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Major depressive disorder is one of the most common mental disorders in children and adolescents. However, whether to use pharmacological interventions in this population and which drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people. We did a network meta-analysis to identify both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents. We included trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, and venlafaxine. Trials recruiting participants with treatment-resistant depression, treatment duration of less than 4 weeks, or an overall sample size of less than ten patients were excluded. We extracted the relevant information from the published reports with a predefined data extraction sheet, and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy (change in depressive symptoms) and tolerability (discontinuations due to adverse events). We did pair-wise meta-analyses using the random-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023. We deemed 34 trials eligible, including 5260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference −0·51, 95% credible interval [CrI] −0·99 to −0·03). In terms of tolerability, fluoxetine was also better than duloxetine (odds ratio [OR] 0·31, 95% CrI 0·13 to 0·95) and imipramine (0·23, 0·04 to 0·78). Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo (5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and 2·80, 1·20 to 9·42, respectively). In terms of heterogeneity, the global I2 values were 33·21% for efficacy and 0% for tolerability. When considering the risk–benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated. National Basic Research Program of China (973 Program).

Major depressive disorder (MDD) is a serious mental illness, characterized by high morbidity, which has increased in recent decades. However, the molecular mechanisms underlying MDD remain unclear. Previous studies have identified altered metabolic profiles in peripheral tissues associated with MDD. Using curated metabolic characterization data from a large sample of MDD patients, we meta-analyzed the results of metabolites in peripheral blood. Pathway and network analyses were then performed to elucidate the biological themes within these altered metabolites. We identified 23 differentially expressed metabolites between MDD patients and controls from 46 studies. MDD patients were characterized by higher levels of asymmetric dimethylarginine, tyramine, 2-hydroxybutyric acid, phosphatidylcholine (32:1), and taurochenodesoxycholic acid and lower levels of l-acetylcarnitine, creatinine, l-asparagine, l-glutamine, linoleic acid, pyruvic acid, palmitoleic acid, l-serine, oleic acid, myo-inositol, dodecanoic acid, l-methionine, hypoxanthine, palmitic acid, l-tryptophan, kynurenic acid, taurine, and 25-hydroxyvitamin D compared with controls. l-tryptophan and kynurenic acid were consistently downregulated in MDD patients, regardless of antidepressant exposure. Depression rating scores were negatively associated with decreased levels of l-tryptophan. Pathway and network analyses revealed altered amino acid metabolism and lipid metabolism, especially for the tryptophan–kynurenine pathway and fatty acid metabolism, in the peripheral system of MDD patients. Taken together, our integrated results revealed that metabolic changes in the peripheral blood were associated with MDD, particularly decreased l-tryptophan and kynurenic acid levels, and alterations in the tryptophan–kynurenine and fatty acid metabolism pathways. Our findings may facilitate biomarker development and the elucidation of the molecular mechanisms that underly MDD.

Tomato juice was fermented by Lactobacillus plantarum and Lactobacillus casei to produce an innovative high-bioactivity probiotic beverage. The levels of lycopene, total carotenoids, ascorbic acid, total phenolic and volatile compounds, 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2’-azinobis-3-ethylbenzotiazo-line-6-sulfonic acid (ABTS) radical scavenging capacities, ferric reducing antioxidant power (FRAP), and Escherichia coli flora, as well as the inhibition of copper-induced human low-density lipoproteins (LDL)-cholesterol oxidation assays, were measured. The results revealed that the ABTS and DPPH inhibition values, as well as the FRAP and total phenolic content, were significantly increased. LDL-cholesterol oxidation was markedly delayed after the addition of the fermented juice. The in vitro inhibitory effects of Escherichia coli flora were substantially increased after being fermented with Lactobacillus plantarum and Lactobacillus casei. The results associated with the volatile compounds indicated that fermentation with Lactobacillus plantarum and Lactobacillus casei is a meaningful strategy for modifying flavors.

