Increased plasma level of kynurenic acid in drug-free patients with first-episode schizophrenia compared to patients with chronic schizophrenia and healthy controls: preliminary data.

BACKGROUND: Kynurenic acid (KYNA) is a metabolite of tryptophan (TRP). KYNA levels have been reported with controversial findings in patients with schizophrenia. AIM: This study aimed to investigate the probable effects of medication and illness chronicity on peripheral KYNA levels in schizophrenia. METHODS: We assessed peripheral (plasma) TRP metabolite levels in 38 drug-free patients with first-episode schizophrenia (FES), 65 patients with chronic schizophrenia (CHS), and 70 healthy controls by using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The symptom severity of patients was evaluated by using the Positive and Negative Syndrome Scale (PANSS). Finally, we analyzed the association of TRP metabolites with symptom severity. RESULTS: We found significantly higher KYNA levels in FES patients than in both healthy controls (p < 0.01) and CHS patients (p < 0.05). No significant association was observed between plasma TRP metabolite levels and PANSS scores in either FES or CHS patients. CONCLUSIONS: In conclusion, elevated plasma KYNA levels may be a promising biomarker in FES patients. Medication and illness chronicity may affect peripheral KYNA levels with a currently unknown mechanism.

A simple spatial working memory and attention test on paired symbols shows developmental deficits in schizophrenia patients.

People with neuropsychiatric disorders such as schizophrenia often display deficits in spatial working memory and attention. Evaluating working memory and attention in schizophrenia patients is usually based on traditional tasks and the interviewer's judgment. We developed a simple Spatial Working Memory and Attention Test on Paired Symbols (SWAPS). It takes only several minutes to complete, comprising 101 trials for each subject. In this study, we tested 72 schizophrenia patients and 188 healthy volunteers in China. In a healthy control group with ages ranging from 12 to 60, the efficiency score (accuracy divided by reaction time) reached a peak in the 20-27 age range and then declined with increasing age. Importantly, schizophrenia patients failed to display this developmental trend in the same age range and adults had significant deficits compared to the control group. Our data suggests that this simple Spatial Working Memory and Attention Test on Paired Symbols can be a useful tool for studies of spatial working memory and attention in neuropsychiatric disorders.

The effect of prohibiting outside food during COVID-19 pandemic on the body weight of schizophrenic patients taking olanzapine or clozapine: a retrospective self-controlled study.

BACKGROUND: Olanzapine and clozapine are atypical antipsychotics (AAPs) with the greatest risk of weight gain, and changes in feeding behavior are among the most important underlying mechanisms. However, few studies have investigated the role of diet-alone interventions in improving individuals' weight gain by taking AAPs. In closed management mental hospitals of China, family members are allowed to bring food to patients regularly, causing patients to have caloric intake added to their 3 daily meals. However, during the global pandemic of coronavirus disease 2019 (COVID-19), bringing food to the hospital was temporarily prohibited in mental health institutions in China to prevent the spread of the virus. This study sought to compare the body weight and body mass index (BMI) changes of patients taking olanzapine or clozapine undergoing diet-alone interventions caused by this prohibition. METHODS: A retrospective self-controlled study was conducted on 90 patients with schizophrenia from a single-center treated with olanzapine or clozapine monotherapy, or combined with aripiprazole or ziprasidone which has a small metabolic impact. A paired-samples t-test was used to compare the changes in body weight and BMI before and after the 3-month prohibition, and general linear regression was used to analyze the effects of gender, age, disease course, duration of drug exposure, and equivalent dose on the BMI improvement. Also, the percentage of people who lost weight and that of individuals who lost 5% of their pre-prohibition body weight were calculated. RESULTS: Paired-samples t-test showed that after 3-month prohibition, the patients' body weight (71.68±6.83 vs. 66.91±7.03, P<0.001) and BMI (26.43±2.11 vs. 24.63±1.81, P<0.001) decreased significantly. Weight loss rate accounted for 99.1%, and weight loss of 5% from the pre-prohibition body weight accounted for 71.8%. General linear regression showed that the duration of drug exposure (ß =-0.678, P<0.001) was significantly and negatively correlated with the BMI changes. No significant correlation of gender, age, disease course, or equivalent dose with BMI changes was found. CONCLUSIONS: Diet-alone interventions facilitate weight loss in chronically hospitalized schizophrenia patients taking AAPs. Conduction of dietary intervention in the early stages of medication may yield greater benefits.

Increased Plasma Kynurenic Acid Levels are Associated with Impaired Attention/Vigilance and Social Cognition in Patients with Schizophrenia.

