Zhiguo Lin

Administration of simvastatin after kainic acid-induced status epilepticus restrains chronic temporal lobe epilepsy.

In this study, we examined the effect of chronic administration of simvastatin immediately after status epilepticus (SE) on rat brain with temporal lobe epilepsy (TLE). First, we evaluated cytokines expression at 3 days post KA-lesion in hippocampus and found that simvastatin-treatment suppressed lesion-induced expression of interleukin (IL)-1β and tumor necrosis factor-α (TNF-α). Further, we quantified reactive astrocytosis using glial fibrillary acidic protein (GFAP) staining and neuron loss using Nissl staining in hippocampus at 4–6 months after KA-lesion. We found that simvastatin suppressed reactive astrocytosis demonstrated by a significant decrease in GFAP-positive cells, and attenuated loss of pyramidal neurons in CA3 and interneurons in dentate hilar (DH). We next assessed aberrant mossy fiber sprouting (MFS) that is known to contribute to recurrence of spontaneous seizure in epileptic brain. In contrast to the robust MFS observed in saline-treated animals, the extent of MFS was restrained by simvastatin in epileptic rats. Attenuated MFS was related to decreased neuronal loss in CA3 and DH, which is possibly a mechanism underlying decreased hippocampal susceptibility in animal treated with simvastatin. Electronic encephalography (EEG) was recorded during 4 to 6 months after KA-lesion. The frequency of abnormal spikes in rats with simvastatin-treatment decreased significantly compared to the saline group. In summary, simvastatin treatment suppressed cytokines expression and reactive astrocytosis and decreased the frequency of discharges of epileptic brain, which might be due to the inhibition of MFS in DH. Our study suggests that simvastatin administration might be a possible intervention and promising strategy for preventing SE exacerbating to chronic epilepsy.

miR-656 Inhibits Glioma Tumorigenesis Through Repression of BMPR1A

Bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-β family, plays critical roles in cell differentiation, modeling and regeneration processes in several tissues. BMP-2 is also closely associated with various malignant tumors. microRNAs negatively and posttranscriptionally regulate gene expression and function as oncogenes or tumor suppressors. Herein, we report that miR-656 expression was significantly downregulated in glioma cell lines and tissues. We identified and confirmed that BMP receptor, type 1A (BMPR1A) is a direct target of miR-656. The expression of BMPR1A was negatively correlated with that of miR-656 in human glioma tissues. We further demonstrated that miR-656 suppressed glioma cell proliferation, neurosphere formation, migration and invasion with or without exogenous BMP-2. Engineered knockdown of BMPR1A diminished the antiproliferation effect of miR-656 in vitro. Moreover, the canonical BMP/Smad and non-canonical BMP/mitogen-activated protein kinase (MAPK) pathways were inhibited by miR-656 overexpression. Several cancer-related signaling molecules, including cyclin B, cyclin D1, matrix metalloproteinase-9, p21 and p27, were also involved in miR-656 function in glioma cells. The tumor-suppressing function of miR-656 was validated using an in vivo intracranial xenograft mouse model. Notably, ectopic expression of miR-656 markedly reduced tumor size and prolonged the survival of mice treated with or without BMP-2. These results elucidate the function of miR-656 in glioma progression and suggest a promising application for glioma treatment.

Long-term seizure outcome for international consensus classification of hippocampal sclerosis: A survival analysis

PURPOSE Surgery is regarded as a common treatment option for patients with mesial temporal lobe epilepsy (MTLE) as a result of hippocampal sclerosis (HS). However, approximately one-third of patients with intractable epilepsy did not become seizure-free after tailored resection strategies. It would be compelling to identify predictive factors of postoperative seizure outcomes. Our aim was to assess the correlation between HS classification and long-term postoperative seizure outcome in patients with MTLE due to HS. METHODS To investigate HS classification, semi-quantitative analysis and immunohistochemical staining of neuronal nuclei (NeuN) were performed on 100 postoperative hippocampal specimens. All patients had a 1-7 year postoperative follow-up. The postoperative seizure outcome was evaluated using International League Against Epilepsy (ILAE) outcome classification. RESULTS Three types of HS were recognized. The highest incidence of initial precipitating injury (IPI) was noted in the HS ILAE type 1 group (53.1%). The most favorable long-term seizure outcome was also noted in the HS ILAE type 1 group. The shortest epilepsy duration was recorded in the HS ILAE type 2 group (mean epilepsy duration=6.64 ± 5.83 years). The completely seizure free rate of patients in all groups declined with an increase in time. CONCLUSIONS Our study for the first time demonstrated a significant correlation between HS ILAE types and long-term postoperative seizure outcome in patients with MTLE due to HS. Therefore, HS ILAE types have predictive value in long-term seizure outcome following epilepsy surgery.

