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Background: Cushing disease (CD) is a rare clinical neuroendocrine disease. CD is characterized by abnormal hypercortisolism induced by a pituitary adenoma with the secretion of adrenocorticotropic hormone. Individuals with CD usually exhibit atrophy of gray matter volume. However, little is known about the alterations in topographical organization of individuals with CD. This study aimed to investigate the structural covariance networks of individuals with CD based on the gray matter volume using graph theory analysis., Methods: High-resolution T1-weighted images of 61 individuals with CD and 53 healthy controls were obtained. Gray matter volume was estimated and the structural covariance network was analyzed using graph theory. Network properties such as hubs of all participants were calculated based on degree centrality., Results: No significant differences were observed between individuals with CD and healthy controls in terms of age, gender, and education level. The small-world features were conserved in individuals with CD but were higher than those in healthy controls. The individuals with CD showed higher global efficiency and modularity, suggesting higher integration and segregation as compared to healthy controls. The hub nodes of the individuals with CD were Short insular gyri (G_insular_short_L), Anterior part of the cingulate gyrus and sulcus (G_and_S_cingul-Ant_R), and Superior frontal gyrus (G_front_sup_R)., Conclusions: Significant differences in the structural covariance network of patients with CD were found based on graph theory. These findings might help understanding the pathogenesis of individuals with CD and provide insight into the pathogenesis of this CD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Objective: Cushing disease (CD) is a rare clinical disease in which brain structural and function are impaired as the result of excessive cortisol. However, little is known whether rich-club organization changes in patients with CD, as visualized on resting-state magnetic resonance imaging (fMRI), can reverse to normal conditions after transsphenoidal surgery (TSS). In this study, we aimed to investigate whether the functional connectivity of rich-club organization is affected and whether any abnormal changes may reverse after TSS., Methods: In this study, 38 patients with active CD, 33 with patients with CD in remission, and 41 age-, sex-, and education-matched healthy control participants underwent resting-state fMRI. Brain functional connectivity was constructed based on fMRI and rich club was calculated with graph theory approach. We constructed the functional brain networks for all participants and calculated rich-club connectivity based on fMRI., Results: We identified left precuneus, right precuneus, left middle cingulum, right middle cingulum, right inferior temporal, right middle temporal, right lingual, right postcentral, right middle occipital, and right precentral regions as rich club nodes. Compared with healthy control participants, rich-club connectivity was significantly lower in patients with active CD (P < 0.001). Moreover, abnormal rich-club connectivity improved to normal after TSS., Conclusions: Our results show rich-club organization was disrupted in patients with active CD with excessive cortisol production. TSS can reverse abnormal rich-club connectivity. Rich club may be a new indicator to investigate the outcomes of TSS and to increase our understanding of the effect of excessive cortisol on brain functional connectivity in patients with CD., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Design: Cushing's disease (CD) is a rare clinical syndrome characterized by chronic exposure to hypercortisolism due to an adrenocorticotropic hormone-secreting pituitary adenoma. The adverse effects of chronic exposure to hypercortisolism on the human brain remain unclear. The purpose of this study was to assess the prevalence of cerebral microbleeds (CMBs) in CD patients and their associations with clinical characteristics., Methods: In this study, 48 active CD patients, 39 remitted CD patients, and 52 healthy control (HC) subjects underwent MRI. CD patients also underwent neuropsychological testing and clinical examinations. The number, locations, and volumes of CMBs were assessed on quantitative susceptibility mapping (QSM) images and with the Microbleed Anatomical Rating Scale. The correlation between CMBs and clinical characteristics was explored., Results: The prevalence of CMBs among active and remitted CD patients was higher than that among HCs (16.3%, 20.5%, and 3.3%, respectively). Moreover, the age of CD patients with CMBs were much younger than HCs with CMBs. Furthermore, the increased number of CMBs in active CD patients was associated with increased cerebrospinal fluid (CSF) volumes in remitted CD patients., Conclusions: Chronic exposure to hypercortisolism may be relevant to CMBs and significantly correlated with altered brain volumes in CD.

XL388 is a highly efficient and orally-available ATP-competitive PI3K-mTOR dual inhibitor. Its activity against glioma cells was studied here. In established and primary human glioma cells, XL388 potently inhibited cell survival and proliferation as well as cell migration, invasion and cell cycle progression. The dual inhibitor induced significant apoptosis activation in glioma cells. In A172 cells and primary human glioma cells, XL388 inhibited Akt-mTORC1/2 activation by blocking phosphorylation of Akt and S6K1. XL388-induced glioma cell death was only partially attenuated by a constitutively-active mutant Akt1. Furthermore, it was cytotoxic against Akt1-knockout A172 glioma cells. XL388 downregulated MAF bZIP transcription factor G (MAFG) and inhibited Nrf2 signaling, causing oxidative injury in glioma cells. Conversely, antioxidants, n-acetylcysteine, pyrrolidine dithiocarbamate and AGI-106, alleviated XL388-induced cytotoxicity and apoptosis in glioma cells. Oral administration of XL388 inhibited subcutaneous A172 xenograft growth in severe combined immunodeficient mice. Akt-S6K1 inhibition and MAFG downregulation were detected in XL388-treated A172 xenograft tissues. Collectively, XL388 efficiently inhibits human glioma cell growth, through Akt-mTOR-dependent and -independent mechanisms.

Purpose: Glucocorticoid (GC) is probably related to biological aging, but the exact mechanism remains unknown. Cushing's disease (CD) could represent a unique human model for examining the effects of prolonged exposure to hypercortisolism and its relationship with aging. Thus, we studied the alterations of neurites in CD patients with Neurite orientation dispersion and density imaging (NODDI)., Methods: CD patients (n = 15) and healthy control subjects (n = 15) were included in this study. Orientation dispersion index (Odi), neurite density index (Ndi), partial fraction of free water (f iso ), partial fraction of extracellular water (f ec ) were examined in a cross-sectional analysis., Results: Significant altered NODDI parameters were found in CD patients. Some of these alterations were correlated with current age. Additionally, increased dendritic density was found in cerebellar of CD patients., Conclusion: Hypercortisolism relative reductions of the dendritic density were correlated with current age in several regions of CD patients. Our study enhances the understanding of the link between the aging and GC., Competing Interests: Declaration of Competing Interest There are no potential conflicts of interest relevant to this article., (Copyright © 2020. Published by Elsevier B.V.)

