HADHA promotes glioma progression by accelerating MDM2-mediated p53 ubiquitination.

Glioma represents a notoriously aggressive and malignant tumor that targets the central nervous system, with a poor prognosis for patients. In this research, we set out to examine the role of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) in glioma, its clinical significance, as well as its potential biological mechanisms. In this study, we used immunohistochemistry staining to assess the expression level of HADHA in glioma tissues. We also evaluated the correlation between HADHA expression and patient survival using the Kaplan-Meier method. To determine the role of HADHA in glioma cells, we conducted loss-of-function assays in vitro and in vivo. Additionally, we utilized co-immunoprecipitation and protein stability assays to investigate the potential mechanisms involving HADHA, MDM2, and p53 in glioma. Our research findings indicate that gliomas exhibit high levels of HADHA. Clinically, high expression of HADHA suggests an increased risk of malignant tumors, recurrence, and reduced survival rates. Functionally, knocking down HADHA can lead to decreased proliferation, enhanced apoptosis, and inhibited migration of glioma cells. Mechanistically, HADHA accelerates MDM2-mediated p53 ubiquitination through interaction with MDM2. Consistently, MDM2 knockdown or overexpression of p53 can attenuate the promoting effect of HADHA overexpression on the malignant progression of glioma. We have discovered a novel role of HADHA in promoting MDM2-mediated p53 ubiquitination, which contributes to the progression of glioma. This finding provides a new perspective to understand the pathogenesis of glioma and offers a potential target for developing innovative therapeutic strategies.

Near-Infrared-II Imaging Revealed Hypothermia Regulates Neuroinflammation Following Brain Injury by Increasing the Glymphatic Influx.

Advanced in vivo imaging techniques have facilitated the comprehensive visual exploration of animal biological processes, leading to groundbreaking discoveries such as the glymphatic system. However, current limitations of macroscopic imaging techniques impede the precise investigation of physiological parameters regulating this specialized lymphatic transport system. While NIR-II fluorescence imaging has demonstrated advantages in peripheral lymphatic imaging, there are few reports regarding its utilization in the glymphatic system. To address this, a noninvasive transcranial macroscopic NIR-II fluorescence imaging model is developed using a cyanine dye-protein coupled nanoprobe. NIR-II imaging with high temporal and spatial resolution reveals that hypothermia can increase the glymphatic influx by reducing the flow rate of cerebrospinal fluid. In addition, respiratory rate, respiratory amplitude, and heart rate all play a role in regulating the glymphatic influx. Thus, targeting the glymphatic influx may alter the trajectory of immune inflammation following brain injury, providing therapeutic prospects for treating brain injury with mild hypothermia.

Effect of boron nitride overlayers on Co@BNNSs/BN-Catalyzed aqueous phase selective hydrogenation of cinnamaldehyde.

The confinement effect known as efficient strategy to enhance the heterocatalytic activity and stability, but a clear view regarding the role of encapsulated overlayers is far from convincing at present, especially, the penetration of substrates with different size. Herein, the experimental evidence about the impacts of BN overlayers on hydrogenation is obtained over Co@BN/BN model catalysts with tuned thinness, in which BN overlayers encapsuled Co particles that dispersed on the defective BN supports, fabricating by the nitridizing of ball-milled BN microplates under NH3 atmosphere. The thinness and crystallinity of BN shells was simply tuned by controlling the pyrolyzed temperature (600-900 °C). The cinnamaldehyde (CAL) selective hydrogenation is taken as probe reaction due to (1) both larger CAL and small H2 molecule involved simultaneously, (2) the middle CC and terminal CO bonds all involved. Combined with structural analysis, the results demonstrate that small H2 molecule can penetrate into the metal-cover interface through the defect sites, then inner Co core dissociate it to atomic H, and the hydrogenation mainly resulting from the spillover of H atoms which occurred on the BN surface. As a result, the thickest BN shells (∼3.4 nm) with ordered-layer-lattice significantly hindered the adsorption and activation of CAL, also the longest H spillover distance led to the lowest activity of Co@BN/BN-900. Instead, Co@BN/BN-600 with merely 2 âˆ¼ 3 overlayers presented the most efficient and highly chemoselective hydrogenation activity. The ultrathin but turbostratic BN overlayers provide more migrating sites also shortened the H spillover distance effectively, and the more favorable CO hydrogenation was also achieved driven by the steric hindrance effect of thinner BN shells. These observations provide new insights towards understanding of confined effect on catalysis process through the accurate regulation of BN shells properties.