Corpus Callosum Atrophy and Cognitive Decline in Early Alzheimer's Disease: Longitudinal MRI Study

Background: We investigated the rate of corpus callosum (CC) atrophy and its association with cognitive decline in early Alzheimers disease (AD). Methods: We used publicly available longitudinal MRI data corresponding to 2 or more visits from 137 subjects characterized using the Clinical Dementia Rating (CDR) score. We classified these subjects into 3 groups according to the progression of their cognitive status: a healthy control group (CDR 0→0, n = 72), a decliner group (CDR 0→0.5, n = 14) and an AD group (CDR 0.5→0.5/1, n = 51). We measured the CC area on the midsagittal plane and calculated the atrophy rate between 2 or more visits. The correlation between the CC atrophy rate and annualized Mini Mental State Examination (MMSE) change was also analyzed. Results: The results indicated that the baseline CC area was larger in the healthy control group compared to the AD group, whereas the CC atrophy rate was higher in the AD group relative to the control and decliner groups. The CC atrophy rate was also correlated with the annualized MMSE change in AD patients (p < 0.05). Conclusion: Callosal atrophy is present even in early AD and subsequently accelerates, such that the rate of CC atrophy is associated with cognitive decline in AD patients.

Protection against cognitive impairment and modification of epileptogenesis with curcumin in a post-status epilepticus model of temporal lobe epilepsy

Epileptogenesis is a dynamic process initiated by insults to the brain that is characterized by progressive functional and structural alterations in certain cerebral regions, leading to the appearance of spontaneous recurrent seizures. Within the duration of the trauma to the brain and the appearance of spontaneous recurrent seizures, there is typically a latent period, which may offer a therapeutic window for preventing the emergence of epilepsy. Previous animal studies have shown that curcumin can attenuate acute seizure severity and brain oxidative stress, but the effect of curcumin on epileptogenesis has not been studied. We examined the effect of continued administration of curcumin during the latent period on epileptogenesis and the deleterious consequences of status epilepticus in adult rats in a post-status epilepticus model of temporal lobe epilepsy induced by kainic acid. We demonstrate that, while administration of curcumin treatment during the latent period does not prevent occurrence of spontaneous recurrent seizures after status epilepticus, it can attenuate the severity of spontaneous recurrent seizures and protect against cognitive impairment. Thus, treatment with curcumin during the latent period following status epilepticus is beneficial in modifying epileptogenesis.

Prognostic value of CA4/DG volumetry with 3 T magnetic resonance imaging on postoperative outcome of epilepsy patients with dentate gyrus pathology

PURPOSE Hippocampal sclerosis (HS), the most common feature of mesial temporal lobe epilepsy (MTLE), is widely accepted as surgical indication for refractory epilepsy. Pathological hallmarks in hippocampal dentate gyrus (DG), including granule cell loss (GCL) and granule cell dispersion (GCD), are known to be closely related to the status epilepticus and spontaneous seizure. Our aim was to assess the association between volumetric changes in the hippocampal CA4/DG determined with 3-Tesla (3T) magnetic resonance imaging (MRI) and the postoperative seizure outcomes in MTLE patients with or without dentate gyrus pathology (DGP). METHODS High-resolution T2- and T1-weighted three-dimensional (3D) MRI scans were performed on 39 MTLE patients before surgery with a 3T Philips scanner. ITK-SNAP software was used for segmentation and volumetry of the CA4/DG segment, and NASP software was used for 3D reconstructions of the CA4/DG region. Immunostaining for Neuronal Nuclei (NeuN) was performed on resected hippocampal specimens after surgery to verify the accuracy of CA4/DG segmentation and histopathological changes in DG. RESULTS The CA4/DG subfield could be precisely segmented with high-resolution 3T MRI and confirmed by comparison of NeuN-immunoreactive slices with MRI results. MTLE patients with DGP showed smaller CA4/DG volume and favorable postoperative seizure outcomes. CONCLUSION The volumetry of CA4/DG was associated with the pathological changes in DG in MTLE patients. The volumetry of CA4/DG with preoperative 3T MRI could predict the postoperative seizure outcomes in those patients.

The effects of simvastatin on hippocampal caspase-3 and Bcl-2 expression following kainate-induced seizures in rats

