Serum concentration of high-mobility group box 1, Toll-like receptor 4 as biomarker in epileptic patients.

Epilepsy is one of the most common neurological diseases with severe outcome. High-mobility Group Box 1/Toll-like Receptor 4 axis is proposed to participate in the epileptogenesis and correlate with seizure severity in animal models. To explore whether HMGB1 and TLR4 could serve as clinical biomarkers in epileptic patients, we recruited a total of 72 epilepsy patients and measured the serum level of HMGB1 and TLR4 by flow fluorescence technology and ELISA respectively. We found that the serum levels of HMGB1 and TLR4 were elevated in epileptic patients. The serum levels of HMGB1 and TLR4 were also significantly higher in drug-resistant group compared with drug-effective group. There was a positive linear correlation between HMGB1 and TLR4 in the study group (R2 = 0.479). The HMGB1 level was found to be related to seizures frequency (F = 6.71, P = 0.012), the duration of disease (F = 6.55, P = 0.013) and drug reactivity (F = 3.96, P = 0.024) in epileptic patients, while TLR4 level was related to seizures frequency (F = 4.68, P = 0.034) and drug reactivity (F = 3.80, P = 0.027). Our result provides experimental evidences that the expression of HMGB1 and TLR4 was correlated with clinical symptom in epileptic patients, which could be used as clinical biomarkers to monitor therapeutic effect.

Structural basis of TRPV3 inhibition by an antagonist.

The TRPV3 channel plays vital roles in skin physiology. Dysfunction of TRPV3 causes skin diseases, including Olmsted syndrome. However, the lack of potent and selective inhibitors impedes the validation of TRPV3 as a therapeutic target. In this study, we identified Trpvicin as a potent and subtype-selective inhibitor of TRPV3. Trpvicin exhibits pharmacological potential in the inhibition of itch and hair loss in mouse models. Cryogenic electron microscopy structures of TRPV3 and the pathogenic G573S mutant complexed with Trpvicin reveal detailed ligand-binding sites, suggesting that Trpvicin inhibits the TRPV3 channel by stabilizing it in a closed state. Our G573S mutant structures demonstrate that the mutation causes a dilated pore, generating constitutive opening activity. Trpvicin accesses additional binding sites inside the central cavity of the G573S mutant to remodel the channel symmetry and block the channel. Together, our results provide mechanistic insights into the inhibition of TRPV3 by Trpvicin and support TRPV3-related drug development.

Establishment and Validation of a Predictive Model for Radiation-Associated Aspiration Pneumonia in Patients with Radiation-Induced Dysphagia after Nasopharyngeal Carcinoma.

Introduction: Radiotherapy for patients with head and neck cancers raises their risk of aspiration pneumonia-related death. We aimed to develop and validate a model to predict radiation-associated aspiration pneumonia (RAP) among patients with dysphagia after radiotherapy for nasopharyngeal carcinoma (NPC). Materials and Methods: A total of 453 dysphagic patients with NPC were retrospectively recruited from Sun Yat-Sen Memorial Hospital from January 2012 to January 2018. Patients were randomly divided into training cohort (n = 302) and internal validation cohort (n = 151) at a ratio of 2 : 1. The concordance index (C-index) and calibration curve were used to evaluate the accuracy and discriminative ability of this model. Moreover, decision curve analysis was performed to evaluate the net clinical benefit. The results were externally validated in 203 dysphagic patients from the First People's Hospital of Foshan. Results: Derived from multivariable analysis of the training cohort, four independent factors were introduced to predict RAP, including Kubota water drinking test grades, the maximum radiation dose of lymph node gross tumor volume (Dmax of the GTVnd), neutrophil count, and erythrocyte sedimentation rate (ESR). The nomogram showed favorable calibration and discrimination regarding the training cohort, with a C-index of 0.749 (95% confidence interval (CI), 0.681 to 0.817), which was confirmed by the internal validation cohort (C-index 0.743; 95% CI, 0.669 to 0.818) and the external validation cohort (C-index 0.722; 95% CI, 0.606 to 0.838). Conclusions: Our study established and validated a simple nomogram for RAP among patients with dysphagia after radiotherapy for NPC.

Efficacy and Safety of Apatinib for Radiation-induced Brain Injury Among Patients With Head and Neck Cancer: An Open-Label, Single-Arm, Phase 2 Study.

