CHST7 Methylation Status Related to the Proliferation and Differentiation of Pituitary Adenomas.

Pituitary adenomas (PAs) are the second most common primary brain tumor and may develop from any of the cell lineages responsible for producing the different pituitary hormones. DNA methylation is one of the essential epigenetic mechanisms in cancers, including PAs. In this study, we measured the expression profile and promoter methylation status of carbohydrate sulfotransferase 7 (CHST7) in patients with PA; then, we investigated the effect of the CHST7 methylation status on the proliferation and differentiation of PAs. The volcano map and Metascape results showed that the levels of CHST7 were related to the lineages' differentiation and the cell adhesion of PAs, and patients with low CHST7 had greater chances of having an SF-1 lineage (p = 0.002) and optic chiasm compression (p = 0.007). Reactome pathway analysis revealed that most of the DEGs involved in the regulation of TP53 regulated the transcription of cell cycle genes (HSA-6791312 and HSA6804116) in patients with high CHST7. Correlation analysis showed that CHST7 was significantly correlated with the eIF2/ATF4 pathway and mitochondrion-related genes. The AUC of ROC showed that CHST7 (0.288; 95% CI: 0.187-0.388) was superior to SF-1 (0.555; 95% CI: 0.440-0.671) and inferior to FSHB (0.804; 95% CI: 0.704-0.903) in forecasting the SF-1 lineage (p < 0.001). The SF-1 lineage showed a higher methylation frequency for CHST7 than the Pit-1 and TBX19 lineages (p = 0.009). Furthermore, as the key molecule of the hypothalamic-pituitary-gonadal axis, inhibin ßE (INHBE) was positively correlated with the levels of CHST7 (r = 0.685, p < 0.001). In summary, CHST7 is a novel pituitary gland specific protein in SF-1 lineage adenomas with a potential role in gonadotroph cell proliferation and lineage differentiation in PAs.

The protective effect of the PDE-4 inhibitor rolipram on intracerebral haemorrhage is associated with the cAMP/AMPK/SIRT1 pathway.

Rolipram specifically inhibits phosphodiesterase (PDE) 4, thereby preventing inactivation of the intracellular second messenger cyclic adenosine monophosphate (cAMP). Rolipram has been shown to play a neuroprotective role in some central nervous system (CNS) diseases. However, the role of PDE4 and the potential protective effect of rolipram on the pathophysiological process of intracerebral haemorrhage (ICH) are still not entirely clear. In this study, a mouse model of ICH was established by the collagenase method. Rolipram reduced brain oedema, blood-brain barrier (BBB) leakage, neuronal apoptosis and inflammatory cytokine release and improved neurological function in our mouse model of ICH. Moreover, rolipram increased the levels of cAMP and silent information regulator 1 (SIRT1) and upregulated the phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, these effects of rolipram could be reversed by the SIRT1 inhibitor sirtinol. In conclusion, rolipram can play a neuroprotective role in the pathological process of ICH by activating the cAMP/AMPK/SIRT1 pathway.

A pro-inflammatory mediator USP11 enhances the stability of p53 and inhibits KLF2 in intracerebral hemorrhage.

Microglial cell activation and neuroinflammation after intracerebral hemorrhage (ICH) lead to secondary brain damage. Ubiquitin-specific protease 11 (USP11) has been correlated with ICH-induced neuron apoptosis. This study aims to explore the molecular mechanism of USP11 regulating neuroinflammation in ICH. First, an ICH rat model was developed by intracranial administration of collagenase. Silencing USP11 was found to alleviate nerve injury in rats with ICH-like symptoms. Then, through loss- and gain-of-function assays, USP11 knockdown was revealed to alleviate ICH-induced symptoms, corresponding to reduced modified neurological severity scores (mNSS) value, brain water content, blood-brain barrier permeability, neuron apoptosis, microglial cell activation, neutrophil infiltration, and inflammatory factor secretion. It was subsequently shown in microglial cells that USP11 stabilized p53 by deubiquitination and p53 targeted the Kruppel-like factor 2 (KLF2) promoter to repress KLF2 transcription, thereby activating the nuclear factor κB (NF-κB) pathway. Further, rescue experiments were conducted in vivo to validate the function of the USP11/p53/KLF2/NF-κB axis in ICH-induced inflammation, which confirmed that USP11 silencing blocked the release of pro-inflammatory cytokines following ICH by downregulating p53, thus protecting against neurological impairment. Hence silencing USP11 may be a novel anti-inflammatory method for ICH treatment.

