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Background: Abnormalities in cortical excitability and plasticity have been considered to underlie the pathophysiology of schizophrenia. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) can provide a direct evaluation of cortical responses to TMS. Here, we employed TMS-EEG to investigate cortical responses to orbitofrontal cortex (OFC) stimulation in schizophrenia., Methods: In total, we recruited 92 drug-naïve patients with first-episode schizophrenia and 51 age- and sex-matched healthy individuals. For each participant, one session of 1-Hz repetitive TMS (rTMS) was delivered to the right OFC, and TMS-EEG data were obtained to explore the change in cortical-evoked activities before and immediately after rTMS during the eyes-closed state. The MATRICS Consensus Cognitive Battery was used to assess neurocognitive performance., Results: The cortical responses indexed by global mean field amplitudes (i.e., P30, N45, and P60) were larger in patients with schizophrenia than in healthy control participants at baseline. Furthermore, after one session of 1-Hz rTMS over the right OFC, the N100 amplitude was significantly reduced in the healthy control group but not in the schizophrenia group. In the healthy control participants, there was a significant correlation between modulation of P60 amplitude by rTMS and working memory; however, this correlation was absent in patients with schizophrenia., Conclusions: Aberrant global cortical responses following right OFC stimulation were found in patients with drug-naïve first-episode schizophrenia, supporting its significance in the primary pathophysiology of schizophrenia., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Non-invasive neuroregulation techniques have been demonstrated to improve certain motor symptoms in Parkinson's disease (PD). However, the currently employed regulatory techniques primarily concentrate on stimulating single target points, neglecting the functional regulation of networks and circuits. The supplementary motor area (SMA) has a significant value in motor control, and its functionality is often impaired in patients with PD. The matching SMA-primary motor cortex (M1) paired transcranial magnetic stimulation (TMS) treatment protocol, which benefits patients by modulating the sequential and functional connections between the SMA and M1, was elucidated in this study., Methods: This was a single-center, double-blind, randomized controlled clinical trial. We recruited 78 subjects and allocated them in a 1:1 ratio by stratified randomization into the paired stimulation ( n  = 39) and conventional stimulation groups ( n  = 39). Each patient underwent 3 weeks of matching SMA-M1 paired TMS or sham-paired stimulation. The subjects were evaluated before treatment initiation, 3 weeks into the intervention, and 3 months after the cessation of therapy. The primary outcome measure in this study was the Unified Parkinson's Disease Rating Scale III, and the secondary outcome measures included non-motor functional assessment, quality of life (Parkinson's Disease Questionnaire-39), and objective assessments (electromyography and functional near-infrared spectroscopy)., Discussion: Clinical protocols aimed at single targets using non-invasive neuroregulation techniques often improve only one function. Emphasizing the circuit and network regulation in PD is important for enhancing the effectiveness of TMS rehabilitation. Pairing the regulation of cortical circuits may be a potential treatment method for PD. As a crucial node in motor control, the SMA has direct fiber connections with basal ganglia circuits and complex fiber connections with M1, which are responsible for motor execution. SMA regulation may indirectly regulate the function of basal ganglia circuits. Therefore, the developed cortical pairing stimulation pattern can reshape the control of information flow from the SMA to M1. The novel neuroregulation model designed for this study is based on the circuit mechanisms of PD and previous research results, with a scientific foundation and the potential to be a means of neuroregulation for PD. Clinical trial registration : ClinicalTrials.gov, identifier [ChiCTR2400083325]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tang, Huang, Zhu, Liang, Sun, Zhang, Tan, Cui, Gong, Wang and Chen.)

It is very crucial to investigate key molecules that are involved in myelination to gain an understanding of brain development and injury. We have reported for the first time that pathogenic variants p.R477H and p.P505S in KARS, which encodes lysyl-tRNA synthetase (LysRS), cause leukoencephalopathy with progressive cognitive impairment in humans. The role and action mechanisms of KARS in brain myelination during development are unknown. Here, we first generated Kars knock-in mouse models through the CRISPR-Cas9 system. Kars knock-in mice displayed significant cognitive deficits. These mice also showed significantly reduced myelin density and content, as well as significantly decreased myelin thickness during development. In addition, Kars mutations significantly induced oligodendrocyte differentiation arrest and reduction in the brain white matter of mice. Mechanically, oligodendrocytes' significantly imbalanced expression of differentiation regulators and increased capase-3-mediated apoptosis were observed in the brain white matter of Kars knock-in mice. Furthermore, Kars mutations significantly reduced the aminoacylation and steady-state level of mitochondrial tRNA Lys and decreased the protein expression of subunits of oxidative phosphorylation complexes in the brain white matter. Kars knock-in mice showed decreased activity of complex IV and significantly reduced ATP production and increased reactive oxygen species in the brain white matter. Significantly increased percentages of abnormal mitochondria and mitochondrion area were observed in the oligodendrocytes of Kars knock-in mouse brain. Finally, melatonin (a mitochondrion protectant) significantly attenuated mitochondrion and oligodendrocyte deficiency in the brain white matter of Kars R504H/P532S mice. The mice treated with melatonin also showed significantly restored myelination and cognitive function. Our study first establishes Kars knock-in mammal models of leukoencephalopathy and cognitive impairment and indicates important roles of KARS in the regulation of mitochondria, oligodendrocyte differentiation and survival, and myelination during brain development and application prospects of melatonin in KARS (or even aaRS)-related diseases., (© 2024 The Author(s). Journal of Pineal Research published by John Wiley & Sons Ltd.)

Background: The occurrence, development, and outbreak of tea diseases and pests pose a significant challenge to the quality and yield of tea, necessitating prompt identification and control measures. Given the vast array of tea diseases and pests, coupled with the intricacies of the tea planting environment, accurate and rapid diagnosis remains elusive. In addressing this issue, the present study investigates the utilization of transfer learning convolution neural networks for the identification of tea diseases and pests. Our objective is to facilitate the accurate and expeditious detection of diseases and pests affecting the Yunnan Big leaf kind of tea within its complex ecological niche., Results: Initially, we gathered 1878 image data encompassing 10 prevalent types of tea diseases and pests from complex environments within tea plantations, compiling a comprehensive dataset. Additionally, we employed data augmentation techniques to enrich the sample diversity. Leveraging the ImageNet pre-trained model, we conducted a comprehensive evaluation and identified the Xception architecture as the most effective model. Notably, the integration of an attention mechanism within the Xeption model did not yield improvements in recognition performance. Subsequently, through transfer learning and the freezing core strategy, we achieved a test accuracy rate of 98.58% and a verification accuracy rate of 98.2310%., Conclusions: These outcomes signify a significant stride towards accurate and timely detection, holding promise for enhancing the sustainability and productivity of Yunnan tea. Our findings provide a theoretical foundation and technical guidance for the development of online detection technologies for tea diseases and pests in Yunnan., (© 2024. The Author(s).)

Objective: Although extensive structural and functional abnormalities have been reported in schizophrenia, the gray matter volume (GMV) covariance of the amygdala remain unknown. The amygdala contains several subregions with different connection patterns and functions, but it is unclear whether the GMV covariance of these subregions are selectively affected in schizophrenia., Methods: To address this issue, we compared the GMV covariance of each amygdala subregion between 807 schizophrenia patients and 845 healthy controls from 11 centers. The amygdala was segmented into nine subregions using FreeSurfer (v7.1.1), including the lateral (La), basal (Ba), accessory-basal (AB), anterior-amygdaloid-area (AAA), central (Ce), medial (Me), cortical (Co), corticoamygdaloid-transition (CAT), and paralaminar (PL) nucleus. We developed an operational combat harmonization model for 11 centers, subsequently employing a voxel-wise general linear model to investigate the differences in GMV covariance between schizophrenia patients and healthy controls across these subregions and the entire brain, while adjusting for age, sex and TIV., Results: Our findings revealed that five amygdala subregions of schizophrenia patients, including bilateral AAA, CAT, and right Ba, demonstrated significantly increased GMV covariance with the hippocampus, striatum, orbitofrontal cortex, and so on (permutation test, P < 0.05, corrected). These findings could be replicated in most centers. Rigorous correlation analysis failed to identify relationships between the altered GMV covariance with positive and negative symptom scale, duration of illness, and antipsychotic medication measure., Conclusion: Our research is the first to discover selectively impaired GMV covariance patterns of amygdala subregion in a large multicenter sample size of patients with schizophrenia., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chang, Liu, Lin, Wang, Zhang, Tian, Liu, Wang, Zhang, Ren, Zhang, Xie, Du, Wei, Wei, Luo, Dong, Li, Zhao, Liang, Zhang, Wang, Yu, Qin and Liu.)

