Tryptophan-kynurenine pathway as a novel link between gut microbiota and schizophrenia: A review

Gut microbiota and its metabolite tryptophan play an important role in regulating neurotransmission, immune homeostasis and oxidative stress which are critical for brain development. The kynurenine pathway is the main route of tryptophan catabolism. Kynurenine metabolites regulate many biological processes including host-microbiome communication, immunity and oxidative stress, as well as neuronal excitability. The accumulation of metabolites produced by kynurenine pathway in brain results in the activation of the immune system (increase in the levels of inflammatory factors) and oxidative stress (production of reactive oxygen species, ROS), which are associated with mental disorders, for example schizophrenia. Thus, it was hypothesized that perturbations in kynurenine pathway could cause activation of immunity, and that oxidative stress may be involved in the etiology of schizophrenia. The present work is a review of the latest studies on the possible role of kynurenine pathway in schizophrenia, and mechanism(s) involved

Analysis of Walking-Edge Effect in Train Station Evacuation Scenarios: A Sustainable Transportation Perspective

Due to the highly developed rail transit over the past decades, the phenomena of complex individual self-organized behaviors and mass crowd dynamics have become a great concern in the train station. In order to understand passengers&rsquo walking-edge effect and analyze the relationship between the layout and sustainable service abilities of the train station, a heuristics-based social force model is proposed to elaborate the crowd dynamics. Several evacuation scenarios are implemented to describe the walking-edge effect in a train station with the evacuation efficiency, pedestrian flow, and crowd density map. The results show that decentralizing crowd flow can significantly increase the evacuation efficiency in different scenarios. When the exits are far away from the central axis of the railway station, the walking-edge effect has little influence on the evacuation efficiency. Obstacles can guide the movement of passengers by channelizing pedestrian flows. In addition, a wider side exit of the funnel-shaped corridors can promote walking-edge effect and decrease the pressure among a congested crowd. Besides providing a modified social force model with considering walking-edge effect, several suggestions are put forward for managers and architects of the train station in designing sustainable layouts. Document type: Articl

Circular Accessible Depth: A Robust Traversability Representation for UGV Navigation

In this paper, we present the Circular Accessible Depth (CAD), a robust traversability representation for an unmanned ground vehicle (UGV) to learn traversability in various scenarios containing irregular obstacles. To predict CAD, we propose a neural network, namely CADNet, with an attention-based multi-frame point cloud fusion module, Stability-Attention Module (SAM), to encode the spatial features from point clouds captured by LiDAR. CAD is designed based on the polar coordinate system and focuses on predicting the border of traversable area. Since it encodes the spatial information of the surrounding environment, which enables a semi-supervised learning for the CADNet, and thus desirably avoids annotating a large amount of data. Extensive experiments demonstrate that CAD outperforms baselines in terms of robustness and precision. We also implement our method on a real UGV and show that it performs well in real-world scenarios.Comment: 13 pages, 8 figure

The nuclear factor-κB inhibitor pyrrolidine dithiocarbamate reduces polyinosinic-polycytidilic acid-induced immune response in pregnant rats and the behavioral defects of their adult offspring

<p>Abstract</p> <p>Background</p> <p>Epidemiological studies have indicated that maternal infection during pregnancy may lead to a higher incidence of schizophrenia in the offspring. It is assumed that the maternal infection increases the immune response, leading to neurodevelopmental disorders in the offspring. Maternal polyinosinic-polycytidilic acid (PolyI:C) treatment induces a wide range of characteristics in the offspring mimicking some schizophrenia symptoms in humans. These observations are consistent with the neurodevelopmental hypothesis of schizophrenia.</p> <p>Methods</p> <p>We examined whether suppression of the maternal immune response could prevent neurodevelopmental disorders in adult offspring. PolyI:C or saline was administered to early pregnant rats to mimic maternal infection, and the maternal immune response represented by tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) levels was determined by enzyme-linked immunosorbent assays (ELISA). The NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) was used to suppress the maternal immune response. Neurodevelopmental disorders in adult offspring were examined by prepulse inhibition (PPI), passive avoidance, and active avoidance tests.</p> <p>Results</p> <p>PolyI:C administration to early pregnant rats led to elevated serum cytokine levels as shown by massive increases in serum TNF-α and IL-10 levels. The adult offspring showed defects in prepulse inhibition, and passive avoidance and active avoidance tests. PDTC intervention in early pregnant rats suppressed cytokine increases and reduced the severity of neurodevelopmental defects in adult offspring.</p> <p>Conclusions</p> <p>Our findings suggest that PDTC can suppress the maternal immune response induced by PolyI:C and partially prevent neurodevelopmental disorders of adult offspring.</p

APOA-I: a possible novel biomarker for metabolic side effects in first episode schizophrenia

