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Cushing's disease (CD) is most common endogenous Cushing's syndrome. This study aimed to assess iron alternations in deep grey matter in CD.A cross-sectional study was performed.In this study, 48 active CD patients, 39 remitted CD patients and 52 healthy control (HC) subjects underwent magnetic resonance imaging.Quantitative susceptibility mapping (QSM).Decreased susceptibility values were found in the bilateral putamen, caudate, red nucleus, subthalamic nucleus and pulvinar nuclei of the thalamus (TL-PLV) in active and remitted patients with CD compared with HCs. Interestingly, in remitted patients with CD, altered susceptibility values were significantly correlated with altered brain volumes in TL-PLV, while TL-PLV may play an essential role as a general regulatory hub for adaptive and flexible cognition.Chronic exposure to hypercortisolism may be related to iron distribution and significantly correlated with altered brain volumes and clinical features in patients with CD.

Acute hemorrhage caused by cerebral arteriovenous malformation (cAVM) during pregnancy is uncommon but life-threatening for both mother and fetus and presents a great challenge to clinical management. However, there is still no consensus on the treatment strategy and the treatment timing of acute hemorrhage from cAVM during pregnancy. The aim of this study was to amalgamate reported case series and our cases regarding the clinical management of pregnant patients under this special condition.We report a case series of 3 pregnant patients with acute hemorrhage caused by cAVM in our hospital. A systematic PubMed search of the English-language literature published between 1970 and 2020 was carried out. Clinical information including patients' age, gestational age, imaging studies, treatment strategy, treatment timing, delivery mode, and outcomes were collected and analyzed.The rebleed rate is about 7.1% and the mortality from rebleeding is up to 25%. Treatment modalities included radical surgery, endovascular embolization, radiosurgery/stereotactic radiosurgery, palliative surgery, and conservative treatment. There were no maternal deaths in either the intrapartum intervention group and the postpartum intervention subgroup of gestational age34 weeks.A high rebleed rate and high mortality from rebleeding indicate that the intervention of ruptured cAVM should not be delayed. Intervention of ruptured cAVM within 2 weeks after initial hemorrhage is advisable in patients at gestational age34 weeks, whereas termination of pregnancy as soon as possible followed by timely intervention of ruptured cAVM is practicable in patients at gestational age ≥34 weeks.

Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is characterized by hypothalamus-pituitary-adrenal axis dysfunction. As the neuroendocrinological axis has been shown to react under the regulation of the central nerve system through the corticotropin-releasing factor (CRF) releasing from the hypothalamic paraventricular nucleus. Whether one of the neuromodulation therapies, vagus nerve stimulation, is able to treat this neuroendocrinological disorder remains unknown. In this study, we explored the effects of vagus nerve stimulation (VNS) on CRF-induced serum ACTH level change in normal rats. After the vagus nerve electrode placement, the ACTH and corticosterone levels were measured multiple times before and after the administration of CRF (2 μg/kg) in switched-ON and -OFF groups, respectively, compared to the control group. Our results showed that 2 h continuous stimulation on the vagus nerve inhibited CRF-induced ACTH release up to 1 h compared with the control group, while the corticosterone level was not influenced. The vagus nerve might be a potential therapeutic target in the treatment of ACTH-dependent Cushing's syndrome disorders involving hypothalamus-pituitary-adrenal axis dysfunction.

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.

Objective: To identify critical roles played by NEK2 in prolactinomas and to clarify the corresponding underlying mechanisms. Methods: We performed RNA-seq on MMQ cell lines treated with the dopamine receptor agonist cabergoline (CAB) to identify genes involved in prolactinoma progression and dopamine receptor-agonist (DA) sensitivity. NEK2 was then selected for further study. The expression of NEK2 was examined using quantitative real-time PCR, western immunoblotting, and immunohistochemistry - both in pituitary adenomas (PA) and in normal pituitary tissue. We used gain-of-function and loss-of-function assays to explore the biologic roles of NEK2 in cell growth in vivo and in vitro. Co-immunoprecipitation was also used to detect the binding between NEK2 and USP7. Results: Herein, we reported that NEK2 was upregulated in prolactinomas, particularly dopamine-resistant prolactinomas. NEK2 overexpression significantly promoted pituitary tumor GH3 and MMQ cell proliferation, and it impaired cellular sensitivity to CAB. Conversely, knockdown of NEK2 inhibited GH3 and MMQ cell growth, and sensitized the cells to CAB. Mechanistically, NEK2 regulated cell proliferation via the Wnt-signaling pathway; and in addition, we demonstrated that USP7 interacted with, deubiquitylated, and stabilized NEK2. Conclusions: Collectively, our results suggest that NEK2 might be a potential therapeutic target for prolactinoma.

