Dissociable salience and default mode network modulation in generalized anxiety disorder: a connectome-wide association study.

Generalized anxiety disorder (GAD) is a common anxiety disorder experiencing psychological and somatic symptoms. Here, we explored the link between the individual variation in functional connectome and anxiety symptoms, especially psychological and somatic dimensions, which remains unknown. In a sample of 118 GAD patients and matched 85 healthy controls (HCs), we used multivariate distance-based matrix regression to examine the relationship between resting-state functional connectivity (FC) and the severity of anxiety. We identified multiple hub regions belonging to salience network (SN) and default mode network (DMN) where dysconnectivity associated with anxiety symptoms (P < 0.05, false discovery rate [FDR]-corrected). Follow-up analyses revealed that patient's psychological anxiety was dominated by the hyper-connectivity within DMN, whereas the somatic anxiety could be modulated by hyper-connectivity within SN and DMN. Moreover, hypo-connectivity between SN and DMN were related to both anxiety dimensions. Furthermore, GAD patients showed significant network-level FC changes compared with HCs (P < 0.01, FDR-corrected). Finally, we found the connectivity of DMN could predict the individual psychological symptom in an independent GAD sample. Together, our work emphasizes the potential dissociable roles of SN and DMN in the pathophysiology of GAD's anxiety symptoms, which may be crucial in providing a promising neuroimaging biomarker for novel personalized treatment strategies.

Eight-month intensive meditation-based intervention improves refractory hallucinations and delusions and quality of life in male inpatients with schizophrenia: a randomized controlled trial.

AIM: This study investigated the impact of an 8-month daily-guided intensive meditation-based intervention (iMI) on persistent hallucinations/delusions and health-related quality of life (QoL) in male inpatients with schizophrenia with treatment-refractory hallucinations and delusions (TRHDs). METHODS: A randomized controlled trial assigned 64 male inpatients with schizophrenia and TRHD equally to an 8-month iMI plus general rehabilitation program (GRP) or GRP alone. Assessments were conducted at baseline and the third and eighth months using the Positive and Negative Syndrome Scale (PANSS), 36-Item Short Form-36 (SF-36), and Five Facet Mindfulness Questionnaire (FFMQ). Primary outcomes measured PANSS reduction rates for total score, positive symptoms, and hallucinations/delusions items. Secondary outcomes assessed PANSS, SF-36, and FFMQ scores for psychotic symptoms, health-related QoL, and mindfulness skills, respectively. RESULTS: In the primary outcome, iMI significantly improved the reduction rates of PANSS total score, positive symptoms, and hallucination/delusion items compared with GRP at both the third and eighth months. Treatment response rates (≥25% reduction) for these measures significantly increased in the iMI group at the eighth month. Concerning secondary outcomes, iMI significantly reduced PANSS total score and hallucination/delusion items, while increasing scores in physical activity and mindfulness skills at both the third and eighth months compared with GRP. These effects were more pronounced with an 8-month intervention compared with a 3-month intervention. CONCLUSIONS: An iMI benefits patients with TRHDs by reducing persistent hallucinations/delusions and enhancing health-related QoL. Longer iMI duration yields superior treatment outcomes.

In vitro evaluation of the toxicological effects of cooking oil fumes using a self-designed microfluidic chip.

Cooking oil fumes (COFs) are widely acknowledged as substantial contributors to indoor air pollution, having detrimental effects on human health. Despite the existence of commercialized in vitro aerosol exposure platforms, assessment risks of aerosol pollutants are primarily evaluated based on multiwell plate experiments by trapping and redissolving aerosols to conduct comprehensive in vitro immersion exposure manner. Therefore, an innovative real-time exposure system for COF aerosol was constructed, featuring a self-designed microfluidic chip as its focal component. The chip was used to assess toxicological effects of in vitro exposure to COF aerosol on cells cultured at the gas-liquid interface. Meanwhile, we used transcriptomics to analyze genes that exhibited differential expression in cells induced by COF aerosol. The findings indicated that the MAPK signaling pathway, known for its involvement in inflammatory response and oxidative stress, played a crucial role in the biological effects induced by COF aerosol. Biomarkers associated with inflammatory response and oxidative stress exhibited corresponding alterations. Furthermore, the concentration of COF aerosol exposure and post-exposure duration exert decisive effects on these biomarkers. Thus, the study suggests that COF can induce oxidative stress and inflammatory response in BEAS-2B cells, potentially exerting a discernible impact on human health.