The purpose of this study was to investigate the change in plasma protein expression in first episode schizophrenia after an 8-week treatment with risperidone, and to explore potential biomarkers for metabolic side effects associated with risperidone treatment. Eighty first-episode schizophrenia patientswere enrolled in the study. Fifteen of the 80 patients were randomly selected to undergo proteomic analysis. Plasma proteins were obtained before and after the 8-week risperidone treatment, and measured using two-dimensional gel electrophoresis (2-DE), Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry(MALDI-TOF/TOF) and peptide mass fingerprinting.Proteins with the highest fold changes after risperidone treatment were then measured for all 80 patients using enzyme linked immunosorbent assay (ELISA). The relationship between changes in plasma protein levels and changes in metabolic parameters after risperidone treatment was examined. In 15 randomly selected patients, approximately 1,500 protein spots were detected in each gel by 2-DE. Of those proteins, 22 spots showed significant difference in abundance after risperidone treatment (p\u27s \u3c 0.05). After MALDI-TOF peptide mass fingerprinting, apolipoprotein A-I (APOA-I) and Guanine Nucleotide Binding Protein, Alpha Stimulating (GNAS), were found to have the highest fold changes.The content of APOA-I was significantly increased, and the content of GNAS was significantly decreased after risperidone treatment (p\u27s\u3c0.05). The analysis in the entire study sample showed similar findings in changes of APOA-I and GNAS after risperidone treatment. Further analysis showed significant relationships between changesin APOA-1 and changes in triglyceride, total cholesterol, and body mass index after controlling for age, gender and family history of diabetes. Similar analysis showed a trend positive relationship between changes in GNAS and changes in BMI. Using proteomic analysis, the study suggested that APOA-I might be a novel biomarkers related to metabolic side effects in first episode schizophrenia treated with risperidone

The Role of Butyric Acid in Treatment Response in Drug-Naive First Episode Schizophrenia

Background: Butyric acid, a major short-chain fatty acid (SCFA), has an important role in the microbiota-gut-brain axis and brain function. This study investigated the role of butyric acid in treatment response in drug-naive first episode schizophrenia. Methods: The study recruited 56 Chinese Han schizophrenia inpatients with normal body weight and 35 healthy controls. Serum levels of butyric acid were measured using Gas Chromatography-Mass Spectrometer (GC-MS) analysis at baseline (for all participants) and 24 weeks after risperidone treatment (for patients). Clinical symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) for patients at both time points. Results: At baseline, there was no significant difference in serum levels of butyric acid between patients and healthy controls (p = 0.206). However, there was a significant increase in serum levels of butyric acid in schizophrenia patients after 24-week risperidone treatment (p = 0.030). The PANSS total and subscale scores were decreased significantly after 24-week risperidone treatment (p\u27s \u3c 0.001). There were positive associations between baseline serum levels of butyric acid and the reduction ratio of the PANSS total and subscale scores after controlling for age, sex, education, and duration of illness (p\u27s \u3c 0.05). Further, there was a positive association between the increase in serum levels of butyric acid and the reduction of the PANSS positive symptoms subscale scores (r = 0.38, p = 0.019) after controlling for potential confounding factors. Conclusions: Increased serum levels of butyric acid might be associated with a favorable treatment response in drug-naive, first episode schizophrenia. The clinical implications of our findings were discussed

Fingolimod exerts in vitro anticancer activity against hepatocellular carcinoma cell lines via YAP/TAZ suppression

Hepatocellular carcinoma (HCC) remains a notably global health challenge with high mortality rates and poor prognosis. The deregulation of the Hippo signalling pathway, especially the overexpression and activation of downstream effector Yes-associated protein (YAP), has been demonstrated to result in the rapid malignant evolution of HCC. In this context, multiple efforts have been dedicated to targeting YAP for HCC therapy, but effective YAP inhibitors are still lacking. In this study, through a YAP-TEAD (8×GTIIC) luciferase reporter assay, we identified fingolimod, an immunomodulatory drug approved for the treatment of multiple sclerosis, as a novel YAP inhibitor. Fingolimod suppressed the proliferation of HCC cell lines by downregulating the protein levels as well as the transactivating function of YAP. Overall, our current study not only identifies fingolimod as a novel YAP-targeting inhibitor, but also indicates that this clinically-approved drug could be utilized as a potential and feasible therapeutic drug for HCC

Insulin Resistance and Oxidative Stress: In Relation to Cognitive Function and Psychopathology in Drug-Naive, First-Episode Drug-Free Schizophrenia