Objectives: This clinical trial primarily aimed to investigate the effects of blonanserin on social functioning in patients with first-episode schizophrenia., Methods: In this prospective, multi-centre, single-arm clinical trial study, blonanserin (flexible oral dose ranging from 8mg to 24mg per day) was given 26 weeks. Outcome measures included the Personal and Social Performance (PSP) scale for evaluating social functioning, the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) for measuring neurocognitive performance, and the Positive and Negative Syndrome Scale (PANSS) for assessing symptom severity. The primary endpoint was social function improvement evaluated by PSP scale at the end of blonanserin treatment. And the secondary endpoint was to validate the efficacy and neurocognitive effects of blonanserin. Adverse drug reactions (ADRs) were also recorded and analysed., Results: A total of 96 patients with first-episode schizophrenia were recruited and proceeded to analysis. Fifty-one participants (53.1%) completed the PSP scale measurements at baseline and week 26. Following 26 weeks of blonanserin treatment, all outcome measurements demonstrated significant improvement during the follow-up period. Notably, PSP scores exhibited a continuous increase up to 68.1% ± 103.7% at the end of the treatment (46.6 ± 14.6 at baseline, 69.4 ± 17.4 at week 26, p<0.001), indicating positive effects on social functioning that were already noticeable by week 8., Conclusion: Blonanserin treatment exhibited favourable effects on social functioning in individuals with first-episode schizophrenia. The results suggest that blonanserin was effective treatment options for patients with schizophrenia encountering functional impairments., Competing Interests: HL was employed by Sumitomo Pharma (Suzhou) Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Sumitomo Pharma (Suzhou) Co., Ltd. The funder had the following involvement in the study: conceptualization, methodology, analysis, and manuscript review & editing., (Copyright © 2024 Gao, Deng, Sheng, Wu, Liu, Yang, Wang, Hu, Wang, Li, Pu and Yu.)

The development of high energy gun propellants faces significant challenges in terms of erosion, partly due to the inadequate effectiveness of erosion inhibitors. In this paper, the influence of quite different flame temperature of five gun-propellants on erosion-reducing efficiency of four representative inhibitors materials (talc/TiO 2 / PDMS/Paraffin) were studied in vented erosion vessel tester. From aspects of morphologies and element compositions of erode steel samples, as well as the pressure and heat generated by propellant burning, the relevant erosion-reducing processes and mechanisms were discussed. The results indicated that erosion inhibitors should be appropriately selected according to the type of gun propellant. The erosion of gun propellants having extremely high flame temperature of 3810 K were hardly reduced using talc, TiO 2 , and PDMS inhibitors, which can generate numerous solid particles aggravating the melt-wipe process. While paraffin exhibits a uniquely positive erosion-reducing efficiency for the gun propellant having a flame temperature of 3810 K, that was attributed to the mitigated melt-wipe process. The inference was further supported by the high-volume cooling gas, resulting from the higher burning pressure of propellants loading with paraffin and excellent heat absorption capacity of paraffin tested with propellants having higher propellant flame temperature. The obtained results indicated that the factors of flame temperature of gun propellants should be taken into the design and composition optimization of an effective inhibitor. This work could provide potential reference for the development of future novel inhibitors, which serves as high energy gun propellants., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Repetitive transcranial magnetic stimulation (rTMS) has been used in the treatment of patients with schizophrenia. The conventional targets of rTMS treatment are the dorsolateral prefrontal cortex (DLPFC) and temporoparietal cortex (TPC). However, the efficacy of these two treatment strategies was quite heterogeneous. Structural and functional abnormalities of the orbitofrontal cortex (OFC) in schizophrenia are closely related to negative symptoms. We sought to determine whether 1 Hz rTMS over the right OFC is effective in treating patients with first-episode schizophrenia. In this study, eighty-nine patients with drug-naïve, first-episode schizophrenia were randomly divided into the rTMS (n = 47) or sham stimulation (n = 42) groups, with both groups receiving twenty sessions of 1 Hz rTMS treatment. The PANSS was assessed at baseline, day 10, and day 20, and MATRICS Consensus Cognitive Battery (MCCB) was implemented to assess the cognitive impairment at baseline and day 20. Results showed that patients in the active rTMS group had more improvement in clinical symptoms and cognitive deficits than patients in sham group at day 20. In conclusion, 1 Hz rTMS over OFC can improve psychotic symptoms and cognitive functions in schizophrenic patients. Our study provides a new alternative for the treatment of negative symptoms and cognitive deficits in schizophrenia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

The potential of reactive oxygen species (ROS) cancer therapy in tumor treatment has been greatly enhanced by the introduction of catalytically superior polyoxometalate (POM)-based nanoplatforms, mainly composed of atomic clusters consisting of pre-transition metals and oxygen. These nanoplatforms have unique advantages, such as Fenton activity at neutral pH, induction of cellular ferroptosis instead of just apoptosis, and sensitivity to external field stimulation. However, there are also inevitable challenges such as neutralization of ROS by the antioxidant system of the tumor microenvironment (TME), hypoxia, and limited hydrogen peroxide concentrations. This review article aims to provide an overview of recent research advancements in POM-based nanoplatforms for ROS therapy from the perspective of chemical reactions and biological processes, addressing endogenous and exogenous factors that affect the antitumor efficacy. Endogenous factors include the mechanism of ROS generation by POM, the impact of pH and antioxidant systems on POM, and the various manners of tumor cell death. Exogenous stimuli mainly include light, heat, X-rays, and electricity. The article analyzes the specific mechanisms of action of each influencing factor in the first two sections, concluding with the limitations of the present study and some possible directions for future research., (© 2023 Wiley-VCH GmbH.)

Background: Frailty is common in Parkinson's disease (PD) and increases vulnerability to adverse outcomes. Early detection of this syndrome aids in early intervention., Aims: To objectively identify frailty at an early stage during routine motor tasks in PD patients using a Kinect-based system., Methods: PD patients were recruited and assessed with the Fried criteria to determine their frailty status. Each participant was recorded performing the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) extremity tasks with a Kinect-based system. Statistically significant kinematic parameters were selected to discriminate the pre-frail from the non-frail group., Results: Of the fifty-two participants, twenty were non-frail and thirty-two were pre-frail. Decreased frequency in finger tapping (P = 0.005), hand grasping (P = 0.002), toe tapping (P = 0.002), and leg agility (P = 0.019) alongside reduced hand grasping speed (P = 0.030), lifting (P < 0.001) and falling speed (P < 0.001) in leg agility were observed in the pre-frail group. Amplitude in leg agility (P = 0.048) and amplitude decrement rate (P = 0.046) in hand grasping showed marginally significant differences between two groups. Moderate discriminative values were found in frequency and speed of the extremity tasks to identify pre-frailty with sensitivity, specificity, and area under the curve (AUC) in the range of 45.00-85.00%, 68.75-100%, and 0.701-0.836, respectively. The combination of frequency and speed in extremity tasks showed moderate to high discriminatory ability, with AUC of 0.775 (95% CI 0.637-0.913, P < 0.001) for upper limb tasks and 0.909 (95% CI 0.832-0.987, P < 0.001) for lower limb tasks. When combining these features in both upper and lower limb tasks, the AUC increased to 0.942 (95% CI 0.886-0.999, P < 0.001)., Conclusions: Our findings demonstrated the promise of utilizing Kinect-based kinematic data from MDS-UPDRS III tasks as early indicators of frailty in PD patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Blonanserin (BNS) had been undergoing post-market surveillance (PMS) since September 2018. Using the surveillance data, we did this analysis to assess the safety and effectiveness of different doses of BNS to explore a sufficient dose range of BNS in Chinese patients with schizophrenia (SZ)., Methods: A 12-week, prospective, observational, single-arm, multicenter, open-label PMS was conducted. In this analysis, we divided the patients from PMS into low, medium to high, and high dose groups based on the dose of BNS they received, with medium to high dose group being the focus. The Brief Psychiatric Rating Scale (BPRS) scores at week 2 or 4, 6 or 8, and 12 were calculated to evaluate the effectiveness of BNS in improving psychiatric symptoms. The safety of BNS was reported as the incidence of adverse drug reactions., Results: 364 patients were included in the medium to high dose group, of which 321 completed the surveillance, with a dropout rate of 11.8%. The mean daily dose was 15.1 ± 1.92 mg. The BPRS total score was 50.1 ± 11.95 at baseline and decreased to 26.6 ± 7.43 at 12 weeks (P < 0.001). When compared with other groups, the median to high dose group achieved significantly more reduction in BPRS score at week 12 (P = 0.004 versus low dose and P = 0.033 versus higher dose). Extrapyramidal symptoms [EPS (46.4%)] were the most common adverse reactions in the medium to high group. The average weight gain during the surveillance was 0.5 ± 2.56 kg and prolactin elevation occurred in 2.2% patients. Most adverse reactions were mild., Conclusions: BNS at medium to high doses (mean 15.1 mg/d) significantly improved symptoms of SZ and was well-tolerated. Most ADRs were mild, and the likelihood of causing metabolic side effects and prolactin elevations was low. Medium to high dose of BNS is a more potent treatment choice for SZ., Trial Registration Number: ChiCTR2100048734. Date of registration: 2021/07/15 (retrospectively registered)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: Schizophrenia (SZ) and intellectual disability (ID) are both included in the continuum of neurodevelopmental disorders (NDDs). DNA methylation is known to be important in the occurrence of NDDs. The family study is conducive to eliminate the effects of relative epigenetic backgrounds, and to screen for differentially methylated positions (DMPs) and regions (DMRs) that are truly associated with NDDs., Methods: Four monozygotic twin families were recruited, and both twin individuals suffered from NDDs (either SZ, ID, or SZ plus ID). Genome-wide methylation analysis was performed in all samples and each family. DMPs and DMRs between NDD patients and unaffected individuals were identified. Functional and pathway enrichment analyses were performed on the annotated genes., Results: Two significant DMPs annotated to CYP2E1 were found in all samples. In Family One, 1476 DMPs mapped to 880 genes, and 162 DMRs overlapping with 153 unique genes were recognised. Our results suggested that the altered methylation levels of FYN , STAT3 , RAC1 , and NR4A2 were associated with the development of SZ and ID. Neurodevelopment and the immune system may participate in the occurrence of SZ and ID., Conclusions: Our findings suggested that DNA methylation participated in the development of NDDs by affecting neurodevelopment and the immune system.