Mindfulness-based intervention improves residual negative symptoms and cognitive impairment in schizophrenia: a randomized controlled follow-up study.

BACKGROUND: Residual negative symptoms and cognitive impairment are common for chronic schizophrenia patients. The aim of this study was to investigate the efficacy of a mindfulness-based intervention (MBI) on negative and cognitive symptoms of schizophrenia patients with residual negative symptoms. METHODS: In this 6-week, randomized, single-blind, controlled study, a total of 100 schizophrenia patients with residual negative symptoms were randomly assigned to the MBI or control group. The 6-week MBI group and the control group with general rehabilitation programs maintained their original antipsychotic treatments. The scores for the Positive and Negative Syndrome Scale (PANSS), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the Symptom Checklist 90 (SCL-90) were recorded at baseline and week 6 to assess psychotic symptoms, cognitive performance, and emotional state, respectively. RESULTS: Compared with general rehabilitation programs, MBI alleviated the PANSS-negative subscore, general psychopathology subscore, and PANSS total score in schizophrenia patients with residual negative symptoms (F = 33.77, pBonferroni < 0.001; F = 42.01, pBonferroni < 0.001; F = 52.41, pBonferroni < 0.001, respectively). Furthermore, MBI improved RBANS total score and immediate memory subscore (F = 8.80, pBonferroni = 0.024; F = 11.37, pBonferroni = 0.006), as well as SCL-90 total score in schizophrenia patients with residual negative symptoms (F = 18.39, pBonferroni < 0.001). CONCLUSIONS: Our results demonstrate that MBI helps schizophrenia patients with residual negative symptoms improve clinical symptoms including negative symptom, general psychopathology symptom, and cognitive impairment. TRIAL REGISTRATION: ChiCTR2100043803.

Histidine Metabolic Pathway Contributes to Clozapine-Induced Sialorrhea Based on Nontargeted Metabolomics.

INTRODUCTION: Clozapine-induced sialorrhea (CIS) is one of the most common side effects of clozapine use, while the mechanism remains unclear. METHODS: A total of 51 schizophrenia patients taking clozapine were selected. Among them, 32 had sialorrhea, and 19 had no sialorrhea. Saliva metabolites were identified using ultra-high-performance liquid chromatography-MS/MS (UHPLC-MS/MS), and the differences in saliva metabolites in each group were analyzed through qualitatively searching HMDB, KEGG, and self-built databases, combined with multivariate statistics. After further evaluation by receiver-operating characteristic curve (ROC) analysis, the screened differential metabolites were enriched and topologically analyzed. RESULTS: The biomarkers potentially related to CIS included 37 differential metabolites involving 17 metabolic pathways, mainly histidine metabolism (p < 0.05, impact = 0.50), pyrimidine metabolism (p < 0.05, impact = 0.08), and ß-alanine metabolism (p < 0.05, impact = 0.06). CONCLUSION: Our study indicates that histidine metabolic pathway may contribute to the mechanism of CIS.

The percentage and clinical correlates of alexithymia in stable patients with schizophrenia.

Alexithymia is a common, but less-recognized affective deficit in patients with schizophrenia. To date, no definitive conclusions have been drawn about the relationship between alexithymia and the clinical symptoms or their clinical correlates, particularly in stable patients with schizophrenia. The purpose of this study was to investigate the link between alexithymia and psychopathological symptoms, as well as any associated correlates, in stable patients with schizophrenia. A total of 435 Chinese patients with schizophrenia were recruited. The Positive and Negative Symptoms Scale (PANSS) was used to evaluate each patient's psychopathological symptoms. The Toronto Alexithymia Scale (TAS-20) was used to measure alexithymia. The percentage of alexithymia was 35.2% in stable patients with schizophrenia. Compared to non-alexithymia patients, patients with alexithymia had higher PANSS total scores, negative subscores, depressive subscores, and cognitive subscores (all p < 0.05). Multivariate regression analysis revealed that the following variables were positively associated with TAS-20 total scores: PANSS negative subscores (ß = 0.274, t = 3.198, p = 0.001) and PANSS depressive subscores (ß = 0.366, t = 2.500, p = 0.013). Education years (ß = - 0.453, t = - 2.824, p = 0.005) was negatively associated with TAS-20 total scores. Our results suggest that the percentage of alexithymia was relatively higher in stable patients with schizophrenia. Education levels, negative symptoms, and depressive symptoms were independently associated with alexithymia in this specific population.