OBJECTIVE: Preclinical studies have reported that abnormal kynurenic acid (KYNA) may play a role in cognitive deficits. Schizophrenia (SCZ) is characterized by a wide range of cognitive deficits that may evolve from abnormal KYNA. This study aimed to explore the relationship between KYNA and cognitive impairment in SCZ, which has not yet been reported. METHODS: We recruited 30 SCZ patients and 34 healthy controls, measured clinical symptoms by using the Positive and Negative Syndrome Scale and performed cognitive tests using the MATRICS Consensus Cognitive Battery (MCCB). Plasma levels of tryptophan, kynurenine, and KYNA were determined by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: We found that plasma KYNA levels were significantly higher in patients than in healthy controls (p=0.009). The cognitive performance of patients in the total MCCB scores and the scores of all subscales were significantly lower than those in healthy controls (all P < 0.01). Correlation analysis showed that KYNA levels were negatively correlated with attention/vigilance (r=-0.457, p=0.019) and social cognition (r=-0.481, p=0.013) only in SCZ patients. CONCLUSION: Our results indicate that elevated plasma KYNA levels may serve as a biomarker of cognitive impairment in SCZ patients.

The protective effects of Mogroside V and its metabolite 11-oxo-mogrol of intestinal microbiota against MK801-induced neuronal damages.

RATIONALE: Animal models, notably with non-competitive NMDA receptor antagonist MK801, are commonly used to investigate the mechanisms of schizophrenia and to pursue its mechanism-related drug discoveries. OBJECTIVES: In the current study, we have extensively examined the protective effects of MogrosideV (MogV), a plant-derived three terpene glucoside known to exhibit anti-oxidative and anti-inflammatory activities. METHODS AND RESULTS: Here, we investigated its protective effects against neuronal damages elicited by MK-801 treatment. Our behavioral experimental results showed that MK-801-induced PPI deficits and social withdrawal were prevented by MogV treatment. Moreover, the cellular and neurochemical responses of MK-801 in medial prefrontal cortical cortex (mPFC) were also ameliorated by MogV treatment. Also, profiling metabolites assay through artificial intestinal microbiota was performed to identify bioactive components of MogV. An in vitro study of primary neuronal culture demonstrated that MogV and its metabolite 11-oxo-mogrol treatment prevented the MK-801-induced neuronal damages through the mechanisms of promoting neurite outgrowth, inhibiting cell apoptosis, and [Ca2+]i release. Additionally, 11-oxo-mogrol reversed inactivation of phosphorylation levels of AKT and mTOR induced by MK801. CONCLUSIONS: These results suggest therapeutic potential of MogV for schizophrenia.

Studies of Interfacial Interaction between Polymer Components on Helical Nanofiber Formation via Co-Electrospinning.

Helical fibers in nanoscale have been of increasing interest due to their unique characteristics. To explore the effect of polymer type on helical fiber formation, three polymer systems, Poly(m-phenylene isophthalamide) (Nomex)/polyurethane (TPU), polystyrene (PS)/TPU and polyacrylonitril (PAN)/TPU are used to fabricate helical nanofibers via co-electrospinning. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and Zeta potential were employed to investigate the interfacial interaction between the two phases of the polymer system. The larger rigidity differential of Nomex and TPU leads to a larger interfacial interaction. The hydrogen bonds help to increase the interfacial interaction between Nomex and TPU components. The attractive force between the chloride-ions contained in Nomex molecules and the free charges on the solution surface lead to a longitudinal interfacial interaction in the Nomex/TPU system. The analysis results provide the explanation of the experimental results that the Nomex/TPU system has the greatest potential for producing helical nanofibers, while the PS/TPU and PAN/TPU systems cannot fabricate helical fibers effectively. This study based on the interfacial interaction between polymer components provides an insight into the mechanism of helical fiber formation.

Loss of Microglia and Impaired Brain-Neurotrophic Factor Signaling Pathway in a Comorbid Model of Chronic Pain and Depression.

Major depressive disorder (MDD) and chronic pain are two complex disorders that often coexist. The underlying basis for this comorbidity is unknown. In the current investigation, microglia and the brain-derived neurotrophic factor (BDNF)-cAMP response element-binding protein (CREB) pathway were investigated. A comorbidity model, with characteristics of both MDD and chronic pain, was developed by the administration of dextran sodium sulfate (DSS) and the induction of chronic unpredictable psychological stress (CUS). Mechanical threshold sensory testing and the visceromotor response (VMR) were employed to measure mechanical allodynia and visceral hypersensitivity, respectively. RT-qPCR and western blotting were used to assess mRNA and protein levels of ionized calcium-binding adaptor molecule 1 (Iba-1), nuclear factor-kappa B (NF-κB), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBa), BDNF, and CREB. In comorbid animals, mechanical allodynia and visceral hypersensitivities were significant with increased mRNA and protein levels for NF-κB-p65 and IκBa. Furthermore, the comorbid animals had deceased mRNA and protein levels for Iba-1, BDNF, and CREB as well as a reduced number and density of microglia in the medial prefrontal cortex (mPFC). These results together suggest that DSS and CUS can induce the comorbidities of chronic pain and depression-like behavior. The pathology of this comorbidity involves loss of microglia within the mPFC with subsequent activation of NF-κB-p65 and down-regulation of BDNF/p-CREB signaling.

