CYP1B1 Genetic Variants (rs10916 and rs2855658) Are Associated with Increased Risk of Ischemic Stroke in Chinese Han Population.

INTRODUCTION: Ischemic stroke (IS) is an extremely complex disease caused by the combined action of multiple environmental and genetic factors. CYP1B1 is a member of the cytochrome P450 protein family, and it is an important human drug-metabolizing enzymes. We aimed to explore the association between CYP1B1 genetic variants and IS risk in Chinese Han population. METHODS: We recruited 1,150 participants to conduct a "case-control" study. The assessment of association between candidate CYP1B1 genetic variants (rs2855658, rs10916, rs162560, rs2567206) and IS risk was performed by SNPStats online software. In addition, false-positive report probability analysis was used to detect whether the positive findings were just chance or noteworthy observations. Finally, the interaction of candidate SNPs in IS risk was evaluated by multifactor dimensionality reduction. RESULTS: The results showed that CYP1B1-rs2855658 was a risk factor for IS among ≥60-year-old (dominant: p = 0.034; overdominant: p = 0.026), smoking (heterozygote: p = 0.009; dominant: p = 0.004; overdominant: p = 0.012; log-additive: p = 0.003), and drinking participants (homozygous: p = 0.036; dominant: p = 0.019; recessive: p = 0.012; log-additive: p = 0.006). CYP1B1-rs10916 also was a risk factor for IS patients among ≥60-year-old (heterozygote: p = 0.047; overdominant: p = 0.048), smoking (dominant: p = 0.050; overdominant: p = 0.049), and drinking participants (dominant: p = 0.019; overdominant: p = 0.038; log-additive: p = 0.013). CONCLUSION: CYP1B1-rs10916 and CYP1B1-rs2855658 can increase the IS risk in Chinese Han population who are ≥60 years old, smoking, or drinking alcohol.

Association of CASZ1 genetic variants with stroke risk in the Chinese population.

BACKGROUND: Stroke is a heterogeneous disease with multiple etiologies, placing a heavy burden on the world. Our purpose was to clarify the association between CASZ1 genetic variants and stroke risk in the Chinese population. METHODS: The Agena MassARRAY platform effectively genotyped three single nucleotide polymorphisms of CASZ1 in recruited 591 stroke patients and 553 healthy controls. Logistic regression genetic models were employed to evaluate the relationship between CASZ1 polymorphisms and stroke risk through odds ratios (ORs) and 95% confidence intervals (CIs). Then, the interaction between CASZ1 variants was detected by multifactor dimensionality reduction (MDR). Moreover, functional enrichment analyses of the CASZ1 gene were performed by Metascape. RESULTS: In this study, CASZ1 rs4845941 and rs778228 were significantly associated with an increased risk of stroke. In particular, the gender-stratified analysis also showed that rs778228 of CASZ1 had an association with higher stroke risk in females. The relationship between stroke susceptibility and the interaction models of rs4845941, rs778228, and rs17035539 forecasted by MDR were analyzed to improve the ability to predict stroke risk. Furthermore, we found CASZ1 and related genes might facilitate the occurrence of stroke. CONCLUSIONS: This study demonstrated that CASZ1 genetic variants (rs4845941 and rs778228) contribute to the occurrence of stroke in the Chinese population, and therefore has important implications for treating and preventing stroke.

Radiological model based on the standard magnetic resonance sequences for detecting methylguanine methyltransferase methylation in glioma using texture analysis.