Sex differences in the association between suicidal ideation and neurocognitive function in Chinese patients with schizophrenia.

There is increasing evidence that sex differences exist in many clinical manifestations of patients with schizophrenia, including suicidal ideation (SI) and neurocognitive function. The present study was performed to explore the sex differences in the association between SI and neurocognitive function in Chinese patients with schizophrenia. A total of 1188 inpatients with schizophrenia were recruited from multicenter psychiatric hospitals. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was utilized to evaluate the neurocognitive function of all patients. The Positive and Negative Syndrome Scale (PANSS) was utilized to assess the psychopathology of patients. The Beck Scale for Suicide Ideation (BSSI) was used to assess the severity of SI. In male patients, the suicide risk score was significantly associated with PANSS negative symptoms (r = 0.167, p = 0.043), visuospatial subscale (r = - 0.261, p = 0.001), and RBANS total scores (r = - 0.172, p = 0.037). Furthermore, multivariate linear regression analysis showed that the visuospatial subscale (ß = - 0.490, t = - 3.273, p = 0.001) was independently associated with the suicide risk score in male patients. In female patients, the suicide risk score was significantly correlated with PANSS positive symptoms (r = 0.249, p = 0.021), negative symptoms (r = 0.394, p < 0.001), general psychopathology (r = 0.276, p = 0.01) and PANSS total score (r = 0.365, p = 0.001). Multivariate linear regression analysis showed that PANSS negative symptoms (ß = 1.849, t = 3.933, p = 0.001) were significantly associated with suicide risk scores in female patients. Our findings indicate that there are sex differences in the association between SI and neurocognitive function in patients with schizophrenia. Based on the findings of our study, gender-specific prevention and intervention strategies may make a difference in reducing SI in Chinese schizophrenia patients.

The association of SOD and HsCRP with the efficacy of sulforaphane in schizophrenia patients with residual negative symptoms.

OBJECTIVES: Emerging evidence indicates a connection between oxidative stress, immune-inflammatory processes, and the negative symptoms of schizophrenia. In addition to possessing potent antioxidant and anti-inflammatory properties, sulforaphane (SFN) has shown promise in enhancing cognitive function among individuals with schizophrenia. This study aims to investigate the efficacy of combined treatment with SFN in patients with schizophrenia who experience negative symptoms and its effect on the levels of superoxide dismutase (SOD) and the inflammatory marker, high-sensitivity C-reactive protein (HsCRP). DESIGN: Forty-five patients with schizophrenia were recruited, who mainly experienced negative symptoms during a stable period. In addition to the original treatments, the patients received SFN tablets at a daily dose of 90 mg for 24 weeks. At baseline, 12 weeks, and 24 weeks, the participants were interviewed and evaluated. The reduction rate of the Positive and Negative Syndrome Scale (PANSS) was used to assess each participant. The side effects scale of Treatment Emergent Symptom Scale (TESS) was applied to assess the adverse reactions. Additionally, the levels of the SOD, HsCRP, and other indicators were examined. RESULTS: The study findings revealed a significant decrease in PANSS negative subscale scores (P < 0.001). Furthermore, there was a significant increase in SOD activity and HsCRP levels (P < 0.001 and P < 0.05). Notably, the group of participants who exhibited a reduction in PANSS negative subscale scores demonstrated a significant improvement in HsCRP levels (P < 0.05). CONCLUSIONS: Our study suggests that SFN may potentially serve as a safe adjunctive intervention to improve the negative symptoms of schizophrenia. The potential mechanism by which SFN improves negative symptoms in schizophrenia patients may involve its anti-inflammatory properties, specifically its ability to reduce HsCRP levels. Trial registration ClinicalTrial.gov (ID: NCT03451734).

Sex-based influential factors for dental caries in patients with schizophrenia.