PURPOSE: The treatment of radiation-induced brain injury (RI) caused by radiation therapy for head and neck cancer is challenging. Antiangiogenic therapy is a promising treatment. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor 2. We aimed to assess the efficacy and safety of apatinib in patients with RI. METHODS AND MATERIALS: In this phase 2, open-label, single-arm, prospective study, we recruited patients aged 35 to 80 years with prior radiation therapy history for head and neck cancer who had newly diagnosed RI at the Sun Yat-sen Memorial Hospital, China. Apatinib was administered at a dosage of 250 mg once daily orally for 4 weeks. A Simon minimax 2-stage design was performed. The primary outcome was the proportion of patients with overall clinical efficacy, defined as a radiographic response of ≥25% reduction in baseline brain edema volume on magnetic resonance fluid attenuated inversion recovery images at week 4. Secondary end points were the overall improvement rate of brain necrosis, neurologic function, and safety. RESULTS: We screened 37 patients, 36 of whom were enrolled between October 17, 2019, and August 3, 2020. At the cutoff date, 36 patients were assessed for efficacy and safety (19 were enrolled in stage 1 and 17 in stage 2). Of the 36 patients evaluated for overall clinical efficacy, 22 patients (61.1%; 95% CI, 43.5%-76.9%) achieved the primary end point at week 4. Among the 31 patients with brain necrosis lesions, 19 patients (61.3%; 95% CI, 42.2%-78.2%) showed improvement of brain necrosis. The most common grade 1 to 2 adverse events were hand-foot syndrome, fatigue, and hypertension There were no treatment-related grade 4 to 5 toxic effects. CONCLUSIONS: Oral apatinib shows promising efficacy and is well-tolerated in patients with RI. Further randomized controlled studies are warranted.

Polycarcin V induces DNA-damage response and enables the profiling of DNA-binding proteins.

To maintain genomic integrity and avoid diseases, the DNA-damage response (DDR) not only detects and repairs DNA lesions, but also contributes to the resistance to DNA-damaging chemotherapeutics. Targeting the DDR plays a significant role in drug discovery using the principle of synthetic lethality. The incomplete current knowledge of the DDR encouraged us to develop new strategies to identify and study its components and pathways. Polycarcin V, belonging to the C-aryl glycoside natural products, is a light-activatable DNA-intercalating agent that causes DNA damage by forming a covalent [2+2] cycloadduct with thymine residue under 365-450 nm of light irradiation in a DNA-sequence-independent manner. Taking advantage of the light-activatable feature and temporal control of DDR, we designed and synthesized polycarcin V-based bifunctional chemical probes, including one that cross-links DNA to DNA-binding protein to explore the DDR induced by polycarcin V and uncover novel DNA-protein interactions. Utilizing this chemical probe and activity-based protein profiling-stable isotope labeling with amino acids in cell culture, we identified 311 DNA-binding protein candidates, including known DDR factors and additional proteins that may be of interest in discovering new biology. We validated our approach by showing that our probe could specifically cross-link proteins involved in nucleotide excision repair (NER) that repair bulky DNA adducts. Our studies showed that the [2+2] cycloadduct formed by polycarcin V could indeed be repaired by NER in vivo. As a DNA-damaging agent, polycarcin V or its drug-like derivative plus blue light showed promising properties for psoriasis treatment, suggesting that it may itself hold promise for clinic applications.

Bevacizumab Combined with Corticosteroids Does Not Improve the Clinical Outcome of Nasopharyngeal Carcinoma Patients With Radiation-Induced Brain Necrosis.

