LncRNA CEBPA-AS1 alleviates cerebral ischemia-reperfusion injury by sponging miR-340-5p regulating APPL1/LKB1/AMPK pathway.

Long non-coding RNAs (lncRNAs) regulate neurological damage in cerebral ischemia-reperfusion injury (CIRI). This study aimed to investigate the biological roles of lncRNA CEBPA-AS1 in CIRI. Middle cerebral artery occlusion and ischemia-reperfusion injury (MCAO/IR) rat model and oxygen-glucose deprivation and reoxygenation (OGD/R) cell lines were generated; the expression of CEBPA-AS1 was evaluated by qRT-PCR. The effects of CEBPA-AS1 on cell apoptosis and nerve damage were examined. The downstream microRNA (miRNA) and mRNA of CEBPA-AS1 were predicted and verified. We found that overexpression of CEBPA-AS1 could attenuate MCAO/IR-induced nerve damage and neuronal apoptosis in the rat model. Knockdown of CEBPA-AS1 aggravated cell apoptosis and enhanced the production of LDH and MDA in the OGD/R cells. Upon examining the molecular mechanisms, we found that CEBPA-AS1 stimulated APPL1 expression by combining with miR-340-5p, thereby regulating the APPL1/LKB1/AMPK pathway. In the rescue experiments, CEBPA-AS1 overexpression was found to attenuate OGD/R-induced cell apoptosis and MCAO/IR induced nerve damage, while miR-340-5p reversed these effects of CEBPA-AS1. In conclusion, CEBPA-AS1 could decrease CIRI by sponging miR-340-5, regulating the APPL1/LKB1/AMPK pathway.

Trigeminal neuralgia caused by a persistent primitive trigeminal artery variant passing through Meckel's cavity: a case report.

BACKGROUND: Persistent primitive trigeminal artery variant (PPTAv) is a rare remnant of the primitive intracranial embryonic anastomotic arteries, and its persistence has an unknown etiology. Trigeminal neuralgia attributed to a PPTAv passing through Meckel's cavity is extremely uncommon. CASE PRESENTATION: A 73-year-old woman presented with right-sided facial pain for 10 years that had failed to respond to medication. Magnetic resonance angiography suggested the presence of a PPTAv compressing the trigeminal nerve, as the abnormal artery originated from the right internal carotid artery. During microvascular decompression (MVD), the offending vessel was inferred to be a PPTAv, as it continued to become the anterior inferior cerebellar artery after passing through Meckel's cavity. Postoperative computed tomography angiography showed the PPTAv continuing posteriorly as the anterior inferior cerebellar artery and supplying the cerebellar hemisphere, which confirmed the intraoperative judgment. The pain resolved after MVD and has not recurred in 12 months of follow-up. CONCLUSION: MVD is the best surgical choice for trigeminal neuralgia combined with a PPTAv. For patients with neurovascular conflicts, particularly those with suspected vascular variations, preoperative imaging examinations play a critical role in meticulously evaluating the anatomical locations of the nerves and blood vessels. Semilunar puncture (for radiofrequency ablation or percutaneous balloon compression) is contraindicated in patients with a PPTAv.

Cavernous hemangioma of the cisternal segment of the auditory nerve: case report.

BACKGROUND: Extraaxial cerebellopontine angle cavernous hemangiomas are rare and their diagnosis and treatment are challenging. CASE PRESENTATION: A 43-year-old female was admitted to the hospital who had repeated hearing loss in her left ear accompanied by tinnitus. Magnetic resonance imaging revealed a hemangioma-like lesion in the left cerebellopontine angle extra-axial cisternal segment. During the surgery, it was found that the lesion was located in the cisternal segment of the root of the auditory nerve. Postoperative pathological examination confirmed that the lesion was a cavernous hemangioma. CONCLUSION: We report a case of cavernous hemangioma in the brain spatula cisternal segment of the left auditory nerve. For cranial nerve CMs early diagnosis and surgical removal may maximize the chance of a positive outcome.

Effect of long-term adjuvant temozolomide chemotherapy on primary glioblastoma patient survival.