BACKGROUND: Schizophrenia is a common mental disorder that seriously affects patients' daily lives and brings heavy psychological and economic burdens to their families and society. The oral problems of patients with schizophrenia are gradually gaining attention, among which dental caries are among the most common oral diseases. Sex differences may be related not only to the various clinical symptoms of schizophrenia but also to different oral hygiene statuses; therefore, the main purpose of this paper is to investigate sex differences related to influencing factors for dental caries in patients with schizophrenia. METHOD: Inpatients with schizophrenia over 18 years old were included in this study, and multidimensional indicators such as demographics, symptom and cognitive impairment assessments, medications, and the caries index of decayed, missing, and filled teeth (DMFT) were collected. An analysis of sex-based influential factors for dental caries in schizophrenia patients was performed. RESULTS: Four-hundred and ninety-six patients with schizophrenia were included, with a mean age of 46.73 ± 12.23 years, of which 142 were females and 354 were males. The mean DMFT was significantly higher in males (8.81 ± 8.50) than in females (5.63 ± 6.61, p < 0.001), and the odd ratio of caries in males to females was significantly higher as well (OR = 2.305, p < 0.001). The influential factors of caries in male patients were independently associated with age and smoking status, in which current smokers were at the highest risk for developing caries, and different smoking statuses had various influencing factors for caries. The influencing factors for caries in female patients were independently associated with age, antipsychotic dose, PANSS-positive symptoms, and MMSE levels. CONCLUSION: Our findings suggest sex differences exist among influential factors for caries in patients with schizophrenia. These risk factors may even be associated with and affect the treatment and prognosis of psychiatric symptoms in patients. Therefore, oral hygiene management of patients with schizophrenia should be enhanced. These differential factors provide new visions and ideas for formulating individual interventions, treatments, and care priorities.

Design of a microfluidic lung chip and its application in assessing the toxicity of formaldehyde.

In this work, a microfluidic lung chip with membrane supporting cell growth that can produce multiple concentration gradients of gas and liquid is introduced. The chip is composed of a gas gradient layer in the upper part, a porous membrane supporting cell growth in the middle and a liquid gradient layer in the lower part. The gas-liquid interface environment of the cells on the membrane can expose the cells to the gas in the upper layer and the liquid in the lower layer at the same time. Then, the chip is applied to the toxicity testing of formaldehyde in A549 cells. The results showed that at 6 × 10-5 mol/L formaldehyde, the survival rate of the cells in four channels were 90, 87, 81, and 71%, which shows a dose-response trend under the influence of different concentrations of formaldehyde. ROS staining results also showed that formaldehyde exposure at 6 × 10-5 mol/L lead to the increase of ROS level in the cells. These results suggest that the chip based on cell growth on membrane could be used for toxicological evaluation of environmental polluting gases.

TRIM27-mediated ubiquitination of PPARγ promotes glutamate-induced cell apoptosis and inflammation.

Neurotoxicity induced by glutamate (Glu) is often used to study the signaling mechanism of neurological disorders. The identification of specific genetic factors that cause Glu-induced neurotoxicity provides evidence for the common pathways of neuronal apoptosis and inflammation. TRIM27 has been found to induce apoptosis and inflammation. Nevertheless, there is little evidence that TRIM27 is associated with Glu-induced neurotoxicity. We found that TRIM27 expression was increased in epilepsy patients and in HT22 cells following Glu treatment. Glu-mediated cell apoptosis, decreased PPARγ expression, and increased levels of cleaved Caspase-3 and IL-1ß expression in HT22 cells were significantly inhibited by TRIM27 knockdown. TRIM27 overexpression significantly induced cell apoptosis and expression of cleaved Caspase-3 and IL-1ß, but inhibited PPARγ expression in HT22 cells, which were reversed by ROZ, suggesting the involvement of PPARγ in TRIM27-mediated cell apoptosis and inflammation in HT22 cells. Mechanically, TRIM27 ubiquitinates and degrades PPARγ, following induces cleaved Caspase-3 and IL-1ß expression. Clinically, increased expression of TRIM27 in epilepsy patients was associated with decreased PPARγ expression. Taken together, our study suggests that TRIM27-mediated ubiquitination of PPARγ promotes Glu-induced HT22 cell apoptosis and IL-1ß release.