MiR-17 and miR-93 Promote Tumor Progression by Targeting p21 in Patients with Chordoma.

OBJECTIVE: MicroRNAs have been implicated in the progression of various cancers. However, the role of microRNAs in chordoma remains to be further elucidated. Here, we purposed to character the role of two microRNAs, miR-17 and miR-93, and their potential mechanisms in chordoma. METHODS: The expression and prognostic value of miR-17 and miR-93 were assessed by the quantitative real-time polymerase chain reaction, Kaplan-Meier survival curve, and Cox regression analysis. The effects of miR-17/93 mimics on chordoma cell proliferation, colony formation, and invasion were analyzed by CCK-8 assay, colony formation assay, and transwell assay. The downstream target of miR-17/93 was further explored via luciferase reporter assay. RESULTS: High expression of miR-17/93 was identified in chordoma tissues, and was associated with poor prognosis. Overexpression of miR-17/93 contributed to cell proliferation, colony formation, and invasion. Mechanistically, we demonstrated that miR-17/93 directly targeted p21 and decreased the expression of p21. Besides, the rescue assay further confirmed the essential role of the miR-17/93-p21 axis in chordoma. CONCLUSION: Our results revealed the potential oncogenic effect of the miR-17/93 on chordoma progression, and suggested that the miR-17/93-p21 axis served as a promising therapeutic target in chordoma.

Silencing long non-coding RNA MIAT ameliorates myocardial dysfunction induced by myocardial infarction via MIAT/miR-10a-5p/EGR2 axis.

Long non-coding RNA (lncRNA) myocardial infarction-associated transcript (MIAT) has been widely-demonstrated to function as diagnostic markers for acute myocardial infarction (MI). This study was designed to explore the modulatory role of MIAT and its underlying molecular mechanism in MI. Firstly, MI mouse model was developed via ligation of the descending branch of the left coronary artery, and cell model was established through exposure to hypoxic conditions. Online prediction indicated that MIAT could bind to microRNA-10a-5p (miR-10a-5p), while miR-10a-5p was highlighted to bind to early growth response gene-2 (EGR2). MIAT and EGR2 were subsequently determined to be highly-expressed, whereas miR-10a-5p was found to be poorly-expressed in cardiomyocytes exposed to hypoxia as well as in MI mice using RT-qPCR and Western blot assay. The binding relationships between MIAT and miR-10a-5p, and between miR-10a-5p and EGR2 were further confirmed by dual-luciferase reporter and RNA immunoprecipitation assays. The results of in vitro and in vivo experimentation also suggested that overexpression of miR-10a-5p or silencing of MIAT and EGR2 reduced cardiomyocyte apoptosis and increased ATP content, thus alleviating the impairment of cardiac function following MI. In a word, inhibition of MIAT protects against cardiac dysfunction induced by MI through the crosstalk with miR-10a-5p/EGR2.

Disruption of microRNA-214 during general anaesthesia prevents brain injury and maintains mitochondrial fusion by promoting Mfn2 interaction with Pkm2.