Endoscopy-assisted high anterior cervical approach in craniovertebral junction (CVJ).

Background: Surgical procedures in the craniovertebral junction (CVJ) suffer from specific challenges due to the proximity between the cranium and spine containing the critical neurovascular structures and the brainstem, respectively. Owing to the complex transitional zone, it is highly challenging for classic surgical approaches to practically acquire the additional exposure to neurovascular structures of the CVJ. Inspired by these facts, we explore the feasibility of an endoscopy-assisted high anterior cervical approach in the CVJ. Methods: To explore the feasibility of an endoscopy-assisted approach, we quantitatively assessed the surgical corridor and extent of exposure of the CVJ in 6 cadaveric specimens using 0° and 30° endoscopes. Results: The applied endoscopes provided adequate exposure to neurovascular structures and the brainstem in the CVJ. Notably, the resection of the anterior arch of C1 is avoided in minimal anterior clivectomy. Further, improved exposure of the CVJ is obtained after removing the odontoid. Conclusion: An endoscope-assisted high anterior cervical approach in the CVJ significantly preserved the cervical spine stability while minimalizing the risk of neurovascular injury within the surgical corridor.

Integrated analysis of competitive endogenous ribose nucleic acids (ceRNAs)-related regulatory networks in invasive and non-invasive non-functioning pituitary adenomas (NFPAs).

Background: This study aims to identify the differentially expressed (DE) non-coding ribose nucleic acids (ncRNAs), messenger RNA (mRNA) expression profiles, and competitive endogenous RNA (ceRNA)-related regulatory networks in invasive and non-invasive nonfunctioning pituitary adenomas (NFPAs). Methods: A full-transcriptome sequencing of invasive and non-invasive NFPAs is carried out to evaluate the expression profiles of circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNA expression profiles. Results: The screening criteria resulted in 118 DEcircRNAs (88 up-regulated and 30 down-regulated), 105 DElncRNAs (68 up-regulated and 37 down-regulated), 43 DEmiRNAs (22 up-regulated and 21 down-regulated), and 268 DEmRNAs (194 up-regulated and 74 down-regulated). Accordingly, a ceRNA regulatory network related to invasive NFPA is constructed. Further, the Gene Ontology and Kyoto Encylopedia of Genes and Genomes analyses showed that circRNAs and lncRNAs in the network are related to chromatin remodeling, participating in the Janus kinase/signal transducer and activator of transcription (JAK-STAT) and calcium signaling pathways. Hsa-miR-1248 showed exceptional connectivity in the ceRNA regulatory network, which could be closely related to the invasiveness of NFPAs. Conclusions: Together, these findings clarified the regulatory mechanisms of invasive and non-invasive NFPAs, providing innovative research avenues and therapeutic targets for invasive NFPAs.

Sulforaphane alleviates hypoxic vestibular vertigo (HVV) by increasing NO production via upregulating the expression of NRF2.

Sulforaphane (SFP) treatment represses oxidative stress by activating NRF2. Meanwhile, SFP may also increase the production of nitric oxide (NO) and activate the signaling pathway of cyclic guanosine monophosphate (cGMP), which is involved in the pathogenesis of hypoxic vestibular vertigo (HVV). However, it remains unknown as whether SFP plays a therapeutic role in the treatment of HVV. A rat model of HVV was established to measure the levels of escape latency, malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) in the aorta tissues. Quantitative real-time PCR was performed to evaluate the expression of NRF2 mRNA, and Western blot and immunohistochemistry were carried out to analyze the expression of NRF2 protein. ELISA was used to examine the production of NO and cGMP. SFP treatment helped to maintain the escape latency and MDA, GSH, SOD concentrations in the brain of HVV rats, and recovered the expression of NRF2 inhibited in the brain of HVV rats. SFP treatment also elevated NO and cGMP production that was down-regulated in the brain of HVV rats. On the cellular level, SFP enhanced the expression of NRF2, reduced the concentrations of MDA, GSH and SOD, and promoted the production of NO and cGMP in a dose-dependent manner. In this study, we treated an animal model of HVV with SFP to investigate its effect on NO production and oxidative stress. Our work provided a mechanistic insight into the therapeutic effect of SFP on the treatment of HVV.