To investigate the whole functional brain networks of active Cushing disease (CD) patients about topological parameters (small world and rich club et al.) and compared with healthy control (NC). Nineteen active CD patients and twenty-two healthy control subjects, matched in age, gender, and education, underwent resting-state fMRI. Graph theoretical analysis was used to calculate the functional brain network organizations for all participants, and those for active CD patients were compared for and NCs. Active CD patients revealed higher global efficiency, shortest path length and reduced cluster efficiency compared with healthy control. Additionally, small world organization was present in active CD patients but higher than healthy control. Moreover, rich club connections, feeder connections and local connections were significantly decreased in active CD patients. Functional network properties appeared to be disrupted in active CD patients compared with healthy control. Analyzing the changes that lead to abnormal network metrics will improve our understanding of the pathophysiological mechanisms underlying CD.

Background: Neural stem cells (NSCs) transplantation is considered a promising treatment for Parkinson's disease. But most NSCs are differentiated into glial cells rather than neurons, and only a few of them survive after transplantation due to the inflammatory environment., Methods: In this study, neural stem cells (NSCs) and microglial cells both forced with the Nurr1 gene were transplanted into the striatum of the rat model of PD. The results were evaluated through reverse transcription polymerase chain reaction (RT-PCR), Western blot, and immunofluorescence analysis., Results: The behavioral abnormalities of PD rats were improved by combined transplantation of NSCs and microglia, both forced with Nurr1. The number of tyrosine hydroxylase+ cells in the striatum of PD rats increased, and the number of Iba1+ cells decreased compared with the other groups. Moreover, the dopamine neurons differentiated from grafted NSCs could still be detected in the striatum of PD rats after 5 months., Conclusions: The results suggested that transplantation of Nurr1-overexpressing NSCs and microglia could improve the inhospitable host brain environments, which will be  a new potential strategy for the cell replacement therapy in PD., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

The adverse effects of hypercortisolism on the human brain have been highlighted in previous studies of Cushing's disease (CD). However, the reversibility of brain damage after the resolution of hypercortisolism remains unclear. Thus, we studied the potential volumetric reversibility in biochemically remitted CD patients. Cross-sectional analysis demonstrated the active CD patients (n = 61) had the smallest gray matter (GM) volumes (553.33 ± 45.90 CM 3 ) among four groups. While the GM volumes of short-term remitted CD patients (586.62 ± 46.89 CM 3 , n = 28) and long-term remitted CD patients (596.58 ± 45.95 CM 3 , n = 35) were between those of the active CD patients and healthy control subjects (628.14 ± 46.88 CM 3 , n = 74). Moreover, significant positive correlations between remitted time and GM volumes were only found in short-term remitted CD patients. On the contrary, the alterations of white matter (WM) in CD patients seem to be independent of concomitant hypercortisolism, persisting after remission. A preliminary longitude analysis also demonstrated similar results. Volumetric reversibility of GM, but not WM is highly prevalent in short-term after resolution of hypercortisolism in Cushing disease. Our study enhances our understanding of the reversible and the irreversible structural alterations in the human brain due to hypercortisolism., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Microglia contribute to the regulation of neuroinflammation and play an important role in the pathogenesis of brain disorders. Thus, regulation of neuroinflammation triggered by activation of microglia has become a promising therapeutic strategy. Here, we investigated the beneficial effects of Gastrodin in activated microglia and analyzed the underlying molecular mechanisms. Microglia activation was regulated by Gastrodin not only in terms of microglia population size but also production of inflammatory mediators. Gastrodin inhibited the expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), cyclin-D1 and Ki67 in lipopolysaccharide (LPS)-stimulated BV-2 or primary microglia. Gastrodin also suppressed the expression of iNOS and Ki67 in activated microglia in three-day-old LPS-injected postnatal rats. In addition, the present results have shown that Gastrodin inhibited LPS-induced phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser 9 and β-catenin activity. We further extended our investigation to determine whether Wnt/β-catenin signaling pathway was involved in the anti-inflammatory and anti-proliferation function of Gastrodin. β-Catenin antagonist (XAV939) was used to block LPS-mediated upregulation of iNOS, TNF-α, cyclin-D1, nitric oxide (NO) and the number of cells in the G2/M+S phase of cell cycle. Moreover, treatment with LiCl, a special Wnt/β-catenin pathway agonist significantly blocked Gastrodin-mediated down-regulation of iNOS, TNF-α, cyclin-D1, NO and the number of cells in the G2/M+S phase of cell cycle in LPS-stimulated BV-2 microglia. Taken together, the present results suggested that Gastrodin mediated anti-inflammatory and anti-proliferation effects in activated microglia by modulating the Wnt/β-catenin signaling pathway., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To summarize the characteristics of patients with pituitary stalk thickening, analyze the association between pituitary stalk width and hypopituitarism, and develop a diagnostic model to differentiate neoplastic and inflammatory origins. Methods: A total of 325 patients with pituitary stalk thickening in a tertiary teaching hospital between January 2012 and February 2018 were enrolled. Basic characteristics and hormonal status were evaluated. Indicators to predict etiology in patients with histologic diagnoses were analyzed. Results: Of the 325 patients, 62.5% were female. Deficiency in gonadotropin was most common, followed by corticotropin, growth hormone, and thyrotropin. The increase in pituitary stalk width was associated with a risk of central diabetes insipidus (odds ratio [OR], 3.57; P <.001) and with a combination of central diabetes insipidus and anterior pituitary deficiency (OR, 2.28; P = .029). The cut-off pituitary stalk width of 4.75 mm had a sensitivity of 69.2% and a specificity of 71.4% for the presence of central diabetes insipidus together with anterior pituitary deficiency. Six indicators (central diabetes insipidus, pattern of pituitary stalk thickening, pituitary stalk width, neutrophilic granulocyte percentage, serum sodium level, and gender) were used to develop a model having an accuracy of 95.7% to differentiate neoplastic from inflammatory causes. Conclusion: Pituitary stalk width could indicate the presence of anterior pituitary dysfunction, especially in central diabetes insipidus patients. With the use of a diagnostic model, the neoplastic and inflammatory causes of pituitary stalk thickening could be preliminarily differentiated. Abbreviations: APD = anterior pituitary dysfunction; AUC = area under the curve; CDI = central diabetes insipidus; GH = growth hormone; MRI = magnetic resonance imaging; OR = odd ratio; PHBS = posterior hypophyseal bright spots; PST = pituitary stalk thickening; PSW = pituitary stalk width.

