Valproate Sodium Protects Blood Brain Barrier Integrity in Intracerebral Hemorrhage Mice.

Valproate sodium (VPA) is a traditional antiepileptic drug with a neuroprotective role in cerebrovascular disease. After intracerebral hemorrhage (ICH), mechanical compression by hematoma, neuroinflammation, oxidative stress, and cytotoxicity of hematoma lysates caused the destruction of the blood brain barrier (BBB). Targeting BBB is a major therapeutic method for patients with ICH. The purpose of the present study was to explore the role of VPA in preserving BBB integrity in the ICH model and investigate the underlying molecular mechanisms. One hundred and thirty-six adult male CD1 mice were randomly divided into five groups in the study. Mice subjected to ICH were administered intraperitoneally with VPA at 3, 24, and 48 h post-ICH, respectively. Neurobehavioral assessments, BBB permeability, Evans blue fluorescence, hematoma volume, and protein expression were evaluated. The administration of VPA reduced BBB permeability and improved the neurobehavior significantly post-ICH. VPA administration significantly decreased the expression of phosphorylated nuclear factor-kappa B (p-NFκB), matrix metalloproteinases 9 (MMP9), tumor necrosis factorα (TNFα), and interleukin-6 (IL-6), while it enhanced the expression of claudin 5 and occludin in the brain. In conclusion, VPA administration maintained the integrity of BBB after experimental ICH, thus reducing brain edema and improving the neurological outcomes. Therefore, VPA administration might be a new therapeutic method to protect BBB integrity for patients with ICH.

Corrigendum: An Overview of Managements in Meningiomas.

[This corrects the article DOI: 10.3389/fonc.2020.01523.].

An Overview of Managements in Meningiomas.

Meningioma is the most frequent primary tumor of the central nervous system. Important advances have been achieved in the treatment of meningioma in recent decades. Although most meningiomas are benign and have a good prognosis after surgery, clinicians often face challenges when the morphology of the tumor is complicated or the tumor is close to vital brain structures. At present, the longstanding treatment strategies of meningioma are mainly surgery and radiotherapy. The effectiveness of systemic therapy, such as chemotherapy or targeted therapy, has not been confirmed by big data series, and some clinical trials are still in progress. In this review, we summarize current treatment strategies and future research directions for meningiomas.

Concurrent Bronchial Artery and Posterior Inferior Cerebellar Artery Microcatheter Interventional Chemotherapy for Adenocarcinoma of the Lung with Solitary Cerebellar Metastasis.

BACKGROUND Lung cancer with intracranial metastasis requires concurrent treatment of the primary lung tumor and the secondary brain tumor. This study aimed to investigate the short-term clinical efficacy of concurrent bronchial artery and posterior inferior cerebellar artery microcatheter interventional chemotherapy for the treatment of adenocarcinoma of the lung with solitary cerebellar metastasis. MATERIAL AND METHODS Seventeen patients with adenocarcinoma of the lung with solitary cerebellar metastasis received concurrent microcatheter interventional chemotherapy via the bronchial artery and posterior inferior cerebellar artery. Two cycles of treatment with teniposide (VM-26), carmustine (BCNU), carboplatin (CBP), and pirarubicin (THP) were performed every four weeks. RESULTS Four patients (23.53%) achieved a complete response (CR), five patients (29.41%) achieved a partial response (PR), seven patients (41.18%) had stable disease (SD), and only one patient (5.88%) developed progressive disease (PD). The objective response rate (ORR) and disease control rate (DCR) were 52.94% (9/17) and 94.12% (16/17), respectively. Four patients (11.76%) developed grade 1/2 chemotherapy toxicity, which included three cases (8.82%) of gastrointestinal toxicity and one case (2.84%) of granulocytopenia, but no grade 3/4 toxicity was found. During microcatheter interventional chemotherapy, three patients (8.82%) developed intracranial complications, including two cases (5.88%) of cerebrovascular spasm and one case (2.94%) of cerebral edema. CONCLUSIONS In 17 patients with adenocarcinoma of the lung with solitary cerebellar metastasis, concurrent microcatheter interventional chemotherapy via the bronchial artery and posterior inferior cerebellar artery was safe and showed short-term efficacy.

Association between expression of HOTAIR and invasiveness of gliomas, and its predictive value.