Acute cerebral venous outflow obstruction during convexity meningioma resection.

BACKGROUND: Cerebral venous outflow obstruction involves idiopathic intracranial hypertension, and the most common related condition is dural venous sinus stenosis or, in other words, an obstruction of the dural venous sinuses. In these cases, the pathological process is often chronic, displays only mild symptoms, and rarely requires urgent surgical intervention. In this study, we present a unique case involving an acute cerebral venous outflow obstruction that occurred during meningioma resection that ultimately had catastrophic consequences. MATERIALS AND METHODS: The patient's preoperative imaging only revealed an unremarkable frontal convexity meningioma with an average diameter exceeding 8 cm. She was admitted for a scheduled right frontoparietal craniotomy for lesion resection. RESULTS: The patient's unique congenital dural venous sinus structure along with a non-surgical epidural hematoma both contributed to a catastrophic outcome, causing a progressive hemispheric encephalocele, significant blood loss, and wound closure difficulties. CONCLUSION: Neurosurgeons should place an additional focus on cerebral venous outflow patency during tumor resection, even if the tumor does not involve the transverse or sigmoid sinuses. It is well known that the tacking sutures play an essential role in preventing an epidural hematoma, but the procedure to mitigate hematomas occurring outside the surgical field of view is not fully recognized by neurosurgeons. If dural tacking sutures are placed after complete tumor resection, the prophylactic effect for preventing EDH in the non-surgical areas may not be guaranteed. Therefore, we strongly advocate for the tacking sutures to be accurately placed before dural incisions are made.

Immune profiling of pituitary tumors reveals variations in immune infiltration and checkpoint molecule expression.

PURPOSE: Pituitary tumors are the second most common primary brain tumors. Functional tumors demonstrate increased PD-L1 expression, but expression of other checkpoint regulators has not been characterized. We sought to characterize the immune microenvironment of human pituitary tumors to identify new treatment opportunities. METHODS: 72 pituitary tumors were evaluated for expression of the immune regulatory markers programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte activation gene 3 (LAG3) and tumor necrosis factor receptor superfamily member 4 (OX40) by immunohistochemistry (IHC). Lymphocyte infiltration, macrophage infiltration, and angiogenesis were analyzed using IHC. Expression of pituitary tumor initiating cell marker CD15 and mismatch repair proteins MutS protein homolog 2 (MSH2) and MutS protein homolog 6 (MSH6) was also assessed. RESULTS: Pituitary tumors were infiltrated by macrophages and T cells, and they expressed varying levels of PD-L1, PD-L2, VISTA, LAG3, and OX40. Functional tumors and tumors with high expression of tumor stem cell markers had higher immune cell infiltration and greater expression of immunosuppressive checkpoint regulators. Increased PD-L1 and LAG3 and reduced VISTA were observed in primary tumors compared to recurrent tumors. CONCLUSION: Immune cell infiltration and checkpoint regulator expression vary depending on functional status and presence of pituitary tumor initiating cells. Functional tumors may have a particularly immunosuppressive microenvironment. Further studies of immune checkpoint blockade of pituitary tumors, particularly functional tumors, are warranted, though combination therapy may be required.

Corrigendum to "Determination of Serum Lost Goodwill Target Proteome in Patients with Severe Traumatic Brain Injury".

[This corrects the article DOI: 10.1155/2015/183821.].

Osteoglycin promotes meningioma development through downregulation of NF2 and activation of mTOR signaling.

