Inhibition of chromosomal region maintenance 1 suppresses the migration and invasion of glioma cells via inactivation of the STAT3/MMP2 signaling pathway

Chromosomal region maintenance 1 (CRM1) is associated with an adverse prognosis in glioma. We previously reported that CRM1 inhibition suppressed glioma cell proliferation both in vitro and in vivo. In this study, we investigated the role of CRM1 in the migration and invasion of glioma cells. S109, a novel reversible selective inhibitor of CRM1, was used to treat Human glioma U87 and U251 cells. Cell migration and invasion were evaluated by wound-healing and transwell invasion assays. The results showed that S109 significantly inhibited the migration and invasion of U87 and U251 cells. However, mutation of Cys528 in CRM1 abolished the inhibitory activity of S109 in glioma cells. Furthermore, we found that S109 treatment decreased the expression level and activity of MMP2 and reduced the level of phosphorylated STAT3 but not total STAT3. Therefore, the inhibition of migration and invasion induced by S109 may be associated with the downregulation of MMP2 activity and expression, and inactivation of the STAT3 signaling pathway. These results support our previous conclusion that inhibition of CRM1 is an attractive strategy for the treatment of glioma.

Inhibition of chromosomal region maintenance 1 suppresses the migration and invasion of glioma cells via inactivation of the STAT3/MMP2 signaling pathway

Chromosomal region maintenance 1 (CRM1) is associated with an adverse prognosis in glioma. We previously reported that CRM1 inhibition suppressed glioma cell proliferation both in vitro and in vivo. In this study, we investigated the role of CRM1 in the migration and invasion of glioma cells. S109, a novel reversible selective inhibitor of CRM1, was used to treat Human glioma U87 and U251 cells. Cell migration and invasion were evaluated by wound-healing and transwell invasion assays. The results showed that S109 significantly inhibited the migration and invasion of U87 and U251 cells. However, mutation of Cys528 in CRM1 abolished the inhibitory activity of S109 in glioma cells. Furthermore, we found that S109 treatment decreased the expression level and activity of MMP2 and reduced the level of phosphorylated STAT3 but not total STAT3. Therefore, the inhibition of migration and invasion induced by S109 may be associated with the downregulation of MMP2 activity and expression, and inactivation of the STAT3 signaling pathway. These results support our previous conclusion that inhibition of CRM1 is an attractive strategy for the treatment of glioma.

Self-assembled angiopep-2 modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles delivery TMZ for glioma synergistic TMZ and RT therapy.

The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GBM). However, TMZ + RT causes excess toxicity in patients. In this study, we prepared angiopep-2 (A2) modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles for TMZ delivery (A2-P(MIs)25/TMZ) to achieve synergistic effects against glioma. This A2-P(MIs)25/TMZ display highly promising advantages: (1) a hydrophobic P-(MIs)25 core where poorly water-soluble TMZ can be encapsulated; (2) nitro groups of the hydrophobic P-(MIs)25 core that are converted into hydrophilic amino groups (P(NH2s)25) under low oxygen conditions to mimic the oxygen-increased sensitization to RT; (3) a lipid monolayer at the interface of the core and the shell to modify the A2 (a specific ligand for low-density lipoprotein receptor-related protein-1 (LRP-1), which are expressed in the blood-brain barrier (BBB) and human glioma cells), thereby enhancing the drug encapsulation efficiency in glioma. These nanoparticles appear as a promising and robust nanoplatforms for TMZ and hypoxic cell radiosensitization delivery.

Reduction-responsive PEtOz-SS-PCL micelle with tailored size to overcome blood-brain barrier and enhance doxorubicin antiglioma effect.

A series of novel reduction-responsive micelles with tailored size were designed and prepared to release doxorubicin (DOX) for treating glioma, which were developed based on amphiphilic block copolymer poly (2-ethyl-2-oxazoline)-b-poly (ε-caprolactone) (PEtOz-SS-PCL) and the micelle size could be regulated by designing the polymer structure. The DOX-loaded PEtOz-SS-PCL micelles had small size and rapid drug release in reductive intracellular environments. Biodistribution and in vivo imaging studies in C6 glioma mice tumor model showed that DOX loaded PEtOz-SS-PCL43 micelles with the smallest size had superior accumulation and fast drug release in tumor sites. In vivo antitumor activity demonstrated that DOX-loaded PEtOz-SS-PCL43 micelles improved antitumor efficacy in contrast to PEtOz-SS-PCL micelles with larger size toward the orthotopic C6-Luci cells-bearing mice. This study shows great potential in tailoring the micelle size and introducing the responsive bonds or compartment for intracellular drug delivery and release in glioma treatment by designing the architecture of the polymer.

