Migration capacity of human umbilical cord mesenchymal stem cells towards glioma in vivo*

High-grade glioma is the most common malignant primary brain tumor in adults.The poor prognosis of glioma,combined with a resistance to currently available treatments,necessitates the development of more effective tumor-selective therapies.Stem cell-based therapies are emerging as novel cell-based delivery vehicle for therapeutic agents.In the present study,we successfully isolated human umbilical cord mesenchymal stem cells by explant culture.The human umbilical cord mesenchymal stem cells were adherent to plastic surfaces,expressed specific surface phenotypes of mesenchymal stem cells as demonstrated by flow cytometry,and possessed multi-differentiation potentials in permissive induction media in vitro.Furthermore,human umbilical cord mesenchymal stem cells demonstrated excellent glioma-specific targeting capacity in established rat glioma models after intratumoral injection or contralateral ventricular administration in vivo.The excellent glioma-specific targeting ability and extensive intratumoral distribution of human umbilical cord mesenchymal stem cells indicate that they may serve as a novel cellular vehicle for delivering therapeutic molecules in glioma therapy.     

Cassane-type diterpenes from Caesalpinia minax induce apoptosis in pituitary adenoma: structure–activity relationship,ER stress and Wnt/β-catenin pathways

Plant-derived natural products have been the highly significant sources of novel antitumor agents. The cassane-type diterpenes of genus Caesalpinia have been reported to bear antiproliferative activities toward different types of cancer cells. In this study, we evaluated the antineoplasmic activities of 16 natural origin cassane-type diterpenes isolated from the CHCl₃ extract of the seeds of C. minax in pituitary adenomas cells and identified caesalpin G (CAG) showed the strongest cytotoxicity. Moreover, we further investigated the structure–activity relationship and molecular mechanism of these derivatives systematically. The results confirmed the unsaturated lactone-type ring, hydroxyl at C-7, and alkenyl at C-11 or C-14 functionality as critical for anticancer activity in this family of natural products. In addition, the mechanism experiments also demonstrated unfolded protein response and ER stress and Wnt/β-catenin pathway were involved in the CAG-induced apoptosis.     

LncRNA 4344 promotes NLRP3-related neuroinflammation and cognitive impairment by targeting miR‐138-5p

ObjectiveCognitive impairment is a common neurological disease of which NLRP3-related neuroinflammation has been demonstrated to be an essential mediator. Previous studies have indicated that long non-coding RNAs (lncRNAs) are critical for the development of neurological disorders. However, the roles and functions of lncRNA 4344 in neuroinflammation during cognitive impairment are unknown and need to be further elucidated.MethodsLipopolysaccharide (LPS)-induced rat cognitive impairment and rat microglia (RM) cell inflammation models were established in vitro and in vivo. The Morris water maze test was used to evaluate the cognitive behavior of the rats. Gene expression was assessed using real-time quantitative polymerase chain reaction, and protein levels using enzyme-linked immunosorbent assay, or western blot analysis. The targeting relationship between lncRNA 4344, miR-138-5p, and NLRP3 was identified using bioinformatics analysis and a dual-luciferase reporter gene assay. Hematoxylin-Eosin and Nissl stainings, terminal deoxynucleotidyl transferase dUTP nick end labeling, or immunofluorescence staining assays were performed to detect pathological changes, neuronal apoptosis, or positive cells in hippocampal tissues, respectively.ResultsThe expression levels of lncRNA 4344 and NLRP3 were upregulated in the hippocampal tissues of LPS-treated rats and RM cells, and showed a strong positive correlation between each other. LncRNA 4344 overexpression further enhanced the expression of NLRP3 and its downstream genes (caspase-1, IL-1β, and IL-18), as well as neuronal apoptosis in LPS-stimulated RM cells, whereas lncRNA 4344 silencing attenuated the inflammatory injuries. Moreover, miR-138-5p was the direct target of lncRNA 4344 and was downregulated in the RM cell inflammation model. We also found that miR-138-5p directly reduced the expression of NLRP3 and its downstream genes. Subsequently, the results of the animal experiments showed that the lncRNA 4344/miR-138-5p/NLRP3 axis plays an essential role in regulating the cognitive behavior, pathological changes and apoptosis of hippocampal neurons, expression of inflammation-related factors (NLRP3, caspase-1, IL-1β, and IL-18), and microglial activation in LPS-induced cognitive impairment rats.ConclusionOur results demonstrated for the first time that lncRNA 4344 regulates NLRP3-related neuroinflammation and cognitive impairment by targeting miR-138-5p, providing a possible target for the treatment of diseases characterized by a cognitive deficit.     

