SOX4-mediated repression of specific tRNAs inhibits proliferation of human glioblastoma cells.

Transfer RNAs (tRNAs) are products of RNA polymerase III (Pol III) and essential for mRNA translation and ultimately cell growth and proliferation. Whether and how individual tRNA genes are specifically regulated is not clear. Here, we report that SOX4, a well-known Pol II-dependent transcription factor that is critical for neurogenesis and reprogramming of somatic cells, also directly controls, unexpectedly, the expression of a subset of tRNA genes and therefore protein synthesis and proliferation of human glioblastoma cells. Genome-wide location analysis through chromatin immunoprecipitation-sequencing uncovers specific targeting of SOX4 to a subset of tRNA genes, including those for tRNAiMet Mechanistically, sequence-specific SOX4-binding impedes the recruitment of TATA box binding protein and Pol III to tRNA genes and thereby represses their expression. CRISPR/Cas9-mediated down-regulation of tRNAiMet greatly inhibits growth and proliferation of human glioblastoma cells. Conversely, ectopic tRNAiMet partially rescues SOX4-mediated repression of cell proliferation. Together, these results uncover a regulatory mode of individual tRNA genes to control cell behavior. Such regulation may coordinate codon usage and translation efficiency to meet the demands of diverse tissues and cell types, including cancer cells.

Guideline conformity to the Stupp regimen in patients with newly diagnosed glioblastoma multiforme in China.

Aims: To determine how consistently Chinese glioblastoma multiforme (GBM) patients were treated according to the Stupp regimen. Patients and methods: The proportion of treatments conforming to the Stupp regimen and reasons for nonconformity were evaluated in 202 newly diagnosed GBM patients. Results: Only 15.8% of GBM patients received treatments compliant with the Stupp regimen. The main deviations were temozolomide dosages >75 mg/m2 (58/120; 48.3%) and treatment durations <42 days (84/120; 70.0%) in the concomitant phase and temozolomide dosages <150 mg/m2 (89/101; 88.1%) in the maintenance phase. Median overall survival (27.09 vs 18.21 months) and progression-free survival (14.27 vs 12.10 months) were longer in patients who received Stupp regimen-compliant treatments. Conclusion: Increased conformity to the Stupp regimen is needed for GBM patients in China.

Lay abstract In 2005 the European Organization for Research and Treatment of Cancer 26981 study led to US FDA approval for the use of temozolomide in combination with radiotherapy to treat glioblastoma multiforme (GBM). The Stupp regimen consists of fractionated focal irradiation in daily fractions of 2 Gy given 5 days/week for 6 weeks (a total of 60 Gy), plus concomitant daily temozolomide (75 mg/m²/day, 7 days/week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150­200 mg/m²/day for 5 days during each 28-day cycle). In 2012 the Chinese guidelines for the diagnosis and treatment of glioma of the CNS recommended the Stupp regimen as first-line therapy for newly diagnosed GBM. In the present study, compliance of GBM treatments with the Stupp regimen in 28 Chinese centers from 2012­2016 was evaluated. Only 15.8% of GBM patients received treatments compliant with the Stupp regimen. The main deviations related to temozolomide dosages and treatment durations in the concomitant and maintenance phases. Median overall survival (27.09 vs 18.21 months) and progression-free survival (14.27 vs 12.10 months) were longer in patients who received Stupp regimen-compliant treatments.

Design, green synthesis, antioxidant activity screening, and evaluation of protective effect on cerebral ischemia reperfusion injury of novel monoenone monocarbonyl curcumin analogs.

