Increased Blood-Brain Barrier Permeability of the Thalamus Correlated With Symptom Severity and Brain Volume Alterations in Patients With Schizophrenia.

BACKGROUND: While direct in vivo data from patients is insufficient, cumulative evidence of microvascular dysfunction has shown that the blood-brain barrier (BBB) is disrupted in schizophrenia. In this study, we attempted to test the hypothesis that greater BBB permeability in patients with schizophrenia was associated with clinical characteristics and brain volumetric alterations using dynamic contrast-enhanced magnetic resonance imaging techniques. METHODS: Structural magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging data from 29 patients with schizophrenia and 18 age- and sex-matched control subjects were obtained. We calculated the volume transfer constant (Ktrans) value and compared the difference between the 2 groups. The regions with an abnormal Ktrans value were extracted as regions of interest (thalamus), and the correlations with clinical characteristics and gray matter volume were analyzed. RESULTS: The results revealed that Ktrans value of the bilateral thalamus was higher in the schizophrenia group as compared to the healthy control group (p < .001). There were significant positive correlations between thalamic mean Ktrans value with disease duration (p < .05) and symptom severity (p < .001). Analysis of the thalamic subregions revealed that BBB disruption was significant in the pulvinar, especially the medial pulvinar nucleus and lateral pulvinar nucleus (p < .001). The correlation between the Ktrans values and the corresponding volumes was negative for the whole brain, the thalamus, and the thalamic subregions. CONCLUSIONS: These results provide the first in vivo evidence of BBB disruption of thalamus in patients with schizophrenia and suggest that BBB dysfunction might contribute to the pathological brain structural alterations in schizophrenia.

Utilizing Network Pharmacology and Molecular Docking Integrated Surface Plasmon Resonance Technology to Investigate the Potential Targets and Mechanisms of Tripterygium wilfordii against Pulmonary Artery Hypertension.

Background: Pulmonary artery hypertension (PAH) is a rare, life-limiting cardiopulmonary disorder characterized by the progressive and remodeling of pulmonary vasculature. Although the development of the technology brings us many approaches for the treatment of PAH, the effect of treatment is unsatisfactory. Tripterygium wilfordii (TW), as a traditional Chinese medicine (TCM), has been widely used in anti-inflammation, anticancer, and other fields. However, the potential of TW in treating PAH is currently unclear. Methods: Active ingredients and their corresponding genes were harvested from the Traditional Chinese Medicine Database and Analysis Platform (TCMSP), CTD, and STITCH. Meanwhile, genes associated with PAH were adopted from OMIM and GeneCards databases. Through Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses, potential targeting KEGG pathways and functions were further collected. Then, STRING was used to generate the protein-protein interaction (PPI) network. The "ingredients-targets-pathway" network was built by Cystoscope. Finally, the binding between active ingredients of TW and corresponding targets of PAH was identified via molecular docking technology and surface plasmon resonance (SPR) experiments. Results: The network pharmacology analysis revealed 36 active ingredients in TW and 150 potential targets related to the treatment of PAH with TW. Moreover, GO enrichment analysis showed that the key function in molecular function (MF) was related to enzyme binding, the key function in biological process (BP) was related to cellular response to organic substance, and the key function in cellular component (CC) was related to KEGG enrichment analysis and found that it was closely related to the IL-17 signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, and apoptosis. At last, molecular docking results revealed that the main active ingredients of TW had a strong binding ability with the PAH target protein. In addition, the SPR experiment revealed that kaempferol was combined with the CASP3 protein rather than PARP1, while triptolide was combined with PARP1 rather than the CASP3 protein. Conclusion: TW may have therapeutic effects on PAH through multitargets and multimethods, which provide a scientific basis for further elaborating the mechanism of Tripterygium wilfordii in the treatment of PAH.

Age-related heterogeneity revealed by disruption of white matter structural networks in patients with first-episode untreated major depressive disorder: WM Network In OA-MDD.