Background: Ziprasidone mesylate injection is an atypical antipsychotic drug which is recently approved in China. In combination with its oral formulation, sequential therapy with ziprasidone brings new interventions to patients with agitation in the acute phase of schizophrenia. The purpose of this 7-day multicenter study conducted in China was to evaluate the efficacy and safety of ziprasidone sequential treatment through intramuscular/oral routes in agitated patients with schizophrenia., Methods: A total of 95 patients were enrolled from three centers in this study. The study duration was 7 days. In the first 3 days, subjects were administered an intramuscular injection of ziprasidone 10-40 mg daily and started sequentially with oral ziprasidone 40-80 mg at dinner (or lunch) from the day of the last intramuscular injection. In the following 4 days, according to the severity of the symptoms and the drug response, 120-160 mg of ziprasidone was orally administered daily. In total, six visits were scheduled to assess the Positive and Negative Syndrome Scale (PANSS), the Behavioral Activity Rating Scale (BARS), the Clinical Global Impression of Severity (CGI-S), and Improvement (CGI-I) scores throughout the procedure. Lastly, adverse events were recorded during treatment., Results: Out of the 95 patients that were enrolled, 83 cases were effectively completed. Visits 3, 4, 6, PANSS, and PANSS-excited component (PANSS-EC) subscale points, and Visit 2-Visit 6 viewpoints, BARS scale points, and baseline scores denote a progressive downward trend (P < 0.001). In this study, 62 adverse events were reported. The most common adverse events were extrapyramidal symptoms (EPS) (23 cases) and excessive sedation(10 cases), and 13 cases of prolonged QTc interval were reported., Conclusions: Ziprasidone IM demonstrated significant and rapid reduction in agitation, and sequential oral formulation keep stability and continuation of the treatment can further ensure efficacy. Ziprasidone sequential therapy may provide a new approach to acute agitation in schizophrenic patients., Trial Registration: The Chinese Clinical Trials Registry; URL: https://www.chictr.org.cn : ChiCTR-OIC-16007970., (© 2023. The Author(s).)

Background: A post-marketing surveillance of blonanserin has been ongoing since September 2018. The aim of this study was to assess the effectiveness and safety of oral blonanserin in Chinese young and middle-aged female patients with schizophrenia in real clinical settings, using the data from the post-marketing surveillance., Methods: A 12-week, prospective, multi-center, open-label, post-marketing surveillance was conducted. Female patients aged 18-40 years were included in this analysis. The Brief Psychiatric Rating Scale (BPRS) was used to evaluate the effectiveness of blonanserin in improving psychiatric symptoms. The incidence of adverse drug reactions (ADRs) such as of extrapyramidal symptoms (EPS), prolactin elevation and the weight gain were used to evaluate the safety profile of blonanserin., Results: A total of 392 patients were included both in the safety and full analysis sets, 311 patients completed the surveillance protocol. The BPRS total score was 48.8 ± 14.11 at the baseline, decreasing to 25.5 ± 7.56 at 12 weeks (P < 0.001, compared with baseline). EPS (20.2%) including akathisia, tremor, dystonia, and parkinsonism were found as the most frequent ADRs. The mean weight gain was 0.27 ± 2.5 kg at 12 weeks from the baseline. Four cases (1%) of prolactin elevation were observed during the period of surveillance., Conclusion: Blonanserin significantly improved the symptoms of schizophrenia in female patients aged 18-40 years; the drug was well tolerated and had a low tendency to cause metabolic side effects, including prolactin elevation in these patients. Blonanserin might be a reasonable drug for the treatment of schizophrenia in young and middle-aged female patients., (© 2023. The Author(s).)

Polymer flooding is one of the techniques used to enhance oil recovery from depleted hydrocarbon reservoirs. Although this technology is popular for this application, the shearing effect in the injection process causes poor performance, which is an obstacle to meeting the needs of the formation. An experimental evaluation of the rheological properties, viscoelasticity, hydrodynamic size, static adsorption, and seepage characteristics of the associated polymer solution before and after shearing was conducted to determine the influence of shearing on the polymer solution. The results show that the effect of shear on the polymer was irreversible, and the properties of the polymer solution damaged by shear were attenuated. After the critical associating concentration, the associated polymer can recover its solution properties through hydrophobic association, which can improve the shear resistance of the polymer solution and make its own rheological law and reduce the viscoelastic change. Although the hydrodynamic size, viscoelasticity, and adsorption capacity of the polymer solution after shear failure decreased, strong flow resistance during porous media seepage and mobility control was achieved. Improving the shear resistance of the polymer solution by increasing the intermolecular force is proposed to develop new polymer systems for subsequent oil displacement.

Dyskinesia is one of the most disabling motor complications in Parkinson's Disease (PD). Sleep is crucial to keep neural circuit homeostasis, and PD patients often suffer from sleep disturbance. However, few prospective studies have been conducted to investigate the association of sleep quality with dyskinesia in PD. The objective of the current study is to investigate the association between sleep quality and dyskinesia and build a prediction model for dyskinesia in PD. We prospectively followed a group of PD patients without dyskinesia at baseline for a maximum of 36 months. Univariable and multivariable Cox regression with stepwise variable selection was used to investigate risk factors for dyskinesia. The performance of the model was assessed by the time-dependent area under the receiver-operating characteristic curve (AUC). At the end of follow-up, 32.8% of patients developed dyskinesia. Patients with bad sleep quality had a significantly higher proportion of dyskinesia compared with those with good sleep quality (48.1% vs. 20.6%, p = 0.023). Multivariable Cox regression selected duration of PD, sleep quality, cognition, mood, and levodopa dose. Notably, high Pittsburgh sleep quality index (PSQI) score was independently associated with an increased risk of dyskinesia (HR = 2.96, 95% CI 1.05-8.35, p = 0.041). The model achieved a good discriminative ability, with the highest AUC being 0.83 at 35 months. Our results indicated that high PSQI score may increase the risk of developing dyskinesia in PD, implying that therapeutic intervention targeting improving sleep quality may be a promising approach to prevent or delay the development of dyskinesia in PD., (© 2022. The Author(s).)

Schizophrenia is an unexplained, complex and serious mental illness. Blonanserin (BNS) is a new antipsychotic drug widely used in the treatment of schizophrenia. However, large-scale clinical studies have not been conducted in China. A multi-center, prospective, open-label, 12-week surveillance was carried out to evaluate the safety and effectiveness of BNS in patients with schizophrenia in China. Safety assessments included adverse drug reactions (ADRs), extrapyramidal symptoms (EPS), akathisia, concomitant medications for EPS by the end of treatment, and the changes in body weight from baseline by the end of treatment. The effectiveness was evaluated by the Brief Psychiatric Rating Scale (BPRS). From September 2018 to May 2020, of the 1,060 patients enrolled, 1,018 were included in the full analysis set (FAS) and safety set (SS), respectively. ADRs were developed in 205 patients among the included, the incidence being 20.1%. ADRs of EPS occurred in 169 patients, the incidence being 16.6%, ADRs of akathisia occurred in 90 patients, the incidence being 8.8%; concomitant therapeutic and prophylactic agents for EPS accounts for 19.2%; 4.0% of patients had a ≥7% increase in body weight from baseline at 12 weeks after initiating treatment. Using the last-observation-carried-forward (LOCF) method, the changes in total BPRS scores were -11.2 ± 10.17 ( N = 1,018), -16.8 ± 12.69 ( N = 1,018) and -20.6 ± 13.99 ( N = 1,018) after 2/4, 6/8, or 12 weeks, respectively. 53.5% (545/1,018) patients showed response to blonanserin treatment in week 12. The post-marketing surveillance results of BNS demonstrates safety profile and effectiveness of the drug., Competing Interests: The authors declare that this study received funding from Sumitomo Pharma Co., Ltd. and Sumitomo Pharma (Suzhou) Co., Ltd. The funder had the following involvement in the study: the study design and the analysis., (Copyright © 2022 Wu, Wang, Liu, Sang, Bo, Yang, Xun, Li, Zhang, Sun, Cai, Deng, Zhao, Li, Liu, Zhan and Chen.)

