechanisms, whereby microbes modulate depressive-like behaviors. RESULTS: In this study, we showed that certain bacteria known to induce Th17 cells are increased in depressed patients and mice exhibiting learned helplessness. Fecal transfers of human depressed patients' microbiomes into germ-free-like mice were sufficient to decrease sociability and increased susceptibility to the learned helplessness paradigm, confirming that the microbiome is sufficient to confer depressive-like behaviors. This microbial effect was dependent on the presence of Th17 cells in the recipient, as germ-free-like recipient mice deficient in Th17 cells were resistant to the behavioral changes induced by the microbiome of depressed patients. CONCLUSION: Altogether, these findings suggest a crucial role of the microbiome/Th17 cell axis in regulating depressive-like behaviors. Video Abstract.
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Microbioma Gastrointestinal , Microbiota , Humanos , Ratones , Animales , Células Th17 , Microbioma Gastrointestinal/fisiología , Depresión/microbiología , HecesRESUMEN
The blood brain barrier (BBB) is a vital structure to protect the brain, tightly filtering the passage of nutrients and molecules from the blood to the brain. This is critical for maintaining the proper functioning of the brain, and any disruption in the BBB has detrimental consequences often leading to diseases. It is not clear whether disruption of the BBB occurs first in depression or is the consequence of the disease, however disruption of the BBB has been observed in depressed patients and evidence points to the role of important culprits in depression, stress and inflammation in disrupting the integrity of the BBB. The mechanisms whereby stress, and inflammation affect the BBB remain to be fully understood. Yet, the role of cytokines in regulating tight junction protein expression seems crucial. Altogether, the findings in depression suggest that acting at the BBB level might provide therapeutic benefit in depression.
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Barrera Hematoencefálica , Depresión , Humanos , Barrera Hematoencefálica/metabolismo , Inflamación/metabolismo , Transporte Biológico , Encéfalo/metabolismoRESUMEN
Major depressive disorder (MDD) is a debilitating disease with a high worldwide prevalence. Despite its greater prevalence in women, male animals are used in most preclinical studies of depression even though there are many sex differences in key components of depression, such as stress responses and immune system functions. In the present study, we found that chronic restraint stress-induced depressive-like behaviors are quite similar in male and female mice, with both sexes displaying increased immobility time in the tail suspension test and reduced social interactions, and both sexes exhibited deficits in working and spatial memories. However, in contrast to the similar depressive-like behaviors developed by male and female mice in response to stress, they displayed different patterns of pro-inflammatory cytokine increases in the periphery and the brain, different changes in microglia, and different changes in the expression of Toll-like receptor 4 in response to stress. Treatment with (+)-naloxone, a Toll-like receptor 4 antagonist that previously demonstrated anti-depressant-like effects in male mice, was more efficacious in male than female mice in reducing the deleterious effects of stress, and its effects were not microbiome-mediated. Altogether, these results suggest differential mechanisms to consider in potential sex-specific treatments of depression.
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Trastorno Depresivo Mayor , Receptor Toll-Like 4 , Animales , Conducta Animal , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Naloxona/farmacología , Estrés Psicológico/tratamiento farmacológicoRESUMEN
The aim of the present study is to analyze the relation between the severity of symptoms in people with ASD on their parents' overload, moderated by parental well-being and the ASD pragmatic level. A sample consisted of 28 fathers and mothers whose children had ASD. The obtained results showed that the higher the ASD severity, the better the parental overload was perceived if parents had low well-being levels. However, this relation did not occur if the parental well-being level was high. Moreover, the relation between severity and parental overload moderated by parental well-being occurred regardless of the pragmatic language level. Therefore, the main results of this study are that the responsibility for parental overload depends more on parental well-being than on the symptom severity of the person with ASD. The relevance of carrying out interventions with not only people with ASD, but also with their parents or caregivers for their well-being is highlighted.