The clinical treatment and prognosis of major depressive disorder (MDD) are limited by the high degree of disease heterogeneity. It is unclear whether there is a potential network mechanism for age-related heterogeneity. We aimed to uncover the heterogeneity of the white matter (WM) network at different ages of onset and its correlation with different symptom characteristics. 85 first-episode MDD patients and 84 corresponding healthy controls (HCs) were recruited and underwent diffusion tensor imaging scans. Structural network characteristics were analyzed using graph theory methods. We observed an accelerated age-related decline of the WM network in MDD patients compared with HCs. Distinct symptom-related networks were identified in three MDD groups with different onset-age. For early-onset MDD (18-29 years; EOD), higher guilt and loss of interest were correlated with the insula, and inferior parietal lobe which in default mode network and salience network. For mid-term-onset MDD (30-44 years; MOD), higher somatic symptoms were correlated with thalamus which in cortico-striatal-thalamic-cortical circuit. For later-onset MDD (45-60 years; LOD), poor sleep symptoms were correlated with the caudate in the basal ganglia, which suggests the cingulate operculum network in the control of sleep. These results supported a circuit-based heterogeneity associated with the age of onset in MDD. Understanding this circuit-based heterogeneity might help to develop a new target for clinical treatment strategies.

Prevalence of depressive disorders and treatment in China: a cross-sectional epidemiological study.

BACKGROUND: In China, depressive disorders have been estimated to be the second leading cause of years lived with disability. However, nationally representative epidemiological data for depressive disorders, in particular use of mental health services by adults with these disorders, are unavailable in China. The present study, part of the China Mental Health Survey, 2012-15, aims to describe the socioeconomic characteristics and the use of mental health services in people with depressive disorders in China. METHODS: The China Mental Health Survey was a cross-sectional epidemiological survey of mental disorders in a multistage clustered-area probability sample of adults of Chinese nationality (≥18 years) from 157 nationwide representative population-based disease surveillance points in 31 provinces across China. Trained investigators interviewed the participants with the Composite International Diagnostic Interview 3.0 to ascertain the presence of lifetime and 12-month depressive disorders according to DSM-IV criteria, including major depressive disorder, dysthymic disorder, and depressive disorder not otherwise specified. Participants with 12-month depressive disorders were asked whether they received any treatment for their emotional problems during the past 12 months and, if so, the specific types of treatment providers. The Sheehan Disability Scale (SDS) was used to assess impairments associated with 12-month depressive symptoms. Data-quality control procedures included logic check by computers, sequential recording check, and phone-call check by the quality controllers, and reinterview check by the psychiatrists. Data were weighted according to the age-sex-residence distribution data from China's 2010 census population survey to adjust for differential probabilities of selection and differential response, as well as to post-stratify the sample to match the population distribution. FINDINGS: 28 140 respondents (12 537 [44·6%] men and 15 603 [55·4%] women) completed the survey between July 22, 2013, and March 5, 2015. Ethnicity data (Han or non-Han) were collected for only a subsample. Prevalence of any depressive disorders was higher in women than men (lifetime prevalence odds ratio [OR] 1·44 [95% CI 1·20-1·72] and 12-month prevalence OR 1·41 [1·12-1·78]), in unemployed people than employed people (lifetime OR 2·38 [95% CI 1·68-3·38] and 12-month OR 2·80 [95% CI 1·88-4·18]), and in people who were separated, widowed, or divorced compared with those who were married or cohabiting (lifetime OR 1·87 [95% CI 1·39-2·51] and 12-month OR 1·85 [95% CI 1·40-2·46]). Overall, 574 (weighted % 75·9%) of 744 people with 12-month depressive disorders had role impairment of any SDS domain: 439 (83·6%) of 534 respondents with major depressive disorder, 207 (79·8%) of 254 respondents with dysthymic disorder, and 122 (59·9%) of 189 respondents with depressive disorder not otherwise specified. Only an estimated 84 (weighted % 9·5%) of 1007 participants with 12-month depressive disorders were treated in any treatment sector: 38 (3·6%) in speciality mental health, 20 (1·5%) in general medical, two (0·3%) in human services, and 21 (2·7%) in complementary and alternative medicine. Only 12 (0·5%) of 1007 participants with depressive disorders were treated adequately. INTERPRETATION: Depressive disorders in China were more prevalent in women than men, unemployed people than employed, and those who were separated, widowed, or divorced than people who were married or cohabiting. Most people with depressive disorders reported social impairment. Treatment rates were very low, and few people received adequate treatment. National programmes are needed to remove barriers to availability, accessibility, and acceptability of care for depression in China. FUNDING: National Health Commission and Ministry of Science and Technology of People's Republic of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Brain structural alterations in MDD patients with gastrointestinal symptoms: Evidence from the REST-meta-MDD project.