Antioxidants with high efficacy and low toxicity have the potential to treat cerebral ischemia reperfusion injury (CIRI). Dienone monocarbonyl curcumin analogs (DMCA) capable of overcoming the instability and pharmacokinetic defects of curcumin possess notable antioxidant activity but are found to be significantly toxic. In this study, a novel skeleton of the monoenone monocarbonyl curcumin analogue sAc possessing reduced toxicity and improved stability was designed on the basis of the DMCA skeleton. Moreover, 32 sAc analogs were obtained by applying a green, simple, and economical synthetic method. Multiple sAc analogs with an antioxidant protective effect in PC12 cells were screened using an H2O2-induced oxidative stress damage model, and quantitative evaluation of structure-activity relationship (QSAR) model with regression coefficient of R2 = 0.918921 was built through random forest algorithm (RF). Among these compounds, the optimally active compound sAc15 elicited a potent protective effect on cell growth of PC12 cells by effectively eliminating ROS generation in response to oxidative stress injury by activating the Nrf2/HO-1 antioxidant signaling pathway. In addition, sAc15 exhibited good protection against CIRI in the mice middle cerebral artery occlusion (MCAO) model. In this paper, we provide a novel class of antioxidants and a potential compound for stroke treatment.

Oridonin interrupts cellular bioenergetics to suppress glioma cell growth by down-regulating PCK2.

We aim to evaluate the tumor metabolic suppressive activity of Oridonin (extract of Rabdosia rubescens) in glioma and elucidate its potential mechanism. Effects of Oridonin on U251/U87 cells were determined by CCK8, RTCA, colony formation, flow cytometry, wound healing, and Transwell assay. Xenograft tumor model to evaluate the effect of Oridonin on glioma cells in vivo. Cellular bioenergetics were measured by Seahorse. RNA-seq was performed to screen potential biological pathways in Oridonin treated cells. Bioinformatics analysis of PCK2 in glioma was performed based on TCGA/CGGA. Endogenous PCK2 was knocked-down by lentivirus packaged shRNA. We found Oridonin significantly inhibited cell growth in U251/U87 in vitro and in vivo. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were decreased in Oridonin-treated U251/U87 cells. Oridonin treatment led to PCK2 down-regulation. Additionally, PCK2 was up-regulated in higher grade glioma and correlated with poor outcomes. Furthermore, PCK2 depletion significantly inhibited cell growth and decreased OCR/ECAR in U251/U87 which coincided with the effects of Oridonin. Therefore, we evaluated the potent anti-tumor property of Oridonin in glioma. Importantly, we demonstrated that PCK2 might be a novel target of Oridonin on glioma by inducing energy crisis and increasing oxidative stress.

Oridonin prevents insulin resistance-mediated cognitive disorder through PTEN/Akt pathway and autophagy in minimal hepatic encephalopathy.

Minimal hepatic encephalopathy (MHE) was characterized for cognitive dysfunction. Insulin resistance (IR) has been identified to be correlated with the pathogenesis of MHE. Oridonin (Ori) is an active terpenoid, which has been reported to rescue synaptic loss and restore insulin sensitivity. In this study, we found that intraperitoneal injection of Ori rescued IR, reduced the autophagosome formation and synaptic loss and improved cognitive dysfunction in MHE rats. Moreover, in insulin-resistant PC12 cells and N2a cells, we found that Ori blocked IR-induced synaptic deficits via the down-regulation of PTEN, the phosphorylation of Akt and the inhibition of autophagy. Taken together, these results suggested that Ori displays therapeutic efficacy towards memory deficits via improvement of IR in MHE and represents a novel bioactive therapeutic agent for treating MHE.

Hydrogen sulphide ameliorates dopamine-induced astrocytic inflammation and neurodegeneration in minimal hepatic encephalopathy.