OBJECTIVE: Glioblastoma multiforme (GBM) is the most common primary malignant central nervous system (CNS) tumor. The Stupp regimen is the standard treatment, although the optimal number of temozolomide (TMZ) treatment cycles remains controversial. We compared the effects of standard 6 cycles versus > 6 cycles of TMZ chemotherapy post-surgery with concurrent chemoradiotherapy on primary GBM patient survival. PATIENTS AND METHODS: We performed a single center retrospective study of GBM patients that underwent total resection, concurrent chemoradiotherapy, and at least 6 cycles of adjuvant TMZ chemotherapy from June 2011 to August 2018. Patients were divided into 2 groups based on adjuvant TMZ treatment plan: Group A(n = 27): standard 6-cycle adjuvant TMZ therapy and Group B(n = 26): > 6 cycles of adjuvant TMZ therapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Continuous variables were analyzed by ANOVA, and the Kaplan-Meier method was used to evaluate PFS and OS. Univariate and multivariate COX analyses determined correlation between survival rates and covariates. We used The Mini Mental State Examination (MMSE) and Karnofsky Performance Status (KPS) to assess patients' neurocognitive function and quality of life. RESULTS: After follow-up, median PFS was 15 months in in Group A (95%CI 9.5-20.5) and 20.1 months in Group B (95%CI 15.9-24.4). Group A median OS was 19.4 months (95%CI 15.5-23.2), compared to 25.6 months in Group B (95%CI 20.4-30.8). The 2-year survival rate of Groups A and B was 36% was 66%, respectively (P = 0.02). and 5-year survival was 7% in both. Multivariate COX regression analysis showed association between patient PFS and long-period adjuvant chemotherapy, but not OS. There were no significant difference in disability or quality of life during treatment with Stupp protocol, but differences in MMSE and KPS were in favour of the Groups B after year 1 of the treatment (P < 0.05). CONCLUSIONS: Long-term adjuvant TMZ chemotherapy was beneficial for PFS and 2-year survival rate in GBM patients, and improved their quality of life contemporarily. But OS was not significantly improved.

Radiation-induced cavernous malformation after stereotactic radiosurgery for cavernous sinus meningioma: a case report.

BACKGROUND: Radiation-induced cavernous malformation (RICM) is a rare sequela of stereotactic radiosurgery (SRS) treatment of intracranial tumors. To date, no study reported on RICM after SRS for meningiomas originating from the skull base. The relationship between locus of initial meningioma and RICM has not been studied. CASE PRESENTATION: A 57-year-old woman presented with persistent headaches and blepharoptosis at initial episode. MRI disclosed a right parasellar lesion, diagnosed as a cavernous sinus meningioma (CSM). After receiving a single-fractionated SRS, headache relieved, but blepharoptosis did not significantly improve. Three years and three months later, she returned with headaches and dizziness. MRI showed an enlarged CSM. Moreover, a new mass-like lesion, suspected hemangioma, appeared in the nearby right temporal lobe. After surgical removal of the new lesion and the CSM, the patient's neurological symptoms significantly improved. Pathology confirmed CSM and temporal RICM. CONCLUSIONS: We report the first rare case of RICM occurring after SRS for CSM. The RICM may be in the same region as the initial tumor. Surgical intervention was preferred for symptomatic RICM and initial meningioma. We recommend long-term regular followup MRIs for patients with meningioma after SRS treatment.

Transcriptome analysis of Pacific white shrimp (Litopenaeus vannamei) challenged by Vibrio parahaemolyticus reveals unique immune-related genes.