This study aims to build a radiological model based on standard MR sequences for detecting methylguanine methyltransferase (MGMT) methylation in gliomas using texture analysis. A retrospective cross-sectional study was undertaken in a cohort of 53 glioma patients who underwent standard preoperative magnetic resonance (MR) imaging. Conventional visual radiographic features and clinical factors were compared between MGMT promoter methylated and unmethylated groups. Texture analysis extracted the top five most powerful texture features of MR images in each sequence quantitatively for detecting the MGMT promoter methylation status. The radiomic signature (Radscore) was generated by a linear combination of the five features and estimates in each sequence. The combined model based on each Radscore was established using multivariate logistic regression analysis. A receiver operating characteristic (ROC) curve, nomogram, calibration, and decision curve analysis (DCA) were used to evaluate the performance of the model. No significant differences were observed in any of the visual radiographic features or clinical factors between different MGMT methylated statuses. The top five most powerful features were selected from a total of 396 texture features of T1, contrast-enhanced T1, T2, and T2 FLAIR. Each sequence's Radscore can distinguish MGMT methylated status. A combined model based on Radscores showed differentiation between methylated MGMT and unmethylated MGMT both in the glioblastoma (GBM) dataset as well as the dataset for all other gliomas. The area under the ROC curve values for the combined model was 0.818, with 90.5% sensitivity and 72.7% specificity, in the GBM dataset, and 0.833, with 70.2% sensitivity and 90.6% specificity, in the overall gliomas dataset. Nomogram, calibration, and DCA also validated the performance of the combined model. The combined model based on texture features could be considered as a noninvasive imaging marker for detecting MGMT methylation status in glioma.

Comparison of Radiomics Analyses Based on Different Magnetic Resonance Imaging Sequences in Grading and Molecular Genomic Typing of Glioma.

OBJECTIVE: To investigate the value of radiomics analyses based on different magnetic resonance (MR) sequences in the noninvasive evaluation of glioma characteristics for the differentiation of low-grade glioma versus high-grade glioma, isocitrate dehydrogenase (IDH)1 mutation versus IDH1 wild-type, and mutation status and 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (+) versus MGMT promoter methylation (-) glioma. METHODS: Fifty-nine patients with untreated glioma who underwent a standard 3T-MR tumor protocol were included in the study. A total of 396 radiomics features were extracted from the MR images, with the manually delineated tumor as the volume of interest. Clinical imaging diagnostic features (tumor location, necrosis/cyst change, crossing midline, and the degree of enhancement or peritumoral edema) were analyzed by univariate logistic regression to select independent clinical factors. Radiomics and combined clinical-radiomics models were established for grading and molecular genomic typing of glioma by multiple logistic regression and cross-validation. The performance of the models based on different sequences was evaluated by using receiver operating characteristic curves, nomograms, and decision curves. RESULTS: The radiomics model based on T1-CE performed better than models based on other sequences in predicting the tumor grade and the IDH1 status of the glioma. The radiomics model based on T2 performed better than models based on other sequences in predicting the MGMT methylation status of glioma. Only the T1 combined clinical-radiomics model showed improved prediction performance in predicting tumor grade and the IDH1 status. CONCLUSIONS: The results demonstrate that state-of-the-art radiomics analysis methods based on multiparametric MR image data and radiomics features can significantly contribute to pretreatment glioma grading and molecular subtype classification.

Blood-Brain Barrier Disruption, Sodium Fluorescein, And Fluorescence-Guided Surgery Of Gliomas.

PURPOSE: Sodium fluorescein (SF) is an ideal dye for intraoperative guided-resection of high-grade gliomas (HGGs). However, it is not well understood whether the SF-guided technique is suitable for different grades of gliomas, and the correlation between fluorescence and pathology is also not yet clear. MATERIALS AND METHODS: In this study, we investigated 28 patients, including 23 patients with HGG and 5 patients with low-grade glioma (LGG). All patients were treated using the SF-guided technique on a Pentero 900 microscope (Carl Zeiss, Oberkochen, Germany). Claudin-5 immunohistochemical (IHC) staining for the tumours and peritumour tissues was analyzed. RESULTS: Intraoperative yellow fluorescence was noted in all the HGGs but not in the LGGs. Claudin-5 expression in the blood brain barrier endothelial cells was downregulated and disconnected in the HGGs (p < 0.05), but had no difference or slightly decreased in the LGGs (p > 0.05). CONCLUSIONS: The SF-guided technique is suitable for HGG surgery but not for LGG surgery. Downregulation of claudin-5 expression may contribute to the presence of yellow fluorescence in the glioma in SF-guided surgery.