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There is a vital need to understand mechanisms contributing to susceptibility to depression to improve treatments for the 11% of Americans who currently suffer from this debilitating disease. The adaptive immune system, comprising T and B cells, has emerged as a potential contributor to depression, as demonstrated in the context of lymphopenic mice. Overall, patients with depression have reduced circulating T and regulatory B cells, "immunosuppressed" T cells, and alterations in the relative abundance of T cell subtypes. T helper (Th) cells have the capacity to differentiate to various lineages depending on the cytokine environment, antigen stimulation, and costimulation. Regulatory T cells are decreased, and the Th1/Th2 ratio and the Th17 cells are increased in patients with depression. Evidence for changes in each Th lineage has been reported to some extent in patients with depression. However, the evidence is strongest for the association of depression with changes in Th17 cells. Th17 cells produce the inflammatory cytokine interleukin (IL)-17A, and the discovery of Th17 cell involvement in depression evolved from the well established link that IL-6, which is required for Th17 cell differentiation, contributes to the onset, and possibly maintenance, of depression. One intriguing action of Th17 cells is their participation in the gut-brain axis to mediate stress responses. Although the mechanisms of action of Th17 cells in depression remain unclear, neutralization of IL-17A by anti-IL-17A antibodies, blocking stress-induced production, or release of gut Th17 cells represent feasible therapeutic approaches and might provide a new avenue to improve depression symptoms. SIGNIFICANCE STATEMENT: Th17 cells appear as a promising therapeutic target for depression, for which efficacious therapeutic options are limited. The use of neutralizing antibodies targeting Th17 cells has provided encouraging results in depressed patients with comorbid autoimmune diseases.
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Depresión , Células Th17 , Animales , Citocinas , Humanos , Ratones , Linfocitos T ReguladoresRESUMEN
Numerous studies report on the synergy between ozonation and photocatalytic oxidation (TiO2/UVA), which could open the way to the application of photocatalytic ozonation (PCOz) in water treatment. With the aim of establishing the existence of this synergy and its origin, in this work, using TiO2 P25, 365 nm UVA LEDs and ozone transferred doses up to 5 mg (mg DOC0)-1 (DOC0 7 - 10 mg L-1), a systematic study has been carried out featuring the effect of pH, alkalinity and water matrix in each of the systems involved in PCOz, with special attention to the role of organics adsorption onto TiO2. In ultrapure water, an increase in pH and carbonates content exerted a slight negative effect on the photocatalytic degradation of primidone (low adsorption onto TiO2 and mainly abated by free HOâ¢), this effect being higher on its mineralization. The negative effect of pH and alkalinity was much stronger for oxalic acid (high tendency to adsorb and mainly oxidized by positive holes). Accordingly, the results obtained at pH < pHpzc (point of zero charge of the catalyst) in ultrapure water cannot at all be extrapolated to secondary effluents, since their composition negatively affects the photocatalytic performance. At the experimental conditions applied, only for the secondary effluent a synergy between O3/UVA and TiO2/UVA systems was observed. This synergy would be related, on the one hand, to the generation, from the matrix itself, of reactive entities or intermediates that promote the decomposition of ozone into HOâ¢; and, on the other hand, to an increase in catalyst activity as the matrix UVA absorption decreases, rather than from direct interactions between both systems. Despite de above, ozone requirement to achieve a significant reduction of DOC is high and would only be an interesting strategy for the elimination of ozone-refractory micropollutants.
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Ozono , Contaminantes Químicos del Agua , Purificación del Agua , Catálisis , Oxidación-Reducción , Titanio , Contaminantes Químicos del Agua/análisisRESUMEN
Mathematical models for the spread of diseases help us understand the mechanisms on how diseases spread, evaluate the possible effects of interventions, predict outcomes of epidemics, and forecast the course of outbreaks. Compartmental models are widely used in synthetic biology since they can represent a biological system as an assembly of various parts or compartments with different functions. Here we present a framework for the analysis of a compartmental model for the transmission of diseases using ordinary differential equations. We apply this method on a study about the spread of tuberculosis.