OBJECTIVE: Our aim was to compare the clinical outcomes of patients treated with bevacizumab combined with corticosteroids and those with bevacizumab monotherapy from a radiation-induced brain necrosis (RN) registry cohort (NCT03908502). METHODS: We utilized clinical data from a prospective RN registry cohort (NCT03908502) from July 2017 to June 2020. Patients were considered eligible if they had symptomatic RN after radiotherapy for nasopharyngeal carcinoma (NPC) and received bevacizumab (5 mg/kg, two to four cycles) with a minimum follow-up time of 3 months. The primary outcome was a 2-month response rate determined by MRI and clinical symptoms. Secondary outcomes included quality of life [evaluated by the abbreviated World Health Organization Quality of Life (WHOQOL-BREF) questionnaire] and cognitive function (evaluated by the Montreal Cognitive Assessment scale) at 2 months, RN recurrence during follow-up, and adverse events. RESULTS: A total of 123 patients (34 in the combined therapy group and 89 in the monotherapy group) were enrolled in our study with a median follow-up time of 0.97 year [interquartile range (IQR) = 0.35-2.60 years]. The clinical efficacy of RN did not differ significantly between patients in these two groups [odds ratio (OR) = 1.642, 95%CI = 0.584-4.614, p = 0.347]. Furthermore, bevacizumab combined with corticosteroids did not reduce recurrence compared with bevacizumab monotherapy [hazard ratio (HR) = 1.329, 95%CI = 0.849-2.079, p = 0.213]. The most common adverse events of bevacizumab were hypertension (17.89%), followed by nosebleed (8.13%) and fatigue (8.13%). There was no difference in grade 2 or more severe adverse events between the two groups (p = 0.811). INTERPRETATION: Our results showed that the treatment strategy of combining bevacizumab with corticosteroids did not lead to better clinical outcomes for RN patients with a background of radiotherapy for nasopharyngeal carcinoma.

Syntheses of Skeletally Diverse Tetracyclic Isodon Diterpenoid Scaffolds Guided by Dienyne Radical Cyclization Logic.

We report herein the diversity-oriented synthesis of various tetracyclic Isodon diterpenoid scaffolds guided by radical cyclization logic. Our substrate-based dienyne radical cyclization approach is distinctive from reagent-based rearrangement approaches that are generally applied in biosynthesis or previous synthetic studies. An unprecedented cyclization at C14 via 1,5-radical translocation/5-exo-trig cyclization is observed, which enriches our radical cyclization pattern. Furthermore, biological evaluations revealed that several new natural product-like compounds showed promising anticancer activities against various cancer cell lines.

A nomogram to predict symptomatic epilepsy in patients with radiation-induced brain necrosis.

OBJECTIVE: To develop and validate a nomogram to predict epilepsy in patients with radiation-induced brain necrosis (RN). METHODS: The nomogram was based on a retrospective analysis of 302 patients who were diagnosed with symptomatic RN from January 2005 to January 2016 in Sun Yat-sen Memorial Hospital using the Cox proportional hazards model. Discrimination of the nomogram was assessed by the concordance index (C index) and the calibration curve. The results were internally validated using bootstrap resampling and externally validated using 128 patients with RN from 2 additional hospitals. RESULTS: A total of 302 patients with RN with a median follow-up of 3.43 years (interquartile range 2.54-5.45) were included in the training cohort; 65 (21.5%) developed symptomatic epilepsy during follow-up. Seven variables remained significant predictors of epilepsy after multivariable analyses: MRI lesion volume, creatine phosphokinase, the maximum radiation dose to the temporal lobe, RN treatment, history of hypertension and/or diabetes, sex, and total cholesterol level. In the validation cohort, 28 out of 128 (21.9%) patients had epilepsy after RN within a median follow-up of 3.2 years. The nomogram showed comparable discrimination between the training and validation cohort (corrected C index 0.76 [training] vs 0.72 [95% confidence interval 0.62-0.81; validation]). CONCLUSION: Our study developed an easily applied nomogram for the prediction of RN-related epilepsy in a large RN cohort. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a nomogram predicts post-RN epilepsy.

Computation-Guided Development of the "Click" ortho-Quinone Methide Cycloaddition with Improved Kinetics.

We report here a deep mechanistic study of the "click" ortho-quinone methide (oQM) cycloaddition between ortho-quinolinone quinone methide (oQQM) and thio-vinyl ether (TV), named as TQ-ligation. DFT calculations revealed the unexpected fact that dehydration of oQQM precursors is the rate-determining step of this transformation, and two highly reactive oQQM precursors were predicted. Guided by the calculations, a new "click" oQM cycloaddition which shows significantly improved kinetics and remarkable efficiency on protein labeling was developed.

Biomimetic Synthesis of Rhytidenone†A and Mode of Action of Cytotoxic Rhytidenone†F.

The rhytidenone family comprises spirobisnaphthalene natural products isolated from the mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of rhytidenone A was achieved by a Michael reaction/aldol/lactonization cascade in a single step from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F was investigated. The pulldown assay coupled with mass spectrometry analysis revealed the target protein PA28γ is covalently attached to rhytidenone F at the Cys92 residue. The interactions of rhytidenone F with PA28γ lead to the accumulation of p53, which is an essential tumor suppressor in humans. Consequently, the Fas-dependent signaling pathway is activated to initiate cellular apoptosis. These studies have identified the first small-molecule inhibitor targeting PA28γ, suggesting rhytidenone F may serve as a promising natural product lead for future anticancer drug development.