BACKGROUND: Hox transcript antisense intergenic RNA (HOTAIR) is upregulated and associated with a poor prognosis in many cancer types. Besides, it is involved in the invasion and metastasis of non-small-cell lung cancer and nasopharyngeal carcinoma. OBJECTIVES: The aim of this study was to investigate the association between the expression of HOTAIR and the grades of gliomas, and to explore its possible mechanism, as well as to evaluate the value of HOTAIR applied in predicting the grades of gliomas. MATERIAL AND METHODS: A total of 123 patients undergoing glioma surgeries were enrolled. Patients with grade I and grade II-IV tumors were regarded as the control group (n = 36) and the case group (n = 87), respectively. The expression of HOTAIR, matrix metalloproteinase 7 (MMP-7), matrix metalloproteinase 9 (MMP-9), and vascular endothelial growth factor (VEGF) was detected with quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in glioma tissues and then compared between grade I and grades II-IV. The correlation between the relative expression of HOTAIR and that of MMP-7, MMP-9 and VEGF was analyzed. Multivariate analysis was performed to identify independent risk factors. Receiver operating characteristic (ROC) curve was employed to evaluate the predictive value. RESULTS: The relative expression of HOTAIR, MMP-7, MMP-9, and VEGF was lower in glioma tissues of grade I than in the case of grades II-IV, and the relative expression of HOTAIR was positively correlated with the relative expression of MMP-7, MMP-9 and VEGF. Multivariate analysis showed that the relative expression of HOTAIR was independently associated with the grades of gliomas, but the relative expression of MMP-7, MMP-9 and VEGF was not. Besides, multivariate analysis showed that the expression level of HOTAIR >0.40 was an independent risk factor for grades II-IV after classifying the relative expression of HOTAIR, and ROC analysis showed that the expression level of HOTAIR >0.40 had a moderate value when applied in predicting grades II-IV. CONCLUSIONS: Hox transcript antisense intergenic RNA might promote the invasion of gliomas through upregulating the expression of MMP-7, MMP-9 and VEGF, and the expression level of HOTAIR >0.40 had a moderate value when applied in predicting grades II-IV.

Administration of rCTRP9 Attenuates Neuronal Apoptosis Through AdipoR1/PI3K/Akt Signaling Pathway after ICH in Mice.

Targeting neuronal apoptosis after intracerebral hemorrhage (ICH) may be an important therapeutic strategy for ICH patients. Emerging evidence indicates that C1q/TNF-Related Protein 9 (CTRP9), a newly discovered adiponectin receptor agonist, exerts neuroprotection in cerebrovascular disease. The aim of this study was to investigate the anti-apoptotic role of CTRP9 after experimental ICH and to explore the underlying molecular mechanisms. ICH was induced in mice via intrastriatal injection of bacterial collagenase. Recombinant CTRP9 (rCTRP9) was administrated intranasally at 1 h after ICH. To elucidate the underlying mechanisms, adiponectin receptor1 small interfering ribonucleic acid (AdipoR1 siRNA) and selective PI3 K inhibitor LY294002 were administered prior to rCTRP9 treatment. Western blots, neurofunctional assessments, immunofluorescence staining, and Fluoro-Jade C (FJC) staining experiments were performed. Administration of rCTRP9 significantly improved both short- and long-term neurofunctional behavior after ICH. RCTRP9 treatment significantly increased the expression of AdipoR1, PI3 K, p-Akt, and Bcl-2, while at the same time was found to decrease the expression of Bax in the brain, which was reversed by inhibition of AdipoR1 and PI3 K. The neuroprotective effect of rCTRP9 after ICH was mediated by attenuation of neuronal apoptosis via the AdipoR1/PI3K/Akt signaling pathway; therefore, rCTRP9 should be further evaluated as a potential therapeutic agent for ICH patients.

Recombinant CTRP9 administration attenuates neuroinflammation via activating adiponectin receptor 1 after intracerebral hemorrhage in mice.

BACKGROUND: Neuroinflammation is a crucial factor contributing to neurological injuries after intracerebral hemorrhage (ICH). C1q/TNF-related protein 9 (CTRP9), an agonist of adiponectin receptor 1 (AdipoR1), has recently been shown to reduce inflammatory responses in systemic diseases. The objective of this study was to investigate the protective role of CTRP9 against neuroinflammation after ICH in a mouse model and to explore the contribution of adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor kappa B (NFκB) pathway in AdipoR1-mediated protection. METHODS: Adult male CD1 mice (n = 218) were randomly assigned to different groups for the study. ICH was induced via intrastriatal injection of bacterial collagenase. Recombinant CTRP9 (rCTRP9) was administered intranasally at 1 h after ICH. To elucidate the underlying mechanism, AdipoR1 small interfering ribonucleic acid (siRNA) and selective phosphorylated AMPK inhibitor Dorsomorphin were administered prior to rCTRP9 treatment. Brain edema, short- and long-term neurobehavior evaluation, blood glucose level, western blot, and immunofluorescence staining were performed. RESULTS: Endogenous CTRP9 and AdipoR1 expression was increased and peaked at 24 h after ICH. AdipoR1 was expressed by microglia, neurons, and astrocytes. Administration of rCTRP9 reduced brain edema, improved short- and long-term neurological function, enhanced the expression of AdipoR1 and p-AMPK, and decreased the expression of phosphorylated NFκB and inflammatory cytokines after ICH. The protective effects of rCTRP9 were abolished by administration of AdipoR1 siRNA and Dorsomorphin. CONCLUSIONS: Our findings demonstrated that administration of rCTRP9 attenuated neuroinflammation through AdipoR1/AMPK/NFκB signaling pathway after ICH in mice, thereby reducing brain edema and improving neurological function after experimental ICH in mice. Therefore, CTRP9 may provide a potential therapeutic strategy to alleviate neuroinflammation in ICH patients.