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Transmisión de Enfermedad Infecciosa , Epidemias , Modelos Biológicos , Biología Sintética , HumanosRESUMEN
Depression is a leading cause of disability worldwide and current treatments are often inadequate for many patients. Increasing evidence indicates that inflammation contributes to susceptibility to depression. We hypothesized that targeting Toll-like receptor 4 (TLR4), one of the main signaling pathways for triggering an inflammatory response, would lessen stress-induced depression-like behaviors in male mice. TLR4 inhibition with the CNS-penetrating drug (+)-naloxone that is a TLR4 antagonist but is inactive at opiate receptors increased resistance to the learned helplessness model of depression and provided an antidepressant-like effect in the tail suspension test. (+)-Naloxone administration also reversed chronic restraint stress-induced impairments in social behavior and novel object recognition. These effects involved blockade of stress-induced activation of glycogen synthase kinase 3ß (GSK3ß), NF-κB, IFN regulatory factor 3 (IRF3) and nitric oxide production, and reduced levels of the cytokines tumor necrosis factor-α (TNFα) and interferon-ß (IFNß). These findings demonstrate that blocking TLR4 with (+)-naloxone effectively diminishes several detrimental responses to stress and raise the possibility that (+)-naloxone may be a feasible intervention for depression.
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Naloxona , Receptor Toll-Like 4 , Animales , Humanos , Masculino , Ratones , FN-kappa B/metabolismo , Naloxona/farmacología , Transducción de Señal , Factor de Necrosis Tumoral alfaRESUMEN
OBJECTIVE: Microbiota dysbiosis has been linked to major depressive disorder, but the mechanisms whereby the microbiota modulates mood remain poorly understood. The authors tested whether specific changes in the microbiome modulate depressive-like behaviors. METHODS: Stools from learned helpless, non-learned helpless, and non-shocked mice were analyzed by V4 16S RNA sequencing to identify gut bacteria associated with learned helplessness and to quantify the level of the quorum-sensing molecule autoinducer-2 (AI-2). T cells were analyzed by flow cytometry, and serum amyloid proteins (SAA) were analyzed by quantitative real-time polymerase chain reaction. Fecal transfer approach and administration of oleic acid and AI-2 were used to determine the effects of the microbiome and quorum-sensing molecules on depressive-like behaviors. RESULTS: Mice deficient in segmented filamentous bacteria (SFB) were resilient to the induction of depressive-like behavior, and were resensitized when SFB was reintroduced in the gut. SFB produces the quorum-sensing AI-2 and promotes the production of SAA1 and SAA2 by the host, which increases T helper 17 (Th17) cell production. Th17 cells were required to promote depressive-like behaviors by AI-2, as AI-2 administration did not promote susceptibility to depressive-like behaviors or SAA1 and SAA2 production in Th17-deficient mice after stress. Oleic acid, an AI-2 inhibitor, exhibited antidepressant properties, reducing depressive-like behavior, intestinal SAA1 and SAA2 production, and hippocampal Th17 cell accumulation. Stool samples from 10 people with current depressive symptoms and 10 matched healthy control subjects were analyzed as well. Patients with current major depressive disorder exhibited increased fecal interleukin 17A, SAA, and SFB levels. CONCLUSIONS: The study results reveal a novel mechanism by which bacteria alter mood.
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Depresión/metabolismo , Microbioma Gastrointestinal/fisiología , Células Th17/fisiología , Adulto , Animales , Trastorno Depresivo Mayor/metabolismo , Modelos Animales de Enfermedad , Heces/química , Femenino , Citometría de Flujo , Microbioma Gastrointestinal/genética , Desamparo Adquirido , Humanos , Interleucina-17/análisis , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Percepción de Quorum , ARN Ribosómico 16S/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína Amiloide A Sérica/análisis , Células Th17/metabolismoRESUMEN
Besides giving rise to oligodendrocytes (the only myelin-forming cell in the Central Nervous System (CNS) in physiological conditions), Oligodendrocyte Precursor Cells (OPCs) are responsible for spontaneous remyelination after a demyelinating lesion. They are present along the mouse and human CNS, both during development and in adulthood, yet how OPC physiological behavior is modified throughout life is not fully understood. The activity of adult human OPCs is still particularly unexplored. Significantly, most of the molecules involved in OPC-mediated remyelination are also involved in their development, a phenomenon that may be clinically relevant. In the present article, we have compared the intrinsic properties of OPCs isolated from the cerebral cortex of neonatal, postnatal and adult mice, as well as those recovered from neurosurgical adult human cerebral cortex tissue. By analyzing intact OPCs for the first time with 1H High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, we show that these cells behave distinctly and that they have different metabolic patterns in function for their stage of maturity. Moreover, their response to Fibroblast Growth Gactor-2 (FGF-2) and anosmin-1 (two molecules that have known effects on OPC biology during development and that are overexpressed in individuals with Multiple Sclerosis (MS)) differs in relation to their developmental stage and in the function of the species. Our data reveal that the behavior of adult human and mouse OPCs differs in a very dynamic way that should be very relevant when testing drugs and for the proper design of effective pharmacological and/or cell therapies for MS.