OBJECTIVE: While gastrointestinal (GI) symptoms are very common in patients with major depressive disorder (MDD), few studies have investigated the neural basis behind these symptoms. In this study, we sought to elucidate the neural basis of GI symptoms in MDD patients by analyzing the changes in regional gray matter volume (GMV) and gray matter density (GMD) in brain structure. METHOD: Subjects were recruited from 13 clinical centers and categorized into three groups, each of which is based on the presence or absence of GI symptoms: the GI symptoms group (MDD patients with at least one GI symptom), the non-GI symptoms group (MDD patients without any GI symptoms), and the healthy control group (HCs). Structural magnetic resonance images (MRI) were collected of 335 patients in the GI symptoms group, 149 patients in the non-GI symptoms group, and 446 patients in the healthy control group. The 17-item Hamilton Depression Rating Scale (HAMD-17) was administered to all patients. Correlation analysis and logistic regression analysis were used to determine if there was a correlation between the altered brain regions and the clinical symptoms. RESULTS: There were significantly higher HAMD-17 scores in the GI symptoms group than that of the non-GI symptoms group (P < 0.001). Both GMV and GMD were significant different among the three groups for the bilateral superior temporal gyrus, bilateral middle temporal gyrus, left lingual gyrus, bilateral caudate nucleus, right Fusiform gyrus and bilateral Thalamus (GRF correction, cluster-P < 0.01, voxel-P < 0.001). Compared to the HC group, the GI symptoms group demonstrated increased GMV and GMD in the bilateral superior temporal gyrus, and the non-GI symptoms group demonstrated an increased GMV and GMD in the right superior temporal gyrus, right fusiform gyrus and decreased GMV in the right Caudate nucleus (GRF correction, cluster-P < 0.01, voxel-P < 0.001). Compared to the non-GI symptoms group, the GI symptoms group demonstrated significantly increased GMV and GMD in the bilateral thalamus, as well as decreased GMV in the bilateral superior temporal gyrus and bilateral insula lobe (GRF correction, cluster-P < 0.01, voxel-P < 0.001). While these changed brain areas had significantly association with GI symptoms (P < 0.001), they were not correlated with depressive symptoms (P > 0.05). Risk factors for gastrointestinal symptoms in MDD patients (p < 0.05) included age, increased GMD in the right thalamus, and decreased GMV in the bilateral superior temporal gyrus and left Insula lobe. CONCLUSION: MDD patients with GI symptoms have more severe depressive symptoms. MDD patients with GI symptoms exhibited larger GMV and GMD in the bilateral thalamus, and smaller GMV in the bilateral superior temporal gyrus and bilateral insula lobe that were correlated with GI symptoms, and some of them and age may contribute to the presence of GI symptoms in MDD patients.

Mindfulness-based cognitive therapy is associated with distinct resting-state neural patterns in patients with generalized anxiety disorder.