The aim of this study was to develop a brief version of cognitive assessment test for evaluating the efficacy of treatments targeting cognitive impairments in Chinese schizophrenia patients, to examine its reliability, and establish normative data. Stratified according to age, gender, and educational level, healthy adult subjects were recruited from fifteen institutions in seven administrative regions of China and 723 valid samples were obtained, of which 50 were retested. Generalized Linear Models were conducted to analyze the effects of age, sex, and education. There was no significant difference between genders, while significant effects were demonstrated respectively among age and education on the normative data of C-BCT. The Cronbach α of C-BCT is 0.75, and the test-retest reliability (ICC) ranged from 0.62 to 0.76. Normative data of C-BCT were generated by gender, age and education, and the effects of these demographic factors were analyzed. It revealed good internal consistency and test-retest reliability of C-BCT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor TZ declared a shared parent affiliation with the author DL at the time of review., (Copyright © 2022 Ye, Xie, Yu, Wu, Liu, Hu, Xu, Liu, Wang, Zhu, Wang, Zou, Li, Guo, Xu, Cheng, Li, Yang, Peng, Li and Shi.)

Background: Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacotherapy for obsessive-compulsive disorder (OCD), but a large proportion of patients do not achieve remission after an adequate SSRI trial. To the best of our knowledge, there have been no well-powered randomized controlled trials (RCTs) of sequenced pharmacotherapy using pragmatic research designs. China provides a unique context for undertaking such a trial that will recruit the largest treatment-naïve participants and systematically compare the efficacy of different sequenced pharmacotherapy., Methods: A pragmatic research design will be adopted, with n = 1,600 treatment-naïve OCD patients initially treated for sertraline for 12 weeks, and with non-remitters then randomized to 5 different augmentation or switching pharmacotherapy options for another 12 weeks. The 5 arms will include: (1) treatment with higher than usual doses of sertraline, (2) switch to fluvoxamine, (3) switch to venlafaxine, (4) augmentation with memantine, and (5) augmentation with aripiprazole., Discussion: China is uniquely positioned to recruit sufficiently large sample sizes of treatment-naïve OCD patients to compare different pharmacotherapy options; data from the proposed trial promises to help inform current clinical practice guidelines by providing important information about optimal pharmacotherapy choice for those who demonstrate no response or response but no remission to first line pharmacotherapy., Trial Registration: The trail was registered on 27 August 2020 in ClinicalTrials.gov (https://register.clinicaltrials.gov/) (NCT04539951)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Gu, Gao, Wang, Fang, Hu, Xiang, Li, Liu, Tang, Wang, Jia, Li, Cheng, Tang, Simpson, Stein and Wang.)

Background: Obsessive-compulsive disorder (OCD) is considered a very debilitating disorder with severe loss of quality of life and income., Aims: This study estimates the quality of life and economic consequences of OCD in China., Methods: The research team interviewed 639 patients with OCD in 13 hospitals in 12 cities in China. The direct method was used to get the direct cost of OCD. Indirect costs associated with OCD were estimated using the human capital approach. Linear regression analysis was conducted for quality of life and generalised linear model analysis was conducted for total cost. Sensitivity analysis was used to analyse the uncertainty of total cost., Results: The mean quality of life score for OCD was 52.78 (20.46). The annual total cost of OCD per capita was 24 503.78 (95% CI: 22 621.53 to 26 386.03) renminbi (RMB) (US$3465.88 (95% CI: US$3199.65 to US$3732.11)). The annual cost of OCD in China was estimated to be 37.74 billion (95% CI: 34.95 billion to 40.53 billion) RMB (equal to US$5.34 billion (95% CI: US$4.94 billion to US$5.73 billion)). Sensitivity analysis showed that the total annual cost of OCD in China was between 23.15 billion RMB (US$3.27 billion) and 370.00 billion RMB (US$52.33 billion). Worse social function status, more psychiatric symptoms and higher Yale Brown Obsessive-Compulsive Scale (Y-BOCS) score were associated with worse quality of life. The numbers of clinic visits and hospitalisations, socioeconomic status, education, Y-BOCS scores and age were found to be significantly associated with total cost., Conclusions: OCD is associated with low quality of life and high costs in China. The findings call for concerted efforts to improve services for patients with OCD.Improvements may include early detection and diagnosis, the provision of evidence-based treatments and relapse prevention strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recently, a burgeoning category of biocompatible botanically derived nanomaterial cellulose nanofibers (CNFs) has captured tremendous attention on account of its entangled nanostructured network, natural abundance, and outstanding mechanical properties. Biomimetically inspired by the superior properties of CNFs, this paper examined them as the coating material to cover cyclotrimethylenetrinitramine (RDX), cyclotetramethylenetetranitramine (HMX), and hexanitrohexaazaisowurtzitane (CL-20) via a facile water suspension method and the ultrasonic technology. The core-shell structure and the composition of energetic crystal@CNF were examined through scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy analyses. The obtained outcomes demonstrated that the dispersibility of the CNF enhanced favorably upon covering the surface of explosive crystals; the interfacial contact ability between CNFs and energetic crystals was also manifested to be increased, which could be ascribed to the interfacial interaction of hydrogen bonds and the electrostatic force of self-assembly. In addition, the stable crystalloid construction of β-HMX and ε-CL-20 has been preserved positively in the preparation process. In comparison with raw explosives, the thermal stability and sensitivity performances of the core-shell structure composites were outstanding. Accordingly, this work demonstrated the rewarding application of coating CNFs uniformly on the surface of energetic crystals, ulteriorly offering a potential fabrication strategy for the embellishment of high-explosive crystals.

Alleviating microglia-mediated neuroinflammation bears great promise to reduce neurodegeneration. Nicotinamide phosphoribosyltransferase (NAMPT) may exert cytokine-like effect in the brain. However, it remains unclear about role of NAMPT in microglial inflammation. Also, it remains unknown about effect of NAMPT inhibition on microglial inflammation. In the present study, we observed that FK866 (a specific noncompetitive NAMPT inhibitor) dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory mediator (interleukin (IL)-6, IL-1β, inducible nitric oxide synthase, nitric oxide and reactive species) level increase in BV2 microglia cultures. FK866 also significantly inhibited LPS-induced polarization change in microglia. Furthermore, LPS significantly increased NAMPT expression and nuclear factor kappa B (NF-κB) phosphorylation in microglia. FK866 significantly decreased NAMPT expression and NF-κB phosphorylation in LPS-treated microglia. Finally, conditioned medium from microglia cultures co-treated with FK866 and LPS significantly increased SH-SY5Y and PC12 cell viability compared with conditioned medium from microglia cultures treated with LPS alone. Our study strongly indicates that NAMPT may be a promising target for microglia modulation and NAMPT inhibition may attenuate microglial inflammation.

Study Objectives: Freezing of gait (FOG) severely impairs life quality of Parkinson disease (PD) patients. The relationship between sleep disturbance and FOG in PD remains unclear, so in this study, we aimed to investigate that relationship., Methods: First, we assessed clinical characteristics of freezers and nonfreezers among PD patients. Next, we assessed clinical characteristics of PD patients with different PDSS1 scores (score on first item of Parkinson's Disease Sleep Scale). Finally, we prospectively followed a cohort of nonfreezers from a baseline clinical visit and to a maximum of 18 months and performed a Cox regression analysis to further investigate the relationship between PDSS1 score and FOG in PD., Results: A total of 163 participants with PD were included in the baseline analysis. The freezers had significantly worse sleep compared with the nonfreezers. The proportion of freezers in the patients with low PDSS1 score (PDSS1 < 6) was significantly higher than that in the patients with high PDSS1 score (PDSS1 ≥ 6). A total of 52 nonfreezers were prospectively followed. During a maximum 18-month follow-up, FOG incidence (73%) in the PDSS1 < 6 group was significantly higher than that (24%) in the PDSS1 ≥ 6 group (P = .008). Low PDSS1 score (hazard ratio = 4.23, 95% CI 1.64-10.92, P = .003) and high levodopa equivalent daily dose (hazard ratio = 4.18, 95% CI 1.62-10.75, P = .003) were significantly associated with an increased hazard of FOG., Conclusions: Our study indicated that low PDSS1 score may be a risk indicator for the development of FOG and provided important insights into potential targets for the prevention/delay of FOG in PD., (© 2021 American Academy of Sleep Medicine.)

Idiosyncratic drug-induced liver injury (IDILI) is an idiosyncratic drug reaction that is specific to an individual and can lead to liver failure and even death. The mechanism of IDILI remains poorly understood, but most IDILI appears to be immune-mediated. We have developed the first validated animal model by using a PD-1 -/- mouse model in combination with anti-CTLA-4 to block immune checkpoints and impair immune tolerance. Treatment of these mice with drugs that cause IDILI in humans led to delayed-onset liver injury with characteristics similar to IDILI in humans. The current study investigates the effects of green tea extract, a weight-loss dietary supplement that has been reported to cause IDILI in humans. Green tea extracts contain a highly variable content of catechins including (-)-epigallocatechin gallate, the major catechin in green tea formulations. If the liver injury caused by green tea extract in humans is immune-mediated, it may occur in our impaired immune tolerance model. Female PD-1 -/- mice treated with anti-CTLA-4 antibody and green tea extract (500 mg/kg), a dose that is considered a no-observed-adverse-effect level for liver in rodents, produced a delayed onset increase in serum alanine transaminase levels and an increase in hepatic CD8 + T cells. In contrast, the response in male PD-1 -/- mice was less pronounced, and there was no evidence of liver injury in wild-type mice. These findings are consistent with the hypothesis that the IDILI caused by green tea extract is immune-mediated and is similar to IDILI caused by medications that are associated with IDILI.