It has been demonstrated that the action of dopamine (DA) could enhance the production of tumour necrosis factor-α (TNF-α) by astrocytes and potentiate neuronal apoptosis in minimal hepatic encephalopathy (MHE). Recently, sodium hydrosulfide (NaHS) has been found to have neuroprotective properties. Our study addressed whether NaHS could rescue DA-challenged inflammation and apoptosis in neurons to ameliorate memory impairment in MHE rats and in the neuron and astrocyte coculture system. We found that NaHS suppressed DA-induced p65 acetylation, resulting in reduced TNF-α production in astrocytes both in vitro and in vivo. Furthermore, decreased apoptosis was observed in neurons exposed to conditioned medium from DA + NaHS-challenged astrocytes, which was similar to the results obtained in the neurons exposed to TNF-α + NaHS, suggesting a therapeutic effect of NaHS on the suppression of neuronal apoptosis via the reduction of TNF-α level. DA triggered the inactivation of p70 S6 ribosomal kinase (S6K1) and dephosphorylation of Bad, resulting in the disaggregation of Bclxl and Bak and the release of cytochrome c (Cyt. c), and this process could be reversed by NaHS administration. Our work demonstrated that NaHS attenuated DA-induced astrocytic TNF-α release and ameliorated inflammation-induced neuronal apoptosis in MHE. Further research into this approach may uncover future potential therapeutic strategies for MHE.

New Measures for the Coronavirus Disease 2019 Response: A Lesson From the Wenzhou Experience.

As the outbreak of coronavirus disease 2019 (COVID-19) has spread globally, determining how to prevent the spread is of paramount importance. We reported the effectiveness of different responses of 4 affected cities in preventing the COVID-19 spread. We expect the Wenzhou anti-COVID-19 measures may provide information for cities around the world that are experiencing this epidemic.

Elevated blood urea nitrogen is associated with recurrence of post-operative chronic subdural hematoma.

BACKGROUND: Chronic subdural hematoma (CSDH) is fundamentally treatable with about a 2-31% recurrence rate. Recently, there has been renewed interest in the association between Blood Urea Nitrogen (BUN) and intracranial lesion. Therefore, this paper attempts to show the relationship between BUN and CSDH recurrence. METHODS: A total of 653 CSDH cases with Burr-hole Irrigation (BHI) were enrolled from December 2014 to April 2019. The analyzed parameters included age, gender, comorbidities, laboratory investigations, medication use and hematoma location. The cases were divided into recurrence and non-recurrence groups while postoperative BUN concentration was further separated into quartiles (Q1 ≤ 4.0 mmol/L, 4.0 < Q2 ≤ 4.9 mmol/L, 4.9 < Q3 ≤ 6.4 mmol/L, Q4 > 6.4 mmol/L). Restricted cubic spline regressions and logistic regression models were performed to estimate the effect of BUN on CSDH recurrence. RESULTS: CSDH recurrence was observed in 96 (14.7%) cases. Significant distinctions were found between recurrence and non-recurrence groups in postoperative BUN quartiles of cases (P = 0.003). After adjusting for the potential confounders, the odds ratio of recurrence was 3.069 (95%CI =1.488-6.330, p = 0.002) for the highest quartile of BUN compared with the lowest quartile. In multiple-adjusted spline regression, a high BUN level visually showed a significantly high OR value of recurrence risk. CONCLUSIONS: Elevated BUN at post-operation is significantly associated with the recurrence of CSDH, and it is indicated that high levels of serum BUN after evacuation may serve as a risk factor for CSDH recurrence.

Polyacrylic acid-coated nanoparticles loaded with recombinant tissue plasminogen activator for the treatment of mice with ischemic stroke.

Nanoparticle-based thrombolysis is a potential new treatment for stroke. The aim of this study was to investigate the efficacy of targeted thrombolysis using recombinant tissue plasminogen activator (rtPA). The rtPA was covalently bound to magnetic nanoparticles (MNP) and maintained at the target site using an external magnet. Polyacrylic acid (PAA)-coated MNP were synthesized and rtPA was then bound to the resultant PAA-MNP via carbodiimide-mediated amide bonds. For the in vitro tests, blood clots were formed in plastic centrifuge tubes with anti-coagulated plasma, thrombin and calcium chloride. For the in vivo tests, mice with ferric chloride-induced distal middle cerebral artery occlusion were treated with phosphate-buffered saline (PBS), MNP, rtPA, or MNP-rtPA (n = 6 mice per group). The binding efficacy was 80.7 ± 1.5 µg rtPA bound to 1 mg PAA-MNP. In the in vitro tests, the mean lysis percentage dramatically increased from 1.28% in the MNP group without rotation to 77.40% in the rtPA + MNP group with rotating magnetic field. The lysis efficiency of MNP-rtPA was 27.3 ± 1.3%, and it increased to 42.8 ± 2.8% with magnetic field rotation. The mean sizes of the infarct areas of the PBS, MNP, rtPA, and MNP-rtPA mouse groups were 20.09 ± 6.07, 18.28 ± 2.69, 8.65 ± 3.63 and 4.40 ± 2.46 mm3, respectively. Thus, targeted MNP-rtPA accelerated thrombolysis and reduced the infarct area in a mouse model of cerebral embolism. This approach may serve as a feasible and effective treatment for embolic cerebral ischemia.

Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance.

Biologic aging results in a chronic inflammatory condition, termed inflammaging, which establishes a risk for such age-related diseases as neurocardiovascular diseases; therefore, it is of great importance to develop rejuvenation strategies that are able to attenuate inflammaging as a means of intervention for age-related diseases. A promising rejuvenation factor that is present in young blood has been found that can make aged neurons younger; however, the component in the young blood and its mechanism of action are poorly elucidated. We assessed rejuvenation in naturally aged mice with extracellular vesicles (EVs) or exosomes extracted from young murine serum on the basis of different spectrums of microRNAs in these vesicles from young and old sera. We found that EVs extracted from young donor mouse serum, rather than EVs extracted from old donor mouse serum or non-EV supernatant extracted from young donor mouse serum, were able to attenuate inflammaging in old mice. Inflammaging is attributed to multiple factors, one of which is thymic aging-released self-reactive T cell-induced pathology. We found that the attenuation of inflammaging after treatment with EVs from young serum partially contributed to the rejuvenation of thymic aging, which is characterized by partially reversed thymic involution, enhancement of negative selection signals, and reduced autoreactions in the periphery. Our results provide evidence for understanding of the potential rejuvenation factor in the young donor serum, which holds great promise for the development of novel therapeutics to reduce morbidity and mortality caused by age-related inflammatory diseases.-Wang, W., Wang, L., Ruan, L., Oh, J., Dong, X., Zhuge, Q., Su, D.-M. Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance.

Global expression profile of tumor stem-like cells isolated from MMQ rat prolactinoma cell.

BACKGROUND: Cancer stem cells (CSCs), which have been isolated from various malignancies, were closely correlated with the occurrence, progression, metastasis and recurrence of the malignant cancer. Little is known about the tumor stem-like cells (TSLCs) isolated from benign tumors. Here we want to explore the global expression profile of RNA of tumor stem-like cells isolated from MMQ rat prolactinoma cells. METHODS: In this study, total RNA was extracted from MMQ cells and MMQ tumor stem-like cells. RNA expression profiles were determined by Agilent Rat 8 × 60 K Microarray. Then we used the qRT-PCR to test the result of Microarray, and found VEGFA had a distinct pattern of expression in MMQ tumor stem-like cells. Then WB and ELISA were used to confirm the VEGFA protein level of tumor sphere cultured from both MMQ cell and human prolactinoma cell. Finally, CCK-8 was used to evaluate the reaction of MMQ tumor stem-like cells to small interfering RNAs intervention and bevacizumab treatment. RESULT: The results of Microarray showed that 566 known RNA were over-expressed and 532 known RNA were low-expressed in the MMQ tumor stem-like cells. These genes were mainly involved in 15 different signaling pathways. In pathway in cancer and cell cycle, Bcl2, VEGFA, PTEN, Jun, Fos, APC2 were up-regulated and Ccna2, Cdc25a, Mcm3, Mcm6, Ccnb2, Mcm5, Cdk1, Gadd45a, Myc were down-regulated in the MMQ tumor stem-like cells. The expression of VEGFA were high in tumor spheres cultured from both MMQ cell and human prolactinomas. Down-regulation of VEGFA by small interfering RNAs partially decreased cell viability of MMQ tumor stem-like cells in vitro. Bevacizumab partially suppressed the proliferation of MMQ tumor stem-like cells. CONCLUSIONS: Our findings characterize the pattern of RNA expression of tumor stem-like cells isolated from MMQ cells. VEGFA may act as a potential therapeutic target for tumor stem-like cells of prolactinomas.