Duration of surgical general anaesthesia is associated with severe brain injury and neurological deficits. The specific mechanisms underlying post-general anaesthesia brain injury, however, still remain to be elucidated. Herein, we explore the role of microRNA-214 (miR-214) in the occurrence of brain injury after general anaesthesia and its underlying mechanism. Hippocampal tissues and neurons were isolated from rats exposed to 2% sevoflurane. TUNEL stains reflect hippocampal neuron apoptosis. Cultured hippocampal neurons stained with JC-1 and MitoTracker dyes were imaged by fluorescence microscope to visualize changes of mitochondrial membrane potential and mitochondrial fusion. Mitochondrial function was evaluated. Mitofusin 2 (Mfn2) binding to miR-214 or pyruvate kinase M2 (Pkm2) was confirmed by co-immunoprecipitation, immunofluorescence, dual luciferase reporter gene and RNA immunoprecipitation assays. After exposure to 2% sevoflurane, up-regulated miR-214 expression and impaired interaction between Mfn2 and Pkm2 were found in rat hippocampal tissues. Rats exposed to 2% sevoflurane also experienced neuronal injury, mitochondrial defects and deficits in the brain-derived neurotrophic factor (Bdnf) signalling. miR-214 was shown to target Mfn2 by impairing its binding with Pkm2. Inhibiting miR-214 expression using its specific inhibitor improved mitochondrial membrane potential, enhanced mitochondrial fusion, maintained mitochondrial function, restored interaction between Mfn2 and Pkm2, and activated the Bdnf signalling in cultured hippocampal neurons. Adenovirus infection of miR-214 inhibitor reduced neuron apoptosis and maintained mitochondrial function in the hippocampus of rats exposed to 2% sevoflurane. Taken together, the study demonstrates inhibition of miR-214 is cerebral protective against brain injury following general anaesthesia.

Endoplasmic reticulum stress potentiates the autophagy of alveolar macrophage to attenuate acute lung injury and airway inflammation.

Endoplasmic reticulum (ER) stress has been reported to play a role in acute lung injury (ALI), yet the in-depth mechanism remains elusive. This study aims to investigate the effect of ER stress-induced autophagy of alveolar macrophage (AM) on acute lung injury (ALI) and airway inflammation using mouse models. ALI models were induced by intranasal instillation of lipopolysaccharide (LPS). The lung weight/body weight (LW/BW) ratio and excised lung gas volume (ELGV) in each group were measured. Mouse bronchoalveolar lavage fluid (BALF) was collected for cell sorting and protein concentration determination. Expression of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) in lung tissues and BALF was also detected. Mouse AMs were isolated to observe the autophagy. Expression of GRP78, PERK, LC3I, LC3II and Beclin1 was further determined. The results indicated that tunicamycin (TM) elevated GRP78 and PERK expression of AMs in ALI mice in a dose-dependent manner. Low dosage of TM abated LC3I expression, increased LC3II and Beclin1 expression, triggered ER stress and AM autophagy, and alleviated pathological changes of AMs in ALI mice. Also, in ALI mice, low dosage of TM attenuated goblet cell proliferation of tracheal wall, and declined LW/BW ratio, ELGV, total cells and neutrophils, protein concentrations in BALF, and IL-6 and TNF-α expression in lung tissues and BALF. Collectively, this study suggests that a low dosage of TM-induced ER stress can enhance the autophagy of AM in ALI mice models, thus attenuating the progression of ALI and airway inflammation.

Silencing of PTEN inhibits the oxidative stress damage and hippocampal cell apoptosis induced by Sevoflurane through activating MEK1/ERK signaling pathway in infant rats.

Phosphatase and tensin homolog (PTEN) is a suppressive player in tumor but its concrete role in oxidative stress (OS) damage and cell apoptosis remains much exploration. Thus, this study is conducted to explore the participation of PTEN and its mechanisms in OS damage and cell apoptosis in hippocampal cells.Infant rats were grouped into normal, Sevo, Sevo + si-negative control (NC), Sevo + si-PTEN and Sevo + si-PTEN + PD (MEK1/ERK signaling pathway inhibitor) groups. Infant hippocampal cells were grouped into blank, Sevo, Sevo + si-NC, Sevo + si-PTEN and Sevo + si-PTEN + PD groups. The expressions of PTEN and MEK1/ERK signaling pathway-related proteins were determined. OS-related indices in hippocampal tissues and cells were detected. Cell apoptosis was detected by flow cytometry.Sevoflurane up-regulated PTEN expression and silencing of PTEN activates MEK1/ERK signaling pathway in hippocampal tissues and cells of infant rats. Silencing of PTEN alleviated hippocampal tissue pathological status and inhibited sevoflurane-induced cell apoptosis in hippocampal tissues of infant rats. Silencing of PTEN alleviated OS damage in hippocampal tissues of infant rats. Silencing of PTEN inhibited sevoflurane-induced apoptosis after OS damage in hippocampal cells of infant rats. Silencing of PTEN reduced sevoflurane-induced OS damage in hippocampal cells of infant rats.Our study demonstrates that PTEN silencing inhibits the OS damage and cell apoptosis in hippocampal cells induced by Sevoflurane through activating MEK1/ERK signaling pathway in infant rats.