Up and Down States of Cortical Neurons in Focal Limbic Seizures.

Recent work suggests an important role for cortical-subcortical networks in seizure-related loss of consciousness. Temporal lobe seizures disrupt subcortical arousal systems, which may lead to depressed cortical function and loss of consciousness. Extracellular recordings show ictal neocortical slow waves at about 1 Hz, but it is not known whether these simply represent seizure propagation or alternatively deep sleep-like activity, which should include cortical neuronal Up and Down states. In this study, using in vivo whole-cell recordings in a rat model of focal limbic seizures, we directly examine the electrophysiological properties of cortical neurons during seizures and deep anesthesia. We found that during seizures, the membrane potential of frontal cortical secondary motor cortex layer 5 neurons fluctuates between Up and Down states, with decreased input resistance and increased firing rate in Up states when compared to Down states. Importantly, Up and Down states in seizures are not significantly different from those in deep anesthesia, in terms of membrane potential, oscillation frequency, firing rate, and input resistance. By demonstrating these fundamental similarities in cortical electrophysiology between deep anesthesia and seizures, our results support the idea that a state of decreased cortical arousal may contribute to mechanisms of loss of consciousness during seizures.

Investigation into attitudes toward epilepsy among non-/neurological doctors and nurses in southern China.

PURPOSE: To assess attitudes concerning epilepsy among non-/neurological medical personnel from basic-level hospitals in southern China and identify significant predictive factors for future stigma reduction interventions. METHOD: The Chinese Public Attitudes Toward Epilepsy (CPATE) scale was administered to 184 neurological and 264 non-neurological medical staff members from basic-level hospitals in southern China. Positively stated items in the PATE scale were reversely scored; in this case, a higher score would indicate a more negative attitude. RESULTS: The mean score of each item among the neurological group was statistically lower than that of the non-neurological group. The mean scores in both the general and personal domains of the CPATE scale were significantly lower among the doctors as compared to nurses. CONCLUSIONS: This was the first study to evaluate the attitudes toward epilepsy among medical personnel with different characteristics in basic-level hospitals in China. Health education can be a new model for stigma-reducing public interventions in China. Future strategies should first focus on improving access to correct knowledge about epilepsy among non-neurological medical staffs. This would be a vital breakthrough point to improve attitudes toward epilepsy in the whole society to help ease the disease burden on people with epilepsy, their families and the community in the years to come.

Mechanisms of decreased cholinergic arousal in focal seizures: In vivo whole-cell recordings from the pedunculopontine tegmental nucleus.

Focal limbic seizures often impair consciousness/awareness with major negative impact on quality of life. Recent work has shown that limbic seizures depress brainstem arousal systems, including reduced action potential firing in a key node: cholinergic neurons of the pedunculopontine tegmental nucleus (PPT). In vivo whole-cell recordings have not previously been achieved in PPT, but are used here with the goal of elucidating the mechanisms of reduced PPT cholinergic neuronal activity. An established model of focal limbic seizures was used in rats following brief hippocampal stimulation under light anesthesia. Whole-cell in vivo recordings were obtained from PPT neurons using custom-fabricated 9-10 mm tapered patch pipettes, and cholinergic neurons were identified histologically. Average membrane potential, input resistance, membrane potential fluctuations and variance were analyzed during seizures. A subset of PPT neurons exhibited reduced firing and hyperpolarization during seizures and stained positive for choline acetyltransferase. These PPT neurons showed a mean membrane potential hyperpolarization of -3.82 mV (±0.81 SEM, P < .05) during seizures, and also showed significantly increased input resistance, fewer excitatory post-synaptic potential (EPSP)-like events (P < .05), and reduced membrane potential variance (P < .01). The combination of increased input resistance, decreased EPSP-like events and decreased variance weigh against active ictal inhibition and support withdrawal of excitatory input as the dominant mechanism of decreased activity of cholinergic neurons in the PPT. Further identifying synaptic mechanisms of depressed arousal during seizures may lead to new treatments to improve ictal and postictal cognition.

Attitudes toward epilepsy among medical staffs in basic-level hospitals from southern China.