Pacific white shrimp (Litopenaeus vannamei) is an important cultural species worldwide. However, Vibrio spp. infections have caused a great economic loss in Pacific white shrimp culture industry. The immune responses of Pacific white shrimp to the Vibrio spp. is not fully characterized. In this study, the transcriptomic profiles of L. vannamei hemocytes were explored by injecting with or without Vibrio parahaemolyticus. Totally, 42,632 high-quality unigenes were obtained from RNAseq data. Comparative genome analysis showed 2258 differentially expressed genes (DEGs) following the Vibrio challenge, including 1017 up-regulated and 1241 down-regulated genes. Eight DEGs were randomly selected for further validation by quantitative real-time RT-PCR (qRT-PCR) and the results showed that are consistent with the RNA-seq data. Due to the lack of predictable adaptive immunity, shrimps rely on an innate immune system to defend themselves against invading microbes by recognizing and clearing them through humoral and cellular immune responses. Here we focused our studies on the humoral immunity, five genes (SR, MNK, CTL3, GILT, and ALFP) were selected from the transcriptomic data, which were significantly up-regulated by V. parahaemolyticus infection. These genes were widely expressed in six different tissues and were up-regulated by both Gram negative bacteria (V. parahaemolyticus) and Gram positive bacteria (Staphylococcus aureus). To further extend our studies, we knock-down those five genes by dsRNA in L. vannamei and analyzed the functions of specific genes against V. parahaemolyticus and S. aureus by bacterial clearance analysis. We found that the ability of L. vannamei was significantly reduced in bacterial clearance when treated with those specific dsRNA. These results indicate that those five genes play essential roles in antibacterial immunity and have its specific functions against different types of pathogens. The obtained data will shed a new light on the immunity of L. vannamei and pave a new way for fighting against the bacterial infection in Pacific white shrimp.

5-LOX Inhibitor Zileuton Reduces Inflammatory Reaction and Ischemic Brain Damage Through the Activation of PI3K/Akt Signaling Pathway.

Previous studies from our laboratories showed that an anti-inflammatory drug, 5-lipoxygenase inhibitor zileuton, attenuates ischemic brain damage via inhibiting inflammatory reaction. However, it was elusive whether zileuton attenuates inflammatory reaction and ischemic brain damage through the modulation of PI3K/Akt signaling pathway. In the present study, we, for the first time, investigated whether PI3K/Akt pathway was involved in zileuton's anti-inflammatory and neuroprotective properties against brain damage following experimental ischemic stroke. Adult male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO), then received treatment with zileuton or vehicle after the onset of ischemia. LY294002 was injected intracerebroventricularly to inhibit the activation of PI3K/Akt signaling pathway selectively. Neurological deficit scores, cerebral infarct volume, morphological characteristic and cerebral water content were assessed 24 h after cerebral ischemia. The enzymatic activity of myeloperoxidase (MPO) was measured 24 h after cerebral ischemia. Expression of p-Akt, t-Akt and COX-2 in ischemic brain were determined by western blot. NF-κB p65 immuno-positive cells in ischemic brain were detected 24 h after cerebral ischemia. The content of TNF-α in blood was examined by ELISA. 5-LOX inhibitor zileuton significantly reduces neurological deficit scores, cerebral infarct volume, cerebral water content, ischemic neuronal injury and the enzymatic activity of MPO, all of which were abolished by LY294002 administration. Zileuton significantly up-regulates the expression of p-Akt, which was inhibited by LY294002 administration. Zileuton significantly down-regulates the over-expression of NF-κB p65 and COX-2, and attenuates the release of TNF-α, all of which were disminished by LY294002 administration. These results suggest that zileuton attenuates ischemic brain damage by inhibiting inflammatory reaction through the activation of PI3K/Akt signaling pathway.

Cordycepin inhibits glioma growth by downregulating PD-L1 expression via the NOD-like receptor/NFKB1/STAT1 axis.

Glioma is a serious primary malignant tumor of the human central nervous system with a poor prognosis and a high recurrence rate; however, inhibition of immune checkpoints can greatly improve the survival rate of patients. The purpose of this study was to investigate the regulation of PD-L1 by cordycepin and the mechanism of its anti-tumor action. The results of previous studies indicate that cordycepin has good anti-proliferative and anti-migratory activities and can induce apoptosis in U251 and T98G cells in vitro. Here, transcriptome sequencing showed that cordycepin may exert anti-tumor effects through the NOD-like receptor signaling pathway. Further intervention with BMS-1, a small molecule inhibitor of PD-L1, was used to explore whether inhibition of PD-L1 affected the regulation of the NOD-like receptor signaling pathway by cordycepin. Mechanistically, on the one hand, cordycepin regulated the expression of NFKB1 and STAT1 through the NOD-like receptor signaling pathway, thereby inhibiting the expression of PD-L1. In addition, inhibition of PD-L1 enhanced the regulation by cordycepin of the NOD-like receptor signaling pathway. On the other hand, cordycepin directly upregulated expression of STAT1 and downregulated that of PD-L1. In vivo studies further showed that cordycepin could downregulate expression of PD-L1 and NFKB1 and upregulate that of STAT1 in glioma xenograft tumor tissues, consistent with the results of in vitro studies. The results suggest that cordycepin may down-regulate the expression of PD-L1 through NOD-like receptor signaling pathway and NFKB signaling pathway, thereby inhibiting the immune escape of glioma, and can be developed as a PD-L1 inhibitor. Our results therefore provide a theoretical foundation for the use of cordycepin in treatment of glioma and enrich our understanding of its pharmacological mechanism.

