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

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

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

Gut microbial biomarkers for the treatment response in first-episode, drug-naive schizophrenia: a 24-week follow-up study

Preclinical studies have shown that the gut microbiota can play a role in schizophrenia (SCH) pathogenesis via the gut-brain axis. However, its role in the antipsychotic treatment response is unclear. Here, we present a 24-week follow-up study to identify gut microbial biomarkers for SCH diagnosis and treatment response, using a sample of 107 first-episode, drug-naive SCH patients, and 107 healthy controls (HCs). We collected biological samples at baseline (all participants) and follow-up time points after risperidone treatment (SCH patients). Treatment response was assessed using the Positive and Negative Symptoms Scale total (PANSS-T) score. False discovery rate was used to correct for multiple testing. We found that SCH patients showed lower alpha-diversity (the Shannon and Simpson\u27s indices) compared to HCs at baseline (p = 1.21 x 10(-9), 1.23 x 10(-8), respectively). We also found a significant difference in beta-diversity between SCH patients and HCs (p = 0.001). At baseline, using microbes that showed different abundance between patients and controls as predictors, a prediction model can distinguish patients from HCs with an area under the curve (AUC) of 0.867. In SCH patients, after 24 weeks of risperidone treatment, we observed an increase of alpha-diversity toward the basal level of HCs. At the genus level, we observed decreased abundance of Lachnoclostridium (p = 0.019) and increased abundance Romboutsia (p = 0.067). Moreover, the treatment response in SCH patients was significantly associated with the basal levels of Lachnoclostridium and Romboutsia (p = 0.005 and 0.006, respectively). Our results suggest that SCH patients may present characteristic microbiota, and certain microbiota biomarkers may predict treatment response in this patient population

Oxidative stress impairs cognitive function by affecting hippocampal fimbria volume in drug-naïve, first-episode schizophrenia

ObjectiveThe aim of the present study was to explore influencing factors of cognitive impairments and their interrelationships in drug-naïve, first-episode schizophrenia (SCZ).MethodsPatients with drug naïve, first episode SCZ and healthy controls (HCs) were enrolled. Cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Serum levels of oxidative stress indices, including folate, superoxide dismutase (SOD), uric acid (UA) and homocysteine (Hcy), were determined after an overnight fast. Hippocampal subfield volumes were measured using FreeSurfer. Mediation models were conducted using the SPSS PROCESS v3.4 macro. A false discovery rate (FDR) correction was applied for multiple comparisons.ResultsSixty-seven patients with SCZ and 65 HCs were enrolled in our study. The patient group had significantly lower serum levels of folate and SOD and higher serum levels of HCY compared with the HCs (all p < 0.05). The patient group had a significantly smaller volume of the whole hippocampus than the HC group (p < 0.05). We also found significant volume differences between the two groups in the following subfields: CA1, molecular layer, GC-ML-DG and fimbria (all p < 0.05, uncorrected). The partial correlation analysis controlling for age and sex showed that the fimbria volume in the patient group was significantly positively associated with NAB scores (r = 0.382, pFDR = 0.024); serum levels of SOD in the patient group showed a significantly positive correlation with fimbria volume (r = 0.360, pFDR = 0.036). Mediation analyses controlling for age and sex showed that the serum levels of SOD in patients with SCZ had significant indirect effects on the NAB scores which were mediated by the fimbria volume [indirect effect = 0.0565, 95% CI from the bootstrap test excluding zero (0.0066 to 0.0891)].ConclusionOxidative stress, a reduction in hippocampal subfield volumes and cognitive impairments occur in early SCZ. Oxidative stress impairs cognitive function by affecting hippocampal subfield volumes

Critical Roles of STAT3 in β-Adrenergic Functions in the Heart

BACKGROUND: β-Adrenergic receptors (βARs) play paradoxical roles in the heart. On one hand, βARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of βARs exert deleterious effects that result in heart failure. The signal transducer and activator of transcription 3 (STAT3) plays a dynamic role in integrating multiple cytokine signaling pathways in a number of tissues. Altered activation of STAT3 has been observed in failing hearts in both human patients and animal models. Our objective is to determine the potential regulatory roles of STAT3 in cardiac βAR-mediated signaling and function. METHODS AND RESULTS: We observed that STAT3 can be directly activated in cardiomyocytes by β-adrenergic agonists. To follow up this finding, we analyzed βAR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute βAR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic β-adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that Gαs and Src kinases are required for βAR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of βAR pathway, including β1AR, protein kinase A, and T-type Ca(2+) channels. CONCLUSIONS: Our data demonstrate for the first time that STAT3 has a fundamental role in βAR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for βAR-mediated cardiac stress adaption, pathological remodeling, and heart failure

Investigation on Certification and Evaluation Method of Harmful Substances Release from Furniture Products in China