Novel Chemicals Derived from Tadalafil Exhibit PRMT5 Inhibition and Promising Activities against Breast Cancer.

Breast cancer seriously endangers women's health worldwide. Protein arginine methyltransferase 5 (PRMT5) is highly expressed in breast cancer and represents a potential druggable target for breast cancer treatment. However, because the currently available clinical PRMT5 inhibitors are relatively limited, there is an urgent need to develop new PRMT5 inhibitors. Our team previously found that the FDA-approved drug tadalafil can act as a PRMT5 inhibitor and enhance the sensitivity of breast cancer patients to doxorubicin treatment. To further improve the binding specificity of tadalafil to PRMT5, we chemically modified tadalafil, and designed three compounds, A, B, and C, based on the PRMT5 protein structure. These three compounds could bind to PRMT5 through different binding modes and inhibit histone arginine methylation. They arrested the proliferation and triggered the apoptosis of breast cancer cells in vitro and also promoted the antitumor effects of the chemotherapy drugs cisplatin, doxorubicin, and olaparib in combination regimens. Among them, compound A possessed the highest potency. Finally, the anti-breast cancer effects of PRMT5 inhibitor A and its ability to enhance chemosensitivity were further verified in a xenograft mouse model. These results indicate that the new PRMT5 inhibitors A, B, and C may be potential candidates for breast cancer treatment.

Sex difference in the interrelationship between TNF-α and oxidative stress status in first-episode drug-naïve schizophrenia.

BACKGROUND: Increasing evidence indicates that dysregulated TNF-α and oxidative stress (OxS) contribute to the pathophysiology of schizophrenia. Additionally, previous evidence has demonstrated sex differences in many aspects of schizophrenia including clinical characteristics, cytokines, and OxS markers. However, to the best of our knowledge, there is no study investigating sex differences in the association between TNF-α, the OxS system, and their interaction with clinical symptoms in schizophrenia patients, especially in first-episode drug-naïve (FEDN) patients. METHODS: A total of 119 FEDN schizophrenia patients and 135 healthy controls were recruited for this study. Serum TNF-α, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA) were measured. The Positive and Negative Syndrome Scale (PANSS) was applied to evaluate psychotic symptoms. Two-way ANOVA, partial correlation analysis, and multivariate regression analysis were performed. RESULTS: A sex difference in MDA levels was demonstrated only in healthy controls (F = 7.06, pBonferroni = 0.045) and not seen in patients. Furthermore, only male patients had higher MDA levels than male controls (F = 8.19, pBonferroni = 0.03). Additionally, sex differences were observed in the association of TNF-α and MDA levels with psychotic symptoms (all pBonferroni < 0.05). The interaction of TNF-α and MDA was only associated with general psychopathology symptom in male patients (B = - 0.07, p = 0.02). CONCLUSION: Our results demonstrate the sex difference in the relationship between TNF-α, MDA, and their interaction with psychopathological symptoms of patients with schizophrenia.

Sex Difference in Comorbid Depression in First-Episode and Drug-Naive Patients With Schizophrenia: Baseline Results From the Depression in Schizophrenia in China Study.

OBJECTIVE: Comorbid depression is common in schizophrenia, and sex differences are prominent in many aspects of schizophrenia. However, few studies have investigated sex difference in comorbid depression in schizophrenia. This large sample study aimed to investigate sex differences in first-episode drug-naive (FEDN) patients with schizophrenia comorbid major depressive episode (SZ-MDE). METHODS: A total of 996 FEDN patients with schizophrenia (472 males/524 females) were recruited. The 17-item Hamilton Depression Rating Scale and Positive and Negative Syndrome Scale (PANSS) were applied. RESULTS: There was no difference in the prevalence of comorbid MDE between male and female patients with schizophrenia. Among SZ-MDE patients, men had more severe psychotic symptoms (scores of PANSS total scale, negative scale, and general psychopathology scale), more severe depressive symptoms, and higher proportion of severe depression than women (all p < .001). The early onset age of schizophrenia, smoking, and PANSS positive score were the risk factors for comorbid MDE only in female patients with schizophrenia (all p < .05). Furthermore, in female patients with SZ-MDE, smoking was associated with the severity category of depression (p = .001, odds ratio = 2.70). Multiple variable regression demonstrated that the Hamilton Depression Rating Scale score correlated with PANSS general psychopathology (p = .01) and total scores (p = .04) in female SZ-MDE. CONCLUSIONS: Our results indicate sex differences in proportion of severe depression, clinical symptoms, and factors of comorbid MDE in FEDN patients with schizophrenia. These sex differences have clinical implications for the treatment of depression as related to the nature and severity of psychopathological symptoms in patients with schizophrenia.