BACKGROUND: Meningiomas are the most common primary intracranial tumors in adults. While a majority of meningiomas are slow growing neoplasms that may cured by surgical resection, a subset demonstrates more aggressive behavior and insidiously recurs despite surgery and radiation, without effective alternative treatment options. Elucidation of critical mitogenic pathways in meningioma oncogenesis may offer new therapeutic strategies. We performed an integrated genomic and molecular analysis to characterize the expression and function of osteoglycin (OGN) in meningiomas and explored possible therapeutic approaches for OGN-expressing meningiomas. METHODS: OGN mRNA expression in human meningiomas was assessed by RNA microarray and RNAscope. The impact of OGN on cell proliferation, colony formation, and mitogenic signaling cascades was assessed in a human meningioma cell line (IOMM-Lee) with stable overexpression of OGN. Furthermore, the functional consequences of introducing an AKT inhibitor in OGN-overexpressing meningioma cells were assessed. RESULTS: OGN mRNA expression was dramatically increased in meningiomas compared to a spectrum of other brain tumors and normal brain. OGN-overexpressing meningioma cells demonstrated an elevated rate of cell proliferation, cell cycle activation, and colony formation as compared with cells transfected with control vector. In addition, NF2 mRNA and protein expression were both attenuated in OGN-overexpressing cells. Conversely, mTOR pathway and AKT activation increased in OGN-overexpressing cells compared to control cells. Lastly, introduction of an AKT inhibitor reduced OGN expression in meningioma cells and resulted in increased cell death and autophagy, suggestive of a reciprocal relationship between OGN and AKT. CONCLUSION: We identify OGN as a novel oncogene in meningioma proliferation. AKT inhibition reduces OGN protein levels in meningioma cells, with a concomitant increase in cell death, which provides a promising treatment option for meningiomas with OGN overexpression.

Determination of Serum Lost Goodwill Target Proteome in Patients with Severe Traumatic Brain Injury.

This study investigates the biokinetics of LGT proteome, a potential biomarker of severe TBI, in serum of severe TBI patients. The LGT proteome presents in the serum of severe TBI patients. The abundance diversity of LGT proteome is closely associated with pathologic condition of TBI patients. Serum LGT proteome may be used as a promising marker for evaluating severity of severe TBI.

[Neuronavigation-guided pure endoscopic endonasai transsphenoidal approach for pituitary adenomas].

OBJECTIVE: To explore the efficacies of neuronavigation-guided pure endoscopic endonasal transsphenoidal approach for removing pituitary adenomas. METHODS: Retrospective analyses were conducted for the clinical data of 139 patients undergoing pure endoscopic endonasal transsphenoidal surgery for pituitary adenomas between July 2011 and July 2014. There were 55 males and 84 females with a mean age of 48. 9 (21 - 73) years. The classifications of Hardy-Wilson were I (n =16), II (n = 39), III (n = 48) and IV (n = 36). Neuronavigation was used in all patients. And neuro-ophthalmological, neuroimaging and endocrinological follow-ups were conducted postoperatively. RESULTS: Total (n = 95, 68. 3%), subtotal (n = 33, 23. 7%) and partial (n = 11, 7. 9%) removals were achieved. For Hardy-Wilson I, gross total removal was achieved (n = 16, 100%); Hardy-Wilson II (n = 35, 89. 7%), Hardy-Wilson III (n = 34, 70. 8%) and Hardy-Wilson IV (n = 10, 27. 8%). Postoperative visual acuity improved (92. 1%, 70/76) and endocrine remission was observed (59. 6%, 53/89). The postoperative complications included cerebrospinal fluid (CSF) leakage (n = 8, 5. 8%), meningitis (n = 3), sellar hematoma (n = 5) and delayed carotid artery rupture (n = 1). And the patient of hemorrhagic shock underwent emergency interventional procedures and was discharged successfully. CONCLUSION: Pure endoscopic endonasal transsphenoidal approach for removing pituitary adenoma is both safe and effective. And its efficacies may further increased through combined neuronavigation.