Quantitative assessment on blood-brain barrier permeability of acute spontaneous intracerebral hemorrhage in basal ganglia: a CT perfusion study.

PURPOSE: Blood-brain barrier (BBB) damage aggravates perihematomal edema, and edema volume predicts prognosis independently. But the BBB permeability at the late stage of acute intracerebral hemorrhage (ICH) patients is uncertain. We aimed to assess the BBB permeability of spontaneous basal ganglia ICH using computed tomographic perfusion (CTP) and investigates its relationship with hematoma and perihematomal edema volume. METHODS: We performed CTP on 54 consecutive ICH patients within 24 to 72 h after symptom onset. Permeability-surface area product (PS) derived from CTP imaging was measured in hematoma, "high-PS spot," perihematoma, normal-appearing, hemispheric, and contralateral regions. Hematoma and edema volumes were calculated from non-contrast CT. RESULTS: "High-PS spot" and perihematoma regions had higher PS than the contralateral regions (p < 0.001). Hematoma PS was lower than that in the contralateral regions (p < 0.001). Perihematoma PS of the large-hematoma group was higher than that of the small-hematoma group (p = 0.011). Perihematomal edema volume correlated positively with hematoma volume (ß = 0.864, p < 0.001) and perihematoma PS (ß = 0.478, p < 0.001). Perihematoma PS correlated positively with hematoma volume (ß = 0.373, p = 0.005). CONCLUSIONS: Locally elevated perihematoma PS was found in most spontaneous basal ganglia ICH patients within 24 to 72 h after symptom onset. Perihematoma PS was higher in larger hematomas and was associated with larger edema volume. At this period, BBB leakage is likely to be an important factor in edema formation.

Improving on Laboratory Traumatic Brain Injury Models to Achieve Better Results.

Experimental modeling of traumatic brain injury (TBI) in animals has identified several potential means and interventions that might have beneficial applications for treating traumatic brain injury clinically. Several of these interventions have been applied and tried with humans that are at different phases of testing (completed, prematurely terminated and others in progress). The promising results achieved in the laboratory with animal models have not been replicated with human trails as expected. This review will highlight some insights and significance attained via laboratory animal modeling of TBI as well as factors that require incorporation into the experimental studies that could help in translating results from laboratory to the bedside. Major progress has been made due to laboratory studies; in explaining the mechanisms as well as pathophysiological features of brain damage after TBI. Attempts to intervene in the cascade of events occurring after TBI all rely heavily on the knowledge from basic laboratory investigations. In looking to discover treatment, this review will endeavor to sight and state some central discrepancies between laboratory models and clinical scenarios.

Computed Tomography Perfusion Deficits during the Baseline Period in Aneurysmal Subarachnoid Hemorrhage Are Predictive of Delayed Cerebral Ischemia.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is a frequent and fearful complication following aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study is to assess the diagnostic accuracy of computed tomography perfusion (CTP) during an admission baseline period for the prediction of DCI. METHODS: Fifty-four aSAH cases were screened by baseline CTP within 3 days after aSAH and were reexamined with CTP 7-17 days after aSAH. Relative cerebral blood volume, relative cerebral blood flow (CBF), and relative mean transit time were measured. DCI was confirmed by a combination of noncontrast CT, CTP reexamination, and clinical assessment of neurologic deficits. Quantitative baseline and reexamination CTP data for all patients were compared between DCI and without DCI groups using Student's t-tests. The quantitative baseline and reexamination CTP data of DCI patients were compared using paired Student's t-tests. The χ2 test was used to evaluate incidences of DCI between different baseline relative CBF levels. The optimal cutoff value for each parameter was established by receiver operating characteristic curve analysis. RESULTS: Of the patients included in this study, 33.3% (18 of 54) developed DCI. There was a significant difference in the incidence of DCI among different baseline relative CBF subsets (χ2 = 38.00, P < .05). A relative CBF of .84 had the highest specificity and sensitivity of predicting DCI. CONCLUSION: CTP parameters during the baseline period can be helpful for the early identification of aSAH patients who are at high risk for DCI.

