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Objective: To investigate the regulatory mechanism of micro ribonucleic acid (miR)-21 in the formation and rupture of intracranial aneurysm through the c-Jun N-terminal kinase (JNK) signaling pathway-mediated inflammatory response. Methods: In the present study, the mice with miR-21 expression deficiency and over-expression in our laboratory were enrolled as the experimental group, while wild-type healthy mice were used as the control group. The mouse model of intracranial aneurysm was established by bilateral carotid artery ligation. The differences in the levels of key genes in the JNK signaling pathway (JNK1 and JNK2) were detected by fluorescence quantitative polymerase chain reaction (qPCR) and western blotting. At the same time, the changes in transcription and translation levels of inflammatory factors, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), in both groups were measured. After the mice were executed by an overdose of anesthesia, the morphology of the aneurysm in different objects was observed by Verhoeff-Van Gieson (EVG) staining and the expressions of TNF-α, JNK1, and JNK2 were determined by immunohistochemistry. Results: Compared with healthy mice, levels of JNK1 and JNK2 in mice with miR-21 deficiency were significantly decreased (P < 0.05) with a significant reduction of inflammatory factors IL-6 and TNF-α (P < 0.05). Compared with healthy mice, levels of JNK1 and JNK2 in mice with miR-21 over-expression were significantly increased (P < 0.05) with significant growing levels of inflammatory factors IL-6 and TNF-α (P < 0.05). The results of EVG staining revealed that the intracranial aneurysm was smaller in mice with miR-21 deficiency [(0.3 ± 0.12) cm] and larger in mice with miR-21 over-expression [(0.8 ± 0.25) cm] and there was a significant difference (P < 0.05). Moreover, the results of immunohistochemistry showed that the expression of TNF-α in intracranial aneurysm was obviously lower in mice with miR-21 deficiency than that in mice with miR-21 over-expression. Conclusion: MiR-21 can promote the production of inflammation-related factors through the JNK signaling pathway, leading to the formation and rupture of an intracranial aneurysm.

Background: Intracranial aneurysm (IA) is a critical acquired cerebrovascular disease that may cause subarachnoid hemorrhage, and nuclear factor-κB (NF-κB)-mediated inflammation is involved in the pathogenesis of IA. Adenomatous polyposis coli (Apc) gene is a tumor suppressor gene associated with both familial and sporadic cancer. Herein, the purpose of our study is to validate effect of Apc gene on IA formation and rupture by regulating the NF-κB signaling pathway mediated inflammatory response. Methods: We collected IA specimens (from incarceration of IA) and normal cerebral arteries (from surgery of traumatic brain injury) to examine expression of Apc and the NF-κB signaling pathway related factors (NF-κB p65 and IκBα). ELISA was used to determine levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β (IL-1β), and IL-6. IA model was established in rats, and Apc-siRNA was treated to verify effect of Apc on IA formation and rupture. Next, regulation of Apc on the NF-κB signaling pathway was investigated. Results: Reduced expression of Apc and IκBα, and increased expression of NF-κB p65 were found in IA tissues. MCP-1, TNF-α, IL-1β, and IL-6 exhibited higher levels in unruptured and ruptured IA, which suggested facilitated inflammatory responses. In addition, the IA rats injected with Apc-siRNA showed further enhanced activation of NF-κB signaling pathway, and up-regulated levels of MCP-1, TNF-α, IL-1β, IL-6, MMP-2, and MMP-9 as well as extent of p65 phosphorylation in IA. Conclusion: Above all, Apc has the potential role to attenuate IA formation and rupture by inhibiting inflammatory response through repressing the activation of the NF-κB signaling pathway.