Smoking Affects the Patterns of Metabolic Disorders and Metabolic Syndrome in Patients With First-Episode Drug-Naive Schizophrenia: A Large Sample Study Based on the Chinese Han Population.

OBJECTIVE: Although metabolic disorders and smoking are common in schizophrenia, few studies have investigated the effects of smoking on metabolic disorders or metabolic syndrome (MetS) in schizophrenia patients, especially in first-episode drug-naïve (FEDN) patients. We sought to investigate the differences in metabolic disorders and MetS between smoking and nonsmoking FEDN schizophrenia patients. METHODS: A total of 428 FEDN schizophrenia patients and 435 controls were recruited. Blood pressure, waist circumference, body mass index (BMI), lipid profiles, and glucose metabolism were measured. The psychopathology was evaluated by Positive and Negative Syndrome Scale. RESULTS: FEDN schizophrenia patients had a higher smoking rate than controls (23.8% vs 14.0%, P < .001). After adjusting for confounding variables, the prevalence of MetS, overweight, hypertension, hypertriglyceridemia, elevated insulin, and insulin resistance in smoking patients was higher than those in nonsmoking patients, while overweight and hypertension were higher in the smoking controls than in nonsmoking controls (all P < .05). In smoking patients, triglyceridemia, high-density lipoprotein cholesterol, and fasting blood glucose were the main contributing components to MetS, while in nonsmoking patients, waist circumference, systolic blood pressure, triglyceridemia, high-density lipoprotein cholesterol, and fasting blood glucose were the main contributing components to MetS. In smoking patients, BMI and homeostatic model assessment for insulin resistance were associated factors of MetS (both P < .05). In nonsmoking patients, sex, BMI, insulin, and homeostatic model assessment for insulin resistance were associated factors of MetS (all P < .05). CONCLUSIONS: Our study indicates that smoking schizophrenia patients have a higher prevalence of MetS and metabolic disorders than nonsmoking patients. Moreover, smoking and nonsmoking patients have different contributing components and associated factors for MetS.

Metformin Attenuates the Metabolic Disturbance and Depression-like Behaviors Induced by Corticosterone and Mediates the Glucose Metabolism Pathway.

BACKGROUND: Metabolism disturbances are common in patients with depression. The drug metformin has been reported to exhibit antidepressant activity. The purpose of this study was to investigate metabolism disturbances induced by corticosterone (CORT) and determine if metformin can reverse these effects and their accompanying depression-like behaviors. METHODS: Rats were exposed to corticosterone with or without metformin administration. Depression-like behaviors were tested. Gene expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. In addition, the metabolites were quantified by LC-MS/MS analysis. RESULTS: Metformin attenuated the depression-like behaviors induced by CORT. Furthermore, metformin reversed disturbances in body weight, serum glucose, and triglyceride levels, as well as hepatic TG levels induced by CORT. Metformin normalized the alterations in the expression of glucose metabolism-related genes (PGC-1α, G6pc, Pepck, Gck, PYGL, Gys2, PKLR, GLUT4) and insulin resistance-related genes (AdipoR1, AdipoR2) in the muscles and livers of rats induced by CORT. Metabolomic analysis showed that metformin reversed the effects of CORT on 11 metabolites involved in the pathways of the tricarboxylic acid cycle, glycolysis, and gluconeogenesis (3-phospho-D-glycerate, ß-D-fructose 6-phosphate, D-glucose 6-phosphate, and pyruvate). CONCLUSION: Our findings suggest that metformin can attenuate metabolism disturbances and depression-like behaviors induced by CORT mediating the glucose metabolism pathway.

Disturbance of Oxidative Stress Parameters in Treatment-Resistant Bipolar Disorder and Their Association With Electroconvulsive Therapy Response.