Objectives: We aim to investigate the joint effect of iron (enhanced neonatal iron intake), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and biochanin A (BA, oral administration) and possible mechanisms for action on behavioral and neurochemical indicators in the mice. Methods: Rotarod test, pole test and swim test were used to evaluate animal behavior. The neurochemical analysis was conducted by HPLC-ECD. Oxidative stress was determined in this study. Further mechanism was investigated through in vitro experiments. Results: Iron and MPTP co-administration significantly induced behavioral deficits and decreased striatal dopamine content in the male and female mice. The co-administration of iron and MPTP also significantly induced redox imbalance in the substantia nigra (SN) of mice. Furthermore, BA significantly improved behavioral deficits and increased striatal dopamine content in the mice co-treated with iron and MPTP. BA also significantly improved redox imbalance in the SN of mice co-administered with iron and MPTP. Finally, we showed that iron and 1-Methyl-4-phenylpyridinium (MPP + ) co-treatment significantly increased superoxide production in microglial cultures by inducing p38 mitogen-activated protein kinase (MAPK) activation. BA also significantly decreased superoxide production and p38 MAPK phosphorylation in the cultures co-treated with iron and MPP + . Conclusion: Iron and MPTP co-treatment may result in worsened behavioral and neurochemical deficits and aggravated redox imbalance through inducing microglial p38 MAPK activation. BA may improve behavioral and neurochemical deficits and redox imbalance through repressing microglial p38 MAPK activation.

Background: The long-term administration of levodopa (L-dopa), the gold-standard treatment for Parkinson's disease (PD), is irreparably associated with L-dopa-induced dyskinesia (LID), which dramatically affects the quality of life of patients. However, the underlying molecular mechanisms of how LID exacerbates remain unknown. Neuroinflammation in the striatum plays an active role in LID. These findings prompt an investigation of non-neuronal mechanisms of LID. This study will examine the effects of systemic inflammation in the development and progression of LID. Methods: To evaluate the possible influence of systemic inflammation in the appearance of LID, the PD rats received an intraperitoneal (IP) injection of various concentrations of lipopolysaccharides (LPS, 1, 2, and 5 mg/kg) or saline. One day later, these PD rats started to receive daily treatment with L-dopa (6 mg/kg) along with benserazide (6 mg/kg) or saline for 21 days, and dyskinesia was evaluated at several time points. Moreover, the activation of microglia and astrocytes and the molecular changes in NR2B and mGLUR5 signaling pathways were measured. Results: We found that systemic inflammatory stimulation with LPS exacerbated the intensity of abnormal involuntary movements (AIMs) induced by L-dopa treatment in 6-hydroxydopamine (6-OHDA) lesioned rats. The LPS injection activated the gliocytes and increased the levels of proinflammatory cytokines in the striatum in LID rats. The PD rats that received the LPS injection showed the overexpression of p-NR2B and NR2B, as well as activated PKC/MEK/ERK and NF-κB signal pathways in response to the L-dopa administration. On the contrary, clodronate-encapsulated liposomes (Clo-lipo), which could suppress the inflammatory response induced by peripheral LPS injection, improved behavioral dysfunction, inhibited neuroinflammation, prevented NR2B overexpression, and decreased the phosphorylation of PKC/MEK/ERK and NF-κB signaling pathways. Conclusion: This study suggests that systemic inflammation, by exacerbating preexisting neuroinflammation and facilitating NR2B subunit activity, may play a crucial role in the development of LID. The administration of Clo-lipo restores the effects of LPS and decreases the susceptibility to LID in 6-OHDA lesioned rats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yan, Song, Zhang, Wang and Liu.)

Background: Smad3 signaling is indicated to regulate microglia activity. Parkinson's disease (PD) neurodegeneration is shown to be associated with aging and neuroinflammation. However, it remains unclear about the relationship among Smad3 signaling, aging, neuroinflammation, and PD., Methods: Rats were treated with SIS3 (a specific inhibitor of Smad3, intranigal injection) and/or lipopolysaccharide (intraperitoneal injection). We investigated the effect of SIS3 and lipopolysaccharide and their mechanism of action on motor behavior and nigrostriatal dopaminergic system in the rats. Furthermore, we explored the effect of SIS3 and LPS and their potential signaling mechanism of action on inflammatory response by using primary microglial cultures. Finally, we investigated the relationship among aging, Smad3 signaling, and neuroinflammation using animals of different ages., Results: Both SIS3 and lipopolysaccharide induced significant behavior deficits and nigrostriatal dopaminergic neurodegeneration in the rats compared with the vehicle-treated (control) rats. Significantly increased behavior deficits and nigrostriatal dopaminergic neurodegeneration were observed in the rats co-treated with SIS3 and lipopolysaccharide compared with the rats treated with vehicle, SIS3, or lipopolysaccharide. Furthermore, both SIS3 and lipopolysaccharide induced significant microglia activation and proinflammatory factor (IL-1β, IL-6, iNOS, and ROS) level increase in the SN of rats compared with the control rats. Significantly enhanced microglial inflammatory response was observed in the rats co-treated with SIS3 and lipopolysaccharide compared with the other three groups. For our in vitro study, both SIS3 and lipopolysaccharide induced significant proinflammatory factor level increase in primary microglia cultures compared with the control cultures. Significantly increased inflammatory response was observed in the cultures co-treated with SIS3 and lipopolysaccharide compared with the other three groups. MAPK (ERK/p38) contributed to microglial inflammatory response induced by co-treatment with SIS3 and lipopolysaccharide. Interestingly, there was decrease in Smad3 and pSmad3 expression (protein) and enhancement of neuroinflammation in the mouse SN with aging. Proinflammatory factor levels were significantly inversely correlated with Smad3 and pSmad3 expression., Conclusion: Our study strongly indicates the involvement of SN Smad3 signaling deficiency in aging and PD neurodegeneration and provides a novel molecular mechanism underlying the participation of aging in PD and helps to elucidate the mechanisms for the combined effect of multiple factors in PD.

Objective: To explore the effect of long-term antipsychotics use on the strength of functional connectivity (FC) in the brains of patients with chronic schizophrenia., Method: We collected resting-state functional magnetic resonance imaging from 15 patients with continuously treated chronic schizophrenia (TCS), 19 patients with minimally TCS (MTCS), and 20 healthy controls (HCs). Then, we evaluated and compared the whole-brain FC strength (FCS; including full-range, short-range, and long-range FCS) among patients with TCS, MTCS, and HCs., Results: Patients with TCS and MTCS showed reduced full-/short-range FC compared with the HCs. No significant differences in the whole-brain FCS (including full-range, short-range, and long-range FCS) or clinical characteristics were identified between patients with TCS and MTCS. Additionally, the FCS in the right fusiform gyrus, right inferior temporal gyrus, and right inferior occipital gyrus negatively correlated with the duration of illness and positively correlated with onset age across all patients with chronic schizophrenia., Conclusions: Regardless of the long-term use of antipsychotics, patients with chronic schizophrenia show decreased FC compared with healthy individuals. For some patients with chronic schizophrenia, the influence of long-term and minimal/short-term antipsychotic exposure on resting-state FC was similar. The decreased full- and short-range FCS in the right fusiform gyrus, right inferior temporal gyrus, and right inferior occipital gyrus may be an ongoing pathological process that is not altered by antipsychotic interventions in patients with chronic schizophrenia. Large-sample, long-term follow-up studies are still needed for further exploration.

Idiosyncratic drug reactions (IDRs) significantly increase the risk of failure in drug development. The major IDR leading to drug candidate failure is idiosyncratic drug-induced liver injury (IDILI). Although most evidence suggests that IDRs are mediated by the immune system, there are other hypotheses, such as mitochondrial dysfunction. Many pharmaceutical companies routinely screen for mitochondrial toxicity in an attempt to "derisk" drug candidates. However, the basic hypothesis has never been rigorously tested. A major assay used for this screening involves measurement of inhibition of the mitochondrial electron transport chain. One study found that the combination of rotenone and isoniazid, which inhibit mitochondrial complex I and II, respectively, were synergistic in causing hepatocyte toxicity in vitro and suggested the combination of another drug that inhibited complex I would increase the risk of isoniazid-induced liver injury in patients. We tested this hypothesis in vivo where wild-type and PD-1-/- mice administered anti-CTLA-4, our impaired immune tolerance mouse model, were given 0.02% (w/v) rotenone in water or 0.1%, 0.05%, and 0.01% (w/w) rotenone alone or in combination with isoniazid in food. The cotreatment led to lethality in 100% of the animals receiving 0.1% rotenone and 0.2% isoniazid and 83% of the animals cotreated with 0.05% rotenone and 0.2% isoniazid in food. Nevertheless, there was no significant increase in GLDH or histological evidence of liver injury. No signs of toxicity were observed in any of the mice given rotenone or isoniazid alone. Even though inhibition of the mitochondrial electron transport chain did not lead to significant liver toxicity, it could provide danger signals that promote immune-mediated liver injury. However, rotenone did not significantly increase the liver injury induced by isoniazid in our impaired immune tolerance model. Overall, we conclude that inhibition of the mitochondrial electron transport chain is not a significant mechanism of IDILI.