OBJECTIVE: The objectives of the study were to assess attitudes toward epilepsy among medical staffs from basic-level hospitals in southern China and identify significant predictive factors for future stigma reduction interventions. METHODS: The Public Attitudes Toward Epilepsy (PATE) scale, a two dimensional 14-item scale addressing two major domains: general domain and personal domain, was administered to 448 medical staffs from basic-level hospitals in southern China. Positively stated items in the PATE scale were reversely scored; in this case, a higher score would indicate a more negative attitude. Also, we compared the overall score and per-item scores of the medical staffs versus those of the general population reported in the previous studies using the same scale. RESULTS: The cumulative score of the medical staffs was 41.65 ±â€¯6.99, which is significantly lower as compared with 51.38 ±â€¯6.80 of the general population (t (645) = -16.473, p < 0.001). The general average score (t (645) = -16.473, p < 0.001) and the mean score in the general domain (t (645) = -22.573, p < 0.001) of the PATE scale were both significantly lower in the medical staffs compared with the general population, whereas there was no significant difference between the two groups in the personal domain (t(645) = -0.180, p = 0.857). Age or years in clinical practice, specialty, and title had a significant impact on both the general domain and personal domain. Residence was the only factor found affecting the medical staffs' attitudes toward epilepsy in the personal domain but not in the general domain. CONCLUSION: Medical staffs from basic-level hospitals in southern China demonstrate significant positive attitudes toward people with epilepsy in general aspects when compared with the general population. However, they still showed negative and conservative attitudes when it comes to the personal domain. Future strategies for stigma-reducing public interventions could focus on increasing better understanding of epilepsy among medical staffs in basic-level hospitals in China.

Axon Initial Segment Structural Plasticity is Involved in Seizure Susceptibility in a Rat Model of Cortical Dysplasia.

Cortical dysplasia is the most common etiology of intractable epilepsy. Both excitability changes in cortical neurons and neural network reconstitution play a role in cortical dysplasia epileptogenesis. Recent research shows that the axon initial segment, a subcompartment of the neuron important to the shaping of action potentials, adjusts its position in response to changes in input, which contributes to neuronal excitability and local circuit balance. It is unknown whether axon initial segment plasticity occurs in neurons involved in seizure susceptibility in cortical dysplasia. Here, we developed a "Carmustine"- "pilocarpine" rat model of cortical dysplasia and show that it exhibits a lower seizure threshold, as indicated by behavior studies and electroencephalogram monitoring. Using immunofluorescence, we measured the axon initial segment positions of deep L5 somatosensory neurons and show that it is positioned closer to the soma after acute seizure, and that this displacement is sustained in the chronic phase. We then show that Nifedipine has a dose-dependent protective effect against axon initial segment displacement and increased seizure susceptibility. These findings further our understanding of the pathophysiology of seizures in cortical dysplasia and suggests Nifedipine as a potential therapeutic agent.

ent-Jungermannenone C Triggers Reactive Oxygen Species-Dependent Cell Differentiation in Leukemia Cells.

Acute myeloid leukemia (AML) is a hematologic malignancy that is characterized by clonal proliferation of myeloid blasts. Despite the progress that has been made in the treatment of various malignant hematopoietic diseases, the effective treatment of AML remains very challenging. Differentiation therapy has emerged as a promising approach for leukemia treatment, and new and effective chemical agents to trigger the differentiation of AML cells, especially drug-resistant cells, are urgently required. Herein, the natural product jungermannenone C, a tetracyclic diterpenoid isolated from liverworts, is reported to induce cell differentiation in AML cells. Interestingly, the unnatural enantiomer of jungermannenone C (1) was found to be more potent than jungermannenone C in inducing cell differentiation. Furthermore, compound 1 targets peroxiredoxins I and II by selectively binding to the conserved cysteine residues and leads to cellular reactive oxygen species accumulation. Accordingly, ent-jungermannenone C (1) shows potential for further investigation as an effective differentiation therapy against AML.