INTRODUCTION: Mindfulness-based cognitive therapy (MBCT) may be effective for generalized anxiety disorder (GAD); however, the neural mechanism is poorly understood. In this study, we examined the potential neural mechanisms through which MBCT may reduce anxiety in patients with mild-to-moderate GAD. METHODS: Eight weekly group MBCT sessions (2 h each) were conducted with 32 GAD patients. Resting-state functional magnetic resonance imaging (fMRI) was used, along with clinical and mindfulness profiles. A regional homogeneity (ReHo) approach was applied, and resting-state functional connectivity in the default mode network (DMN) using the posterior cingulate cortex (PCC) seed was examined. RESULTS: MBCT reduced the anxiety and increased the mindfulness abilities of patients. After MBCT, patients had reduced ReHo in broad regions of the limbic system, along with increased DMN functional connectivity in the anterior cingulate cortex (ACC) and bilateral insula. Overlapping regions of reduced ReHo and increased DMN functional connectivity were observed in the mid-cingulate cortex (MCC) and bilateral insula. The increased PCC-ACC and PCC-insula functional connectivity following MBCT were related to anxiety improvements, suggesting a potential therapeutic mechanism for mindfulness-based therapies. DISCUSSION: Group MBCT treatment appears to have effectively reduced anxiety symptoms in patients with mild-to-moderate GAD. Activation and functional connectivity appeared significantly different across some limbic regions after MBCT treatment. The salience network showed reduced ReHo and increased connectivity to the PCC. The DMN functional connectivity of the MCC may indicate reduced anxiety and improved mindfulness in GAD patients.

BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis.

For tumors to progress efficiently, cancer cells must overcome barriers of oxidative stress. Although dietary antioxidant supplementation or activation of endogenous antioxidants by NRF2 reduces oxidative stress and promotes early lung tumor progression, little is known about its effect on lung cancer metastasis. Here, we show that long-term supplementation with the antioxidants N-acetylcysteine and vitamin E promotes KRAS-driven lung cancer metastasis. The antioxidants stimulate metastasis by reducing levels of free heme and stabilizing the transcription factor BACH1. BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells. Targeting BACH1 normalized glycolysis and prevented antioxidant-induced metastasis, while increasing endogenous BACH1 expression stimulated glycolysis and promoted metastasis, also in the absence of antioxidants. We conclude that BACH1 stimulates glycolysis-dependent lung cancer metastasis and that BACH1 is activated under conditions of reduced oxidative stress.

Psychotomimetic effects of different doses of MK-801 and the underlying mechanisms in a selective memory impairment model.

Although N-methyl-d-aspartate receptor antagonists-induced hypoglutamate rodent models are the most well-established models for preclinical studies of schizophrenia-related deficits, they also evoke a wide spectrum of psychotomimetic side effects. It is significant to increase the specificity of hypoglutamate rodent models. In this study, the recognition memory was evaluated in rats by object recognition test (ORT), sensorimotor gating was evaluated by prepulse inhibition of the startle reflex (PPI), and locomotor activity was measured using open field test. High-performance liquid chromatography was used to measure neurotransmitters content in the medial prefrontal cortex (mPFC) and thalamus (THA). Total Akt and phospho-Akt protein was measured by Western blots. Results showed that 0.3mg/kg of MK-801 was most effective in inducing locomotion. 0.3mg/kg of MK-801 was most effective in decreasing PPI. 0.03mg/kg of MK-801 was most effective in decreasing object memory while not affecting exploration manners in the training session. 0.03mg/kg of MK-801 significantly increased HVA and Glu content in the mPFC. 0.1mg/kg of MK-801 significantly decreased GABA content in the THA. 0.03mg/kg of MK-801 significantly decreased Akt phosphorylation in the mPFC, which was related to the ORT index. In conclusion, a dose of 0.03mg/kg MK-801 can establish a "pure" memory impairment model without contaminations of sensorimotor gating and locomotor activity. MK-801-induced cognitive deficits is associated with increased DA metabolites and glutamate content in the mPFC and decreased GABA content in the THA as well as decrease in Akt phosphorylation in the mPFC.

The volumetric and shape changes of the putamen and thalamus in first episode, untreated major depressive disorder.