Purpose: Transsphenoidal surgery (TSS) is the first-line treatment for Cushing’s disease (CD), even with negative preoperative MRI results. It is not rare that patients experiencing hypercortisolism persistence or recurrence have negative MRI after the initial surgery. We aim to analyze the efficacy of repeat surgery in these two groups of patients and assess if there is association of the positive MRI finding with early remission.Patients and methods: Clinical, imaging and biochemical information from 42 patients who underwent repeat surgery by a single neurosurgeon between 2002 and 2021 were retrospectively analyzed. The endocrinological, histopathological and surgical outcomes before and after the repeat surgery of 14 CD patients with negative MRI findings were compared with 28 patients with positive findings.Results: Immediate remission was achieved in 29 patients (69.0%) underwent repeat surgery. Of all patients, 28 (66.7%) had MRI findings consistent with solid lesion. There was no difference of remission rate between the recurrence group and the persistence group (77.8% vs. 57.1%, Odds Ratio = 2.625, 95% Confidence Interval =0.651 to 10.586). In patients with remission after the repeat surgery was not associated with the positive MRI finding (Odds Ratio = 3.667, 95% Confidence Interval = 0.920 to 14.622).Conclusions: In terms of recurrence, the repeat surgery with either positive or negative MRI showed a reasonable remission rate. For persistent disease with positive MRI finding, repeat surgery is still an option, while more solid evidence is needed to define if the negative MRI is predictor for failure reoperation of persistent hypercortisolism.

Intracerebral hemorrhage (ICH) is a common acute nervous system disease with high mortality and severe disability. Mesenchymal stem cells (MSCs) have been reported to promote neurogenesis and to alleviate side effects in areas of brain injury areas. The Hippo pathway regulates diverse cellular processes, including cell survival, proliferation, differentiation, and organ size. Here, we found that transplantation of bone marrow MSCs (BM-MSCs) into the brains of mice could alleviate ICH-mediated injury and protect astrocytes from apoptosis by regulating mammalian sterile 20-like kinase (MST)1 and Yes-associated protein (YAP). Knocking down of MST1 by si-RNA triggered YAP nuclear translocation. We further demonstrated that astrocytes undergo astroglial-mesenchymal phenotype switching and become capable of proliferating after BM-MSC transplantation via the Hippo signaling pathway. Together, our identification of the Hippo pathway in mediating the beneficial effects of BM-MSCs may provide a novel therapeutic target in the treatment and management of ICH.

Background Brain tumors, whether primary or secondary, have limited information about proteomic changes despite advances in the understanding of the driver gene mutations and heterogeneity within tumor cells. In this study, we for the first time systematically analyzed the proteome of tumor tissues from patients with brain metastases (BrMs) and gliomas. Methods We assembled the most common primary tumors as follows: gliomas from WHO grade II to IV with or without IDH1 mutations; and BrMs with a wide range, including lung cancer (L.C), breast cancer (B.C), ovarian cancer (O.C), and colorectal cancer (C.C). A total of 29 tissue samples were analyzed by label free quantitative mass spectrometry-based proteomics. Results In total, 8,370 protein groups were identified, and approximately 4,000 quantified protein groups were adopted for further analysis. Proteomic analysis of metastatic tumors reveals conserved features across multiple cancers. While proteomic heterogeneities were found for discriminating low- and high-grade of gliomas, as well as IDH1 mutant and wild-type gliomas. And distinct pathway-level differences among these two types of brain malignancies were revealed. The characteristic pathways of BrMs focused on proliferation and immunomodulation after colonizing the brain, whereas invasion processes were notably activated in gliomas. Conclusion We elucidated an extensive proteomic landscape of BrMs and gliomas, providing information for the development of potential therapeutic and diagnostic strategies for type-specific brain tumors.