OBJECTIVE: Electroconvulsive therapy (ECT) is an effective option for treatment-resistant bipolar disorder (trBD). However, the mechanisms of its effect are unknown. Oxidative stress is thought to be involved in the underpinnings of BD. Our study is the first, to our knowledge, to report the association between notable oxidative stress parameters (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], catalase [CAT], and malondialdehyde [MDA]) levels and ECT response in trBD patients. METHODS: A total 28 trBD patients and 49 controls were recruited. Six-week ECT and naturalistic follow-up were conducted. SOD, GSH-Px, CAT, and MDA levels were measured by enzyme-linked immunosorbent assay, and the 17-item Hamilton Depression Rating Scale and Young Mania Rating Scale were administered at baseline and the end of the 6th week. MANCOVA, ANCOVA, 2 × 2 ANCOVA, and a multiple regression model were conducted. RESULTS: SOD levels were lower in both trBD mania and depression (P = .001; P = .001), while GSH-Px (P = .01; P = .001) and MDA (P = .001; P = .001) were higher in both trBD mania and depression compared with controls. CAT levels were positively associated with 17-item Hamilton Depression Rating Scale scores in trBD depression (radjusted = 0.83, P = .005). MDA levels in trBD decreased after 6 weeks of ECT (P = .001). Interestingly, MDA levels decreased in responders (P = .001) but not in nonresponders (P > .05). CONCLUSIONS: Our study indicates that decreased SOD could be a trait rather than a state in trBD. Oxidative stress levels are associated with illness severity and ECT response. This suggests that the mechanism of oxidative stress plays a crucial role in the pathophysiology of trBD.

Four new diarylheptanoids from Rhizoma Zingiberis.

Four new diarylheptanoids, (1S, 3R, 5R, 6R)-1, 5-epoxy-3, 6 dihydroxy-1-(4-hydroxy-3, 5-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl) heptane (1), (1R, 3R, 5S)-1, 5-epoxy-3-acetoxy-1-(4, 5-dihydroxy-3-methoxyphenyl)-7-(3, 4- hydroxyphenyl) heptane (2), (3R, 5S, 6R, 7S)-3, 6-epoxy-7-hydroxyl-1-(4-hydroxyphenyl)-7-(3-methoxy-4-hydroxyphenyl) heptane (3), (E)-3-keto-1-(3-methoxy-4-hydroxyphenyl)-7-(4, 5-dihydroxy-3-methoxyphenyl)-4- heptene (4), were isolated from Rhizoma Zingiberis, and their structures were determined based on HR-ESI-MS and extensive spectroscopic techniques (UV, IR, 1D-NMR and 2D-NMR). Compounds 1-4 exhibited no cytotoxicity against HepG2 cell lines.

TGFß1 transduction enhances immunomodulatory capacity of neural stem cells in experimental autoimmune encephalomyelitis.

Bone marrow-derived neural stem cells (BM-NSCs) have therapeutic effect on EAE, an animal model of multiple sclerosis. However, the beneficial effect is suboptimal due to the limited immunomodulatory capacity of these cells. In this study, we engineered BM-NSCs with inducible TGFß1, a potent immunosuppressive cytokine, to enhance their anti-inflammatory capacity. We found that i.v. injected TGFß1-BM-NSCs more effectively suppressed clinical severity, inflammation and demyelination of the central nervous system of EAE mice. Transduction of TGFß1 resulted in a higher percentage of Tregs and lower percentage of Th1 and Th17 cells in the periphery, with increased production of IL-10, and reduced production of IFN-γ, IL-17 and GM-CSF. Moreover, myelin-specific splenic proliferation was also inhibited more profoundly by TGFß1-BM-NSCs. We also found that TGFß1-BM-NSCs have the capacity to switch microglia from M1 to M2 phenotype. On the other hand, transduction of TGFß1 did not affect proliferative ability and differentiating potential of BM-NSCs in vitro and in vivo. Together, these findings demonstrate that transduction of TGFß1 significantly enhanced the immunomodulatory capacity of BM-NSCs for EAE treatment, through inducing Tregs and an M2 phenotype of macrophages/microglia, while retaining their capacity for neural cell differentiation. Thus, our study provides an easily accessible, inducible and effective therapy for CNS inflammatory demyelination.