Schizophyllum commune fruiting body polysaccharides inhibit glioma by mediating ARHI regulation of PI3K/AKT signalling pathway.

Glioma poses a serious threat to human health and has a high mortality rate. Therefore, developing natural anti-tumour drugs for cancer treatment is an urgent priority. Schizophyllum commune is an edible and medicinal fungus, with polysaccharides as its main active components, which may have anti-tumour properties. Herein, we characterised S. commune fruiting body polysaccharides (SCFP) structure and evaluated its anti-glioma activity in vitro and in vivo. UV and FTIR spectra, high-performance gel chromatography, and monosaccharide composition analyses demonstrated that SCFP was a heteropolysaccharide with a molecular weight of 290.92 kDa. Among the monosaccharide compositions, mannose, galactose, and glucose were the most abundant. SCFP significantly inhibited the survival of the glioma cell lines U251 and U-87MG. U251 xenograft tumours treated with SCFP via gavage showed a 47.39 % inhibition, with no significant toxic side effects observed. SCFP upregulated aplasia Ras homologue member I (ARHI) expression, thereby regulating PI3K/AKT signalling, inhibiting tumour migration, and inducing apoptosis, to inhibit tumour growth. Furthermore, SCFP treatment increased the relative abundance of beneficial bacteria, including Akkermansia muciniphila, Ligilactobacillus murinus, and Parabacteroides goldsteinii, in tumour-bearing mice and restored the gut microbiota structure to that of the normal group (NG group) mice without tumours. Thus, SCFP has the potential for application as a natural anticancer drug.

Integrated bioinformatics and validation to construct lncRNA-miRNA-mRNA ceRNA network in status epilepticus.

Background: Status epilepticus (SE) is a neurologic emergency with characteristic of prolonged seizure activity. However, the investigation of lncRNA based competing endogenous RNAs (ceRNAs) network in SE still requires further elucidation. This study aims to construct the ceRNA network and uncover the related mechanism in SE. Methods: The C57BL/6 mice pilocarpine-induced (SE) model was established (i.p. injection, 300 mg/kg) (n = 3). RNA-Sequencing was carried out and identified the differential expressed genes (DEGs). GO annotations, KEGG, and GSEA analysis were performed to study the underlying mechanism and pathways of the DEGs. Further, the protein-protein interaction (PPI) network and ceRNA network were visualized by Cytoscape software. The expression level of differential expressed genes involved in the ceRNA network was detected by qRT-PCR. Results: A total of 345 DE-mRNAs, 84 DE-lncRNAs, and 5 DE-miRNAs were screened out. Subsequently, the functional analysis suggested that angiogenesis, inflammation, and neuron related biological processes were enriched in SE. The constructed ceRNA network-1 contained 7 up-regulated DE-mRNAs (Arid5a, Adm, Insig1, Midn, Btaf1, Per1, Slc25a25), 1 down-regulated DE-miRNA (mmu-miR-6413), and 1 up-regulated DE-lncRNA (Zmiz1os1). The ceRNA network-2 contained 2 down-regulated DE-mRNAs (Rab27a and Lrp2), 1 up-regulated DE-miRNAs (mmu-miR-139-5p), and 1 down-regulated DE-lncRNA (Gm15883). Conclusion: For the first time this study present the expression profile and potential function of lncRNAs in C57BL/6 mice with SE. These results provided novel insights into the discovery of genetic biomarkers for SE.

Clinical features, surgical treatment, and long-term outcomes of moyamoya disease in a single institution of Fujian, Southeast China: A retrospective study.