Objective: To analyze the indication and the outcome of trans-sphenoidal surgery (TSS) in Cushing's disease (CD) with negative high dose dexamethasone suppression tests (HDDST) results. Methods: Eighteen cases of ACTH-dependent Cushing's syndrome (CS) with negative HDDST results in the Department of Neurosurgery in Shanghai Ruijin Hospital from January 2015 to December 2017 were retrospectively reviewed. All patients underwent TSS. There were 5 males and 13 females, with an average age of (41±14) years. Results: All patients underwent bilateral inferior petrosal sinus sampling (BIPSS) before the surgery and got evidence of pituitary origin of ACTH secretion. They were thus indicated for TSS. Immediate post-operative remission was achieved in ratio 17/18. There were no recurrences within a flow-up of 1 to 3 years. Pituitary ACTH secreting adenomas were pathologically confirmed in 15 cases, including the one who did not achieve post-operative remission. Thus, all 18 patients with negative HDDST results can finally be confirmed as CD. Conclusions: HDDST alone is not sufficient to eliminate CD. For patients with ACTH-dependent CS with negative HDDST results, BIPSS should be further performed. The fact of post-operative remission and the pathological confirm of ACTH secreting pituitary adenoma may add final evidence to the diagnosis of CD.

Introduction: Neural stem cells (NSCs) are the most promising cells for cell replacement therapy for Parkinson's disease (PD). However, a majority of the transplanted NSCs differentiated into glial cells, thereby limiting the clinical application. Previous studies indicated that chronic neuroinflammation plays a vital role in the degeneration of midbrain DA (mDA) neurons, which suggested the developing potential of therapies for PD by targeting the inflammatory processes. Thus, Nurr1 (nuclear receptor-related factor 1), a transcription factor, has been referred to play a pivotal role in both the differentiation of dopaminergic neurons in embryonic stages and the maintenance of the dopaminergic phenotype throughout life., Aim: This study investigated the effect of Nurr1 on neuroinflammation and differentiation of NSCs cocultured with primary microglia in the transwell coculture system., Results: The results showed that Nurr1 exerted anti-inflammatory effects and promoted the differentiation of NSCs into dopaminergic neurons., Conclusions: The results suggested that Nurr1 protects dopaminergic neurons from neuroinflammation insults by limiting the production of neurotoxic mediators by microglia and maintain the survival of transplanted NSCs. These phenomena provided a new theoretical and experimental foundation for the transplantation of Nurr1-overexpressed NSCs as a potential treatment of PD., (© 2018 John Wiley & Sons Ltd.)

Melanoma antigen A6 (MAGEA6)/TRIM28 complex is a cancer-specific ubiquitin ligase, which degradates tumor suppressor protein AMP-activated protein kinase (AMPK). We show that MAGEA6 is uniquely expressed in human glioma tissues and cells, which is correlated with AMPKα1 downregulation. It is yet absent in normal brain tissues and human astrocytes/neuronal cells. MAGEA6 knockdown by targeted-shRNA in glioma cells restored AMPKα1 expression, causing mTORC1 in-activation and cell death/apoptosis. Reversely, AMPKα1 knockdown or mutation ameliorated glioma cell death by MAGEA6 shRNA. In vivo, Glioma xenograft tumor growth in mice was largely inhibited following expressing MAGEA6 shRNA. AMPKα1 upregulation and mTORC1 inhibition were observed in MAGEA6 shRNA-bearing xenograft tissues. Collectively, MAGEA6 promotes glioma cell survival possibly via targeting AMPKα1., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: The data on patients with short-term remission of Cushing's disease (CD) might provide information that is not available from previous long-term remission studies. We aimed to investigate structural changes in the brain in these patients and to examine whether these changes were associated with clinical characteristics., Design: A cross-sectional study was performed., Methods: Thirty-four patients with CD (14 with CD in short-term remission and 20 with active CD) and 34 controls matched for age, sex and education underwent clinical evaluation and magnetic resonance imaging brain scans. Biometric measurements, disease duration and remission duration data were collected. Grey matter volumes in the whole brain were examined using voxel-based morphometry (VBM)., Results: No differences were observed in the grey matter volumes of the medial frontal gyrus (MFG) and cerebellum between the patients with remitted CD and healthy controls, whereas patients with active CD had smaller grey matter volumes in these two regions compared with controls and patients with remitted CD. Furthermore, significant correlations were found between remission time and grey matter values in these regions in short-term remission patients with CD. Additionally, greater grey matter volumes in the bilateral caudate of short-term remission patients with CD were observed., Conclusions: Trends for structural restoration were found in CD patients with short-term remission. This finding was associated with the number of days elapsed since curative surgery and the current age of the patients. This study enhances our understanding of potential reversibility after the resolution of hypercortisolism in CD patients., (© 2017 John Wiley & Sons Ltd.)