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Major depression is a prevalent, debilitating disease, yet therapeutic interventions for depression are frequently inadequate. Many clinical and pre-clinical studies have demonstrated that depression is associated with aberrant activation of the inflammatory system, raising the possibility that reducing inflammation may provide antidepressant effects. Using the learned helplessness mouse model, we tested if susceptibility or recovery were affected by deficiency in either of two receptors that initiate inflammatory signaling, Toll-like receptor-4 (TLR4) and TLR2, using knockout male mice. TLR4-/- mice displayed a strong resistance to learned helplessness, confirming that blocking inflammatory signaling through TLR4 provides robust protection against this depression-like behavior. Surprisingly, TLR2-/- mice displayed increased susceptibility to learned helplessness, indicating that TLR2-mediated signaling counteracts susceptibility. TLR2-mediated signaling also promotes recovery, as TLR2-/- mice demonstrated a severe impairment in recovery from learned helplessness. That TLR2 actually protects from learned helplessness was further verified by the finding that administration of the TLR2 agonist Pam3CSK4 reduced susceptibility to learned helplessness. Treatment with Pam3CSK4 also reversed chronic restraint stress-induced impaired sociability and impaired learning in the novel object recognition paradigm, demonstrating that TLR2 stimulation can protect from multiple impairments caused by stress. In summary, these results demonstrate that TLR2-mediated signaling provides a counter-signal to oppose deleterious effects of stress that may be related to depression, and indicate that TLR2 and TLR4 act oppositely to balance mood-relevant responses to stress.
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Depresión , Receptor Toll-Like 2 , Animales , Inflamación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Receptor Toll-Like 2/genéticaRESUMEN
T helper type 17 (Th17) cells are recognized as important contributors to the deleterious effects of several neurological and psychiatric diseases. Clarifying mechanisms that control the production of Th17 cells may therefore provide new strategies for developing novel interventions in a broad spectrum of disorders. Th17 cell differentiation is promoted by glycogen synthase kinase-3 (GSK3), but the mechanisms for this are only beginning to be understood. Using T-cell-selective depletion of GSK3ß and multiple selective pharmacological GSK3 inhibitors, we found that GSK3 inhibition decreased C-C motif chemokine (ccl)20, C-C motif chemokine receptor (ccr)6, interleukin (IL)-9, Runt-related transcription factor (Runx)1, interferon regulatory factor (Irf)4 and c-maf mRNA expression after 2 days of Th17 cell differentiation in vitro. These effects were found to be independent of the master regulator transcription factor retinoic acid receptor-related orphan receptor γT (RORγT), as GSK3 inhibition still reduced Th17 cell differentiation in RORγT-depleted cells. Because IL-9 was approximately ninefold down-regulated in GSK3ß-/- CD4 cells, we tested if reintroduction of IL-9 during Th17 cell differentiation abolished the inhibition by GSK3 deficiency of Th17 cell differentiation. We found that IL-9 over-expression was sufficient to reverse the inhibition of Th17 cell differentiation by GSK3 inhibition or depletion. We found that IL-9 enhances Th17 cell differentiation in part through signal transducer and activator of transcription 3 (STAT3) activation, and IL-9 also enhances STAT3 binding to the IL-17a promoter. Altogether, these findings suggest that IL-9 might be an important mediator of GSK3ß-dependent enhancement of Th17 cell differentiation.