At present, detailed demographic and clinical data of moyamoya disease (MMD) in the population of Southeast China are lacking. Therefore, this study aimed to evaluate the epidemiological and clinical features of MMD in Southeast China. Our cohort included 170 patients diagnosed with MMD over the preceding 5 years. Clinical characteristics were obtained through a retrospective chart review, while follow-up information and outcomes were obtained through clinical visits and imaging. The median age at symptom onset was 49 years (range 4-73), with a peak in the age distribution observed at 41 to 60 years. The female-to-male ratio was 1.125 (90/80), and the ratio of the ischemic type to the hemorrhagic type was 2.33 (119/50). The most common initial symptom was an ischemic event. The 5-year Kaplan-Meier risk of stroke was 4.9% for all patients treated with surgical revascularization. Of all patients, 83.9% were able to live independently with no significant disability, and 89.8% showed improved cerebral hemodynamics. Our study provided detailed demographic and clinical data on Southeastern Chinese patients with MMD, which was consistent with findings in other parts of China. Raising clinical awareness of MMD in primary hospitals is important to facilitate early diagnosis and timely treatment of MMD patients.

Hippocampus protection from apoptosis by Baicalin in a LiCl-pilocarpine-induced rat status epilepticus model through autophagy activation.

BACKGROUND: Autophagy is associated with hippocampal injury following status epilepticus (SE) and is considered a potential therapeutic mechanism. Baicalin, an emerging multitherapeutic drug, has shown neuroprotective effects in patients with nervous system diseases due to its antioxidant properties. AIM: To investigate the potential role of autophagy in LiCl-pilocarpine-induced SE. METHODS: The drugs were administered 30 min before SE. Nissl staining showed that Baicalin attenuated hippocampal injury and reduced neuronal death in the hippocampus. Western blotting and terminal deoxynucleotidyl transferase dUTP nick end labeling assay confirmed that Baicalin reversed the expression intensity of cleaved caspase-3 and apoptosis in hippocampal CA1 following SE. Fur-thermore, western blotting and immunofluorescence staining were used to measure the expression of autophagy markers (p62/SQSTM1, Beclin 1, and LC3) and apoptotic pathway markers (cleaved caspase-3 and Bcl-2). RESULTS: Baicalin significantly upregulated autophagic activity and downregulated mitochondrial apoptotic pathway markers. Conversely, 3-methyladenine, a commonly used autophagy inhibitor, was simultaneously administered to inhibit the Baicalin-induced autophagy, abrogating the protective effect of Baicalin on the mitochondrial apoptotic level. CONCLUSION: We illustrated that Baicalin-induced activation of autophagy alleviates apoptotic death and protects the hippocampus of SE rats.

Schisandrin B Protects against Ischemic Brain Damage by Regulating PI3K/AKT Signaling in Rats.

OBJECTIVE: To explore the effect and mechanism of schisandrin B (Sch B) in the treatment of cerebral ischemia in rats. METHODS: The cerebral ischemia models were induced by middle cerebral artery occlusion (MCAO) and reperfusion. Sprague-Dawley rats were divided into 6 groups using a random number table, including sham, MCAO, MCAO+Sch B (50 mg/kg), MCAO+Sch B (100 mg/kg), MCAO+Sch B (100 mg/kg)+LY294002, and MCAO+Sch B (100 mg/kg)+wortmannin groups. The effects of Sch B on pathological indicators, including neurological deficit scores, cerebral infarct volume, and brain edema, were subsequently studied. Tissue apoptosis was identified by terminal transferase-mediated dUTP nick end-labeling (TUNEL) staining. The protein expressions involved in apoptosis, inflammation response and oxidative stress were examined by immunofluorescent staining, biochemical analysis and Western blot analysis, respectively. The effect of Sch B on phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling was also explored. RESULTS: Sch B treatment decreased neurological deficit scores, cerebral water content, and infarct volume in MCAO rats (P<0.05 or P<0.01). Neuronal nuclei and TUNEL staining indicated that Sch B also reduced apoptosis in brain tissues, as well as the Bax/Bcl-2 ratio and caspase-3 expression (P<0.01). Sch B regulated the production of myeloperoxidase, malondialdehyde, nitric oxide and superoxide dismutase, as well as the release of cytokine interleukin (IL)-1 ß and IL-18, in MCAO rats (P<0.05 or P<0.01). Sch B promoted the phosphorylation of PI3K and AKT. Blocking the PI3K/AKT signaling pathway with LY294002 or wortmannin reduced the protective effect of Sch B against cerebral ischemia (P<0.05 or P<0.01). CONCLUSIONS: Sch B reduced apoptosis, inflammatory response, and oxidative stress of MCAO rats by modulating the PI3K/AKT pathway. Sch B had a potential for treating cerebral ischemia.