Exposure to chronic hypercortisolism has multiple adverse effects on brain biology in humans. Cushing's disease (CD) represents a unique and natural human model for examining the effects of hypercortisolism on the brain. This cross-sectional study used Diffusional Kurtosis Imaging (DKI) to investigate the microstructure alterations in both white matter (WM) and gray matter (GM) of CD patients and to determine the relationship of these changes with clinical characteristics. DKI images were obtained from 15 active CD patients. DKI parametric maps were estimated through voxel-based analyses (VBA) and compared with 15 healthy controls matched for age, sex and education. In addition, correlations were analyzed between the altered DKI parameters and clinical characteristics. Compared with healthy controls, CD patients mainly exhibited significantly altered diffuse parameters in the GM and WM of the left medial temporal lobe (MTL). The mean values of increased radial diffusivity (RD) of CD patients in GM of the left hippocampus/parahippocampal gyrus correlated positively with the clinical severity of CD. Additionally, we also found altered kurtosis parameters in the cerebellum and frontal lobe. DKI imaging of CD patients could represent complementary information in both white matter and gray matter. The impairment of the left MTL might explain some part of the memory and cognition impairments in CD patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Context and Objective: Cushing's disease (CD) provides a unique and naturalist model for studying the influence of hypercortisolism on the human brain and the reversibility of these effects after resolution of the condition. This cross-sectional study used resting-state fMRI (rs-fMRI) to investigate the altered spontaneous brain activity in CD patients and the trends for potential reversibility after the resolution of the hypercortisolism. We also aim to determine the relationship of these changes with clinical characteristics and cortisol levels., Subjects and Methods: Active CD patients (n = 18), remitted CD patients (n = 14) and healthy control subjects (n = 22) were included in this study. Amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values were calculated to represent spontaneous brain activity., Results: Our study resulted in three major findings: (i) active CD patients showed significantly altered spontaneous brain activity in the posterior cingulate cortex (PCC)/precuneus (PCu), occipital lobe (OC)/cerebellum, thalamus, right postcentral gyrus (PoCG) and left prefrontal cortex (PFC); (ii) trends for partial restoration of altered spontaneous brain activity after the resolution hypercortisolism were found in several brain regions; and (iii) active CD patients showed a significant correlation between cortisol levels and ALFF/ReHo values in the PCC/PCu, a small cluster in the OC and the right IPL., Conclusions: This study provides a new approach to investigating brain function abnormalities in patients with CD and enhances our understanding of the effect of hypercortisolism on the human brain. Furthermore, our explorative potential reversibility study of patients with CD may facilitate the development of future longitudinal studies., (© 2016 John Wiley & Sons Ltd.)

Background: Two recent whole-exome sequencing researches identifying somatic mutations in the ubiquitin-specific protease 8 (USP8) gene in pituitary corticotroph adenomas provide exciting advances in this field. These mutations drive increased epidermal growth factor receptor (EGFR) signaling and promote adrenocorticotropic hormone (ACTH) production. This study was to investigate whether the inhibition of USP8 activity could be a strategy for the treatment of Cushing's disease (CD)., Methods: The anticancer effect of USP8 inhibitor was determined by testing cell viability, colony formation, apoptosis, and ACTH secretion. The immunoblotting and quantitative reverse transcription polymerase chain reaction were conducted to explore the signaling pathway by USP8 inhibition., Results: Inhibition of USP8-induced degradation of receptor tyrosine kinases including EGFR, EGFR-2 (ERBB2), and Met leading to a suppression of AtT20 cell growth and ACTH secretion. Moreover, treatment with USP8 inhibitor markedly induced AtT20 cells apoptosis., Conclusions: Inhibition of USP8 activity could be an effective strategy for CD. It might provide a novel pharmacological approach for the treatment of CD.

Here, we studied the anti-glioma cell activity by a novel AMP-activated protein kinase (AMPK) activator GSK621. We showed that GSK621 was cytotoxic to human glioma cells (U87MG and U251MG lines), possibly via provoking caspase-dependent apoptotic cell death. Its cytotoxicity was alleviated by caspase inhibitors. GSK621 activated AMPK to inhibit mammalian target of rapamycin (mTOR) and downregulate Tetraspanin 8 (Tspan8) in glioma cells. AMPK inhibition, through shRNA knockdown of AMPKα or introduction of a dominant negative (T172A) AMPKα, almost reversed GSK621-induced AMPK activation, mTOR inhibition and Tspan8 degradation. Consequently, GSK621's cytotoxicity in glioma cells was also significantly attenuated by AMPKα knockdown or mutation. Further studies showed that GSK621, at a relatively low concentration, significantly potentiated temozolomide (TMZ)'s sensitivity and lethality against glioma cells. We summarized that GSK621 inhibits human glioma cells possibly via activating AMPK signaling. This novel AMPK activator could be a novel and promising anti-glioma cell agent.

Aim: Carvacrol (2-methyl-5-isopropylphenol), a phenolic monoterpene in the essential oils of the genera Origanum and Thymus, has been shown to exert a variety of therapeutic effects. Here we examined whether carvacrol protected neuroblastoma SH-SY5Y cells against Fe(2+)-induced apoptosis and explored the underlying mechanisms., Methods: Neuroblastoma SH-SY5Y cells were incubated with Fe(2+) for 24 h, and the cell viability was assessed with CCK-8 assay. TUNEL assay and flow cytometric analysis were performed to evaluate cell apoptosis. The mRNA levels of pro-inflammatory cytokines and NF-κB p65 were determined using qPCR. The expression of relevant proteins was determined using Western blot analysis or immunofluorescence staining., Results: Treatment of SH-SY5Y cells with Fe(2+) (50-200 μmol/L) dose-dependently decreased the cell viability, which was significantly attenuated by pretreatment with carvacrol (164 and 333 μmol/L). Treatment with Fe(2+) increased the Bax level and caspase-3 activity, and decreased the Bcl-2 level, resulting in cell apoptosis. Furthermore, treatment with Fe(2+) significantly increased the gene expression of IL-1β, IL-6 and TNF-α, and induced the nuclear translocation of NF-κB. Treatment with Fe(2+) also significantly increased the phosphorylation of p38, ERK, JNK and IKK in the cells. Pretreatment with carvacrol significantly inhibited Fe(2+)-induced activation of NF-κB, expression of the pro-inflammatory cytokines, and cell apoptosis. Moreover, pretreatment with carvacrol inhibited Fe(2+)-induced phosphorylation of JNK and IKK, but not p38 and ERK in the cells., Conclusion: Carvacrol protects neuroblastoma SH-SY5Y cells against Fe(2+)-induced apoptosis, which may result from suppressing the MAPK/JNK-NF-κB signaling pathways.