Schizophrenia symptomatic associations with diffusion tensor imaging measured fractional anisotropy of brain: a meta-analysis.

PURPOSE: Several studies have examined the relationships between diffusion tensor imaging (DTI)-measured fractional anisotropy (FA) and the symptoms of schizophrenia, but results vary across the studies. The aim of this study was to carry out a meta-analysis of correlation coefficients reported by relevant studies to evaluate the correlative relationships between FA of various parts of the brain and schizophrenia symptomatic assessments. METHODS: Literature was searched in several electronic databases, and study selection was based on précised eligibility criteria. Correlation coefficients between FA of a part of the brain and schizophrenia symptom were first converted into Fisher's z-scores for meta-analyses, and then overall effect sizes were back transformed to correlation coefficients. RESULTS: Thirty-three studies (1121 schizophrenia patients; age 32.66 years [95% confidence interval (CI) 30.19, 35.13]; 65.95 % [57.63, 74.28] males) were included in this meta-analysis. Age was inversely associated with brain FA (z-scores [95% CI] -0.23 [-0.14, -0.32]; p Ë‚ 0.00001). Brain FA of various areas was inversely associated with negative symptoms of schizophrenia (z-score -0.30 [-0.23, -0.36]; p Ë‚ 0.00001) but was positively associated with positive symptoms of schizophrenia (z-score 0.16 [0.04, 0.27]; p = 0.007) and general psychopathology of schizophrenia (z-score 0.26 [0.15, 0.37]; p = 0.00001). CONCLUSION: Although, DTI-measured brain FA is found to be inversely associated with negative symptoms and positively associated with positive symptoms and general psychopathology of schizophrenia, the effect sizes of these correlations are low and may not be clinically significant. Moreover, brain FA was also negatively associated with age of patients.

[Effect of curcumin on oligomer formation and mitochondrial ATP-sensitive potassium channels induced by overexpression or mutation of α-synuclein].

OBJECTIVE: To investigate the effect of curcumin on oligomer formation and mitochondrial ATP-sensitive potassium channels (mitoKATP) induced by overexpression or mutation of α-synuclein. METHODS: Recombinant plasmids α-synuclein-pEGFP-A53T and α-synuclein-pEGFP-WT were transfected into PC12 cells by lipofectamin method, and intervened by application of curcumin (20 µmol/L) and 5-hydroxydecanoate (5-HD). Oligomer formation in the cultured cells was identified by Western blotting and Dot blotting. Cytotoxicity and apoptosis of the PC12 cells were measured by lactate dehydrogenase (LDH) and JC-1 assays. mitoKATP were identified by Western blotting and whole cell patch clamp. RESULTS: Curcumin has significantly reduced the oligomer formation induced by overexpression or mutation of α-synuclein in the cultured cells. LDH has decreased by 36.3% and 23.5%, and red/green fluorescence ratio of JC-1 was increased respectively by 48.46% and 50.33% after application of curcumin (P<0.05). Protein expression of Kir6.2 has decreased and mitoKATP channel current has significantly increased (P<0.05). CONCLUSION: Curcumin can inhibit α-synuclein gene overexpression or mutation induced α-synuclein oligomers formation. It may block apoptosis induced by wild-type overexpression or mutation of α-synuclein. By stabilizing mitochondrial membrane potential. Opening of mitoKATP channel may have been the initiating protective mechanism of apoptosis induced by wild-type overexpression or mutation of α-synuclein. Curcumin may antagonize above cytotoxicity through further opening the mitoKATP channel.

Chromatin Licensing and DNA Replication Factor 1 (CDT1) Is a Potential Prognostic Biomarker Involved in the Malignant Biological Behavior of Glioma.