Hearing loss after lumbar puncture

We report a 63-year-old man who developed transient acute on chronic hearing loss after a lumbar puncture performed to investigate raised intracranial pressure. He was subsequently found to have stenosis of the distal left transverse sinus, which was treated with stenting.     

Inhibition of phosphodiesterase-4 suppresses HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation in mice exposed to chronic unpredictable mild stress

Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg, i.g.) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1β. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.     

Endovascular treatment combined with vertebral artery endarterectomy for patients with acute tandem vertebrobasilar artery occlusion

PurposeTo evaluate the safety and efficacy of endovascular treatment combined with vertebral artery endarterectomy in patients with acute tandem vertebrobasilar artery occlusion.MethodsFrom April 2017 to March 2019, three patients with acute basilar artery occlusion combined with ostial vertebral occlusion in our institution were enrolled in the study. They underwent endovascular treatment combined with vertebral artery endarterectomy. The clinical, technical and functional outcomes of the patients were retrospectively analysed.ResultsAll three patients in the study underwent complete recanalization. The modified Thrombolysis in Cerebral Infarction (mTICI) grade was 2b/3 in all patients. The modified Rankin Scale (mRS) score was 0–2 for the three patients at 3 months. Follow-up CT scans revealed no cerebral haemorrhage, and no patients died during follow-up. All patients achieved good clinical outcomes after the combined treatment.ConclusionEndovascular treatment combined with vertebral artery endarterectomy is a feasible method to treat patients with acute basilar artery occlusion combined with ostial vertebral occlusion, especially when the guidewire cannot pass through the ostium of the dominant vertebral artery occlusion.     

A panel of four cytokines predicts the prognosis of patients with malignant gliomas

A comprehensive evaluation of cytokine levels in patients with gliomas could provide important information for the progression and host responses of gliomas. We studied a panel of 120 cytokines and growth factors and investigated their prognostic values for glioma. A protein antibody array was first performed to study the prognostic significance of 120 cytokines in the plasma samples of 45 glioblastoma patients prior to craniotomy or biopsy procedure. An independent set of plasma samples from 260 patients with astrocytomas (80 grade II, 80 grade III, 100 grade IV) with complete clinicopathologic data and follow-ups were used for validation. Ten cytokines were identified by significance analysis of microarray, in which four were associated with poor prognosis (IL-15, MCP-1, GDNF, IL-1R4/ST2), and six were associated with good prognosis (IGFBP-6, MIP-1δ, ICAM-3, IL-7, MIP-3β, and sgp130) of the glioblastoma patients. Moreover, a 4-cytokine panel composed of IL-7, IL1R4/ST2, sgp130 and MCP-1 showed significant correlation with overall survival of the glioblastoma patients (HR 2.068; 95 % CI 1.357–3.153; p = 0.001). In the validation set, the cytokine panel was significantly correlated with overall survival in the 260 glioma patients (HR 3.480, 95 % CI 1.890–6.422) in multivariate Cox regression analysis. It also showed strong correlation with survival in patients with malignant gliomas (grade III: HR 2.790, 95 % CI 1.597–3.984, p = 0.002; grade IV: HR 1.753; 95 % CI 1.502–2.255, p < 0.001). This panel of four cytokines: IL-7, IL1R4/ST2, sgp130, and MCP-1 can serve as a prognostic marker for patients with malignant gliomas.