Antibacterial and anticancer PDMS surface for mammalian cell growth using the Chinese herb extract paeonol(4-methoxy-2-hydroxyacetophenone).

Polydimethylsiloxane (PDMS) is widely used as a cell culture platform to produce micro- and nano-technology based microdevices. However, the native PDMS surface is not suitable for cell adhesion and is always subject to bacterial pollution and cancer cell invasion. Coating the PDMS surface with antibacterial or anticancer materials often causes considerable harm to the non-cancer mammalian cells on it. We have developed a method to fabricate a biocompatible PDMS surface which not only promotes non-cancer mammalian cell growth but also has antibacterial and anticancer activities, by coating the PDMS surface with a Chinese herb extract, paeonol. Coating changes the wettability and the elemental composition of the PDMS surface. Molecular dynamic simulation indicates that the absorption of paeonol onto the PDMS surface is an energy favourable process. The paeonol-coated PDMS surface exhibits good antibacterial activity against both Gram-positive and Gram-negative bacteria. Moreover considerable antibacterial activity is maintained after the coated surface is rinsed or incubated in water. The coated PDMS surface inhibits bacterial growth on the contact surface and promotes non-cancer mammalian cell growth with low cell toxicity; meanwhile the growth of cancer cells is significantly inhibited. Our study will potentially guide PDMS surface modification approaches to produce biomedical devices.

[Biocompatibility of polyurethane-BaFe(12)O(19 ) composite microsphere as a new endovascular embolization material].

OBJECTIVE: To investigate the biocompatibility of polyurethane-BaFe(12)O(19) magnetic composite microsphere as a new endovascular embolization material. METHODS: The biocompatibility of BaFe(12)O(19) particle was evaluated in vitro using Ames test, cell toxicity test, acute and subacute systemic toxicity test, hemolysis test, bleeding time and clotting time test and blood clotting function assay. RESULTS: Ames test showed that the MR values of this particle leaching solution were all less than 2 without mutagenicity. Cell toxicity test showed that leaching solution at different concentrations had grade I toxicity on L929 cells. Acute and subacute systemic toxicity test showed that the experimental animals had good general condition without obvious pathological abnormality. The hemolysis rate of experimental group was 2.43%, which met the ISO standard (no more than 5%). The bleeding time and clotting time in mice were comparable between the experimental group and control group (P>0.05). There were no significant differences in blood clotting function between experimental group and control group (P>0.05). CONCLUSION: The material has no obvious toxicity or mutagenicity, and does not cause hemolysis or hemopexis or affect the bleeding time and clotting time. Polyurethane-BaFe(12)O( 19) particle possesses satisfactory biocompatibility.

Functional analysis of neuron-like cells differentiated from neural stem cells derived from bone marrow stroma cells in vitro.

The transversal differentiation of bone marrow stroma cell (BMSCs) into neural stem cells (NSCs) has attracted much attention in recent years because of their therapeutic potential. However, the problem in therapeutic application of NSCs was how to confirm whether neuron-like cells differentiated from bone marrow stroma cell-derived neural stem cells (BMSCs-D-NSCs) possess corresponding functions of neurochemistry and electrophysiology. In the present study, we tried to affirm the function of neuron-like cells differentiated from BMSCs-D-NSCs in vitro. The BMSCs were harvested by gradient centrifugation in Ficoll-Paque and cultured in "NSCs medium". Immunocytochemistry was used to detect positive expression of neuron-specific nuclear protein (NeuN) in neuron-like cells derived from the BMSCs-D-NSCs. High-pressure liquid chromatography (HPLC) was used to identify neuron-like cells by detecting excitable amino acids [aspartic acid (Asp), glutamic acid (Glu)], inhibited amino acids [glycine (Gly), gamma (gamma) -aminobutyric acid (GABA), alanine (Ala)] or monoamines [noradrenaline (NE), 5-hydroxytryptamine (5-HT), dopamine (DA)]. Electrophysiological properties of the neuron-like cells were also examined using patch clamp analysis to verify their neuron-like functions. It was found that the neuron-like cells differentiated from the BMSCs-D-NSCs could express positive NeuN, synthesize and excrete amino acids, and show some typical electrophysiological properties including the typical Na+ and K+ ion channel membrane current under the voltage patch clamp condition, the typical static electrical membrane potential under the current patch clamp condition, and the differential membrane capacitance and resistance values in series between undifferentiated BMSCs-D-NSCs and differentiated neuron-like cells under the whole-cell patch clamp condition. The neuron-like cells differentiated from BMSCs-D-NSCs exhibit both neuron-like biochemical function and some corresponding electrophysiological properties.