Extensive research has been carried out on the metabolomic changes in animal models of depression; however, there is no general agreement about which metabolites exhibit constant changes. Therefore, the aim of this study was to identify consistently altered metabolites in large-scale metabolomics studies of depression models. We performed vote counting analyses to identify consistently upregulated or downregulated metabolites in the brain, blood, and urine of animal models of depression based on 3743 differential metabolites from 241 animal metabolomics studies. We found that serotonin, dopamine, gamma-aminobutyric acid, norepinephrine, N-acetyl-L-aspartic acid, anandamide, and tryptophan were downregulated in the brain, while kynurenine, myo-inositol, hydroxykynurenine, and the kynurenine to tryptophan ratio were upregulated. Regarding blood metabolites, tryptophan, leucine, tyrosine, valine, trimethylamine N-oxide, proline, oleamide, pyruvic acid, and serotonin were downregulated, while N-acetyl glycoprotein, corticosterone, and glutamine were upregulated. Moreover, citric acid, oxoglutaric acid, proline, tryptophan, creatine, betaine, L-dopa, palmitic acid, and pimelic acid were downregulated, and hippuric acid was upregulated in urine. We also identified consistently altered metabolites in the hippocampus, prefrontal cortex, serum, and plasma. These findings suggested that metabolomic changes in depression models are characterized by decreased neurotransmitter and increased kynurenine metabolite levels in the brain, decreased amino acid and increased corticosterone levels in blood, and imbalanced energy metabolism and microbial metabolites in urine. This study contributes to existing knowledge of metabolomic changes in depression and revealed that the reproducibility of candidate metabolites was inadequate in previous studies.

Supported atomic metal sites have discrete molecular orbitals. Precise control over the energies of these sites is key to achieving novel reaction pathways with superior selectivity. Here, we achieve selective oxygen (O 2 ) activation by utilising a framework of cerium (Ce) cations to reduce the energy of 3 d orbitals of isolated copper (Cu) sites. Operando X-ray absorption spectroscopy, electron paramagnetic resonance and density-functional theory simulations are used to demonstrate that a [Cu(I)O 2 ] 3− site selectively adsorbs molecular O 2 , forming a rarely reported electrophilic η 2 -O 2 species at 298 K. Assisted by neighbouring Ce(III) cations, η 2 -O 2 is finally reduced to two O 2− , that create two Cu–O–Ce oxo-bridges at 453 K. The isolated Cu(I)/(II) sites are ten times more active in CO oxidation than CuO clusters, showing a turnover frequency of 0.028 ± 0.003 s −1 at 373 K and 0.01 bar P CO . The unique electronic structure of [Cu(I)O 2 ] 3− site suggests its potential in selective oxidation. Precise control over the energy of atomic metal sites is key to unlocking novel reaction pathways. Here, the authors achieve selective oxygen activation by the isolated copper site on ceria, due to its reduced 3 d orbital energy via cerium induced electron withdrawing effect.

Major depressive disorder (MDD) is a serious mental illness. Increasing evidence from both animal and human studies suggested that the gut microbiota might be involved in the onset of depression via the gut–brain axis. However, the mechanism in depression remains unclear. To explore the protein changes of the gut–brain axis modulated by gut microbiota, germ-free mice were transplanted with gut microbiota from MDD patients to induce depression-like behaviors. Behavioral tests were performed following fecal microbiota transplantation. A quantitative proteomics approach was used to examine changes in protein expression in the prefrontal cortex (PFC), liver, cecum, and serum. Then differential protein analysis and weighted gene coexpression network analysis were used to identify microbiota-related protein modules. Our results suggested that gut microbiota induced the alteration of protein expression levels in multiple tissues of the gut–brain axis in mice with depression-like phenotype, and these changes of the PFC and liver were model specific compared to chronic stress models. Gene ontology enrichment analysis revealed that the protein changes of the gut–brain axis were involved in a variety of biological functions, including metabolic process and inflammatory response, in which energy metabolism is the core change of the protein network. Our data provide clues for future studies in the gut–brain axis on protein level and deepen the understanding of how gut microbiota cause depression-like behaviors.