Background: Idebenone is an antioxidant and a coenzyme Q10 analog that has been used to treat neurodegeneration disease. Some studies show idebenone exerts anti-inflammatory effects. However, whether idebenone can be used to reduce the neuroinflammation in Parkinson's disease (PD) has been little studied. Methods: The study investigated the potential anti-inflammatory effects of idebenone in vitro and in vivo , using cell models of Lipopolysaccharide (LPS)-simulated BV2 cells and animal models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD with or without idebenone. To verify how idebenone exerts its effects on the BV2 cell activation and PD model, we performed the mechanistic studies in vitro and in vivo . Results: In vitro study showed that pretreatment with idebenone could attenuate the production of pro-inflammatory factors in LPS-stimulated BV2 cells and promoted a phenotypic switch from the M1 state to the M2 state. Mechanistically, idebenone reduced the activation of the MAPK and NF-κB signaling pathway upon LPS stimulation. Furthermore, in vivo experiments confirmed that pretreatment with idebenone could ameliorate MPTP-induced neurodegeneration and modulate microglia phenotypes through inhibition of the MAPK and NF-κB signaling pathway in the SN. Conclusion: These results suggest that idebenone ameliorates the neurological deficits related to PD and this effect is partly mediated by inhibiting the neuroinflammation and modulating microglia phenotypes.

Background: Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Inflammatory cytokines in the peripheral immune system can induce neuroinflammation in central nervous system (CNS). Whether the peripheral immune system is involved in PD is unclear. The present study investigated the contribution of the peripheral immune system to the neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) model of PD. Methods: MPTP was intraperitoneally injected into mice to generate a PD model. Mice received clodronate liposomes every 3 days to deplete peripheral macrophages. The percentages of macrophages were measured by flow cytometry at 1, 3, and 7 days after MPTP injection. Neurobehavioral parameters, protein expression, inflammatory cytokines release, and microglia activation were measured by the open field test, western blotting, quantitative polymerase chain reaction (qPCR), and immunofluorescence staining, respectively at 7 days after MPTP injection. Results: Our study revealed that intraperitoneal injection of MPTP could increase peripheral M1 macrophages levels. It also can induce T cells infiltration and cytokine release. Depletion of M1 macrophages by clodronate liposomes suppressed these inflammatory effects and blunted the loss of TH+ nigral neurons and functional impairments caused by MPTP. Conclusion: Our results indicated the critical role of M1 macrophages in the pathogenesis of PD and proposed inhibition of M1 macrophages as a promising therapeutic approach for neurodegeneration.

Increasing evidences show that the etiology of Parkinson's disease (PD) is multifactorial. Studying the combined effect of several factors is becoming a hot topic in PD research. On one hand, iron is one of the essential trace metals for human body; on the other hand, iron may be involved in the etiopathogenesis of PD. In our present study, the rats with increased neonatal iron (120 μg/g bodyweight) supplementation were treated with rotenone (0.5 mg/kg) when they were aged to 14 weeks. We observed that iron and rotenone co-treatment induced significant behavior deficits (time-dependent) and striatal dopamine depletion in the male and female rats, while they did not do so when they were used alone. No significant change in striatal 5-hydroxytryptamine content was observed in the male and female rats with iron and rotenone co-treatment. Also, iron and rotenone co-treatment significantly decreased substantia nigra TH expression in the male rats. Furthermore, co-treatment with iron and rotenone significantly induced malondialdehyde increase and glutathione decrease in the substantia nigra of male and female rats. There was no significant change in cerebellar malondialdehyde and glutathione content of the rats co-treated with iron and rotenone. Interestingly, biochanin A significantly attenuated striatal dopamine depletion and improved behavior deficits (dose-dependently) in the male and female rats with iron and rotenone co-treatment. Biochanin A treatment also significantly alleviated substantia nigra TH expression reduction in the male rats co-treated with iron and rotenone. Finally, biochanin A significantly decreased malondialdehyde content and increased glutathione content in the substantia nigra of male and female rats with iron and rotenone co-treatment. Our results indicate that iron and rotenone co-treatment may result in aggravated neurochemical and behavior deficits through inducing redox imbalance and increased neonatal iron supplementation may participate in the etiopathogenesis of PD. Moreover, biochanin A may exert dopaminergic neuroprotection by maintaining redox balance.

There is an increasing interest in searching biomarkers for schizophrenia (SZ) diagnosis, which overcomes the drawbacks inherent with the subjective diagnostic methods. MicroRNA (miRNA) fingerprints have been explored for disease diagnosis. We performed a meta-analysis to examine miRNA diagnostic value for SZ and further validated the meta-analysis results. Using following terms: schizophrenia/SZ, microRNA/miRNA, diagnosis, sensitivity and specificity, we searched databases restricted to English language and reviewed all articles published from January 1990 to October 2016. All extracted data were statistically analyzed and the results were further validated with peripheral blood mononuclear cells (PBMNCs) isolated from patients and healthy controls using RT-qPCR and receiver operating characteristic (ROC) analysis. A total of 6 studies involving 330 patients and 202 healthy controls were included for meta-analysis. The pooled sensitivity, specificity and diagnostic odds ratio were 0.81 (95% CI: 0.75-0.86), 0.81 (95% CI: 0.72-0.88) and 18 (95% CI: 9-34), respectively; the positive and negative likelihood ratio was 4.3 and 0.24 respectively; the area under the curve in summary ROC was 0.87 (95% CI: 0.84-0.90). Validation revealed that miR-181b-5p, miR-21-5p, miR-195-5p, miR-137, miR-346 and miR-34a-5p in PBMNCs had high diagnostic sensitivity and specificity in the context of schizophrenia. In conclusion, blood-derived miRNAs might be promising biomarkers for SZ diagnosis.

Background and purpose: It remains unclear about the etiopathogenesis of cognitive impairment (CI) in Parkinson's disease (PD). Since diabetes mellitus (DM) has been shown to be associated with CI in several diseases, we examined the association between CI and dysglycemia in PD. Methods: Enrolled PD patients completed a series of clinical and neuropsychological assessments. Motor symptoms were determined by Hohen-Yahr staging (H-Y staging) and Unified Parkinson's Disease Rating Scale - motor score (UPDRS-III). Neuropsychological functions were evaluated by the Mini Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Hamilton Anxiety and Depression Scales. Moreover, fasting glucose, fasting insulin, glycosylated hemoglobin A1c (HbA1c) and oral glucose tolerance test were performed to assess glucose metabolism. Results: MoCA and MMSE scores in PD patients with DM group (PD-DM) were significantly lower than those in PD patients without DM group (PD-nDM). Consistently, PD-DM group showed significantly higher constituent ratio of CI than PD-nDM group. In addition, MoCA scores in HbA1c ≥ 6.5% group and HbA1c ≥ 7% group were significantly lower than those in the corresponding control groups. MoCA score in IR ≥ 3 group was significantly lower than that in IR < 3 group. Furthermore, MoCA score was negatively correlated with H-Y staging, HbA1c and insulin resistance, respectively. Finally, regression analysis indicated that H-Y staging and HbA1c ≥ 7% were independent risk factors of CI in PD. Conclusion: CI may be tightly associated with dysglycemia in, at least partially, PD patients. Importantly, H-Y staging and HbA1c ≥ 7%, two independent risk factors of CI in PD, may serve as key biomarkers in future PD clinical practice.

Background: The long-term intermittent Levodopa (L-dopa) stimulation contributes to an aberrant activation of D1 receptor (D1R) mediated extracellular signal-regulated kinases1/2 (ERK1/2) in the striatal medium spiny neurons, resulting in the occurrence of L-dopa induced dyskinesia (LID). Recently, a novel signaling pathway, D1R/Shp-2/ERK1/2, was proposed to be required for the occurrence of LID. Here we designed the study in which two different methods of L-dopa delivery [continuous dopamine stimulation (CDS) vs. intermittent dopamine stimulation] were used to further identify: (1) the role of D1R/Shp-2/ERK1/2 signaling pathway in the occurrence of LID; (2) whether CDS alleviated LID though preventing the over-expression of the D1R/Shp-2/ERK1/2 signaling pathway. Methods: 6-OHDA-lesioned rat models of Parkinson's disease (PD) were randomly divided into two groups to receive intermittent L-dopa stimulation (L-dopa/benserazide standard group, LS group) or CDS (L-dopa/benserazide loaded microspheres, LBM group) for 21 days. Dyskinesia and anti-parkinsonian effect were compared between the two groups through the AIMs assessment and cylinder test. The critical protein changes in the D1R/Shp-2/ERK1/2 signaling pathway were compared between the two groups through Western blotting. Results: Intermittent L-dopa administration induced serious dyskinetic movements in the 6-OHDA-lesioned rats, and the anti-parkinsonian effect of L-dopa was gradually counteracted by the occurrence of dyskinesia. Intermittent L-dopa administration enhanced the expression of membrane D1R, and induced a robust increase of phosphorylation of Shp-2, Src, DARPP-32, and ERK1/2 in the 6-OHDA-lesioned striatum. In contrast, CDS played a dose-dependent anti-parkinsonian role, without inducing such apparent dyskinetic movements. Moreover, CDS induced no change of membrane D1R expression or phosphorylation of Shp-2, Src, DARPP-32, and ERK1/2 in the 6-OHDA-lesioned striatum. Conclusion: The aberrant activation of D1R/Shp-2 complex was evidenced to be required for the D1R mediating ERK1/2 phosphorylation and the occurrence of LID. CDS effectively prevented the overexpression of D1R/Shp-2/ERK1/2 signaling pathway, resulting in the reduction of LID in 6-OHDA-lesioned rats model of PD.