Glioma is the primary malignant tumor with the highest incidence rate in the adult central nervous system. The application of bioinformatics methods to analyze the RNA sequences of multiple gliomas revealed that the CDT1 gene has a significant impact on the cell cycle of glioma cells. Subsequently, we comprehensively and systematically investigated the expression of CDT1 in gliomas through bioinformatics analysis, clinical tissue specimens, and in vitro functional experiments. Our study is the first to report the expression of CDT1 in glioma. Our findings demonstrate that CDT1 plays a crucial role in the proliferation and invasion of glioma. Additionally, our bioinformatics analysis identified several other genes and signaling pathways that are dysregulated in multifocal gliomas, providing potential targets for further research and drug development.

H2S inhibits LiCl/pilocarpine-induced seizures and promotes neuroprotection by regulating TRPV2 expression via the AC3/cAMP/PKA pathway.

It is widely acknowledged that epilepsy is a neurological disorder characterized by recurrent and atypical neuronal discharges, resulting in transient dysfunction within the brain. The protective role of hydrogen sulfide (H2S) in epilepsy has been elucidated by recent studies, but the underlying mechanisms remain poorly understood. To investigate this, the concentration of H2S was measured by spectrophotometry and a fluorescent probe in LiCl/Pilocarpine (LiCl/Pilo)-induced seizures in rats. The localization of proteins was examined using immunofluorescence. Electroencephalogram and behavioral tests were employed to evaluate the occurrence of seizures. Neuropathological changes in the hippocampus were examined by hematoxylin-eosin staining, Nissl staining, and transmission electron microscopy. Through proteomics and bioinformatics analysis, we identified the differential proteins in the hippocampus of rats following H2S intervention. Protein changes were detected through western blotting. The results showed that H2S treatment significantly alleviated seizures and minimized post-seizures neurological damage in rats. Proteomics analysis revealed adenylate cyclase 3 (AC3) as a protein potentially targeted by H2S. Moreover, the AC3 activator forskolin reversed the downregulation effect of H2S on the AC3/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/transient receptor potential vanilloid 2 (TRPV2) signaling pathway. In conclusion, H2S targets and downregulates the expression of AC3, thereby modulating the AC3/cAMP/PKA signaling pathway to regulate the expression of TRPV2 in LiCl/Pilo-induced seizures, ultimately leading to seizure inhibition and neuroprotection.

[Preparation and in vitro study of a high molecular weight contrast agent targeting hepatoma cells].

OBJECTIVE: To prepare a specific high molecular weight polymer contrast agent capable of specifically targeting hepatocarcinoma cells (HCC) and to investigate its affinity in vitro using HepG2 cells. METHODS: The high molecular weight polymer polylactic-co-glycolic acid (PLAG)-COOH was prepared by the double emulsion technique. PLAG-COOH microbubbles were combined with glypican-3 (GPC3) antibody to generate HCC targeting high molecular polymer ultrasound contrast agents by the carbodiimide method. The affinity for HCC cells was confirmed by measuring attachment to cultured HepG2 cells by flow cytometry and comparing the results with the properties observed for non-targeted high molecular weight polymer ultrasound contrast agents. RESULTS: The average diameter of the targeted high molecular weight polymer ultrasound contrast agents was (800+/-10) nm. In vitro targeting of HepG2 cells showed that many of the targeted high molecular weight polymer ultrasound contrast agents attached tightly to the cell surface and that the GPC3-PLGA has a particularly strong targeting ability. CONCLUSION: A HCC-specific high molecular contrast agent, GPC3-PLGA, was synthesized and evidenced a strong targeting ability towards HepG2 cells in vitro. This new agent may be exploited to improve diagnosis of liver cancer at the molecular level.

Association Between HTRA1, GAS6 and IFNGR2 Gene Polymorphisms and Stroke Susceptibility in the Chinese Han Population.