A Prospective Study of Comparing the Application of Two Generation Scoring Systems in Patients with Acute Cerebral Infarction.

INTRODUCTION: This study aims to compare the value of acute physiologic and chronic health evaluation scoring systems (APACHE II and APACHE III) among patients with acute cerebral infarction. METHODS: The APACHE II and APACHE III scores were determined in 399 patients with acute cerebral infarction within 24 h of admission in order to investigate their predictive value for prognosis in acute cerebral infarction. The area under the ROC curve was used to measure the ability of two scoring systems in predicting the prognosis of patients, and the area under the curve of the two scoring systems was compared. RESULTS: The APACHE II and APACHE III scoring systems demonstrated good predictive value for prognosis in acute cerebral infarction, and the areas under the receiver operating characteristic were 0.808 and 0.818, respectively. There was no significant difference in the area under the curve between these two scoring systems. CONCLUSION: Both the APACHE II and APACHE III scoring systems had good predictive value for prognosis in acute cerebral infarction, and there was no obvious difference between these two systems. Preference was suggested for APACHE II.

Influence of blood glucose level on the prognosis of patients with diabetes mellitus complicated with ischemic stroke.

We carried out this meta-analysis for the aim of exploring the influence of diabetes mellitus (DM) on the prognosis of patients with ischemic stroke. Relevant studies were identified using computerized databases supplemented with manual search strategies. The included studies were strictly followed the inclusion and exclusion criteria. Case-control studies which related to the influence of DM on the prognosis of patients with ischemic stroke were selected. Statistical analyses were implemented with the STATA version 12.0 statistical software. Our current meta-analysis initially retrieved 253 studies (227 in Chinese and 26 in English), 13 studies (6 in English and 7 in Chinese) were eventually incorporated in this meta-analysis. These 13 case-control studies included 8463 patients altogether (3249 patients with DM complicated with ischemic stroke and 5214 patients with ischemic stroke). The results of this meta-analysis manifested that there was a significant difference of the blood glucose level at 48 h after stroke between patients with DM complicated with ischemic stroke and patients with ischemic stroke (standard mean difference [SMD] =1.27, 95% confidence interval [CI] =0.02-2.51, P = 0.047); however, the effectiveness, fatality, and the National Institutes of Health Stroke Scale (NIHSS) score in patients with DM complicated with ischemic stroke, and patients with ischemic stroke had no significant difference (effectiveness: risk ratio [RR] = 0.88, 95% CI = 0.75-1.03, P = 0.121; fatality: RR = 1.29, 95% CI = 0.97-1.71, P = 0.081; NIHSS score: SMD = -0.14, 95% CI = -1.56-1.28, P = 0.849). The current evidence suggests that there is statistical difference of the blood glucose level at 48 h after stroke between patients with DM complicated with ischemic stroke and patients with ischemic stroke, but there is no statistical difference of prognostic indicators between patients in two groups. Thus, our study provides certain clinical value.

Effects of microRNA-206 and its target gene IGF-1 on sevoflurane-induced activation of hippocampal astrocytes in aged rats through the PI3K/AKT/CREB signaling pathway.

The study aims to explore the effects of microRNA-206 (miR-206) targeting IGF-1 on the activation of hippocampal astrocytes in aged rats induced by sevoflurane through the PI3K/AKT/CREB signaling pathway. Wistar rats and astrocytes were divided into the normal/blank, sham/negative control (NC), sevoflurane (sevo), miR-206 mimics+sevo, miR-206 inhibitors+sevo, miR-206 NC+sevo, IGF-1 shRNA+sevo, and miR-206 inhibitors+IGF-1 shRNA+sevo groups. The Morris water maze test was exhibited to assess the cognitive functions. Glial fibrillary acidic protein (GFAP) expression was detected by immunofluorescence assay. Western blotting and RT-qPCR were used to detect the expression of miR-206, IGF-1, PI3K, AKT, CREB, pPI3K, pAKT, pCREB, cytochrome-c (Cyt-c), and caspase-3. Cell viability and apoptosis were detected by MTT assay and annexin V/PI double staining respectively. Mitochondrial transmembrane potential (MTP) were determined by flow cytometry. The IGF-1 shRNA+sevo group showed reduced miR-206 expression. Compared with the normal/blank group, the sevo, and miR-206 NC+sevo groups showed decreased miR-206 and GFAP expressions, cell viability and MTP but increased expressions of IGF-1, PI3K, AKT, CREB, pPI3K, pAKT, pCREB, Cyt-c and caspase-3, as well as cell apoptosis. Similar trends were observed in the miR-206 inhibitors+sevo group when compared with the sevo group. The study provides evidence that miR-206 alleviates the inhibition of activation of hippocampal astrocytes in aged rats induced by sevoflurane by targeting IGT-1 through suppressing the PI3K/AKT/CREB signaling pathway.