Purpose: Transsphenoidal surgery is the first-line treatment for Cushing’s disease (CD), even with negative preoperative magnetic resonance imaging (MRI) results. Some patients with persistent or recurring hypercortisolism have negative MRI findings after the initial surgery. We aimed to analyze the efficacy of repeat surgery in two groups of patients and determine if there is an association between positive MRI findings and early remission. Patients and Methods: Clinical, imaging, and biochemical information of 42 patients who underwent repeat surgery by a single neurosurgeon between 2002 and 2021 was retrospectively analyzed. We compared the endocrinological, histopathological, and surgical outcomes before and after repeat surgery among 14 CD patients with negative MRI findings and 28 patients with positive MRI findings. Results: Immediate remission was achieved in 29 patients (69.0%) who underwent repeat surgery. Among all patients, 28 (66.7%) had MRI findings consistent with solid lesions. There was no significant difference in remission rates between the recurrence and persistence groups (77.8% vs. 57.1%, odds ratio = 2.625, 95% confidence interval = 0.651 to 10.586). Patients in remission after repeat surgery were not associated with positive MRI findings (odds ratio = 3.667, 95% confidence interval = 0.920 to 14.622). Conclusions: In terms of recurrence, repeat surgery in patients with either positive or negative MRI findings showed reasonable remission rates. For persistent disease with positive MRI findings, repeat surgery is still an option; however, more solid evidence is needed to determine if negative MRI findings are predictors for failed reoperations for persistent hypercortisolism.

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 lOR], 3.57; P 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

Yong Yang,1,* Guoying Deng,2,* Peng Wang,1 Guangzhao Lv,1 Rui Mao,1 Yuhao Sun,3 Baofeng Wang,3 Xijian Liu,4 Liuguan Bian,3 Dong Zhou1 1Department of Neurosurgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 2Trauma Center, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 201620, People’s Republic of China; 3Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, People’s Republic of China; 4College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, 201620, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liuguan BianDepartment of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, People’s Republic of ChinaTel +86 21 64370045 Ext 666091Fax +86 21 64333548Email blg11118@rjh.com.cnDong ZhouDepartment of Neurosurgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, No. 106 Zhongshan Er Road, Yuexiu District, Guangzhou, 510080, People’s Republic of ChinaTel +86 20 83827812 Ext 61521Email zhoudong5413@163.comBackground: Intracerebral hemorrhage (ICH) is a common neurological crisis leading to high mortality and morbidity. Oxidative stress-induced secondary injury plays a critical role in neurological deterioration. Previously, we synthesized a porous Se@SiO2 nanocomposite and identified their therapeutic role in osteonecrosis of the femoral head. Whether this nanocomposite is neuroprotective remains to be elucidated.Methods: A porous Se@SiO2 nanocomposite was synthesized, and its biosafety was determined using a CCK-8 assay. The neuroprotective effect was evaluated by TUNEL staining, and intracellular ROS were detected with a DCFH-DA probe in SH-SY5Y cells exposed to hemin. Furthermore, the effect of the nanocomposite on cell apoptosis, brain edema and blood–brain barrier permeability were evaluated in a collagenase-induced ICH mouse model. The potential mechanism was also explored.Results: The results demonstrated that Se@SiO2 treatment significantly improved neurological function, increased glutathione peroxidase activity and downregulated malonaldehyde levels. The proportion of apoptotic cells, brain edema and blood–brain barrier permeability were reduced significantly in ICH mice treated with Se@SiO2 compared to vehicle-treated mice. In vitro, Se@SiO2 protected SH-SY5Y cells from hemin-induced apoptosis by preventing intracellular reactive oxygen species accumulation.Conclusion: These results suggested that the porous Se@SiO2 nanocomposite exerted neuroprotection by suppressing oxidative stress. Se@SiO2 may be a potential candidate for the clinical treatment of ICH and oxidative stress-related brain injuries.Keywords: selenium nanocomposites, oxidative stress, blood–brain barrier, brain edema, apoptosis