Effect of endovascular cooling on perioperative brain injury in patients undergoing intracranial aneurysm resection / 中华麻醉学杂志

Objective To investigate the effect of endovascular cooling on perioperative brain injury in patients undergoing intracranial aneurysm resection.Methods Sixteen Hunt-Hess Ⅱ -Ⅳ patients of both sexes aged 18-64 yr undergoing intracranial aneurysm resection were randomly divided into 2 groups(n = 8 each): mild hypothermia group(group MHT)and nonnothermia group(group NT).A CL-2295AE catheter was placed in the femoral vein after anesthesia induction to perform endovascular cooling.Bladder temperature was reduced to 34 ℃ and maintained for 24 h.The hemodynamic parameters were recorded during and after operation.Coagulantion function and electrolyte levels were determined at 24 h before operation and at 12 and 24 h after operation.The serum neuron-specific enolase(NSE)and S100B concentrations were determined at 1 d before operation and at 1,3and 7 d after operation by ELISA.Neurological function was assessed with GOS grade at 1 and 3 months after operation.Results There was no significant difference in hemodynamic parameters,electrolyte levels(Na+ ,K+ ,Ca2+)and coagulantion function(PT,APTT,Plt)between the two groups(P ＞ 0.05).The GOS grade was significantly higher,while serum NSE and S100B concentrations were significantly lower after operation in group MHT than in group NT(P ＜ 0.05).Conclusion Endovascular cooling(34℃,24 h)can reduce the brain injury safely and effectively during the perioperative period in patients undergoing intracranial aneurysm resection and improve the prognosis.

Study on neuronal apoptosis induced by hypoxia or traumatic injury in rats / 中华创伤杂志(英文版)

OBJECTIVE: To explore the relationship between neuronal apoptosis and hypoxia or traumatic injury. METHODS: Rat neurons primarily cultured in vitro were treated w ith hypoxia (the hypoxia group) or traumatic injury (the trauma group). The neur onal apoptosis was evaluated with microscope, TUNEL (terminal deoxynucleotidyl t ransferase mediated X-dUTPnick end labeling) staining, flow cytometry, agarose gel electrophoresis and immunohistochemistry RESULTS: Morphological changes of apoptosis appeared in the t reated neurons and the DNA fragmentation showed "ladder" break. The apoptotic index was 10.8% in the hypoxia group and 4.8% in the trauma group, while it was only 1.6% in the control group. The expression of apoptosis-associated genes (c-myc, fas and fasL) increased. CONCLUSIONS: Hypoxia or traumatic injury can induce neuronal ap optosis, and its molecular mechanism is probably related to the expressions of a poptosis-associated genes.

Development of an electrocircuit controlled impact device for injuring spinal cord in adult rats / 中华创伤杂志

Objective To develop a new impact device that can cause different levels of spinal cord injury in adult rats so as to provide a scientific means for standard spinal cord injury model in adult rats. Methods First, two laser heads were installed beside the impacting hammer in order to define the dropping point of imparting hammer through the focus of the two tracts of lasers. A height controlled electrocircuit was designed to control the rotation of the minitype dynamo that regulated the height of impacting hammer precisely via the worm gear. Meanwhile, a time controlled electrocircuit was made so as to secure that the process of injury could be finished within 10 millionseconds constantly according to the technique of weight dropping and the principle of electromagnetic electromagnetism respectively. Results The present impact device could produce different levels of spinal cord injury in adult rats within special times, heights and dropping points. Conclusion We have successfully produced an electro-circuit controlled impact device with laser defining position that is simple and easy to use for making controllable and precise injury models.

Association of oxidative stress inducing neuronal apoptosis with c-Myc,Fas-FasL and nuclear factor-?B / 中华创伤杂志

Objective To explore the relationship between oxidative stress inducing neuronal apoptosis and the protein expressions of c-Myc, Fas-FasL and nuclear factor ?B (NF-?B) in neurons. Methods The primarily cultured neurons of SD rat in vitro were divided into 5 groups: Group A (control), Group B (treated with hypoxia), Group C (treated with small dose of H 2O 2), Group D (treated with hypoxia and SOD) and Group E (treated with H 2O 2 and SOD). Then, the neuronal apoptosis was elevated with TUNEL,Gel electrophoresis and flow cytometry. The protein expressions of c-Myc, Fas-FasL and NF-?B were detected with immunohistochemistry. Results Apoptosis rates of the Groups B and C were 6 and 8 times than that of the Group A respectively ( P