Spontaneous intercalation of long-chain alkyl ammonium into edge-selectively oxidized graphite to efficiently produce high-quality graphene.

Mass production of high-quality graphene nanosheets (GNs) is essential for practical applications. We report that oxidation of graphite by low concentration KMnO4 at relatively high temperature (60 °C) leads to edge-selectively oxidized graphite (EOG) which preserves the high crystalline graphitic structure on its basal planes while the edges are functionalized by oxygen-containing groups. Long-chain tetradecyl-ammonium salt (C14N⁺) could be spontaneously intercalated into EOG to form intercalated EOG-C14N⁺ compounds. Gentle and short-time sonication of EOG-C14N⁺ in toluene can full exfoliate EOG into edge-oxidized graphene nanosheets (EOGNs) with concentration of 0.67 mg/ml, monolayer population up to 90% and lateral size from 1 µm to >100 µm. The EOG and EOGN films show excellent electrical conductance, which is far superior to their graphene oxide (GO) counterparts. Our method provides an efficient way to produce high-quality GNs, and the resultant EOG also can be directly used for production of multifunctional materials and devices.

Comparison of the neural differentiation potential of human mesenchymal stem cells from amniotic fluid and adult bone marrow.

Human mesenchymal stem cells (MSCs) are considered a promising tool for cell-based therapies of nervous system diseases. Bone marrow (BM) has been the traditional source of MSCs (BM-MSCs). However, there are some limitations for their clinical use, such as the decline in cell number and differentiation potential with age. Recently, amniotic fluid (AF)-derived MSCs (AF-MSCs) have been shown to express embryonic and adult stem cell markers, and can differentiate into cells of all three germ layers. In this study, we isolated AF-MSCs from second-trimester AF by limiting dilution and compared their proliferative capacity, multipotency, neural differentiation ability, and secretion of neurotrophins to those of BM-MSCs. AF-MSCs showed a higher proliferative capacity and more rapidly formed and expanded neurospheres compared to those of BM-MSCs. Both immunocytochemical and quantitative real-time PCR analyses demonstrated that AF-MSCs showed higher expression of neural stemness markers than those of BM-MSCs following neural stem cell (NSC) differentiation. Furthermore, the levels of brain-derived growth factor and nerve growth factor secreted by AF-MSCs in the culture medium were higher than those of BM-MSCs. In addition, AF-MSCs maintained a normal karyotype in long-term cultures after NSC differentiation and were not tumorigenic in vivo. Our findings suggest that AF-MSCs are a promising and safe alternative to BM-MSCs for therapy of nervous system diseases.

Vasculogenic mimicry is a prognostic factor for postoperative survival in patients with glioblastoma.

A previous report has confirmed the existence and clinical significance of vasculogenic mimicry (VM) in glioma. However, its conclusions about the negative clinical significance of VM in glioblastoma are based on a small group of patients and, thus, might be unconvincing. The aim of the present study was to reevaluate the clinical significance of VM in glioblastoma. Patients were classified as VM-positive or VM-negative according to CD34 and periodic acid-Schiff staining. The association between VM and the clinical characteristics of the patients was analyzed. Univariate and multivariate analyses were carried out to identify the independent prognostic factors for overall survival using the Cox regression hazard model. Survival times were estimated using the Kaplan-Meier method and compared using the log-rank test. Of all 86 glioblastomas, 23 were found to have VM. The presence of VM in glioblastoma was not associated with gender, age, Karnofsky performance status, hydrocephalus, tumor burden, microvessel density, tumor relapse, or the extent of tumor resection. The univariate and multivariate analyses revealed that VM is an independent prognostic factor for overall survival. The median survival time for patients with VM was 11.17 months compared with 16.10 months for those without VM (P = 0.017). In addition to VM, an age of 65 years or older, a KPS of 60 or less, a large tumor burden are significant prognostic factors for patient survival. Our data suggest that VM might be an independent adverse prognostic factor in newly diagnosed GBM, further prospective studies are needed to answer this question.