The brain edema following intracerebral hemorrhage (ICH) plays a key role in the recovery process. Protocatechuic acid (PCA) has been proved possessing neuroprotection in ICH. Here we tried to explore its value in brain edema after ICH and reveal underlying mechanisms. ICH model was created in C57 mice using collagenase IV. PCA was injected intraperitoneally at 30 mg/kg every 24 h in PCA group. On day 3 after ICH, the water content of hemorrhagic ipsilateral hemisphere in PCA group was significantly reduced compared with vehicle group. AQP4, the main water channel, was remarkably decreased in PCA group. Additionally, ZO-1 and occludin expression were increased in PCA group. The bEnd.3 cells were cultured to understand the effect of PCA on the blood-brain barrier (BBB) integrity. Compare to hemin treated group, plus PCA enhanced the expression of HO-1 and Nrf2 nuclear translocation. Furtherly, the overexpression of HO-1, ZO-1, occludin, in the PCA treatment group was inhibited after knockdown of Nrf2. Taken together, our results proved PCA alleviated brain edema and BBB disruption in ICH by promoting the Nrf2/HO-1 signaling pathway.

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.

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.

Background. Deep brain stimulation (DBS) for Parkinson’s disease (PD) has evolved as a well-established treatment in neurosurgery, and identifying appropriate surgical candidates could contribute to better DBS outcomes. The Florida Surgical Questionnaire for Parkinson Disease (FLASQ-PD) is a reasonable screening tool for assessing DBS candidacy in PD patients; however, a Chinese version of FLASQ-PD is needed for functional neurosurgery units in China. In this study, we translated the FLASQ-PD to Chinese and assessed its reliability and validity for Chinese PD patients. Methods. The FLASQ-PD was translated before the study formally started. A single-center retrospective analysis of FLASQ-PD was performed at the Ruijin Hospital, affiliated with Shanghai Jiaotong University School of Medicine, between July and December 2019. The Unified Parkinson Disease Rating Scale III (UPDRS-III) was also used to assess PD patients on and off medication. All patients were evaluated for surgical candidacy by specialists. Results. Overall, 115 PD patients, 25 with parkinsonism and six with multiple system atrophy were consecutively included. Internal consistency of the Chinese FLASQ-PD was roughly adequate (Cronbach’s alpha = 0.664). There were significant differences in mean total scores of the Chinese FLASQ-PD between the diagnostic (Kruskal–Wallis H value = 37.450, p ≤ 0.001 ) and surgery-candidacy groups (H = 48.352, p ≤ 0.001 ). Drug improvements in UPDRS-III scores were mildly correlated with the Chinese FLASQ-PD scores in the surgery-ready group (Pearson correlation = 0.399, p = 0.001 ). Conclusions. The Chinese FLASQ-PD, which is a simple and efficient screening tool for clinicians, was developed and initially validated in this retrospective single-center study.

Intracerebral hemorrhage (ICH) is a particularly severe form of stroke, and reactive astrogliosis is a common response following injury to the central nervous system (CNS). Mesenchymal stem cells (MSCs) are reported to promote neurogenesis and alleviate the late side effects in injured brain regions. Gap junctions (Gjs) are abundant in the brain, where the richest connexin (Cx) is Cx43, most prominently expressed in astrocytes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor regulating antioxidant reactions. Here, we aimed to explore whether bone marrow MSCs (BM-MSCs) could alleviate brain injury and protect astrocytes from apoptosis, by regulating Cx43 and Nrf2. We validated the effect of BM-MSC transplantation in an ICH model in vivo and in vitro and detected changes using immunofluorescence, as well as protein and mRNA expression of glial fibrillary acidic protein (GFAP), vimentin (VIM), Cx43, Nrf2, and heme oxygenase-1 (HO-1). Our results showed that BM-MSC transplantation attenuated brain injury after ICH and upregulated VIM expression in vivo and in vitro. Additionally, Cx43 upregulation and Nrf2 nuclear translocation were observed in astrocytes cocultured with BM-MSC. Knockdown of Cx43 by siRNA restrained Nrf2 nuclear translocation. Cx43 and Nrf2 had a connection as determined by immunofluorescence and coimmunoprecipitation. We demonstrated that astrocytes undergo astroglial-mesenchymal phenotype switching and have anti-apoptotic abilities after BM-MSC transplantation, where Cx43 upregulation triggers Nrf2 nuclear translocation and promotes its phase II enzyme expression. The Cx43/Nrf2 interaction of astrocytes after BM-MSC transplantation may provide an important therapeutic target in the management of ICH.