The enteric nervous system (ENS) is involved in the initiation and development of the pathological process of Parkinson's disease (PD). The effect of rotenone on the ENS may trigger the progression of PD through the central nervous system (CNS). In this study, we used RNA-sequencing (RNA-seq) analysis to examine differential expression genes (DEGs) and pathways induced by in vitro treatment of rotenone in the enteric nervous cells isolated from rats. We identified 45 up-regulated and 30 down-regulated genes. The functional categorization revealed that the DEGs were involved in the regulation of cell differentiation and development, response to various stimuli, and regulation of neurogenesis. In addition, the pathway and network analysis showed that the Mitogen Activated Protein Kinase (MAPK), Toll-like receptor, Wnt, and Ras signaling pathways were intensively involved in the effect of rotenone on the ENS. Additionally, the quantitative real-time polymerase chain reaction result for the selected seven DEGs matched those of the RNA-seq analysis. Our results present a significant step in the identification of DEGs and provide new insight into the progression of PD in the rotenone-induced model.

Introduction: This study evaluated the effectiveness and safety of amisulpride in Chinese schizophrenia patients., Methods: A multicenter, single-arm Phase IV study (NCT01795183). Chinese patients with schizophrenia received amisulpride for 8 weeks. The primary endpoint was ≥50% decrease in Positive and Negative Syndrome Scale total score from Baseline to Week 8., Results: A total of 316 patients were enrolled; 295 were included in the effectiveness analysis; 66.8% (197/295) achieved ≥50% decrease in Positive and Negative Syndrome Scale total score from Baseline to Week 8. Nine patients discontinued treatment because of adverse events., Discussion: Amisulpride had clinical effectiveness and was relatively well tolerated in Chinese patients with schizophrenia., (© 2016 The Authors Asia-Pacific Psychiatry Published by John Wiley & Sons Australia, Ltd.)

Aging is a prominent risk factor for the occurrence and progression of Parkinson disease (PD). Aging animals are more significant for PD research than young ones. It is promising to develop effective treatments for PD through modulation of aging-related molecules. Sirtuin 2 (SIRT2), a strong deacetylase highly expressed in the brain, has been implicated in the aging process. In our present study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 12mg/kg once daily) was observed to bring about significant behavioral deficits and striatal dopamine depletion in aging male and female mice, while it did not do so in young animals. MPTP did not cause significant reduction in striatal 5-hydroxytryptamine content in aging male and female mice. Furthermore, we observed that MPTP treatment resulted in significant reduction in GSH content and significant increase in MDA content and SIRT2 expression in the substantia nigra (SN) of aging mice, while it did not do so in young animals. Importantly, we observed that AK-7 (a selective SIRT2 inhibitor) significantly improved behavior abnormality and neurochemical deficits in aging male and female mice treated with MPTP. Significant increase in GSH content and significant decrease in MDA content were also observed in the SN of aging male and female mice co-treated with MPTP and AK-7 compared with the MPTP-treated animals. Our results indicated that MPTP induce aging-related neurochemical and behavioural deficits and dysfunction of redox network in male and female mice and AK-7 may be neuroprotective in PD through modulating redox network., (Copyright © 2016 Elsevier Inc. All rights reserved.)

While several morphometric studies have postulated a critical contribution of the cingulate cortex (CC) to the pathophysiology of schizophrenia based on abnormalities in CC volume, other studies have been inconclusive. Most such studies have focused only on changes in cortical volume, whereas other morphometric parameters such as surface area and cortical thickness could be more relevant and possibly account for these discrepancies. Furthermore, factors such as antipsychotic drug use and treatment duration may also influence cortical morphology. To clarify the association between schizophrenia and CC deficits, we investigated morphometric abnormalities of the CC in antipsychotic drug (AD)-naïve chronic schizophrenia patients by comparing T1-weighted magnetic resonance images (T1WI-MRI) from patients (n=17) to healthy controls (n=17) using the surface-based morphometry program FreeSurfer. Partial correlations were examined between abnormal morphometric measures and both clinical variables and cognitive performance scores. Compared to healthy controls, drug-naïve schizophrenia patients exhibited significantly lower volumes in both left rostral anterior CC (rACC) and left posterior CC (PCC). These reductions in CC volume resulted from reduced surface area rather than reduced cortical thickness. There was also a significant relationship between left PCC volume and working memory in patients. No significant correlations were observed between CC volume and clinical variables. The results suggest that abnormalities in the CC as manifested by reduced surface area may contribute to cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled SI: PSC and the brain., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Aging is a critical risk factor for Parkinson's disease. Silibinin, a major flavonoid in Silybum marianum, has been suggested to display neuroprotective properties against various neurodegenerative diseases. In the present study, we observed that neonatal iron (120 μg/g body weight) supplementation resulted in significant abnormality of behavior and depletion of striatal dopamine (DA) in the aging male and female rats while it did not do so in the young male and female rats. No significant change in striatal serotonin content was observed in the aging male and female rats with neonatal supplementation of the same dose of iron. Furthermore, we found that the neonatal iron supplementation resulted in significant increase in malondialdehyde (MDA) and decrease in glutathione (GSH) in the substantia nigra (SN) of the aging male and female rats. No significant change in content of MDA and GSH was observed in the cerebellum of the aging male and female rats with the neonatal iron supplementation. Interestingly, silibinin (25 and 50 mg/kg body weight) treatment significantly and dose-dependently attenuated depletion of striatal DA and improved abnormality of behavior in the aging male and female rats with the neonatal iron supplementation. Moreover, silibinin significantly reduced MDA content and increased GSH content in the SN of the aging male and female rats. Taken together, our results indicate that elevated neonatal iron supplementation may result in neurochemical and behavioral deficits in the male and female rats with aging and silibinin may exert dopaminergic neuroprotection by maintaining redox balance.

Aging is one of the strongest risk factors for Parkinson's disease (PD). SIRT2 has been implicated in the aging process. It is pertinent to investigate the role of SIRT2 in aging-related dopaminergic neurotoxicity and to develop effective therapeutic strategies for PD through the use of aging animals. In this study, we observed that rotenone induced significant behavior abnormality and striatal dopamine depletion in aging rats, while it did not do so in young rats. No significant change in striatal serotonin level was observed in the aging rats after rotenone administration. There was also aging-related rotenone-induced increase in substantia nigra (SN) SIRT2 expression in the rats. In addition, there was aging-related rotenone-induced SN malondialdehyde (MDA) increase and glutathione (GSH) decrease in the rats. No significant changes in cerebellar SIRT2, MDA, or GSH levels were observed in the aging rats after rotenone administration. Striatal dopamine content was significantly inversely correlated with SN SIRT2 expression in the rats. AK-7 significantly diminished striatal dopamine depletion and improved behavior abnormality in the rotenone-treated aging rats. Furthermore, AK-7 significantly decreased MDA content and increased GSH content in the SN of rotenone-treated aging rats. Finally, the effect of AK-7 on dopaminergic neurons and redox imbalance was supported by the results from primary mesencephalic cultures. Our study helps to elucidate the mechanism for the participation of aging in PD and suggests that SN SIRT2 may be involved in PD neurodegeneration, that AK-7 may be neuroprotective in PD, and that maintaining redox balance may be one of the mechanisms underlying neuroprotection by AK-7.

Impaired iron homeostasis may cause damage to dopaminergic neurons and is critically involved in the pathogenesis of Parkinson's disease. At present, very little is understood about the effect of neonatal iron intake on behavior in aging animals. Therefore, we hypothesized that increased neonatal iron intake would result in significant behavior abnormalities and striatal dopamine depletion during aging, and Sirtuin 2 contributes to the age-related neurotoxicity. In the present study, we observed that neonatal iron intake (120 μg/g per day) during postnatal days 10-17 resulted in significant behavior abnormalities and striatal dopamine depletion in aging rats. Furthermore, after AK-7 (a selective Sirtuin 2 inhibitor) was injected into the substantia nigra at postnatal 540 days and 570 days (5 μg/side per day), striatal dopamine depletion was significantly diminished and behavior abnormality was improved in aging rats with neonatal iron intake. Experimental findings suggest that increased neonatal iron intake may result in Parkinson's disease-like neurochemical and behavioral deficits with aging, and inhibition of Sirtuin 2 expression may be a neuroprotective measure in Parkinson's disease.