Aim: Aquaporins (AQPs) are the water-channels that play important roles in brain water homeostasis and in cerebral edema induced by brain injury. In this study we investigated the relationship between AQPs and a neuroprotective agent curcumin that was effective in the treatment of brain edema in mice with intracerebral hemorrhage (ICH)., Methods: ICH was induced in mice by autologous blood infusion. The mice immediately received curcumin (75, 150, 300 mg/kg, ip). The Rotarod test scores, brain water content and brain expression of AQPs were measured post ICH. Cultured primary mouse astrocytes were used for in vitro experiments. The expression of AQP1, AQP4 and AQP9 and NF-κB p65 were detected using Western blotting or immunochemistry staining., Results: Curcumin administration dose-dependently reduced the cerebral edema at d 3 post ICH, and significantly attenuated the neurological deficits at d 5 post ICH. Furthermore, curcumin dose-dependently decreased the gene and protein expression of AQP4 and AQP9, but not AQP1 post ICH. Treatment of the cultured astrocytes with Fe(2+) (10-100 μmol/L) dose-dependently increased the expression and nuclear translocation of NF-κB p65 and the expression of AQP4 and AQP9, which were partly blocked by co-treatment with curcumin (20 μmol/L) or the NF-κB inhibitor PDTC (10 μmol/L)., Conclusion: Curcumin effectively attenuates brain edema in mice with ICH through inhibition of the NF-κB pathway and subsequently the expression of AQP4 and AQP9. Curcumin may serve as a potential therapeutic agent for ICH.

The ubiquitin-protein ligase E3C (UBE3C) belongs to the E3 ligase enzyme family and implicates in the ubiquitin-proteasome pathway, thus regulates physiological and cancer-related processes. Here, we investigated the expression and roles of UBE3C in glioma. We demonstrated that UBE3C was overexpressed in glioma tissues and cell lines. Inhibition of UBE3C expression in glioma cells significantly decreased cell migration and invasion in vitro. Mechanistically, we disclosed that UBE3C physically interacted with and ubiquitinated tumor suppressor gene annexin A7 (ANXA7), resulting in ubiquitination and degradation of ANXA7. Our results also revealed that increased UBE3C expression was accompanied by a reduction in ANXA7 protein expression in glioma tissues, but not ANXA7 mRNA. Importantly, the inhibition of ANXA7 expression in gliomas cells with UBE3C interference could rescue the cell invasion. Clinically, UBE3C overexpression significantly correlated with high-grade tumors (p < 0.05), poor overall survival, and early tumor recurrence. Thus, our data reveal that high UBE3C expression contributes to glioma progression by ubiquitination and degradation of ANXA7, and thus presents a novel and promising target for glioma therapy.

Tumor cell invasion and proliferation remain the overwhelming causes of death for malignant glioma patients. To establish effective therapeutic methods, new targets implied in these processes have to be identified. Tetraspanin 8 (Tspn8) forms complexes with a large variety of trans-membrane and/or cytosolic proteins to regulate several important cellular functions. In the current study, we found that Tspn8 was over-expressed in multiple clinical malignant glioma tissues, and its expression level correlated with the grade of tumors. Tspn8 expression in malignant glioma cells (U251MG and U87MG lines) is important for cell proliferation and migration. siRNA-mediated knockdown of Tspn8 markedly reduced in vitro proliferation and migration of U251MG and U87MG cells. Meanwhile, Tspn8 silencing also increased the sensitivity of temozolomide (TMZ), and significantly increased U251MG or U87MG cell death and apoptosis by TMZ were achieved with Tspn8 knockdown. We observed that Tspn8 formed a complex with activated focal adhesion kinase (FAK) in both human malignant glioma tissues and in above glioma cells. This complexation appeared required for FAK activation, since Tspn8 knockdown inhibited FAK activation in U251MG and U87MG cells. These results provide evidence that Tspn8 contributes to the pathogenesis of glioblastoma probably by promoting proliferation, migration and TMZ-resistance of glioma cells. Therefore, targeting Tspn8 may provide a potential therapeutic intervention for malignant glioma., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The malignant glioma remains one of the most aggressive human malignancies with extremely poor prognosis. Glioma cell invasion and migration are the main causes of death. In the current study, we studied the expression and the potential functions of tetraspanin 8 (Tspan8) in malignant gliomas. We found that Tspan8 expression level is high in both malignant glioma tissues and in several human glioma cell lines, where it formed a complex integrin α3 and rictor, the latter is a key component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Disruption of this complex, through siRNA-mediated knockdown of anyone of these three proteins, inhibited U251MG glioma cell migration in vitro. We further showed that Tspan8-rictor association appeared required for mTORC2 activation. Knockdown of Tspan8 by the targeted siRNAs prevented mTOR-rictor (mTORC2) assembly as well as phosphorylation of AKT (Ser-473) and protein kinase C α (PKCα) in U251MG cells. Together, these results demonstrate that over-expressed Tspan8 in malignant glioma forms a complex with rictor and integrin α3 to mediate mTORC2 activation and glioma cell migration. Therefore, targeting Tspan8-rictor-integrin α3 complex may provide a potential therapeutic intervention for malignant glioma.