Chordoid glioma (CG) of the third ventricle is a rare type of brain tumor. Here, we present a case, review of the literature and proposed a treatment strategy for this rare tumor. Here, A 33-years-old woman presented with the menstrual disorder and progressive obesity. Magnetic resonance imaging showed a large irregularly circular tumor in the third ventricle. The tumor was subtotally resected by microsurgery via the right modified port approach. Immunohistochemical staining was positive for glial fibrillary acidic protein (GFAP), Vimentin and transcription termination factor-1 (TTF-1), and the Ki-67 proliferation index was low (5%), which indicating CG. Residual tumor decreased after treated by Gamma Knife radiosurgery (GKRS) with a dose of 15 Gy. During 30 months of follow-up, the tumor did not recur, and the patient suffered no complications. The diagnosis of CG requires a combination of clinical presentation, neuroimaging, and pathology. The ideal therapy is gross total resection (GTR) of the tumor. However, GTR is usually difficult and carries a high risk of postoperative complications because of the tumor location. This case indicates that planed subtotal resection followed by GKRS with a proper marginal dose could be a good treatment strategy for CG.

Background: Diagnosis of thyrotropin (TSH)-secreting pituitary adenomas (TSHoma) before surgery remains a challenge, especially for microadenomas. We aimed to establish a short-term somatostatin an...

Reactive astrogliosis is a common response to insults to the central nervous system, but the mechanism remains unknown. In this study, we found the temporal and spatial differential expression of glial fibrillary acidic protein (GFAP) and Vimentin in the intracerebral hemorrhage (ICH) mouse brain, indicating that the de-differentiation and astroglial-mesenchymal transition (AMT) of astrocytes might be an early event in reactive astrogliosis. Further we verified the AMT finding in purified astrocyte cultures exposed to hemoglobin (Hb). Additionally, Connexin 43 (Cx43) downregulation and YAP nuclear translocation were observed in Hb-activated astrocytes. Knocking down Cx43 by siRNA triggered YAP nuclear translocation. Cx43 and YAP were physically associated as determined by immunofluorescence and co-immunoprecipitation. We propose that astrocytes undergo AMT during Hb-induced activation where Cx43 downregulation facilitates YAP nuclear translocation is a novel mechanism involved in this process. Cx43-YAP interaction may represent a potential therapeutic target for modulating astrocyte activation.

Oxidative stress mediated secondary injury contributes to neurological deterioration after intracerebral hemorrhage (ICH). Astrocytes, the most dominant cells in the central nervous system (CNS), play key roles in maintaining redox homeostasis by providing oxidative stress defense. Hemoglobin (Hb), the primary component released by hemolysis, is an effective activator of astrocytes. Hemin, the product of Hb degradation, is highly toxic due to the induction of reactive oxygen species (ROS). We speculate that Hb-activated astrocytes are resistant to hemin-induced toxicity. To verify our speculation, Hb-pretreated astrocytes were exposed to hemin, intracellular ROS accumulation and cell apoptosis were evaluated. Heme oxygenase 1 (HO-1) and nuclear transcription factor-erythroid 2 related factor (Nrf2) expression were observed to explore the potential mechanism. The results demonstrated that Hb induced upregulation and nuclear translocation of Nrf2 in astrocytes, resulted in HO-1 upregulation, which contributed to reduced ROS accumulation and apoptosis rate. Knocking down Nrf2 expression by siRNA suppressed Hb-induced upregulation of HO-1 expression and increased the susceptibility of Hb-pretreated astrocytes to hemin-induced toxicity. Taken together, Hb-activated astrocytes acquired resistance to hemin-induced toxicity via Nrf2/HO-1 pathway. This phenomenon can be considered as the adaptive self-defense in the pathological process of ICH. Hb pre-warned astrocytes and enhanced their capability of handling the coming hemin "flood". Nrf2/HO-1 may be employed as a target for neuroprotection after ICH.