Schistosomiasis is the second most important parasitic disease worldwide. Schistosomiasis japonica is a unique species endemic to southern China, and schistosomiasis is characterized by severe liver injury, inflammation, liver granuloma, and subsequent liver fibrosis. However, the pathological mechanism of this disease remains unclear. Mass spectrometry imaging (MSI) is a versatile technique that integrates the molecular specificity of mass spectrometry (MS) with spatial imaging information, which could provide an accurate method for observing disease progression. In this study, we used an air flow-assisted desorption electrospray ionization (AFADESI-MSI) platform to detect a wide range of metabolites and visualize their distribution in the liver tissue of mice infected with Schistosoma japonicum. In the negative ion mode analysis, 21 and 25 different metabolites were detected in the early and chronic stages of infection, respectively. Thirteen characteristic metabolites and 3 metabolic pathways related to disease development may be involved in the chronicity of schistosomiasis. There were more than 32 and 40 region-specific changes in the abundance of a wide range of metabolites (including carbohydrates, amino acids, nucleotides, and fatty acids) in the livers of mice at two different infection times, which also revealed the heterogeneous metabolic characteristics of the liver egg granulomas of S. japonicum. In a chronic infection model with S. japonicum, oral treatment with praziquantel significantly alleviated most metabolic disorders, including fatty acid and pyrimidine metabolism. Surprisingly, Upase1, a key enzyme in uridine metabolism, was significantly upregulated 6 weeks after infection, and liver uridine levels were negatively correlated with the abundance of multiple lipid-associated metabolites. Further studies revealed that in vitro uridine supplementation inhibited the activation of LX-2 cells, restored the homeostasis of fatty acid metabolism through the peroxisome proliferator-activated receptor γ (PPARγ) pathway, and played an antifibrotic role. Our findings provide new insights into the molecular mechanisms of S. japonicum-induced liver fibrosis and the potential of targeting uridine metabolism in disease therapy.

While these findings are novel and objective, we feel it may be necessary to interpret the data with caution regarding to equating the decrease of occludin expression with blood-brain barrier dysfunction in this and other related research. Since its discovery by Shoichiro Tsukita, a pioneer in the field of tight junction, most of the data in literature about the causal role of occludin in barrier function are from in vitro experiments. [...]occludin-deficient mice do not display a perturbation of barrier function, with a complex pathophysiological and inexplicable phenotype [2] which even disappointed its discoverer Shoichiro Tsukita. [...]few reports regarding the in vivo barrier function of occludin mainly focused on epithelial cells [3]. In another recent report dedicated to the memory of Dr. Shoichiro Tsukita, occludin deficiency in mice causes deafness while not affecting the tight junction structure or barrier [5]. [...]due to the lack of vascular barrier disruption in occludin-deficient mice, additional in vivo animal experiments may be needed to make the conclusions for those studying the role of occludin in vascular barrier function in vivo and those using occludin expression as an indicator of blood-brain barrier function more reliable.

Background:Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD).Methods:Systematic searches resulted in 18 RCTs (total n = 4422) of seven different types and different dosages of atypical antipsychotics and a placebo that were included in the review.Results:All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (odds ratios [ORs] ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250–350mg daily) had significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD = -0.38; SMD = -0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250–350mg daily).Conclusions:All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects.

Serotonin (5-HT) is a neurotransmitter that has been linked to tumorigenesis. Whether and how 5-HT modulates cells in the microenvironment to regulate tumor metastasis is largely unknown. Here, we demonstrate that 5-HT was secreted by neuroendocrine prostate cancer (NEPC) cells to communicate with neutrophils and to induce the formation of neutrophil extracellular traps (NETs) in the liver, which in turn facilitated the recruitment of disseminated cancer cells and promoted liver metastasis. 5-HT induced histone serotonylation (H3Q5ser) and orchestrated histone citrullination (H3cit) in neutrophils to trigger chromatin decondensation and facilitate the formation of NETs. Interestingly, we uncovered in this process a reciprocally reinforcing effect between H3Q5ser and H3cit and a crosstalk between the respective writers enzyme transglutaminase 2 (TGM2) and peptidylarginine deiminase 4 (PAD4). Genetic ablation or pharmacological targeting of TGM2, or inhibition of the 5-HT transporter (SERT) with the FDA-approved antidepressant drug fluoxetine reduced H3Q5ser and H3cit modifications, suppressed NET formation, and effectively inhibited NEPC, small-cell lung cancer, and thyroid medullary cancer liver metastasis. Collectively, the 5-HT-triggered production of NETs highlights a targetable neurotransmitter/immune axis that drives liver metastasis of NE cancers.