Glioblastoma is a malignant brain tumor originating in the central nervous system. Successfully therapy of this disease required the efficient delivery of therapeutic agents to the tumor cells and tissues. Delivery of anticancer drugs using novel nanocarriers is promising in glioma treatment.Polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) were constructed for the delivery of temozolomide (TMZ). The anti-tumor effects of the three kinds of nanocarriers were compared to provide the optimum choice for gliomatosis cerebri treatment.TMZ-loaded PNPs (T-PNPs), SLNs (T-SLNs), and NLCs (T-NLCs) were formulated. Their particle size, zeta potential, drug encapsulation efficiency (EE), and drug loading (DL) capacity were evaluated. Anti-tumor efficacies of the three kinds of nanocarriers were evaluated on U87 malignant glioma cells (U87 MG cells) and mice-bearing malignant glioma model.T-NLCs displayed the best anti-tumor activity than other formulations in vivo and in vitro. The most significantly glioma inhibition was observed on NLCs formulations than PNPs and SLNs.This work demonstrates that NLCs can deliver TMZ into U87MG cells more efficiently, with higher inhibition efficacy than PNPs and SLNs. T-NLCs could be an excellent drug delivery system for glioblastoma chemotherapy.

Jicai Zhang, Xiang Xiao, Jianming Zhu, Ziyun Gao, Xianliang Lai, Xingen Zhu, Guohua Mao Department of Neurosurgery, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China Purpose: Glioblastoma multiforme (GBM) is the most common malignant brain tumor originating in the central nervous system in adults. Based on nanotechnology such as liposomes, polymeric nanoparticles, and lipid nanoparticles, recent research efforts have been aimed to target drugs to the brain. Methods: In this study, lactoferrin- and arginine–glycine–aspartic acid (RGD) dual-ligand-comodified, temozolomide and vincristine-coloaded nanostructured lipid carriers (L/R-T/V-NLCs) were introduced for GBM combination therapy. The physicochemical properties of L/R-T/V-NLCs such as particle size, zeta potential, and encapsulated efficiency are measured. The drug release profile, cellular uptake, cytotoxicity, tissue distribution, and antitumor activity of L/R-T/V-NLCs are further investigated in vitro and in vivo. Results: L/R-T/V-NLCs were stable with nanosize and high drug encapsulation efficiency. L/R-T/V-NLCs exhibited sustained-release behavior, high cellular uptake, high cytotoxicity and synergy effects, increased drug accumulation in the tumor tissue, and obvious tumor inhibition efficiency with low systemic toxicity. Conclusion: L/R-T/V-NLCs could be a promising drug delivery system for glioblastoma chemotherapy. Keywords: gliomatosis cerebri, combination therapy, nanostructured lipid carriers, lactoferrin, arginine–glycine–aspartic acid peptide, vincristine, temozolomide

Co-delivery of gene and anticancer drug into the same cancer cells or tissues by multifunctional nanocarriers may provide a new paradigm in cancer treatment. In this study, nanostructured lipid carriers (NLCs) were constructed as multifunctional nanomedicine for co-delivery of enhanced green fluorescence protein plasmid (DNA) and temozolomide (TMZ).TMZ- and DNA-loaded NLCs (TMZ/DNA-NLCs) were prepared. Their particle size, zeta potential, gene-loading capacity (GL) and drug encapsulation efficiency (EE) were evaluated. In vitro cytotoxicity study TMZ/DNA-NLCs was tested in U87 malignant glioma cells (U87 MG cells). In vivo gene transfection and anti-tumor efficacy of the carriers were evaluated on mice bearing malignant glioma model.The optimum TMZ/DNA-NLCs formulations with the particle size of 179 nm and with a +23 mV surface charge; got 91% of GL and 83% of EE. The growth of U87 MG cells in vitro was obviously inhibited. TMZ/DNA-NLCs also displayed the highest gene transfection efficiency and the best antitumor activity than other formulations in vivo.The results demonstrated that TMZ/DNA-NLCs were efficient in selective delivery to malignant glioma cells. Also TMZ/DNA-NLCs transfer both drug and gene to the gliomatosis cerebri, enhance the antitumor capacity and gene transfection efficacy. Thus, TMZ/DNA-NLCs could prove to be a superior co-delivery nanomedicine to achieve therapeutic efficacy and this report could be a new promising strategy for treatment in malignant gliomatosis cerebri.

Sodium ferulate induces bone marrow mesenchymal stem cells to differentiate into neural cells by NF-κB signal pathway