Objective: The present study aimed to examine whether insulin resistance and oxidative stress are associated with cognitive impairment in first-episode drug-free schizophrenia (SZ) patients. Methods: Ninety first-episode SZ patients and 70 healthy controls were enrolled. Fasting insulin (FINS) and markers of oxidative stress [oxidized glutathione (GSSG), superoxide dismutase (SOD), nitric oxide (NO) and uric acid (UA) levels] were measured in serum before pharmacological treatment was initiated. Psychiatric symptoms and cognitive function were assessed with the Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB), respectively. In addition, the homeostatic model assessment of insulin resistance (HOMA-IR) was also studied. Results: HOMA-IR and serum levels of GSSG and NO were significantly higher in SZ patients than in healthy controls (P \u3c 0.001), while the serum levels of SOD were significantly lower than in healthy controls (P \u3c 0.001). HOMA-IR, GSSG and NO levels were significantly correlated to the total cognitive function scores of the patient group (r = -0.345,-0.369,-0.444, respectively, P \u3c 0.05). But these factors were not co-related to the cognitive functions in the healthy control group. And, levels of SOD, UA were not associated with the total cognitive function scores in both the patient and the healthy control groups. NO was positively correlated with general pathological and the total score in the PANSS, and was negatively correlated with six cognitive domains (r = -0.316 to -0.553, P \u3c 0.05). Conclusions: The levels of insulin resistance and oxidative stress are elevated, and correlated with the severity of cognitive impairment in drug-naive, first-episode SZ patients. Treatment approaches targeting on reducing insulin resistance and oxidative stress may improve cognitive function in SZ patients

Association between Ghrelin gene (GHRL) polymorphisms and clinical response to atypical antipsychotic drugs in Han Chinese schizophrenia patients

<p>Abstract</p> <p>Background</p> <p>Ghrelin (<it>GHRL</it>) is a pivotal peptide regulator of food intake, energy balance, and body mass. Weight gain (WG) is a common side effect of the atypical antipsychotics (AAPs) used to treat schizophrenia (SZ). Ghrelin polymorphisms have been associated with pathogenic variations in plasma lipid concentrations, blood pressure, plasma glucose, and body mass index (BMI). However, it is unclear whether <it>GHRL </it>polymorphisms are associated with WG due to AAPs. Furthermore, there is no evidence of an association between <it>GHRL </it>polymorphisms and SZ or the therapeutic response to AAPs. We explored these potential associations by genotyping <it>GHRL </it>alleles in SZ patients and controls. We also examined the relation between these SNPs and changes in metabolic indices during AAP treatment in SZ subgroups distinguished by high or low therapeutic response.</p> <p>Methods</p> <p>Four SNPs (Leu72Met, -501A/C, -604 G/A, and -1062 G > C) were genotyped in 634 schizophrenia patients and 606 control subjects.</p> <p>Results</p> <p>There were no significant differences in allele frequencies, genotype distributions, or the distributions of two SNP haplotypes between SZ patients and healthy controls (<it>P </it>> 0.05). There was also no significant difference in symptom reduction between genotypes after 8 weeks of AAP treatment as measured by positive and negative symptom scale scores (PANSS). However, the -604 G/A polymorphism was associated with a greater BMI increase in response to AAP administration in both APP responders and non-responders as distinguished by PANSS score reduction (<it>P </it>< 0.001). There were also significant differences in WG when the responder group was further subdivided according to the specific AAP prescribed (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>These four <it>GHRL </it>gene SNPs were not associated with SZ in this Chinese Han population. The -604 G/A polymorphism was associated with significant BW and BMI increases during AAP treatment. Patients exhibiting higher WG showed greater improvements in positive and negative symptoms than patients exhibiting lower weight gain or weight loss.</p

Fat-mass and obesity-associated gene polymorphisms and weight gain after risperidone treatment in first episode schizophrenia

BACKGROUND: Obesity induced by antipsychotics severely increases the risk of many diseases and significantly reduces quality of life. Genome Wide Association Studies has identified fat-mass and obesity-associated (FTO) gene associated with obesity. The relationship between the FTO gene and drug-induced obesity is unclear. METHOD: Two hundred and fifty drug naive, Chinese Han patients with first-episode schizophrenia were enrolled in the study, and genotyped for four single nucleotide polymorphisms (SNPs rs9939609, rs8050136, rs1421085 and rs9930506) by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing. Body weight and body mass index (BMI) were measured at baseline and six months after risperidone treatment. RESULTS: At baseline, body weight and BMI of TT homozygotes were lower than those of A allele carriers in rs9939609; body weight of AA homozygotes was higher than those of G allele carriers in rs9930506 (p\u27s \u3c 0.05). After 6 months of risperidone treatment, body weight and BMI of TT homozygotes were lower than those of A allele carriers in rs9939609 (p\u27s \u3c 0.01); body weight and BMI of CC homozygotes were lower than those of A allele carriers in rs8050136 (p\u27s \u3c 0.05); body weight of AA homozygotes was higher than those of G allele carriers in rs9930506 (p\u27s \u3c 0.05). After controlling for age, gender, age of illness onset, disease duration, weight at baseline and education, weight gain of TT homozygotes at 6 months remained to be lower than those of A allele carriers in rs9939609 (p \u3c 0.01); weight gain of CC homozygotes at 6 months was lower than those of A allele carriers in rs8050136 (p = 0.01). Stepwise multiple regression analysis suggested that, among 4 SNPs, rs9939609 was the strongest predictor of weight gain after 6 months of risperidone treatment (p = 0.001). CONCLUSIONS: The FTO gene polymorphisms, especially rs9939609, seem to be related to weight gain after risperidone treatment in Chinese Han patients with first episode schizophrenia