The ages of a fruticose lichen of Usnea aurantiacoatra (Jacq.) Bory, from Fildes Peninsula, King George Island, Southwest Antarctic, were determined by radiocarbon (14C), and it is 1993-1996 at bottom and 2006-2007 at top of the lichen branch. The growth rates of U. aurantiacoatra calculated are 4.3 to 5.5 mm year(-1) based on its length and ages. The comparisons show that the growth rates of U. aurantiacoatra are higher than those of U. antarctica (0.4 to 1.1 mm year(-1)). The growth rates of fruticose lichens are always higher, usually >2 mm year(-1), than those of crustose ones, usually <1 mm year(-1), in polar areas. A warming trend on Fildes Peninsula is recorded in the period from 1969 to 2010 obviously: the mean annual temperature rose from -2.75 to -1.9°C and the average temperature of summer months from 0.95 to 1.4°C, as well as the average temperature of winter months from -6.75 to -5.5°C. The alteration of lichen growth rates in polar areas may respond to the climatic and environmental changes, and the lichens may act as bio-monitor of natural condition.

Glioblastoma multiforme (GBM) is the most common malignant tumor in adults' central nervous system (CNS). The development of novel anti-cancer agents for GBM is urgent. In the current study, we found that gambogic acid induced growth inhibition and apoptosis in cultured U87 glioma cells, which was associated with Akt/mTORC1 (mTOR complex 1) signaling in-activation. To restore Akt activation by introducing a constitutively active (CA) Akt attenuated gambogic acid-induced cytotoxicity against U87 cells. For mechanism study, we found that gambogic acid induced LRIG1 (leucine-rich repeat and Ig-like domain-containing-1) upregulation, which was responsible for EGFR (epidermal growth factor receptor) degradation and its downstream Akt/mTORC1 inhibition. Further, we provided evidence to support that AMPK (AMP-activated protein kinase) activation mediated gambogic acid-induced LRIG1 upregulation, U87 cell apoptosis and growth inhibition, while AMPK inhibition by shRNA or compound C reduced gambogic acid-induced EGFR/Akt inhibition and cytotoxicity in U87 cells. We here proposed novel signaling mechanism mediating gambogic acid-induced cytotoxic effects in glioma cells., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Necroptosis was reported as one backup way of programmed cell death when apoptosis was blocked, and the receptor interacting protein 1 was considered as the key necroptosis regulator protein. Here, we report the neuroprotective effects of curcumin which attenuates necroptosis. Primary cortical neurons were cultured and were injured by ferrous chloride, z.vad.fmk was applied to block apoptosis, curcumin was administrated to protect neurons, necrostatin-1 was applied to inhibit necroptosis if needed. Cell viability was measured by detecting lactate dehydrogenase activity in lysates of surviving cells, and assessed by cell counting kit-8. The expression of receptor interacting protein 1 was detected by immunoblot and immunofluorescence. Results showed that necroptosis mainly occurred in the concentrations of ferrous chloride ranging from 100 to 200μM, curcumin attenuated necroptosis in a dose-dependent manner. Furthermore, curcumin decreased expression of receptor interacting protein 1 in a dose- and time-dependent manner. Taken together, these findings suggest that curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis., (Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

MicroRNAs (miRNAs) play important roles in the regulation of gene expressions. Aberrant expression of miRNAs is implicated in a variety of biological and pathological processes, including the tumorigenesis of glioma (GM). Though the molecular mechanisms of protein kinase B (AKT) survival signal have been comprehensively explored, the role of miR-149 in glioblastoma (GBM) and its regulation on AKT signaling have not yet been ascertained. The present study aimed to elucidate the role and molecular mechanisms of miR-149 in U251 GM cells. Using a gain-of-function approach, we investigated the effects of lentivirus-mediated overexpression of miR-149 on the expression of phosphated-AKT1 (p-AKT1), proliferating cell nuclear antigen (PCNA), matrix metallopeptidase-2 (MMP-2) and CyclinD1 in U251 cells and nude mice subcutaneous xenograft tumors by Real-time PCR, Western blot and immunohistochemical assays. Proliferative activities indicated by MTT assay, invasive potential by Transwell and cycle distribution by flow cytometry were carried out for functional analysis of U251 cells after infection with miR-149 mimic. As a consequence, miR-149 inhibited the expression of p-AKT1, PCNA, CyclinD1 and MMP-2, reduced the proliferative activities and invasive potential, and induced cycle arrest in G0/G1 phase in U251 cells. In conclusion, our findings show that miR-149 as tumor suppressor may be involved in the proliferation and invasion of GM cells via blockade of the AKT1 signaling, and be considered as a candidate target for the treatment of cancer.

Choroid plexus papillomas are rare tumors of the central nervous system and are usually confined to the ventricular system. We illustrated a primary choroid plexus papilloma in the pituitary fossa. A 31-year-old female presented with amenorrhea and intermittent galactorrhoea, with no visual complaints in the last 2 years. Endocrine testing showed no hormone excess or deficiency of the pituitary and target glands, except for a higher prolactin level (56 ng/ml). A sharply circumscribed regular mass in the sellar region occupying the entire sella turcica and extending into the suprasellar cistern was demonstrated on MR imaging with gadolinium diethylenetriamine pentaacetic acid. The patient underwent an endonasal trans-sphenoidal approach. Complete microsurgical excision and complete preservation of the normal pituitary gland was achieved, with normal prolactin level. The histopathology showed that the lesion was a choroid plexus papilloma. Theories of the origin, the differential diagnosis, and treatment of the rare tumor are discussed.

Daily ozone column densities were monitored by Passive DOAS (differential optical absorption spectroscopy) from December 10th, 2008 to Feb 19th, 2009 at Zhongshan Station, Antarctic (69 degrees 22'24" S, 76 degrees 22'14" E). Considering the absorption of O3, OClO, NO2, O4, BrO and the Ring effect, ozone slant column densities were retrieved using the zenith scattered sunlight as the light source. The results showed that there was no obvious "ozone hole" during the monitoring period, but ozone VCD (vertical column density) had greatly changed within short time scale, especially in middle December and early February. The analysis of passive DOAS and Brewer measurements of ozone VCD showed good agreement with the correlative coefficient of 0.863, while satellite board OMI measurements with the correlative coefficient of 0.840, which confirmed the validity of the monitoring of Passive DOAS.