Background: Stroke has a high disability rate, and 30% of stroke cases have an unknown cause. Accurate diagnosis and treatment of stroke requires consideration of several rare heritable and non-heritable factors. Objective: This study aimed to evaluate the impacts of three genetic polymorphisms (rs369149111 in HTRA1, rs1803628 in GAS6 and rs9808753 in IFNGR2) on stroke susceptibility among the Chinese Han population. Methods: Three single nucleotide polymorphisms (SNPs) from 623 stroke cases and 572 healthy controls were genotyped by the Agena MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis to evaluate the associations of three SNPs with stroke susceptibility. Additionally, SNP-SNP interactions were analyzed by multifactor dimensionality reduction (MDR). Results: As demonstrated by the overall analysis, rs9808753 in IFNGR2 (allele: OR = 1.25, 95% CI = 1.06-1.47, p = 0.007; homozygous: OR = 1.59, 95% CI = 1.14-2.23, p = 0.007; dominant: OR = 1.31, 95% CI = 1.02-1.67, p = 0.032; recessive: OR = 1.42, 95% CI = 1.05-1.91, p = 0.022; additive: OR = 1.26, 95% CI = 1.07-1.48, p = 0.007) was associated with an increased susceptibility to stroke. Besides, stratification analysis suggested that rs9808753 was associated with an increased risk of stroke in subgroup aged ≤ 64 years, males and drinkers (p < 0.05). And rs1803628 in GAS6 was significantly associated with an increased susceptibility to stroke in non-smokers (p < 0.05). Conclusion: A risk-increasing effect of IFNGR2 rs980875 on stroke was detected in this study, which further broadens the understanding of the relationship between genetic polymorphisms and stroke susceptibility.

[1H magnetic resonance spectroscopy in the evaluation of high intensity focused ultrasound ablation for primary liver cancer].

To investigate the clinical value of 1H magnetic resonance spectroscopy (1H MRS) in the evaluation of high intensity focused ultrasound (HIFU) ablation for primary liver cancer. Routine magnetic resonance sequences, contrast-enhanced magnetic resonance imaging and respiratory-triggered single voxel point resolved spectroscopy sequence (PRESS) were performed on 24 patients with primary liver cancer before and after HIFU ablation. A respiratory-triggered axial T2 weighted imaging (T2WI) was used as localizer for PRESS. Spectroscopy data was transmitted to a personal computer and was post-processed with a custom software (Saker, provided by Ning Jing, an engineer in GE Healthcare). It would be considered "technical success" if the baselines of spectra were stable and main metabolites were without overlapping and could be identified. Integral areas of choline (Cho) peak at 3.2 parts per million (ppm) and lipid (Lip) peak at 1.3 ppm were measured, and the choline to lipid (Cho/Lip) ratios were calculated. The differences of areas of Cho, Lip peak and Cho/Lip ratios before and after HIFU ablation were compared by using paired samples t test, and a P value of less than 0.05 was considered statistically significant. The technical success rate of 1H-MRS was 87.50% (42/48). Integral areas of Cho peak and Lip peak of 20 patients with satisfied spectra were measured, and the Cho/Lip ratios were calculated. The Integral area of Cho peak decreased from 34 597+/-6 802 before HIFU ablation to 6 372+/-2 466 after HIFU ablation (t = 18.02, P less than 0.01). The Integral area of Lip peak increased from 147 948+/-16 317 before HIFU ablation to 149 069+/-16 345 after HIFU ablation (t = -15.11, P less than 0.01). The Cho/Lip ratio decreased from 0.23+/-0.03 before HIFU ablation to 0.04+/-0.02 after HIFU ablation (t = 25.32, P less than 0.01). 1H-MRS could provide information of metabolites changes of primary liver cancer after HIFU ablation and could be used as a complementary sequence to other magnetic resonance sequences to evaluate all around primary liver cancer after HIFU ablation.

Tumor-treating fields (TTFields)-based cocktail therapy: a novel blueprint for glioblastoma treatment.