Antiproliferative and apoptosis-inducing activity of schisandrin B against human glioma cells.

BACKGROUND: Malignant glioma is the most devastating and aggressive tumour in the brain and is characterised by high morbidity, high mortality and extremely poor prognosis. The main purpose of the present study was to investigate the effects of schisandrin B (Sch B) on glioma cells both in vitro and in vivo and to explore the possible anticancer mechanism underlying Sch B-induced apoptosis and cell cycle arrest. METHODS: The anti-proliferative ability of Sch B on glioma cells were assessed by MTT and clony formation assays. Flow cytometric analysis was used to detect cell cycle changes. Apoptosis was determined by Hoechst 33342 staining and annexin V/PI double-staining assays. The mitochondrial membrane potential was detected by Rhodamine 123 staining. The in vivo efficacy of Sch B was measured using a U87 xenograft model in nude mice. The expressions of the apoptosis-related and cell cycle-related proteins were analysed by western blot. Student's t-test was used to compare differences between treated groups and their controls. RESULTS: We found that Sch B inhibited growth in a dose- and time-dependent manner as assessed by MTT assay. In U87 and U251 cells, the number of clones was strongly suppressed by Sch B. Flow cytometric analysis revealed that Sch B induced cell cycle arrest in glioma cells at the G0/G1 phase. In addition, Sch B induced glioma cell apoptosis and reduced mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Mechanically, western blot analysis indicated that Sch B induced apoptosis by caspase-3, caspase-9, PARP, and Bcl-2 activation. Moreover, Sch B significantly inhibited tumour growth in vivo following the subcutaneous inoculation of U87 cells in athymic nude mice. COCLUSIONS: In summary, Sch B can reduce cell proliferation and induce apoptosis in glioma cells and has potential as a novel anti-tumour therapy to treat gliomas.

Whole-brain 320-detector row dynamic volume CT perfusion detected crossed cerebellar diaschisis after spontaneous intracerebral hemorrhage.

INTRODUCTION: The purpose of this study was to evaluate the value of 320-detector row CT used to detect crossed cerebellar diaschisis (CCD) in patients with unilateral supratentorial spontaneous intracerebral hemorrhage (SICH). METHODS: We investigated 62 of 156 patients with unilateral supratentorial SICH using 320-detector row CT scanning. Regional cerebral blood flow (rCBF), cerebral blood volume (rCBV), mean transit time (rMTT), and time to peak (rTTP) levels were measured in different regions of interest (ROIs) that were manually outlined on computed tomography perfusion (CTP) for the cerebrum, including normal-appearing brain tissue that surrounded the perilesional low-density area (NA) and the perihematomal low-density area (PA) in all patients and the cerebellum (ipsilateral and contralateral) in CCD-positive patients. RESULTS: Of 62 cases, a total of 14 met the criteria for CCD due to cerebellar perfusion asymmetry on CTP maps. In the quantitative analysis, significant differences were found in the perfusion parameters between the contralateral and ipsilateral cerebellum in CCD-positive cases. No significant differences were found between the CCD-positive group and the CCD-negative group according to the hematoma volume, NIHSS scores, and cerebral perfusion abnormality (each P > 0.05). The correlation analysis of the degree of NA, PA perfusion abnormality, and the degree of CCD severity showed negative and significant linear correlations (R, -0.66∼-0.56; P < 0.05). CONCLUSION: 320-detector row CT is a robust and practicable method for the comprehensive primary imaging work-up of CCD in unilateral supratentorial SICH patients.