Serum Resistin Levels May Contribute to an Increased Risk of Acute Cerebral Infarction.

The objective of this study was to investigate the association between serum resistin levels and acute cerebral infarction (ACI). PubMed, SpringerLink, Wiley, EBSCO, Ovid, Web of Science, Wanfang, China National Knowledge Infrastructure, and VIP databases (last updated search in October 2014) were exhaustively searched, and data from the eligible studies were extracted and analyzed to assess the association between serum resistin levels and ACI. STATA software (version 12.0, Stata Corporation, College Station, TX, USA) was utilized for data analysis. Ten studies including 1829 ACI patients and 1557 healthy controls were eligible for inclusion in the meta-analysis. Our major result revealed that ACI patients exhibited higher serum resistin levels compared with healthy controls. Asubgroup analysis based on ethnicity showed a significant association between serum resistin levels and ACI in Asians, but surprisingly not in Caucasians. The results of our meta-analysis suggest that serum resistin levels are associated with an increased risk of ACI.

Association Between Interleukin-1A, Interleukin-1B, and Bridging integrator 1 Polymorphisms and Alzheimer's Disease: a standard and Cumulative Meta-analysis.

Alzheimer's disease (AD) has been one of the most prevalent health problems among senior population. Interleukin-1A (IL-1A) and IL-1B are two isoforms of IL-1. Recent studies suggested that certain polymorphisms on these two genes are associated with AD. Bridging integrator 1 (BIN1) is considered as common genetic risk factors for AD, whereas different studies have provided various conclusions regarding its role in AD. This study was designed to justify the association between multiple gene polymorphisms and AD through an evidence synthesis approach. We conducted a literature search to identify relevant articles published from 2000 to 2015 from PubMed, Embase, and Cochrane Library, in accordance with inclusion criteria. Pooled odds ratios (ORs) were calculated for the allele model. The effect estimates were summarized by both standard and cumulative meta-analysis. Finally, 54 articles with 88 independent studies were enrolled in this meta-analysis. Mutants in rs1800587 of IL-1A, rs1143634 of IL-1B, rs12989701, and rs744373 of BIN1 were significantly associated with AD onset. The difference effect of same single nucleotide polymorphisms (SNPs) on various ethnicities was also observed in our results. The present meta-analysis suggested that IL-1A, IL-1B, and BIN1 were candidate genes for AD pathogenesis. Polymorphisms of IL-1A, IL-1B, and BIN1 are associated with AD onset.

Involvement of the Wnt signaling pathway and cell apoptosis in the rat hippocampus following cerebral ischemia/reperfusion injury.

We investigated the role of the Wnt signaling pathway in cerebral ischemia/reperfusion injury by examining ß-catenin and glycogen synthase kinase-3ß protein expression in the rat hippocampal CA1 region following acute cerebral ischemia/reperfusion. Our results demonstrate that cell apoptosis increases in the CA1 region following ischemia/reperfusion. In addition, ß-catenin and glycogen synthase kinase-3ß protein expression gradually increases, peaking at 48 hours following reperfusion. Dickkopf-1 administration, after cerebral ischemia/reperfusion injury, results in decreased cell apoptosis, and ß-catenin and glycogen synthase kinase-3ß expression, in the CA1 region. This suggests that ß-catenin and glycogen synthase kinase-3ß, both components of the Wnt signaling pathway, participate in cell apoptosis following cerebral ischemia/reperfusion injury.