Background: Microglial activation plays an important role in neurodegenerative diseases by producing several proinflammatory enzymes and proinflammatory cytokines. The phenolic glucoside gastrodin, a main constituent of a Chinese herbal medicine, has been known to display anti-inflammatory properties. The current study investigates the potential mechanisms whereby gastrodin affects the expression of potentially pro-inflammatory proteins by cultured murine microglial BV-2 cells stimulated with lipopolysaccharide (LPS)., Methodology/principal Findings: BV-2 cells were pretreated with gastrodin (30, 40, and 60 µM) for 1 h and then stimulated with LPS (1 µg/ml) for another 4 h. The effects on proinflammatory enzymes, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and proinflammatory cytokines, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), are analysed by double-immunofluorescence labeling and RT-PCR assay. To reveal the mechanisms of action of gastrodin we investigated the involvement of mitogen-activated protein kinases (MAPKs) cascades and their downstream transcription factors, nuclear factor-κB (NF-κB) and cyclic AMP-responsive element (CRE)-binding protein (CREB). Gastrodin significantly reduced the LPS-induced protein and mRNA expression levels of iNOS, COX-2, TNF-α, IL-1β and NF-κB. LPS (1 µg/ml, 30 min)-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) and this was inhibited by pretreatment of BV-2 cells with different concentrations of gastrodin (30, 40, and 60 µM). In addition, gastrodin blocked LPS-induced phosphorylation of inhibitor κB-α (IκB-α) (and hence the activation of NF-κB) and of CREB, respectively., Conclusion and Implications: This study indicates that gastrodin significantly attenuate levels of neurotoxic proinflammatory mediators and proinflammatory cytokines by inhibition of the NF-κB signaling pathway and phosphorylation of MAPKs in LPS-stimulated microglial cells. Arising from the above, we suggest that gastrodin has a potential as an anti-inflammatory drug candidate in neurodegenerative diseases.

Objective: The purpose of this study was to define the clinical features and the surgical technique of unilateral hemilaminectomy for treating intramedullary cavernous malformations., Materials and Methods: Retrospective chart was performed in 16 patients with histologically diagnosed intramedullary cavernous malformations. All patients were treated with unilateral hemilaminectomy and microsurgical resection of the malformations. The pre- and postoperative neurological state was evaluated using Frankel scale., Results: There were nine females and seven males (mean age 38 years) harbouring symptomatic intramedullary cavernous malformations. The annual retrospective haemorrhage rate was 3.1% per patient/year. All cavernous malformations were completely resected. Twelve of 16 patients experienced the improvement of the neurological state and in four patients, clinical features remained unchanged during the follow-up period. Static and dynamic plain radiograph film showed none of them had spinal deformity or spinal instability., Conclusion: According to the defined bleeding risk, symptomatic and MRI-morphologically growing intramedullary cavernous malformations should be totally surgically removed, to avoid the recurrence and rebleeding of the residue. A least traumatic myelotomy, as well as a meticulous microsurgical technique and the intraoperative somatosensory evoked potentials monitoring, together with selection of a minimally invasive microsurgical approach (hemilaminectomy), leads to a favourable outcome and prevents additional morbidity.

Background: Schwannoma is the tumor arising mainly from the cranial and spinal nerves. Bilateral vestibular schwannoma is the hallmark of neurofibromatosis type 2 (NF2). The NF2 gene has been cloned with comprehensive analysis of its mutations in schwannoma. However, most studies focused on vestibular schwannoma. There are differences in proliferation of tumor cell and ultrastructure between vestibular and spinal schwannomas. It is unknown whether genetic alterations in vestibular schwannoma are different from those in non-vestibular schwannoma. We analyzed the loss of heterozygosity (LOH) on chromosome 22 in patients with sporadic schwannoma including vestibular and spinal schwannomas and correlated this genetic alteration with tumor proliferation., Methods: In 54 unrelated patients without clinical NF1 or NF2, 36 patients had sporadic vestibular schwannoma, and 18 dorsal spinal root schwannoma. Four highly polymorphic linkage to NF2 gene microsatellite DNA markers (D22S264, D22S268, D22S280, CRYB2) were used to analyze LOH. The proliferative index was evaluated by Ki-67 and proliferative cell nuclear antigen (PCNA) immunostaining. Student's t test was used to analyze the difference of the proliferative index between schwannoma with LOH and that without LOH. The difference of the frequency of LOH in vestibular and spinal schwannomas was investigated by the chi-square test., Results: Twenty-three schwannomas (42.6%, 23/54) showed allele loss. The frequency of LOH in vestibular schwannoma was significantly higher than that in spinal schwannoma (chi2 = 5.14, P < 0.05). The proliferative index of schwannoma with LOH was significantly higher than that without LOH (tki-67 = 2.97, P = 0.0045; tPCNA = 2.93, P = 0.0051)., Conclusions: LOH on chromosome 22 is a frequent event in the tumorigenesis of sporadic schwannoma. And, there is a correlation between LOH on chromosome 22 and proliferative activity in schwannoma. The frequency of LOH in vestibular schwannoma is significantly different from that in spinal schwannoma.

Posttraumatic tremor is often one of the causes of disability in head injury patients. Usually, pharmacotherapy for this type of tremor is not effective. Since early 1970s, surgical ablation of the ventral thalamus has been used to treat various types of tremor. Nowadays, deep brain stimulation (DBS) confirms its efficacy in alleviating different forms of tremor, including posttraumatic tremor. Such therapy has been reported achieving around 80% success rate in the treatment of posttraumatic tremor. These successful results suggest that the application of DBS therapy can be considered as one of the alternative treatments for minimizing the tremor occurring from different pathologies.