Glioblastoma is one of the most common malignant tumors in the central nervous system. Due to the high plasticity, heterogeneity and complexity of the tumor microenvironment, these tumors are resistant to almost all therapeutic strategies when they reach an advanced stage. Along with being a unique and effective way to kill cancer cells, tumor-treating fields (TTFields) has emerged as a breakthrough among glioblastoma therapies since the advent of temozolomide (TMZ), and the combination of these treatments has gradually been promoted and applied in the clinic. The combination of TTFields with other therapies is particularly suitable for this type of "cold" tumors and has attracted a large amount of attention from clinicians and researchers in the era of cancer cocktail therapy. Here, we introduced the current treatment regimen for glioblastoma, highlighting the unique advantages of TTFields in the treatment of glioblastoma. Then, we summarized current glioblastoma clinical trials that combine TTFields and other therapies. In addition, the main and potential mechanisms of TTFields were introduced to further understand the rationale for each combination therapy. Finally, we focused on the most advanced technologies applied in glioblastoma research and treatment and the prospect of their combination with TTFields. This review provides a unique overview of glioblastoma treatment.

A Novel Glucose Metabolism-Related Gene Signature for Overall Survival Prediction in Patients with Glioblastoma.

INTRODUCTION: Glioblastoma (GBM) is one of the most frequent primary intracranial malignancies, with limited treatment options and poor overall survival rates. Alternated glucose metabolism is a key metabolic feature of tumour cells, including GBM cells. However, due to high cellular heterogeneity, accurately predicting the prognosis of GBM patients using a single biomarker is difficult. Therefore, identifying a novel glucose metabolism-related biomarker signature is important and may contribute to accurate prognosis prediction for GBM patients. METHODS: In this research, we performed gene set enrichment analysis and profiled four glucose metabolism-related gene sets containing 327 genes related to biological processes. Univariate and multivariate Cox regression analyses were specifically completed to identify genes to build a specific risk signature, and we identified ten mRNAs (B4GALT7, CHST12, G6PC2, GALE, IL13RA1, LDHB, SPAG4, STC1, TGFBI, and TPBG) within the Cox proportional hazards regression model for GBM. RESULTS: Depending on this glucose metabolism-related gene signature, we divided patients into high-risk (with poor outcomes) and low-risk (with satisfactory outcomes) subgroups. The results of the multivariate Cox regression analysis demonstrated that the prognostic potential of this ten-gene signature is independent of clinical variables. Furthermore, we used two other GBM databases (Chinese Glioma Genome Atlas (CGGA) and REMBRANDT) to validate this model. In the functional analysis results, the risk signature was associated with almost every step of cancer progression, such as adhesion, proliferation, angiogenesis, drug resistance, and even an immune-suppressed microenvironment. Moreover, we found that IL31RA expression was significantly different between the high-risk and low-risk subgroups. CONCLUSION: The 10 glucose metabolism-related gene risk signatures could serve as an independent prognostic factor for GBM patients and might be valuable for the clinical management of GBM patients. The differential gene IL31RA may be a potential treatment target in GBM.

[CT image of liver secondary lymphoma].

OBJECTIVE: To analyze the CT image characteristics of liver secondary lymphoma. METHODS: The medical records of 13 patients were reviewed. There were 12 non-Hodgkin lymphoma cases and 1 Hodgkin lymphoma case. Abdomen CT scan was performed in all cases, plain scan and enhanced CT scan were performed in 11 cases, plain CT scan was performed in 2 cases. RESULTS: Of the 13 cases, 11 were nodular type, 1 was diffuse type, and 1 was mixed type. Plain CT scan showed low density, enhanced CT showed circular enhancement in 1 case, mild to midrange delayed enhancement in 1 case, midrange enhancement in 1 case, mild enhancement in 2 cases, blood vessel floating sign in 3 cases, no enhancement in 6 cases. CONCLUSIONS: The characteristics of liver secondary lymphoma CT image of liver secondary lymphoma includes blood vessel floating sign and enhancement.

Organoid models of glioblastoma: advances, applications and challenges.