The Impact of Volume Factor on the Long-Term Outcome of Gamma Knife Radiosurgery for Sporadic Cerebral Cavernous Malformations.

OBJECTIVE: We aimed to evaluate the long-term outcome of gamma knife radiosurgery (GKRS) for the treatment of sporadic cerebral cavernous malformation (CCM), especially the influence of lesion volume on annual hemorrhage rate (AHR) of patients with CCM after GKRS. METHODS: Fifty-one single-lesion patients with a history of hemorrhage who underwent radiosurgery at our institution were included and divided into 2 groups (A and B), based on their lesion volume. Group A included 25 patients with lesion volumes >1 cm3, whereas group B included 26 patients with lesion volumes ≤1 cm3. The clinical data of the patients were retrospectively analyzed. RESULTS: All patients were followed up for more than 4 years after GKRS. The calculated AHR before GKRS was 18.49% in group A and 10.16% in group B. The calculated AHR after GKRS was 5.43% and 0.99% for groups A and B, respectively. Significant differences in AHR after GKRS were identified between group A and group B (P = 0.011). Thirty-seven patients with sporadic CCM (14 in group A, 23 in group B) experienced symptom improvement, and significant differences in symptom improvement were observed between group A and group B (P = 0.009). CONCLUSIONS: GKRS decreased the risk of hemorrhage and was beneficial for symptomatic improvement in patients with sporadic CCM with a history of hemorrhage. The long-term clinical outcomes for patients with sporadic CCM with small lesion volumes (≤1 cm3) were better than those of patients with sporadic CCM with large lesion volumes (>1 cm3).

Exploring the mechanism of cordycepin combined with doxorubicin in treating glioblastoma based on network pharmacology and biological verification.

BACKGROUND: Glioblastoma is the most common and fatal primary malignant tumor in the central nervous system, and the prognosis is poor. Currently, there are no effective treatments for glioblastoma. Cordycepin is a natural active substance with significant anticancer activity and doxorubicin is a broad-spectrum anticancer drug. Cordycepin administered with doxorubicin is a potential drug combination for the treatment of glioblastoma. However, the mechanism of action for this drug combination has not yet been elucidated. AIM OF THE STUDY: To explore the complex mechanism of cordycepin combined with doxorubicin against glioblastoma using network pharmacology and biological verification. MATERIALS AND METHODS: We used an MTT assay, colony formation assay, and scratch healing to detect the growth, proliferation, and migration of LN-229, U251 and T98G cells. Putative targets and the potential mechanism of action for the drug combination in glioblastoma were obtained through online databases, network construction, and enrichment analyses. We verified the expression of EMT-related genes and identified important therapeutic targets by western blot. RESULTS: In this study, the combination of doxorubicin and cordycepin was found to significantly inhibit cell proliferation and migration and can induce apoptosis. These effects are better together than with either drug alone. The drug combination inhibited EMT by upregulating the expression of E-cadherin protein and downregulating the expression of N-cadherin, ZEB1, and Twist1 proteins. There were 71 potential targets for the drug combination in glioblastoma, and Kyoto Encyclopedia of Genes and Genome analysis suggested that the anticancer process may be mediated by proteoglycans in cancer, the tumor necrosis factor signaling pathway, microRNA in cancer, pathways in cancer, and other pathways. To study the molecular mechanism of anticancer activity, we detected the expression of target proteins with downregulated expression of NFKB1, MAPK8, MYC, and MMP-9 proteins and upregulated expression of cleaved caspase 3 that promoted the apoptosis of LN-229 cells. CONCLUSIONS: This study shows that the drug combination of doxorubicin and cordycepin effectively inhibits the growth and proliferation of LN-229 cells through multiple targets and multiple pathways, and the combination inhibits cell invasion and migration by regulating the EMT switch of tumor cells. Our findings provide new ideas about, and a theoretical basis for, the treatment of glioblastoma.