Glioma derived isocitrate dehydrogenase-2 mutations induced up-regulation of HIF-1α and ß-catenin signaling: possible impact on glioma cell metastasis and chemo-resistance.

The identification of heterozygous mutations (with an incidence up to 85%) in either the R132 residue of isocitrate dehydrogenase-1 (IDH1) or the R172 residue of IDH2 in human low-grade diffuse gliomas was remarkable because no oncogenic pathway had been previously documented correlated with these enzymes. In spite of a recent surge in elucidating the tumorigenic activity of IDH mutations in glioblastoma, the underlying biological mechanisms remain poorly understood. We showed here that C6 glioma cells transiently over-expressing IDH2(R172G) induced nuclear accumulation of ß-catenin, up-regulation of HIF-1α signaling and corresponding proteins expression that were closely related with tumor invasion and chemo-resistance. These results demonstrated a functional model in which IDH mutations were closely interrelated with glioma progression and could hold some therapeutic implications for future human glioma treatment.

Molecular targeting of malignant glioma cells with an EphA2-specific immunotoxin delivered by human bone marrow-derived mesenchymal stem cells.

Immunotoxins have shown great promise as an alternative treatment for brain malignancies such as gliomas, but their failure to penetrate into the tumor mass remains a major problem. Mesenchymal stem cells exhibit tropism to tumor tissue and may serve as a cellular vehicle for the delivery and local production of antitumor agents. In this study, we used human bone marrow-derived mesenchymal stem cells (hMSCs) as a vehicle for the targeted delivery of EphrinA1-PE38, a very specific immunotoxin against the EphA2 receptor that is overexpressed in gliomas. hMSCs were transduced with adenovirus to express secretable EphrinA1-PE38. Our invitro assays confirmed the expression, release and selective killing effect of the immunotoxin produced by hMSCs. Furthermore, the intratumoral injection of engineered hMSCs was effective at inhibiting tumor growth in a malignant glioma tumor model. These results indicate that gene therapy utilizing EphrinA1-PE38-secreting hMSCs may provide a novel approach for the local treatment of malignant gliomas.

ß-catenin as a potential key target for tumor suppression.

ß-catenin is a multifunctional protein identified to be pivotal in embryonic patterning, organogenesis and adult homeostasis. It plays a critical structural role in mediating cadherin junctions and is also an essential transcriptional co-activator in the canonical Wnt pathway. Evidence has been documented that both the canonical Wnt pathway and cadherin junctions are deregulated or impaired in a plethora of human malignancies. In the light of this, there has been a recent surge in elucidating the mechanisms underlying the etiology of cancer development from the perspective of ß-catenin. Here, we focus on the emerging roles of ß-catenin in the process of tumorigenesis by discussing novel functions of old players and new proteins, mechanisms identified to mediate or interact with ß-catenin and the most recently unraveled clinical implications of ß-catenin regulatory pathways toward tumor suppression.

Recombinant scorpion insect excitatory toxin BmK IT accelerates the growth of insect Spodoptera frugiperda 9 cells.

Several scorpion insect toxins are selectively active on the lepidopterous and dipterous insects. The gene encoding insect excitatory neurotoxin (BmK IT) from the scorpion Buthus martensii Karsch was expressed in Escherichia coli BL21(DE3) at a high level of 3 mg/0.5 L using the prokaryotic expression system pTWIN1. Colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), whole-cell patch-clamp technique and immunofluorescence assays were used to evaluate the toxicity of rBmK IT to insect Spodoptera frugiperda 9 (Sf9) cells and to analyze the potential mechanism of this toxicity. rBmK IT accelerated the growth of Sf9 cells in a dose-dependent manner. Voltage-gating sodium channel activity could not be detected in Sf9 cells using a whole-cell patch-clamp technique. However, immunofluorescence analysis clearly showed co-localization of tetrodotoxin (TTX) and rBmK IT on the Sf9 cell membrane, which demonstrated that rBmK IT could bind to and act on the voltage-gated sodium channels on the Sf9 cells by the high affinity action power. The findings presented in this study are essential for further study of this peptide.