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.

SummaryContext 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.

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.

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 (fiso), partial fraction of extracellular water (fec) 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.

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 CM3) among four groups. While the GM volumes of short-term remitted CD patients (586.62 ± 46.89 CM3, n = 28) and long-term remitted CD patients (596.58 ± 45.95 CM3, n = 35) were between those of the active CD patients and healthy control subjects (628.14 ± 46.88 CM3, 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.

Background: Diagnosis of thyroid-stimulating hormone (TSH)-secreting pituitary adenomas (TSHoma) before surgery remains a challenge, especially microadenomas. We aimed to establish a short-term somatostatin analogues (SSA) test to differentiate TSHoma from resistance of thyroid hormone (RTH). Methods: We first evaluated the sensitivity and specificity of SSA test in a retrospective cohort (TSHoma, N=32; RTH, N=20). We then applied the SSA test in a perspective SITSH cohort without THRB gene mutation (pituitary microadenoma, N=10; negative pituitary imaging, N=7). Findings: In the retrospective cohort, both TSHoma and RTH patients showed a decrease of TSH at the start of the SSA test, but the velocity of TSH slowly decreased in RTH patients after 2 h. The suppression ratio of TSH at 24 h versus 2 h and 0 h in TSHoma patients was remarkably greater than in RTH patients. The 24 h versus 2 h suppression ratio showed the best diagnostic accuracy at a cut-point of 44·46%, with sensitivity as 95·00%, specificity as 93·75%. In the perspective cohort, 10/17 patients diagnosed as TSHoma with mean TSH suppression ratio of 68·91%, in which seven patients with microadenoma received pituitary surgery and achieved euthyroid with positive TSH staining in the resected tissues. Interestingly, two patients with negative pituitary imaging showed TSH suppression ratio greater than 44·46% and developed microadenomas at follow-up. Interpretation: A short-term SSA test provides an alternative diagnostic approach for TSHoma, especially microadenoma. It may also diagnose TSHoma in very early stage before positive findings in pituitary imaging. Funding Statement: This study was sponsored by the grants from National Science Foundation of China (81570702, 81400772, 81700686). Foundation of Health and Family planning Commission of Shanghai (20174Y0204). National International Science Cooperation Foundation (2015DFA30560). The National Key Research and Development Program of China (2016YFC0901503). Declaration of Interests: The authors state: "No conflicts of interest to declare." Ethics Approval Statement: The board of medical ethics of Ruijin Hospital approved the study, and all patients provided informed written consent.

Protocatechuic acid (PCA) has been well studied for its neuroprotection value in several diseases, but the effect in intracerebral haemorrhage (ICH) has not been reported. Here we verified the protection of PCA in ICH, and investigated the relative mechanisms. ICH model mice were established by injection of collagenase IV. The mice were treated with PCA once per day for 3 days, starting immediately after operation. The modified neurological severity score (mNSS) of mice at 1st, 3rd and 7th day after operation were recorded. And some of mice were euthanized at 3rd day to compare brain water content, pro-inflammatory cytokines expression, and cell apoptosis in perihematomal tissue. Additionally, SH-SY5Y cells were treated hemin to mimic secondary injury of ICH. Cells were incubated with PCA for treatment. The cell viability, ROS, apoptosis rate and protein expression of apoptosis-relative protein and MAPKs and NF-κB were detected and analysed. The results revealed PCA alleviated the cerebral oedema at 3rd post ICH, and significantly improved neurological functions. PCA also attenuated the protein and gene expression of TNF-а, IL-1β and IL-6 vivo. PCA dose-dependently decreased the generation of ROS and apoptosis rate. Furthermore, PCA treatment dose-dependently decreased the expression of bax, cleaved caspase-3, increased bcl-2 expression; PCA downregulated P38/JNK-NF-κB pathway. In conclusion, PCA effectively improves prognosis of ICH mice by inhibiting oxidative stress, inflammation and apoptosis. The mechanism possibly results of downregulating of P38/JNK-NF-κB pathway, and PCA can be a potential therapeutic agent for ICH.