Furniture products are the main sources of indoor air pollution due to the emission of formaldehyde and volatile organic compounds (VOCs). It is great significant to establish a scientific certification and evaluation system to promote furniture manufacturers to reduce the harmful substances release in furniture products and protect human health in China. This paper describes an investigation on release of formaldehyde, soluble heavy metals, benzene, toluene, xylene and other substances from 28 furniture products by dryer method and environmental chamber method. Studies on current development status of certification and evaluation of harmful substance release from furniture products in China were carried out. Case study of certification and evaluation method suitable for furniture production industry was made, and the existing problems and suggestions were provided for improvement of certification and evaluation method system based on the characteristics of furniture industry

Establishment of an assistive diagnostic model for schizophrenia with oxidative stress biomarkers

Objective: In this study, alterations in oxidative stress-related indicators were evaluated in drug-naïve, first-episode schizophrenia (SCZ) patients, and the effectiveness of blood serum glucose, superoxide dismutase (SOD), bilirubin in the objective assistive diagnosis of schizophrenia was explored.Materials and methods: We recruited 148 drug-naïve, first-episode SCZ patients and 97 healthy controls (HCs). Blood biochemical indexes including blood glucose, SOD, bilirubin and homocysteine (HCY) in participants were measured, the indexes were compared between patients with SCZ and HCs. The assistive diagnostic model for SCZ was established on the basis of the differential indexes.Results: In SCZ patients, the blood serum levels of glucose, total (TBIL), indirect bilirubin (IBIL) and homocysteine (HCY) were significantly higher than those in HCs (p < 0.05), and the serum levels of SOD were significantly lower than those in HCs (p < 0.05). There was a negative correlation between SOD with the general symptom scores and total scores of PANSS. After risperidone treatment, the levels of uric acid (UA) and SOD tended to increase in patients with SCZ (p = 0.02, 0.19), and the serum levels of TBIL and HCY tended to decrease in patients with SCZ (p = 0.78, 0.16). The diagnostic model based on blood glucose, IBIL and SOD was internally cross-validated, and the accuracy was 77%, with an area under the curve (AUC) of 0.83.Conclusion: Our study demonstrated an oxidative state imbalance in drug-naïve, first-episode SCZ patients, which might be associated with the pathogenesis of the disease. Our study proved that glucose, IBIL and SOD may be potential biological markers of schizophrenia, and the model based on these markers can assist the early objective and accurate diagnosis of schizophrenia

Dysfunctional oxidative stress response in first-episode of schizophrenia

Purpose: To investigate the probable effect of oxidative stress on cognitive deficits in schizophrenia. Methods: A total of 149 first-episode schizophrenia (FES) patients and 65 healthy controls were enrolled in this study. Psychiatric symptoms were evaluated using Positive and Negative Syndrome Scale, while cognitive function was assessed using MATRICS Consensus Cognitive Battery. Oxidative parameters, including glutathione (GSH), thioredoxin (TRX), nitric oxide (NO), homocysteine (Hcy) and superoxide dismutase (SOD)]; hypersensitive C-reactive protein (Hs-CRP, an inflammation marker); lipopolysaccharide (LPS) and CD4+T cell sub-sets (Th1, Th2, Th17 and Treg cells) were measured in all subjects, while PANSS was evaluated in FES patients only. Results: Levels of the oxidants, NO, Hcy and inflammatory parameters (Hs-CRP, LPS, Th1, Th2 and Th17) were higher in FES patients than in controls (p < 0.05). In contrast, levels of antioxidants (GSH and SOD) in FES patents were lower than those in controls (p < 0.05). Moreover, TRX was higher in schizophrenia patients than in controls (p < 0.05). The changes in levels of these biomarker indicated oxidative stress responses. There were statistically significant differences in hemogram and T cell subtype between FES and control (p < 0.05). Results from fMRI analysis revealed schizophrenia- induced lesions in the encephalic region associated with cognition function. Conclusion: Oxidative stress (OS) induces immune response which eventually leads to impairment of cognition

Original Article Clinicopathological significance of PTEN and PI3K/AKT signal transduction pathway in non-small cell lung cancer

Abstract: A high frequency of mutations at the PTEN locus has been noticed in carcinoma of lung. However, the role of PTEN alternations and its association with outcome variables in the genesis of lung carcinoma are not understood fully. The purpose of our study was to examine the impact of EGFR, TGF-α, P-AKT and PTEN in the genesis of non-small cell lung cancer (NSCLC). Total numbers of 66 histopathologically confirmed cases of NSCLC and 10 cases of benign control samples embedded with wax were studied. We assessed EGFR, TGF-α and P-AKT by the use of specific antibody through immunohistochemistry as directed by the manufacturer, and detected PTEN expression by in situ hybridization. There were progressive loss of PTEN expression and significant increasing in EGFR, TGF-α, P-AKT expression from benign samples to NSCLC (p<0.05). The overexpression of EGFR, TGF-α, P-AKT and loss of PTEN expression were correlated to differentiation extent of cancer tissue, metastasis of lymph nodes and histological classification. Thus, alteration of EGFR, TGF-α, P-AKT and PTEN are likely important molecular events in pathogenesis and carcinogenesis of NSCLC