The high mortality and poor clinical prognosis of glioblastoma multiforme (GBM) are concerns for many GBM patients as well as clinicians and researchers. The lack of a preclinical model that can easily be established and accurately recapitulate tumour biology and the tumour microenvironment further complicates GBM research and its clinical translation. GBM organoids (GBOs) are promising high-fidelity models that can be applied to model the disease, develop drugs, establish a living biobank, mimic therapeutic responses and explore personalized therapy. However, GBO models face some challenges, including deficient immune responses, absent vascular system and controversial reliability. In recent years, considerable progress has been achieved in the improvement of brain tumour organoid models and research based on such models. In addition to the traditional cultivation method, these models can be cultivated via genetic engineering and co-culture of cerebral organoids and GBM. In this review, we summarize the applications of GBM organoids and related advances and provide our opinions on associated limitations and challenges.

MDM2 promotes the proliferation and inhibits the apoptosis of pituitary adenoma cells by directly interacting with p53.

INTRODUCTION: Pituitary adenomas constitute one of the most common intracranial tumours. The mouse double minute 2 homologue (MDM2) is considered as an important oncogene in many tumours, but it has been little studied in pituitary adenomas and the mechanism is not well understood. The purpose of this study was to investigate the function of MDM2 and its primary mechanism of action in pituitary adenoma cells. MATERIAL AND METHODS: The expression of MDM2 in pituitary adenoma cell lines and normal cells was determined by real-time polymerase chain reaction (RT-PCR). The proliferation and apoptosis of pituitary adenoma cells after inhibition of MDM2 expression were detected by MTS and flow cytometry, respectively. The protein expressions of MDM2 and p53 were detected by western blot. Co-IP was used to detect the direct binding between MDM2 and p53. RESULTS: The results of RT-PCR showed that MDM2 was significantly up-regulated in pituitary adenoma cell lines. Inhibition of MDM2 suppressed the proliferation and promoted apoptosis of pituitary adenoma cells. However, inhibiting the expression of MDM2 can promotethe protein expression of p53. The results of co-IP showed that MDM2 interacted with p53 by direct combination. Then, we inhibited the expressions of p53 and MDM2 simultaneously in the pituitary adenoma cells by co-transfecting siRNAs, and the results showed that, compared with the group that inhibited MDM2 alone, cell proliferation of the co-transfected group increased and apoptosis of the cotransfected group decreased, which was similar to the NC group. CONCLUSIONS: Taken together, these results suggest that MDM2 promoted the proliferation and inhibited the apoptosis of pituitary adenoma cells by directly interacting with p53 in pituitary adenoma cells. Therefore, MDM2-p53 may serve as a novel marker and therapeutic target for pituitary adenomas.

[Establishment of liver fibrosis in rabbit model and quantitative study on hepatic perfusion with dynamic whole-liver 3D MR imaging].

OBJECTIVE: To investigate the ideal approach in creating rabbit model of hepatic fibrosis and to evaluate the feasibility and value of dynamic whole-liver 3D magnetic resonance (MR) perfusion-weighted imaging (PWI) in the quantitative study on the staging of hepatic fibrosis. METHODS: Rabbit model of hepatic fibrosis was created by intraperitoneal injection of 5% and 100% carbon tetrachloride (0.1 ml/kg, once a week) respectively. MR perfusion weighted imaging was performed at the 6th, 8th, 10th and 12th week since injection. The time of peak (TOP), the time to peak (TTP), the maximum slope of increase(MSI) and the maximal relative signal increase (MRSI) of portal vein and hepatic parenchyma were analyzed quantitatively, and were compared with pathological results. Comparison of different concentrations of CCl4 was analyzed using chi-square test. Inter-group comparison of perfusion parameters was analyzed using one-way ANOVA P less than 0.05 was regarded as statistically significant. RESULTS: 40% of the rabbits treated with 5% carbon tetrachloride developed hepatic fibrosis, while 75% of the rabbits treated with 100% carbon tetrachloride developed hepatic fibrosis; the mortality rate is significantly different between these two groups (X2=5.013, P less than 0.05). PWI examination was successfully achieved in 31 rabbits, liver perfusion baseline was stable, and good TIC curve was obtained. With the progress of hepatic fibrosis, TOP and TTP of portal vein and hepatic parenchyma were increased, and MSI and MRSI were decreased. There were significant differences among stage of S0-S2, S3 and S4. CONCLUSIONS: The method (100% carbon tetrachloride intraperitoneal injection, 0.1 ml/kg, once a week) has high success rate of creating rabbit model of hepatic fibrosis. The stage of hepatic fibrosis could be evaluated quantitatively with dynamic whole-liver 3D MR perfusion-weighted imaging.