Objectives: To analyze the molecular genetic alteration of sporadic vestibular schwannomas from the People's Republic of China and to correlate these alterations with the tumor behaviors., Methods: Four highly polymorphic microsatellite DNA markers were used to observe the frequency of loss of heterozygosity (LOH) in chromosome 22. The NF2 gene mutations were detected by Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing. The schwannomin/merlin (S/M) expression was examined using anti-NF2 (A-19) IgG under immunohistochemistry and western blot. The proliferative index (LI) of vestibular schwannoma was evaluated by proliferative cell nuclear antigen investigation., Results: Sixteen vestibular schwannomas (44.4%) showed allele loss. We found 22 mutations in 36 schwannomas. The LI and the growth rate of schwannomas with LOH or mutation were significantly higher than those without LOH or mutation. All of these vestibular schwannomas showed no immunoreaction to anti-NF2(A-19) IgG by immunohistochemistry. By immunoblotting technique, reduced expression of S/M was found in 31 cases (86%). The growth index of schwannomas with severely reduced expression of S/M was significantly higher than those with moderately reduced or normal expression., Conclusion: The molecular genetic changes in sporadic vestibular schwannomas from Chinese patients were similar to the previous reports. We demonstrate the relationship between tumor behaviors and genetic alteration (including LOH and mutation of NF2 gene). We propose that inactivation of S/M, may be an important step in tumorigenesis of sporadic vestibular schwannoma.

The objective of this paper was to review temporal bone chondroblastomas in regard to their presentation, radiographic findings, histopathology, and treatment. A case report of a 38-year-old man who presented with the left-sided hearing impairment and temporal swelling was reviewed. A CT scan revealed an osteolytic lobulated expansile mass. MRI depicted two cystic components with fluid-fluid level and enhanced solid mass. Immunohistochemical study of S-100 was performed using avidinbiotin-complex method. The tumor was totally removed, with eroded squamous bone and temporal muscle, via the left zygomatic-extended middle fossa approach. The pathology of the tumor showed that the tumor cell was spindle-shaped, along with multinucleated giant cells. These cells had oval to polygonal nuclei; some cells showed grooved nuclei. Intercelluar calcification and hemorrhagic components were also observed in the tumor. Tumor cells were strongly positive for S-100 protein. Temporal bone chondroblastomas are extremely rare osseous tumors with only 45 cases previously reported in the published literature. They may be confused with more common lesions seen in the temporal bone. Diagnostic radiology, including CT and/or MRI, as well as immunohistochemical staining with S-100 protein, may assist in making the diagnosis. Treatment is complete surgical excision with preservation of vital neurovascular structures.

Background: Although there were several clinical and experimental studies discussing the pathogenesis of dural arteriovenous fistula (DAVF), the pathological process leading to intracranial DAVF so far remains unknown. In this study, we investigated the expression of vascular growth factors in order to elucidate the possible role of these factors for the development of DAVF and to study the biological activity of this uncommon lesion., Methods: We examined the histological features, proliferative and angiogenic capacities of the tissue specimens obtained from 6 patients who underwent surgery at our institution. Immunohistochemical staining for vascular endothelial growth factor (VEGF), its receptors Flk-1 and Flt-1, ephrin-B2, MIB-1 and proliferating cell nuclear antigen (PCNA) was performed using standard immunohistochemical techniques., Results: A positive immunostaining was found for all antibodies studied except MIB-1, whereas nuclear endothelial expression of PCNA was observed in only 3/6 cases. VEGF stained positive in all of the available specimens (6/6). Flk-1 showed a positive immunoreaction in only 2/6 cases and Flt-1 in 4/6 cases. Ephrin-B2 was expressed in the majority (5/6) of the cases., Conclusions: These results support the hypothesis that DAVFs might be acquired dynamic vascular malformations with low biological activity. Vascular growth factors like VEGF and ephrin-B2 might play a pivotal role in the formation of DAVF.

Objective: To estimate outcomes of patients with acute subdural hematomas by analysing the hematoma thickness, midline shift and the differences between them., Methods: Ninety-five patients with acute subdural hematoma were retrospectively studied by calculating hematoma thickness, midline shift and their difference with a statistical analysis of Kaplan-Meier, Wilcoxon-Mann-Whitney U test., Results: The hematoma thickness ranged from 5.0 to 40.0 mm and midline shift was from 0 to 35.0 mm. Among these patients, 51% died and 49% survived after surgery. 18 patients (19%) showed good or satisfactory results. Kaplan-Meier analysis proved that the survival for patients with hematoma thickness approximately equal to l7 mm and a midline shift 15 mm or whose midline shift exceeded hematoma thickness by 2.2 mm, the survival rate was 50%. Glasgow outcome scale scores were correlated significantly with these parameters., Conclusion: The hematoma thickness, midline shift and their difference provided a database from which criteria could be derived, that is crucial for prognosis estimation.

Endothelin-mediated vasoconstriction may theoretically aggravate ischemic neuronal damage. Although investigators have demonstrated that endothelins are produced by cerebral microvessel endothelial cells, astrocytes and neurons in vitro, whether endothelins are produced during cerebral ischemia is still unclear. The purpose of this study, therefore, was to measure endothelin-1 in brain tissue and plasma following middle cerebral artery occlusion and to examine the relationship between brain tissue and plasma endothelin-1 levels. The middle cerebral artery of rabbits was occluded for 2, 4 or 24 h. The amount of endothelin-1 in both brain tissue and plasma was determined by RIA. The results demonstrate that the concentrations of endothelin-1 in the ischemic brain tissue and plasma are both significantly increased after focal cerebral ischemia (P < 0.01). The data confirm that an acute and marked increase of endothelin-1 in brain tissue and plasma is associated with focal ischemic events. The possibility that endothelin-1 has a role in neuronal cell damage following focal ischemia warrants further attention.