Status epilepticus (SE) causes neuronal loss and apoptosis by inducing several apoptosis-regulatory genes. Two such genes, cysteinyl aspartate-specific protease-3 (caspase-3), an apoptosis activator, and B-cell leukemia-2 (Bcl-2), an apoptosis suppressor, are tightly regulated for their expression and activation. Statins, inhibitors of HMG-CoA reductase, have been recently recognized as neuroprotective drugs. However, their underlying mechanisms are still unclear. In this study, we examined the neuroprotective effects of simvastatin in a rat model of SE induced by kainic acid (KA). Feeding of simvastatin for 3 days after kainate injection rescued SE-induced neuronal apoptosis, as determined by histological examination of brain sections at the level of the dorsal hippocampus. Semi-quantitative RT-PCR showed that SE treatment markedly increased caspase-3 mRNA expression and reduced Bcl-2 mRNA expression in the hippocampus. Similarly, western blot analysis and immunohistochemical analysis of the rat hippocampus demonstrated that under SE treatment, caspase-3 protein levels significantly increased and peaked at 72 h, whereas Bcl-2 protein levels decreased from 6-24 h following SE. Interestingly, simvastatin could reverse the aforementioned SE-induced changes, suggesting that the neuroprotective effects of simvastatin against neuronal apoptosis may be achieved by inhibiting caspase-3 expression and increasing Bcl-2 expression.

Tumor Associated with CD70 Expression is Involved in Promoting Tumor Migration and Macrophage Infiltration in GBM

Tumor migration/metastasis and immunosuppression are major obstacles in effective cancer therapy. Incidentally, these 2 hurdles usually coexist inside tumors, therefore making therapy significantly more complicated, as both oncogenic mechanisms must be addressed for successful therapeutic intervention. Our recent report highlights that the tumor expression of a TNF family member, CD70, is correlated with poor survival for primary gliomas. In this study, we investigated how CD70 expression by GBM affects the characteristics of tumor cells and the tumor microenvironment. We found that the ablation of CD70 in primary GBM decreased CD44 and SOX2 gene expression, and inhibited tumor migration, growth and the ability to attract monocyte‐derived M2 macrophages in vitro. In the tumor microenvironment, CD70 was associated with immune cell infiltrates, such as T cells; myeloid‐derived suppressor cells; and monocytes/macrophages based on the RNA‐sequencing profile. The CD163+ macrophages were far more abundant than T cells were. This overwhelming level of macrophages was identified only in GBM and not in low‐grade gliomas and normal brain specimens, implying their tumor association. CD70 was detected only on tumor cells, not on macrophages, and was highly correlated with CD163 gene expression in primary GBM. Additionally, the co‐expression of the CD70 and CD163 genes was found to correlate with decreased survival for patients with primary GBM. Together, these data suggest that CD70 expression is involved in promoting tumor aggressiveness and immunosuppression via tumor‐associated macrophage recruitment/activation. Our current efforts to target this molecule using chimeric antigen receptor T cells hold great potential for treating patients with GBM.

Centrosomal Protein of 55 Regulates Glucose Metabolism, Proliferation and Apoptosis of Glioma Cells via the Akt/mTOR Signaling Pathway.

Introduction: Glioma is one of the most common and most aggressive brain tumors in humans. The molecular and cellular mechanisms responsible for the onset and the progression of glioma are elusive and controversial. Centrosomal protein of 55 (CEP55) was initially described as a highly coiled-coil protein that plays critical roles in cell division, but was recently identified as being overexpressed in many human cancers. The function of CEP55 has not previously been characterized in glioma. We aim to discover the effect and mechanism of CEP55 in glioma development. Method: qRT-PCR and immunohistochemistry were used to analyze CEP55 expression. Glucose uptake, western blot, MTS, CCK-8, Caspase-3 activity and TUNEL staining assays were performed to investigate the role and mechanism of CEP55 on glioma cell process. Results: We found that the levels of CEP55 expression were upregulated in glioma. In addition, CEP55 appeared to regulate glucose metabolism of glioma cells. Furthermore, knockdown of CEP55 inhibited cell proliferation and induced cell apoptosis in glioma. Finally, we provided preliminary evidence that knockdown of CEP55 inhibited glioma development via suppressing the activity of Akt/mTOR signaling. Conclusions: Our results demonstrated that CEP55 regulates glucose metabolism, proliferation and apoptosis of glioma cells via the Akt/mTOR signaling pathway, and its promotive effect on glioma tumorigenesis can be a potential target for glioma therapy in the future.

miR-422a Inhibits Glioma Proliferation and Invasion by Targeting IGF1 and IGF1R

Glioma is a common type of malignant brain tumor characterized by aggressive metastasis capability. Recent evidence has suggested that noncoding RNAs, including microRNAs, have important functions in the pathophysiology of glioma development. In this study, we investigated the biological function of miR-422a in human glioma. We found that miR-422a was downregulated in glioma tissues. We also demonstrated that expression of miR-422a in glioma cells markedly suppressed cell proliferation, migration, and invasion. In addition, we identified insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) as inhibitory targets of miR-422a in glioma cells. We established that the expression levels of miR-422a were negatively correlated with the expression levels of IGF1/IGF1R and the clinical parameters in glioma patients. An IGFR inhibitor, AG1024, completely blocked the activity of miR-442a on glioma cell proliferation and invasion, which further confirmed that miR-422a functions through IGF1 and IGF1R.