A complex association between ABCA7 genotypes and blood lipid levels in Southern Chinese Han patients of sporadic Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by progressive cognitive decline. It can be divided into familial AD (FAD) and sporadic AD (SAD) based on the family history. Recently dysregulation of cholesterol homeostasis has been implicated in the development of late-onset AD. ATP-binding cassette transporter A7 (ABCA7) gene, regulating the transport of cholesterol, has been recently identified as a susceptible gene of AD by several large genome-wide association studies. To test the genetic effect of ABCA7 rs3764650 on blood lipid levels in Southern Chinese Han population and investigate the risk factors of SAD, a total of 118 SAD patients and 120 healthy matched controls were recruited and the genotyping in ABCA7 rs3764650 was conducted on the Sequenom MassARRAY iPLEX platform. Meanwhile, the levels of fasting lipid profile and mini-mental state examination (MMSE) scores were tested. There was significant difference in genotype distribution between SAD patients and controls (p=0.001). While the difference of ABCA7 rs3764650 allele distribution between SAD patients and controls was only significant in APOEε4-noncarriers (p=0.039). The association between blood lipid levels and ABCA7 rs3764650 genotypes was influenced by APOEε4 status. In APOEε4-noncarriers of SAD, the total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels in GG genotype group were significantly lower than those in GT and TT genotype groups (all p<0.05). Whereas no significant difference of blood lipid levels was found among three genotypes in APOEε4-carriers of SAD and controls. Additionally, logistic regression analysis showed that lower high-density lipoprotein cholesterol (HDL-C) levels (p=0.015, OR=5.669) and GG genotype (p=0.013, OR=8.318) were positively associated with SAD. Our results suggest that GG genotype of ABCA7 rs3764650 was a risk factor of SAD in Southern Chinese Han population as well as lipid homeostasis.

Deciphering TAL effectors for 5-methylcytosine and 5-hydroxymethylcytosine recognition.

DNA recognition by transcription activator-like effector (TALE) proteins is mediated by tandem repeats that specify nucleotides through repeat-variable diresidues. These repeat-variable diresidues form direct and sequence-specific contacts to DNA bases; hence, TALE-DNA interaction is sensitive to DNA chemical modifications. Here we conduct a thorough investigation, covering all theoretical repeat-variable diresidue combinations, for their recognition capabilities for 5-methylcytosine and 5-hydroxymethylcytosine, two important epigenetic markers in higher eukaryotes. We identify both specific and degenerate repeat-variable diresidues for 5-methylcytosine and 5-hydroxymethylcytosine. Utilizing these novel repeat-variable diresidues, we achieve methylation-dependent gene activation and genome editing in vivo; we also report base-resolution detection of 5hmC in an in vitro assay. Our work deciphers repeat-variable diresidues for 5-methylcytosine and 5-hydroxymethylcytosine, and provides tools for TALE-dependent epigenome recognition.Transcription activator-like effector proteins recognise specific DNA sequences via tandem repeats. Here the authors demonstrate TALEs can recognise the methylated bases 5mC and 5hmC, enabling them to detect epigenetic modifications.

DISC1 Regulates the Proliferation and Migration of Mouse Neural Stem/Progenitor Cells through Pax5, Sox2, Dll1 and Neurog2.

Background: Disrupted-in-schizophrenia 1 (DISC1) regulates neurogenesis and is a genetic risk factor for major psychiatric disorders. However, how DISC1 dysfunction affects neurogenesis and cell cycle progression at the molecular level is still unknown. Here, we investigated the role of DISC1 in regulating proliferation, migration, cell cycle progression and apoptosis in mouse neural stem/progenitor cells (MNSPCs) in vitro. Methods: MNSPCs were isolated and cultured from mouse fetal hippocampi. Retroviral vectors or siRNAs were used to manipulate DISC1 expression in MNSPCs. Proliferation, migration, cell cycle progression and apoptosis of altered MNSPCs were analyzed in cell proliferation assays (MTS), transwell system and flow cytometry. A neurogenesis specific polymerase chain reaction (PCR) array was used to identify genes downstream of DISC1, and functional analysis was performed through transfection of expression plasmids and siRNAs. Results: Loss of DISC1 reduced proliferation and migration of MNSPCs, while an increase in DISC1 led to increased proliferation and migration. Meanwhile, an increase in the proportion of cells in G0/G1 phase was concomitant with reduced levels of DISC1, but significant changes were not observed in the number MNSPCs undergoing apoptosis. Paired box gene 5 (Pax5), sex determining region Y-box 2 (Sox2), delta-like1 (Dll1) and Neurogenin2 (Neurog2) emerged as candidate molecules downstream of DISC1, and rescue experiments demonstrated that increased or decreased expression of either molecule regulated proliferation and migration in DISC1-altered MNSPCs. Conclusion: These results suggest that Pax5, Sox2, Dll1 and Neurog2 mediate DISC1 activity in MNSPC proliferation and migration.