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Glucógeno Sintasa Quinasa 3/metabolismo , Interleucina-9/metabolismo , Células Th17/inmunología , Animales , Diferenciación Celular , Células Cultivadas , Subunidades alfa del Factor de Unión al Sitio Principal/genética , Glucógeno Sintasa Quinasa 3/genética , Interleucina-17/genética , Activación de Linfocitos , Depleción Linfocítica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Regiones Promotoras Genéticas/genética , Factor de Transcripción STAT3/genéticaRESUMEN
The generation of hydroxyl radicals (â¢OH) during the chlorination of air saturated solutions of different hydroxyphenols (hydroquinone, resorcinol, catechol, gallic and tannic acids) at pH 7 has been determined by the formation of phenol (in presence of benzene in excess) or 2-hydroxyterephthalic acid (in presence of terephthalic acid). Formation of â¢OH was only detected during the chlorination of o- or p-hydroxyphenols, compounds that react with chlorine by electron transfer forming the corresponding semiquinones/quinones. In aerated solutions, oxygen is reduced by the semiquinone to the superoxide radical, O2â¢-, which reacts with HOCl to â¢OH. Compared to the studied o-hydroxyphenols, the lower reactivity of hydroquinone towards chlorine favours the reaction between chlorine and O2â¢-, and its â¢OH formation potential is â¼50 times higher. The extent of â¢OH generated increased with the concentration of the hydroxyphenol and chlorine, but the â¢OH yield (moles formed per mole of hydroxyphenol eliminated), decreased due to the formation of the quinone, that acts as O2â¢- scavenger. The yield was almost not affected by the pH (6 ≤ pH ≤ 7.5), whereas a strong impact of dissolved O2 was observed. The â¢OH production was null in absence of O2 and 2.5-3 times higher at oxygen saturated conditions compared to air-saturated. Contrary to chlorination, during bromination of hydroquinone â¢OH was not formed, which can be attributable to a much faster consumption of the oxidant, with no chance for O2â¢- to react with bromine. Formation of â¢OH during the chlorination of different NOM extracts (SRHA, SRFA, PLFA and Nordic Lake NOM) and water from Lake Greifensee (Switzerland) was also studied using terephthalic acid as â¢OH scavenger. For SRHA, SRFA and Nordic Lake NOM (all of allochthonous origin and presenting high electron-donating capacity, EDC), â¢OH yields expressed as moles formed per mole of DOC0 (%), were between 1.1 and 2.0, similar to that of hydroquinone (â¼1.5). For PLFA and Lake Greifensee water (autochthonous, lower EDC) much lower â¢OH yields were observed (0.1-0.3). Both chlorination rate and EDC, the later favouring the formation/stabilization of O2â¢-, seem to be key factors involved in â¢OH generation during the chlorination of NOM. A mechanism for these findings is proposed based on kinetic simulations of hydroquinone chlorination at pH 7.
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Halogenación , Radical Hidroxilo , Cloro , Extractos Vegetales , SuizaRESUMEN
In this work, primidone, a high persistent pharmacological drug typically found in urban wastewaters, was degraded by different ozone combined AOPs using TiO2 P25 and commercial WO3 as photocatalyst. The comparison of processes, kinetics, nature of transformation products, and ecotoxicity of treated water samples, as well as the influence of the water matrix (ultrapure water or a secondary effluent), is presented and discussed. In presence of ozone, primidone is rapidly eliminated, with hydroxyl radicals being the main species involved. TiO2 was the most active catalyst regardless of the water matrix and the type of solar (global or visible) radiation applied. The synergy between ozone and photocatalysis (photocatalytic ozonation) for TOC removal was more evident at low O3 doses. In spite of having a lower band gap than TiO2 P25, WO3 did not bring any beneficial effects compared to TiO2 P25 regarding PRM and TOC removal. Based on the transformation products identified during ozonation and photocatalytic ozonation of primidone (hydroxyprimidone, phenyl-ethyl-malonamide, and 5-ethyldihydropirimidine-4,6(1H,5H)-dione), a degradation pathway is proposed. The application of the different processes resulted in an environmentally safe effluent for Daphnia magna.