Free radical damage caused by ferrous iron is involved in the pathogenesis of secondary brain injury after intracerebral hemorrhage (ICH). NF-E2-related factor 2 (Nrf2), a major phase II gene regulator that binds to antioxidant response element, represents an important cellular cytoprotective mechanism against oxidative damage. We hypothesized that Nrf2 might protect astrocytes from damage by Fe(2+) . Therefore, we examined cytotoxicity in primary astrocytes induced by iron overload and evaluated the effects of Fe(2+) on Nrf2 expression. The results demonstrated that 24-h Fe(2+) exposure exerted time- and concentration-dependent cytotoxicity in astrocytes. Furthermore, Fe(2+) exposure in astrocytes resulted in time- and concentration-dependent increases in Nrf2 expression, which preceded Fe(2+) toxicity. Nrf2-specific siRNA further knocked down Nrf2 levels, resulting in greater Fe(2+) -induced astrocyte cytotoxicity. These data indicate that induction of Nrf2 expression could serve as an adaptive self-defense mechanism, although it is insufficient to completely protect primary astrocytes from Fe(2+) -induced neurotoxicity.

Methylation of the neurofibromatosis type 2 (NF2) gene in low-grade meningioma (WHO grade I) has crucial roles in tumorigenesis and development. Meningioma formation might also occur in the setting of an inflammatory microenvironment. However, the association between inflammation and the methylation of NF2 remains unclear. The present study investigates the role and regulatory mechanism of IL-1β, one of the most important pro-inflammatory cytokines, in the methylation of NF2 in benign meningioma. Three primary low-grade meningioma cells and leptomeningeal cells were cultured. CCK-8 and BrdU assays demonstrated that proliferation of meningioma/leptomeningeal cells treated with IL-1β occurred in a dose- and time-dependent manner. Methylation-specific PCR verified that IL-1β induced methylation of the NF2 promoter and decreased NF2/merlin expression in meningioma/leptomeningeal cells. Real-time PCR, western blotting, and immunofluorescence showed that IL-1β up-regulated DNMT1 in meningioma cells and DNMT1/3b in leptomeningeal cells but did not up-regulate DNMT3a. After co-treatment with the DNMT inhibitor 5-Aza-2'-deoxycytidine and DNMT siRNA, methylation of NF2 induced by IL-1β was attenuated and merlin expression was restored. Furthermore, we showed that DNMT1 in meningiomas and DNMT1/3b in leptomeninges were regulated via activation of the MAPK (p38, ERK, JNK) and NF-κB pathways. These results suggest that IL-1β induces methylation of NF2 by up-regulating DNMT1 in benign meningioma cells and DNMT1/3b in leptomeningeal cells via MAPK and NF-κB pathways. Therefore, NF2 methylation is a linker between IL-1β and tumor development, and DNMTs might be potential therapeutic targets in meningioma for regulating NF2 and inhibiting tumor development. © 2016 Wiley Periodicals, Inc.

Cushing's disease is caused by pituitary corticotroph adenoma, and the pathogenesis of it has remained obscure. Here, we showed that cold inducible RNA binding protein (CIRP) was markedly elevated in corticotroph tumors. Forced overexpression of CIRP in murine AtT20 pituitary corticotroph cell line increased corticotroph precursor hormone proopiomelanocortin (POMC) transcription, ACTH secretion and cellular proliferation. In vivo, CIRP overexpression promotes murine corticotroph tumor growth and enhances ACTH production. Mechanistically, we show that CIRP could promote AtT20 cells proliferation by inducing cyclinD1 and decreasing p27 expression via Erk1/2 signaling pathway. Clinically, CIRP overexpression is significantly correlated with Cushing's disease recurrence. CIRP appears to play a critical tumorigenesis function in Cushing's disease and its expression might be a useful biomarker for tumor recurrence.

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.

Rosai-Dorfman disease (RDD) is an uncommon systemic histioproliferative disease process characterized by sinus histiocytosis with massive lymphadenopathy, and isolated transcranial RDD (ITRDD) is extremely rare. We report a patient with giant ITRDD with diffuse involvement of nasal and paranasal tissues, showing favorable response to postoperative steroid therapy.