Previous MRI studies confirmed abnormalities in the limbic-cortical-striatal-pallidal-thalamic (LCSPT) network or limbic-cortico-striatal-thalamic-cortical (LCSTC) circuits in patients with major depressive disorder (MDD), but few studies have investigated the subcortical structural abnormalities. Therefore, we sought to determine whether focal subcortical grey matter (GM) changes might be present in MDD at an early stage. We recruited 30 first episode, untreated patients with major depressive disorder (MDD) and 26 healthy control subjects. Voxel-based morphometry was used to evaluate cortical grey matter changes, and automated volumetric and shape analyses were used to assess volume and shape changes of the subcortical GM structures, respectively. In addition, probabilistic tractography methods were used to demonstrate the relationship between the subcortical and the cortical GM. Compared to healthy controls, MDD patients had significant volume reductions in the bilateral putamen and left thalamus (FWE-corrected, p < 0.05). Meanwhile, the vertex-based shape analysis showed regionally contracted areas on the dorsolateral and ventromedial aspects of the bilateral putamen, and on the dorsal and ventral aspects of left thalamus in MDD patients (FWE-corrected, p < 0.05). Additionally, a negative correlation was found between local atrophy in the dorsal aspects of the left thalamus and clinical variables representing severity. Furthermore, probabilistic tractography demonstrated that the area of shape deformation of the bilateral putamen and left thalamus have connections with the frontal and temporal lobes, which were found to be related to major depression. Our results suggested that structural abnormalities in the putamen and thalamus might be present in the early stages of MDD, which support the role of subcortical structure in the pathophysiology of MDD. Meanwhile, the present study showed that these subcortical structural abnormalities might be the potential trait markers of MDD.

The beneficial effects of n-3 polyunsaturated fatty acids on diet induced obesity and impaired glucose control do not require Gpr120.

GPR120 (Ffar4) has been postulated to represent an important receptor mediating the improved metabolic profile seen upon ingestion of a diet enriched in polyunsaturated fatty acids (PUFAs). GPR120 is highly expressed in the digestive system, adipose tissue, lung and macrophages and also present in the endocrine pancreas. A new Gpr120 deficient mouse model on pure C57bl/6N background was developed to investigate the importance of the receptor for long-term feeding with a diet enriched with fish oil. Male Gpr120 deficient mice were fed two different high fat diets (HFDs) for 18 weeks. The diets contained lipids that were mainly saturated (SAT) or mainly n-3 polyunsaturated fatty acids (PUFA). Body composition, as well as glucose, lipid and energy metabolism, was studied. As expected, wild type mice fed the PUFA HFD gained less body weight and had lower body fat mass, hepatic lipid levels, plasma cholesterol and insulin levels and better glucose tolerance as compared to those fed the SAT HFD. Gpr120 deficient mice showed a similar improvement on the PUFA HFD as was observed for wild type mice. If anything, the Gpr120 deficient mice responded better to the PUFA HFD as compared to wild type mice with respect to liver fat content, plasma glucose levels and islet morphology. Gpr120 deficient animals were found to have similar energy, glucose and lipid metabolism when fed HFD PUFA compared to wild type mice. Therefore, GPR120 appears to be dispensable for the improved metabolic profile associated with intake of a diet enriched in n-3 PUFA fatty acids.

Association study of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism with auditory P300 in Chinese Han patients with schizophrenia.

Several studies have reported associations between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and P300 event-related potentials in schizophrenic patients. But there has been no research to study the association between the P300 component and the Val158Met polymorphism in Chinese Han schizophrenia patients. Therefore, the present article was aimed at investigating the relationship of the Val158Met polymorphism with P300 in Chinese schizophrenic patients. The Val158Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 287 schizophrenia patients and 84 healthy control subjects. P300 recordings were obtained in a subsample. A significant difference was not observed between the patients and control subjects in the genotype distributions and allele frequencies. P300 amplitude in schizophrenia patients was significantly lower than that of controls. The P300 latency in schizophrenia patients was also significantly longer than that of controls. The P300 latency of Met homozygotes was significantly shorter than that of Val/Met and of Val/Val carriers at Cz and Pz. The latency of Val/Met carriers was significantly shorter than that of Val/Val carriers at Pz. The results did not suggest an association between the polymorphism in the COMT gene and susceptibility to schizophrenia in the Chinese Han population. However, the COMT Val158Met polymorphism might be a susceptibility variant for P300 abnormality in Chinese Han schizophrenia.