The inactivation of JAK2/STAT3 signaling and desensitization of M1 mAChR in minimal hepatic encephalopathy (MHE) and the protection of naringin against MHE.

BACKGROUND: We previously reported that elevation of intracranial dopamine (DA) levels from cirrhotic livers is implicated in the pathogenesis of minimal hepatic encephalopathy (MHE). Intracellular events in neurons, which lead to memory loss in MHE by elevated DA, however, remain elusive. METHODS: In our present study, an MHE rat model, a DA - intracerebroventricularly (i.c.v.) injected rat model and DA-treated primary cortical neurons (PCNs) were used to study this issue using behavioral tests, double-labeled fluorescent staining, immunoblotting, and semi-quantitative RT-PCR. RESULTS: Cognitive impairment was observed in MHE rats and DA (10 µg, i.c.v.)-treated rats. The levels of DA in the cerebral cortex of both MHE and DA (10 µg)-treated rats were increased. DA conversely modulated the p-JAK2/p-STAT3 levels in PCNs. In accordance, DA downregulated an anacetylcholine-producing enzyme, choline acetyltransferase (ChAT), and desensitized the M1-type muscarinic acetylcholine receptor (M1 mAChR). Furthermore, naringin completely restored cognitive function in MHE/DA (10 µg)-treated models by activating the JAK2/STAT3 axis, paralleling the upregulation of ChAT and sensitization of M1 mAChR. CONCLUSIONS: We propose a hypothesis accounting for memory impairment related to MHE: DA-dependent inactivation of the JAK2/STAT3 axis causes memory loss through cholinergic dysfunction. Our findings provide not only a novel pathological hallmark in MHE but also a novel target in MHE therapy.

Inhibition of mammalian target of rapamycin improves neurobehavioral deficit and modulates immune response after intracerebral hemorrhage in rat.

BACKGROUND: Mammalian target of rapamycin (mTOR), a serine/threonine kinase, regulates many processes, including cell growth and the immune response. mTOR is also dysregulated in several neurological diseases, such as traumatic brain injury (TBI), stroke, and neurodegenerative disease. However, the role of mTOR in intracerebral hemorrhage (ICH) remains unexplored. The aims of our study were to determine whether inhibiting mTOR signaling could affect the outcome after ICH and to investigate the possible underlying mechanism. METHODS: A rat ICH model was induced by intracerebral injection of collagenase IV into the striatum, and mTOR activation was inhibited by administration of rapamycin. mTOR signaling activation was determined by western blotting. Neurobehavioral deficit after ICH was determined by a set of modified Neurological Severity Scores (mNSS). The levels of CD4+CD25+Foxp3+ regulatory T cells (Tregs) and cytokines were examined using flow cytometry and ELISA, respectively. RESULTS: Our results demonstrated thatmTOR signaling was activated 30 minutes and returned to its basal level 1 day after ICH. Increased p-mTOR, which mean that mTOR signaling was activated, was predominantly located around the hematoma. Rapamycin treatment significantly improved the neurobehavioral deficit after ICH, increased the number of Tregs, increased levels of interleukin-10 and transforming growth factor-ß and reduced interferon-γ both in peripheral blood and brain. CONCLUSIONS: Our study suggests that mTOR improves ICH outcome and modulates immune response after ICH.

Glial scar formation occurs in the human brain after ischemic stroke.

Reactive gliosis and glial scar formation have been evidenced in the animal model of ischemic stroke, but not in human ischemic brain. Here, we have found that GFAP, ED1 and chondroitin sulphate proteoglycans (CSPG) expression were significantly increased in the cortical peri-infarct regions after ischemic stroke, compared with adjacent normal tissues and control subjects. Double immunolabeling showed that GFAP-positive reactive astrocytes in the peri-infarct region expressed CSPG, but showed no overlap with ED1-positive activated microglia. Our findings suggest that reactive gliosis and glial scar formation as seen in animal models of stroke are reflective of what occurs in the human brain after an ischemic injury.