Increased plasma leptin as a novel predictor for psychopathological depressive symptoms in chronic schizophrenia.

BACKGROUND: Depressive symptoms are often seen in schizophrenia. The overlap in presentation makes it difficult to distinguish depressive symptoms from the negative symptoms of schizophrenia. The adipokine leptin was found to be altered in both depression and schizophrenia. There are few studies focusing on the prediction of leptin in diagnosis and evaluation of depressive symptoms in schizophrenia. OBJECTIVEAIMS: To assess the plasma leptin level in patients with schizophrenia and its relationships with depressive symptoms. METHODS: Cross-sectional studies were applied to (1) compare the levels of plasma leptin between schizophrenia (n=74) and healthy controls (n=50); and (2) investigate the relationship between plasma leptin levels and depressive subscores. RESULTS: (1) Plasma leptin levels were significantly higher in patients with schizophrenia than in healthy controls. (2) Correlation analysis revealed a significant negative association between leptin levels and the depressed factor scores on the Positive and Negative Syndrome Scale (PANSS). (3) Stepwise multiple regression analyses identified leptin as an influencing factor for depressed factor score on PANSS. CONCLUSION: Leptin may serve as a predictor for the depressive symptoms of chronic schizophrenia.

Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy.

Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti-MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.

The Interaction of TXNIP and AFq1 Genes Increases the Susceptibility of Schizophrenia.

Although previous studies showed the reduced risk of cancer in patients with schizophrenia, whether patients with schizophrenia possess genetic factors that also contribute to tumor suppressor is still unknown. In the present study, based on our previous microarray data, we focused on the tumor suppressor genes TXNIP and AF1q, which differentially expressed in patients with schizophrenia. A total of 413 patients and 578 healthy controls were recruited. We found no significant differences in genotype, allele, or haplotype frequencies at the selected five single nucleotide polymorphisms (SNPs) (rs2236566 and rs7211 in TXNIP gene; rs10749659, rs2140709, and rs3738481 in AF1q gene) between patients with schizophrenia and controls. However, we found the association between the interaction of TXNIP and AF1q with schizophrenia by using the MDR method followed by traditional statistical analysis. The best gene-gene interaction model identified was a three-locus model TXNIP (rs2236566, rs7211)-AF1q (rs2140709). After traditional statistical analysis, we found the high-risk genotype combination was rs2236566 (GG)-rs7211(CC)-rs2140709(CC) (OR = 1.35 [1.03-1.76]). The low-risk genotype combination was rs2236566 (GT)-rs7211(CC)-rs2140709(CC) (OR = 0.67 [0.49-0.91]). Our finding suggested statistically significant role of interaction of TXNIP and AF1q polymorphisms (TXNIP-rs2236566, TXNIP-rs7211, and AF1q-rs2769605) in schizophrenia susceptibility.

The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia.

The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2) is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia) and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445) and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445) and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605), in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605) may be involved in the susceptibility to paranoid schizophrenia.

Conversion of the surface property of oleic acid stabilized silver nanoparticles from hydrophobic to hydrophilic based on host-guest binding interaction.

This paper describes a general method to change the surface property of the oleic acid stabilized silver nanoparticles and successful tranferring of the silver nanoparticles from the organic phase into the aqueous phase. By vigorous shaking of a biphasic mixture of the silver organosol protected with oleic acid and p-sulfonated calix[4]arene (pSC4) aqueous solution, it is believed that an inclusion complex is formed between oleic acid molecules and pSC4, and the protective layer of the silver nanoparticles shifts from hydrophobic to hydrophilic in nature, which drives the transfer of silver nanoparticles from the organic phase into the aqueous phase. The efficiency of the phase transfer to the aqueous solution depends on the initial pSC4 concentration. The pSC4-oleic acid inclusion complex stabilized nanoparticles can be stable for long periods of time in aqueous phase under ambient atmospheric conditions. The procedure of phase transfer has been independently verified by UV-vis, transmission electron microscopy, Fourier transform infrared, and 1H nuclear magnetic resonance techniques.