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Óxidos/química , Ozono/química , Primidona/análisis , Titanio/química , Tungsteno/química , Contaminantes Químicos del Agua/análisis , Animales , Catálisis , Daphnia/efectos de los fármacos , Daphnia/crecimiento & desarrollo , Radical Hidroxilo/química , Cinética , Oxidación-Reducción , Procesos Fotoquímicos , Luz Solar , Rayos Ultravioleta , Agua/química , Purificación del AguaRESUMEN
Major depressive disorder (MDD) is a prevalent and debilitating disorder, often fatal. Treatment options are few and often do not provide immediate relief to the patients. The increasing involvement of inflammation in the pathology of MDD has provided new potential therapeutic avenues. Cytokine levels are elevated in the blood and cerebrospinal fluid of MDD patients whereas immune cells often exhibit an immunosuppressed phenotype in MDD patients. Blocking cytokine actions in patients exhibiting MDD show some antidepressant efficacy. However, the role of cytokines, and the immune response in MDD patients remain to be determined. We reviewed here the roles of the innate and adaptive immune systems in MDD, as well as potential mechanisms whereby the immune response might be regulated in MDD.
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We characterised the expression of semaphorin (sema)3A, sema7A and their receptors in the immune and the central nervous system (CNS) at different stages of experimental autoimmune encephalomyelitis (EAE). We also studied their expression in neonatal and adult oligodendrocyte progenitor cell (OPC) and in mature oligodendrocyte cultures. Our results show that sema3A is increased in the CNS and decreased in the immune system upon EAE induction. However, sema7A expression is increased in both the CNS and the immune system during EAE. We also detected sema3A, sema7A and their receptors in neonatal and adult OPCs and in mature oligodendrocytes. These data suggest that sema3A and sema7A are involved in the pathogenesis of EAE, in the modulation of the immune response and in the neurodegeneration that take place in the CNS. Sema7A may represent an intriguing potential therapeutic target for the treatment of both the neurodegenerative and immune-mediated disease processes in MS.
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Antígenos CD/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Semaforina-3A/inmunología , Semaforinas/inmunología , Animales , Antígenos CD/genética , Encéfalo/inmunología , Encéfalo/patología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/genética , Citometría de Flujo , Regulación de la Expresión Génica , Immunoblotting , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Oligodendroglía/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Semaforina-3A/genética , Semaforinas/genética , Médula Espinal/inmunología , Médula Espinal/patologíaRESUMEN
Phenolic compounds are known structural moieties of natural organic matter (NOM), and their reactivity is a key parameter for understanding the reactivity of NOM and the disinfection by-product formation during oxidative water treatment. In this study, species-specific and/or apparent second order rate constants and mechanisms for the reactions of bromine and chlorine have been determined for various phenolic compounds (phenol, resorcinol, catechol, hydroquinone, phloroglucinol, bisphenol A, p-hydroxybenzoic acid, gallic acid, hesperetin and tannic acid) and flavone. The reactivity of bromine with phenolic compounds is very high, with apparent second order rate constants at pH 7 in the range of 10(4) to 10(7) M(-1) s(-1). The highest value was recorded for the reaction between HOBr and the fully deprotonated resorcinol (k = 2.1 × 10(9) M(-1) s(-1)). The reactivity of phenolic compounds is enhanced by the activating character of the phenolic substituents, e.g. further hydroxyl groups. With the data set from this study, the ratio between the species-specific rate constants for the reactions of chlorine versus bromine with phenolic compounds was confirmed to be about 3000. Phenolic compounds react with bromine or chlorine either by oxidation (electron transfer, ET) or electrophilic aromatic substitution (EAS) processes. The dominant process mainly depends on the relative position of the hydroxyl substituents and the possibility of quinone formation. While phenol, p-hydroxybenzoic acid and bisphenol A undergo EAS, hydroquinone, catechol, gallic acid and tannic acid, with hydroxyl substituents in ortho or para positions, react with bromine by ET leading to quantitative formation of the corresponding quinones. Some compounds (e.g. phloroglucinol) show both partial oxidation and partial electrophilic aromatic substitution and the ratio observed for the pathways depends on the pH. For the reaction of six NOM extracts with bromine, electrophilic aromatic substitution accounted for only 20% of the reaction, and for one NOM extract (Pony Lake fulvic acid) it accounted for <10%. This shows that for natural organic matter samples, oxidation (ET) is far more important than bromine incorporation (EAS).