Effect of baicalin on matrix metalloproteinase-9 expression and blood-brain barrier permeability following focal cerebral ischemia in rats.

Focal cerebral ischemia results in an increased expression of matrix metalloproteinase-9 (MMP-9), which induces vasogenic brain edema via disrupting the blood-brain barrier (BBB) integrity. Recent studies from our laboratory showed that baicalin reduces ischemic brain damage by inhibiting inflammatory reaction and neuronal apoptosis in a rat model of focal cerebral ischemia. In the present study, we first explored the effect of baicalin on the neuronal damage, brain edema and BBB permeability, then further investigated its potential mechanisms. Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO). Baicalin was administrated by intraperitoneally injected twice at 2 and 12 h after the onset of MCAO. Neuronal damage, brain edema and BBB permeability were measured 24 h following MCAO. Expression of MMP-9 protein and mRNA were determined by western blot and RT-PCR, respectively. Expression of tight junction protein (TJP) occludin was detected by western blot. Neuronal damage, brain edema and BBB permeability were significantly reduced by baicalin administration following focal cerebral ischemia. Elevated expression of MMP-9 protein and mRNA were significantly down-regulated by baicalin administration. In addition, MCAO caused the decreased expression of occludin, which was significantly up-regulated by baicalin administration. Our study suggested that baicalin reduces MCAO-induced neuronal damage, brain edema and BBB permeability, which might be associated with the inhibition of MMP-9 expression and MMP-9-mediated occludin degradation.

[Microsurgical removal of olfactory groove meningiomas].

OBJECTIVE: To explore an effective method for further improving the surgical results of treatment of olfactory groove meningiomas. METHODS: Sixty seven cases of olfactory groove meningiomas were treated by microneurosurgery, among which fifty seven were de novo cases, eight were recurrent tumors and the other two re-recurrent cases. Modified Derome approach was used in 12 cases, bilateral subfrontal approach in 28 cases, modified pterional approach in 21 cases and unilateral subfrontal approach in six cases. Tumors were resected microsurgically with radical removal of invaded dura, bone, and paranasal sinus mucosa. Reconstruction was performed in patients with skull base defect. RESULTS: Simpson grade I removal was accomplished in 59 cases, grade II in seven cases and grade IV in one case. Among 57 patients with de novo tumor, Simpson I resection was accomplished in 54 cases. Postoperative rhinorrhea and intracranial infection occurred in one case and was cured after temporal lumbar CSF drainage and antibiotic therapy. Two patients (2.9%) died within one month after operation, i.e.one aged patient of heart failure and the other of severe hypothalamus complication. Forty seven patients (72.3%) were followed up from one to ten years with an average of five years and four months. With the exception of two cases died, among the alive 45 patients, there were only three patients with tumor recurrence, which had undergone Simpson II or IV tumor resection. No recurrence was found in cases with Simpson I tumor removal. Previous blurred vision was not improved in three patients, hemiparalysis in two patients, and the other patients recovered well, resuming previous jobs or being able to take care themselves. CONCLUSIONS: Total tumor removal (Simpson I) should be the surgical goal for treatment of olfactory groove meningiomas, especially for de novo cases. An appropriate approach is fundamental in the effort to remove an OGM totally. Appropriate anterior skull base reconstruction with vascularized material is important and mandatory.

Optimal concentration of necrostatin-1 for protecting against hippocampal neuronal damage in mice with status epilepticus.