N-Acetyl Serotonin Protects Neural Progenitor Cells Against Oxidative Stress-Induced Apoptosis and Improves Neurogenesis in Adult Mouse Hippocampus Following Traumatic Brain Injury.

In this study, with primary mouse neural progenitor cells (NPCs), we investigated the neuroprotective effect of a tropomyosin-related kinase receptor B (TrkB) agonist, N-acetyl serotonin (NAS), against hydrogen peroxide (H2O2)-induced toxicity. We found that pre-incubation with NAS not only ameliorates H2O2-induced cell viability loss, lactate dehydrogenase (LDH) release, and proliferative and migratory capacity impairments, but counteracts H2O2-triggered production of nitric oxide (NO), reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-deoxyguanosine (8-OHdG) in a dose-dependent manner. Additionally, pre-treatment with NAS was able to attenuate H2O2-induced apoptosis in NPCs, evidenced by the decreased percentage of apoptotic cells and altered expression of apoptosis-related factors. Furthermore, in differentiated NPCs, NAS improves H2O2-induced reduction in neurite growth. Mechanistic studies revealed that the protective effects of NAS in NPCs may be mediated by the TrkB/PI3K/Akt/ cAMP response element binding protein (CREB) signaling cascades. In a mouse traumatic brain injury (TBI) model, we found that systemic administration of 30 mg/kg NAS could improve hippocampal neurogenesis, manifested by the increased number of SOX-2-positive cells and increased expression of phosphorylated CREB in the dentate gyrus (DG) area. Treatment with NAS also ameliorates cognitive impairments caused by TBI, as assessed by Y-maze and contextual and cued fear conditioning tests. Taken together, these results provide valuable insights into the neuroprotective and neuroregenerative effects of NAS, suggesting it may have therapeutic potential for the treatment of TBI.

Potential Neuroprotective Effect of miR-451 Against Cerebral Ischemia/Reperfusion Injury in Stroke Patients and a Mouse Model.

OBJECTIVE: Recently, microRNAs (miRs) have been reported to be novel regulators in ischemic stroke. In this study, we investigated the pattern of miR-451 expression along with its clinical application in human ischemic stroke and in an in vivo mouse model. METHODS: The level of miR-451 was evaluated in patients and mice after ischemic stroke. National Institute of Health Stroke Scale scores and brain infarct volume were analyzed to the correlation of miR-451 expression and clinical information. In addition, blood samples and brain tissues were collected from an established middle cerebral artery occlusion model consisting of 12 adult male mice at 24 hours after the middle cerebral artery occlusion. RESULTS: The results showed that miR-451 levels in the circulating blood of ischemic stroke patients were greatly decreased compared with the control. Further correlation analysis revealed a negative association between miR-451 and National Institute of Health Stroke Scale scores (r = -0.6104, P < 0.001) and infarct volume (r = -0.5442, P < 0.001). Moreover, miR-451 was down-regulated in response to middle cerebral artery occlusion in vivo, along with a negative correlation between miR-451 in brain and blood (r = 0.9240, P < 0.01). In addition, forced expression of miR-451 weakened ischemic brain infarction and apoptosis levels in focal ischemia-stroked mice, while downregulation of miR-451 significantly augmented ischemic injury. CONCLUSIONS: In conclusion, miR-451 displays the neuroprotective effect in ischemic stroke and might serve as a novel therapeutic target of ischemic stroke.