Objective: The pathophysiology of chronic schizophrenia may reflect long term brain changes related to the disorder. The effect of chronicity on intrinsic functional connectivity patterns in schizophrenia without the potentially confounding effect of antipsychotic medications, however, remains largely unknown., Method: We collected resting-state fMRI data in 21 minimally treated chronic schizophrenia patients and 20 healthy controls. We computed regional functional connectivity strength for each voxel in the brain, and further divided regional functional connectivity strength into short-range regional functional connectivity strength and long-range regional functional connectivity strength. General linear models were used to detect between-group differences in these regional functional connectivity strength metrics and to further systematically investigate the relationship between these differences and clinical/behavioral variables in the patients., Results: Compared to healthy controls, the minimally treated chronic schizophrenia patients showed an overall reduced regional functional connectivity strength especially in bilateral sensorimotor cortex, right lateral prefrontal cortex, left insula and right lingual gyrus, and these regional functional connectivity strength decreases mainly resulted from disruption of short-range regional functional connectivity strength. The minimally treated chronic schizophrenia patients also showed reduced long-range regional functional connectivity strength in the bilateral posterior cingulate cortex/precuneus, and increased long-range regional functional connectivity strength in the right lateral prefrontal cortex and lingual gyrus. Notably, disrupted short-range regional functional connectivity strength mainly correlated with duration of illness and negative symptoms, whereas disrupted long-range regional functional connectivity strength correlated with neurocognitive performance. All of the results were corrected using Monte-Carlo simulation., Conclusions: This exploratory study demonstrates a disruption of intrinsic functional connectivity without long-term exposure to antipsychotic medications in chronic schizophrenia. Furthermore, this disruption was connection-distance dependent, thus raising the possibility for differential neural pathways in neurocognitive impairment and psychiatric symptoms in schizophrenia., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Disconnection in white matter (WM) pathway and alterations in gray matter (GM) structure have been hypothesized as pathogenesis in schizophrenia. However, the relationship between the abnormal WM integrity and the alteration of GM in anatomically connected areas remains uncertain. Moreover, the potential influence of antipsychotic medication on WM anisotropy and cortical morphology was not excluded in previous studies. In this study, a total number of 34 subjects were enrolled, including 17 medicated-naïve chronic schizophrenia patients and 17 healthy controls. Tract-based spatial statistics (TBSS) were applied to investigate the level of WM integrity. The FreeSurfer surface-based analysis was used to determine GM volume, cortical thickness and the surface area of GM regions which corresponded to abnormal WM fiber tracts. We observed that patients possessed lower fractional anisotropy (FA) values in the left inferior fronto-occipital fasciculus (IFOF) and left inferior longitudinal fasciculus (ILF), along with smaller GM volume and cortical thinning in temporal lobe than the healthy controls, which reflected the underlying WM and GM disruption that contributed to the disease. In the patient population, the lower connectivity of ILF and IFOF was positively associated with cortical thickness in left lateral orbitofrontal cortex, superior temporal gyrus and lingual gyrus in males, and positively correlated with GM volume in left lateral orbitofrontal cortex in females. On the other hand, it was negatively correlated with cortical area of middle temporal gyrus in males and temporal pole in females respectively, but not when genders were combined. These findings suggested that abnormal WM integrity and anatomical correspondence of GM alterations in schizophrenia were interdependent on gender-separated analysis in patients with schizophrenia. Moreover, combining TBSS and FreeSurfer might be a useful method to provide significant insight into interacting processes related to WM fiber tracts and GM changes in schizophrenia., (© 2013.)

Background: Disrupted white matter (WM) integrity is the pathological hallmark of schizophrenia. Previous studies have reported the cognitive deficits that are associated with WM disruption in schizophrenia with anti-psychiatric treatment. However, no study has yet revealed the correlation between cognition and WM abnormalities in never-medicated chronic schizophrenia., Methods: We used the diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) approach to investigate the whole-brain difference in the WM fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) values between 17 schizophrenia patients and 17 healthy controls matched in age, gender and education level. Patients' cognition was assessed through the MATRICS Consensus Cognitive Battery (MCCB). We explored the association between WM reduction and cognitive, clinical characteristics (severity of clinical symptoms, age, age of onset, illness duration)., Results: Voxel-wise statistics revealed that schizophrenia patients showed significant FA reduction in left inferior longitudinal fasciculus (ILF) and left inferior fronto-occipital fasciculus (IFOF), and no difference in MD, AD or RD as compared to healthy subjects. Furthermore, in the patients group, lower FA value of the left ILF and left IFOF significantly correlated with worse processing speed, as well as verbal learning and visual learning abilities. There was no correlation between the FA value and the severity of clinical symptoms, age, and age of onset or illness duration., Conclusion: Our results provide evidence to support that the disconnection of WM pathways may contribute to the pathophysiology of schizophrenia and suggest that the disturbance of left ILF and left IFOF integrity may contribute to cognitive deficits in schizophrenia, independent of effects of antipsychotic medication., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Increasing evidences suggest that activated microglia may contribute to neurodegeneration in Parkinson's disease (PD). In the present study, primary ventral mesencephalic (VM) cultures from E14 rats and PC12 cells were utilized as in vitro models to examine the mechanism underlying microglia activation mediated dopaminergic neurodegeneration. Using lipopolysaccharide (LPS) (1-100 ng/ml) as a tool, we observed that microglia activation-mediated a selective dopaminergic neurodegeneration in VM neuron-glia cultures, which was supported by the further study showing that conditioned medium (CM) from microglia-enriched cultures treated with LPS (10-100 ng/ml) decreased PC12 cell viability. The results from antibody neutralization, NO inhibition and superoxide neutralization suggested that the dopaminergic cell death was due to the production of microglia-derived proinflammatory factors (TNF-alpha, NO and superoxide), among which reactive oxygen species (ROS) might outweigh proinflammatory cytokines. Apoptosis assay on PC12 cells and primary dopaminergic neurons showed that apoptosis was a mechanism for both microglia activation-mediated dopaminergic cell death. Through Western blot and immunocytochemistry, we found that caspase-3 activation was involved in both dopaminergic cell injuries. Finally, the results from laser scanning confocal microscope demonstrated that PC12 cell intracellular free Ca(2+) ([Ca(2+)](i)) increased early after CM treatment. [Ca(2+)](i) increase involved influx of calcium from the extracellular milieu and release from intracellular stores and participated in the CM-induced PC12 cell apoptosis. Further investigations indicated that TNF-alpha, IL-1beta, NO and superoxide contributed at different degrees to CM-induced [Ca(2+)](i) increase and apoptosis in PC12 cells. Using primary VM cultures and PC12 cells, our study shows the roles of proinflammatory factors, apoptosis, caspase-3 activation and Ca(2+) disturbance in microglia activation-mediated dopaminergic cell degeneration. Understanding the mechanism for microglia activation-mediated dopaminergic neurodegeneration may contribute to the development of new neuroprotective strategies against PD.

Several lines of neuroimmunological evidence correlate the development of the inflammatory responses of the brain with the formation of amyloid plaques associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease. Within this context, we tested the ability of interleukin-1beta (IL-1beta) to regulate the processing of beta-amyloid precursor protein (beta-APP) in neuroglioma U251 cells. Our findings have shown that short-term treatment with IL-1beta (2 hr) resulted in a concentration-dependent decrease in the amount of the cell-associated form of beta-APP in U251 cells as compared to untreated cells, whereas a 2-hr treatment with IL-1beta led to increased release of secreted APP(alpha) fragment (sAPP(alpha)) into the conditioned media of the cells. The fact that sAPP(alpha) is an alpha-secretase cleavage metabolite of the cell-associated form of beta-APP, and the observation that IL-1beta-induced sAPP(alpha) release could be blocked by tissue inhibitors of metalloproteinases-1 (alpha-secretase inhibitors), suggested that alpha-secretase might be involved in IL-1beta-induced-sAPP(alpha) release. Moreover, to determine whether an intracellular signaling pathway mediates the IL-1beta-induced increase in sAPP(alpha) secretion, we used various specific signaling inhibitors and found that sAPP(alpha) release is significantly blocked by the mitogen-activated protein kinase (MEK1/2) inhibitor PD98059 and the c-Jun N-terminal kinase inhibitor SP600125. These findings suggested that the mechanism of IL-1beta-induced-sAPP(alpha) release is dependent on MEK1/2- and JNK-activated alpha-secretase cleavage in neuroglioma U251 cells., ((c) 2005 Wiley-Liss, Inc.)

To investigate the capability of Sprague-Dawley rat bone marrow stromal cells to secrete glial cell line-derived neurotrophic factors (GDNF), we detected expression of GDNF messenger RNA and protein in bone marrow stromal cells of Sprague-Dawley rats by reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. The GDNF messenger RNA and protein were detected in culture medium and total cell protein when bone marrow stromal cells were cultured for 3 days. The levels of GDNF in culture medium and total cell protein increased gradually after 3, 7 and 10 days of culture. Rat bone marrow stromal cells have the potential to secrete GDNF. Furthermore, the ability of secretion is determined by the surrounding microenvironment and self-growth status.

Inflammation participates in the pathogenesis and progression of Parkinson's disease, in which microglia play a key role. Inhibition of microglia activation has been shown to attenuate inflammation-mediated dopaminergic neurodegeneration. In this study, we found that genistein, the primary soybean isoflavone, concentration-dependently attenuated the lipopolysaccharide-induced decrease in dopamine uptake and loss of tyrosine hydroxylase-immunoreactive neurons in rat mesencephalic neuron-glia cultures. Genistein also inhibited lipopolysaccharide-induced microglia activation and production of tumor necrosis factor-alpha, nitric oxide and superoxide in mesencephalic neuron-glia cultures and microglia-enriched cultures. Our results indicate that genistein may protect dopaminergic neurons from lipopolysaccharide-induced injury and its effective inhibition of microglia activation may be one of the mechanisms.