Hippocampal neurons undergo various forms of cell death after status epilepticus. Necrostatin-1 specifically inhibits necroptosis mediated by receptor interacting protein kinase 1 (RIP1) and RIP3 receptors. However, there are no reports of necroptosis in mouse models of status epilepticus. Therefore, in this study, we investigated the effects of necrostatin-1 on hippocampal neurons in mice with status epilepticus, and, furthermore, we tested different amounts of the compound to identify the optimal concentration for inhibiting necroptosis and apoptosis. A mouse model of status epilepticus was produced by intraperitoneal injection of kainic acid, 12 mg/kg. Different concentrations of necrostatin-1 (10, 20, 40, and 80 µM) were administered into the lateral ventricle 15 minutes before kainic acid injection. Hippocampal damage was assessed by hematoxylin-eosin staining 24 hours after the model was successfully produced. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, western blot assay and immunohistochemistry were used to evaluate the expression of apoptosis-related and necroptosis-related proteins. Necrostatin-1 alleviated damage to hippocampal tissue in the mouse model of epilepsy. The 40 µM concentration of necrostatin-1 significantly decreased the number of apoptotic cells in the hippocampal CA1 region. Furthermore, necrostatin-1 significantly downregulated necroptosis-related proteins (MLKL, RIP1, and RIP3) and apoptosis-related proteins (cleaved-Caspase-3, Bax), and it upregulated the expression of anti-apoptotic protein Bcl-2. Taken together, our findings show that necrostatin-1 effectively inhibits necroptosis and apoptosis in mice with status epilepticus, with the 40 µM concentration of the compound having an optimal effect. The experiments were approved by the Animal Ethics Committee of Fujian Medical University, China (approval No. 2016-032) on November 9, 2016.

LncRNA TUG1 inhibits neuronal apoptosis in status epilepticus rats via targeting the miR-421/mTOR axis.

Status epilepticus (SE) induces apoptosis of hippocampal neurons. However, the underlying mechanism in SE is not fully understood. Recently, lncRNA TUG1 is reported as a significant mediator in neuronal development. In present study, we aimed to investigate whether lncRNA TUG1 induces apoptosis of hippocampal neurons in SE rat models. TUG1 expression in serum of normal volunteers and SE patients, SE rats and neurons with epileptiform discharge was detected. SE rat model was established and intervened with TUG1 to evaluate hippocampal neuronal apoptosis. The experiments in vitro were further performed in neurons with epileptiform discharge to verify the effects of TUG1 on neuronal apoptosis of SE rats. The downstream mechanism of TUG1 was predicted and verified. miR-421 was intervened to perform the rescue experiments. Levels of oxidative stress and inflammation-related factors and mTOR pathway-related proteins in SE rats and hippocampal neurons were detected. TUG1 was highly expressed in serum of SE patients, SE rats and neurons with epileptiform discharge. Inhibition of TUG1 relieved pathological injury, oxidative stress and inflammation and reduced neuronal apoptosis in SE rats, which were further verified in hippocampal neurons. TUG1 upregulated TIMP2 expression by targeting miR-421. Overexpressed miR-421 inhibited hippocampal neuronal apoptosis. TUG1 knockout inactivated the mTOR pathway via the miR-421/TIMP2 axis to relieve neuronal apoptosis, oxidative stress and inflammation in SE rats and hippocampal neurons. Taken together, these findings showed that downregulation of lncRNA TUG1 inhibited apoptosis of hippocampal neurons in SE rats, and attenuated oxidative stress and inflammation damage through regulating the miR-421/mTOR axis.

Baicalin Reduces Early Brain Injury after Subarachnoid Hemorrhage in Rats.

OBJECTIVE: To evaluate the effect of baicalin on subarachnoid hemorrhage (SAH) in rats and explore the potential mechanisms. METHODS: Sprague-Dawley rats underwent experimental SAH and received treatment with baicalin at 10 or 50 mg/kg after 2 and 12 h of SAH. Neurological scores, brain water content, Evans-blue extravasation, and levels of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), myeloperoxidase (MPO), and malondialdehyde (MDA) were measured 24 h after SAH. Expression of nuclear factor erythroid-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), matrix metalloproteinase-9 (MMP-9), aquaporin 4 (AQP4), occludin, and zonulaoccludens-1 (ZO-1) were detected in the brain by Western blot. Heme oxygenase-1 (HO-1) was detected by quantitative polymerase chain reaction, and tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were assessed by enzyme-linked immunosorbent assay. RESULTS: Baicalin attenuated EBI 24 h after SAH in rats (P<0.05). Baicalin elevated neurological scores, GSH-Px, SOD, and increased the expression of Nrf2, NQO1, HO-1, occludin, and ZO-1 in SAH rats (P<0.05 or P<0.01). Baicalin reduced MPO, MDA, and the expression of MMP-9, AQP4, TNF-α, and IL-1ß (P<0.05 or P<0.01). CONCLUSION: Baicalin reduced SAH-induced EBI, partially via activation of the Nrf2/HO-1 pathway and inhibition of MMP-9 and AQP4.